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STATUS
EPILEPTICUS
UPDATE
Jo Wilmshurst
Department of Paediatric Neurology
Red Cross Children’s Hospital
 What are the protocols?
 How should we monitor these children?
Definitions
 Status epilepticus: Generalised
convulsions > 30 minutes = brain
damage / neuronal cell death
 Refractory status: Generalised
convulsions > 1hour, resistant to
level 1-2/3 intervention – i.e. need
PICU intervention
 The longer it takes to gain control
the worse the outcome and the
harder it will be to terminate Sz
 Outcome influenced by underlying
aetiology – encephalitis worst result
Scott et al, ARCH 1998
Holtkamp et al; JNNP 2005
Causes
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Fever
Medication change
Unknown
Metabolic
Congenital
Anoxic
Other (trauma, vascular, infection, tumour, drugs)
36%
20%
9%
8%
7%
5%
15%
Haafiz et al; Ped Emerg Care 1999
Mortality
 Adults
 Children
15-22%
3-32%
 No figures for SA
Fountain et al; Epilepsia 2000
Lacroix et al; CCM 1994
Sahin et al; Epilepsia 2001
Optimal intervention times
 Children > 5 years : typical GTCS seizure
duration < 5 minutes
 Younger children and infants: paucity of data.
Suggested time frame for a typical GTCS is
less than 10-15 minutes.
 Mean age for status in children 3.4 years
Lowenstein DH, Bleck T, Macdonald RL. Epilepsia 1999;40(1):120-2
Singh et al 2010 Neurology
Diagnostic assessment of the child
with status epilepticus
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Blood glucose
Anti-epileptic drug (AED) levels.
Toxicology testing
Blood cultures
 Lumbar puncture
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(as clinically indicated & all children < 18 months)
 Neuroimaging:
Insufficient evidence for routine neuroimaging (8% yield)
Indications:
 When convulsive status is unexplained
 the patient remains unconscious,
 or new focal neurological signs become apparent.

Evidence- based quideline American Academy of Neurology (ANN) and Child Neurology Society (CNS)
Brain Monitoring
 Continuous
 Non-invasive
 Highly sensitive to a variety of brain insults
 Reasonably specific
 User friendly
 Not too expensive!
Kurtz et al Curr Opin Crit Care 2009
Monitoring
cEEG (continuous EEG – full head montage)
 The Gold standard – not viable in most SA settings
 Non-convulsive seizures
 Ischaemia
aEEG (Amplitude-integrated EEG)
 Assessing if burst suppression attained
 Non-convulsive seizures
 Potential artefact
 Need to remember overall underlying cause usually
the defining feature for the outcome of the child.
The future?
 Basic external monitoring (BP, sats, HR) often
underestimates true cerebral function
 Cerebral Near-infrared spectroscopy (cNIRS)
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Non-invasive
Used as a tool to assess regional brain
saturations (RSO2)
Available in SA!
 Comparison studies with serological markers
(S100beta and NSE) – performed well (better
infact)
Subbaswamy et al Neurocrit Care 2009
Treatment of Status Epilepticus
 Pre hospital treatment
 A&E treatment
 In-hospital treatment (Ward/High care)
 Anaesthesia (ICU)
What recommendations exist
for managing Status
Epilepticus in Children?
Mayo Clinic
Boston Children’s hospital
European expert opinion 2007
European expert opinion 2007
Children’s Hospital of Philadelphia
Red Cross
Guidelines
APLS guidelines
(2005; The convulsing child)
ABCD
↓
(Level 1) Lorazepam IV/IO or diazepam pr / midazolam
buccal
↓
Lorazepam IV / IO
↓
Paraldehyde pr
(Level 2)
↓
Phenytoin IV / IO / Phenobarbitone IV / IO
↓
(Level 3)
RSI with Thiopental
Level one
 Arrival – First Hosp
intervention
 Benzodiazepine
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Diazepam PR/IV/IO
Midazolam IN/SL/IV/IO
Lorazepam IV/PR/IO
 Repeat if necessary
 Good specialist consistency, good study data
Scott et al;Lancet 1999
Jeannet et al;Europ J Paed Neurol 1999
DeNegri et al; Pediatr Drugs 2001
Diazepam versus Lorazepam
 Both are equally effective at aborting status epilepticus.
 IV lorazepam vs IV diazepam
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Rectal lorazepam might be more effective than rectal
diazepam
 Lorazepam:
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Substantial longer duration of anti-seizure activity (lipidsoluble)
Less seizure recurrence and fever repeat doses required.
Appleton R et al Cochrane Database Syst Rev 2008 Jul 16;(3)
Transmucosal
pharmacological therapy
 Intranasal midazolam as effective
as intravenous diazepam
 Buccal midazolam as effective as rectal diazepam.
 Intravenous formulations of midazolam (given buccal
or intranasal routes) are relatively inexpensive.
 Caregivers prefer intranasal midazolam to rectal
diazepam.
Appleton R et al Cochrane Database Syst Rev 2008 Jul 16;(3)
Paraldehyde
 Treatment with IV phenytoin as a second-line therapy
was associated with a 9-times greater likelihood of
seizure termination than was treatment with
paraldehyde
Chin R, Neville B et al Lancet Neurol 2008;7:696-703
Level 2 intervention
 Phenytoin IV
 over 20 mins, cardiac monitor, large vein, not mixed with
glucose
 Phenobarbitone IV/IM
 Push, flush through, monitor for resp depression and
hypotension
 Both agents fairly accepted
 BUT studies becoming more limited
 small numbers
 less children
Shanner et al;Neurol 1988
Prasad et al;Ann Neurol 2002
Phenytoin
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Takes 30 minutes to administer
Requires a syringe driver
Requires a large IV (NOT central) line
Requires cardiac monitoring for potential cardiac
toxicity
 Can only be given by IV route
 Cannot be repeated
 It not as effective as phenobarbitone
DeToledo & Ramsay; Drug Saf 2000
Trieman et al; NEJM 1998
Fosphenytoin
 More favourable vehicle that does not contain proylene glycol
and pH 8.6-9
 Administer in dextrose containing IV solutions at a more
rapid rate.
 Equally effective: Time for conversion of pro-drug to active drug
(8-15minutes) = therapeutic phenytoin concentrations reached
at the same time.
 Cost: Fosphenytoin 3 times equivalent dose of IV Phenytoin.
 Benefit: More favorable side effect profile (purple glove
syndrome)
Experimental Rescue therapy
 NG phenobarbitone
 20mg/kg given during level 2 intervention
 Provided good airway protection and ability for gastric absorption
…
 Study at Red Cross (Wilmshurst et al J Paed Child Health 2009)
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Any child / infant entering established status (Level 2)
1-4 hours to therapeutic levels
SAFE
No need for repeat dosage for therapeutic levels but for control
of seizures could safely repeat
Good viable addition to the protocol – especially where
parenteral access or supply lacking
Syed et al;Dev Pharmacol Ther 1986
Yska et al;Pharm World Sci 2000
Yukuwa et al;J Clin Pharm Ther 2005
Level 3 intervention
 Basically heading into refractory status
 Disastrous situation
 Resistant seizures –
 prob exacerbated by underlying cause ( eg
encephalitis),
 secondary complications from drugs
 hypotension,
 respiratory depression
 all affecting brain perfusion
Sahin et al;Neurol 2003
Scott et al, ARCH 1998
Holtkamp et al; JNNP 2005
Level 3 intervention:
Treatment of refractory SE
 No prospective randomised trials comparing the
effects of anesthetics in the treatment of RSE.
 Safety data lacking.
Options:
 Barbiturate anesthetics: Pentobarbital (US)
Thiopental (Europe Aus)
 Propofol
 Midazolam.
 Evidence based medicine: No recommendations on
data available.
 Even in a large survey of neurologists in USA – little
consensus for 3rd / 4th line intervention (J Neurol Sci
2003)
Rosenow et al;Epileptic Disord 2002
Midazolam infusion
 Requires a syringe driver
 Greater risk of airway suppression (especially following
previous Benzo boluses)
 Takes long time to gain control (range 15 mins – 4.5
hours)
 Potential for children left with prolonged seizures and
irreversible neuronal cell death in centres without high
care facilities
 NOTE: Excluded from APLS guidelines
Rivera et al; CCM 1993
Lal Koul et al; ARCH 1997
Ozdemir et al; Seizure 2005
CLONAZEPAM INFUSION
NO EVIDENCE
Thiopentone
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Poor anticonvulsant
Marked haemodynamic effects
Prolonged drug effects if infusion used
Local ICU capacity limited
 Staffing
 Monitoring
 Anaesthetic experience
Very-high-dose Phenobarbitone
 Both barbiturates and benzodiazepines exert a primary effect on
the GABA receptor complex.
 No antiepileptic ceiling effect ! No maximum dose beyond which
further doses are likely to be ineffective >200mgkg!
Complications:
 Sedative and respiratory-depressant properties more likely in
combination with benzodiazepines.
 Hypotension unusual and related to the highest Phenobarbitone
levels and easily controllable.
 Complications usually related to underlying aetiology
Crawford et al; Neurol 1988
Intravenous Sodium Valproate
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FDA approved 1996.
Not in APLS guidelines
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No reports of respiratory depression or hypotension.
Caution in children with underlying liver disease or suspected mitochondrial
disorder.
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Potential hepatic encephalopathy
Comparative studies:
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Intravenous Sodium Valproate vs Diazepam infusion
Intravenous Sodium Valproate vs Phenytoin.
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No large studies measuring efficacy
Larger paediatric focused studies are needed
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Still need syringe driver
Very expensive
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Drug of choice: Absence status
Limdi et al; Neurology 2005
Rossetti & Bromfield; Neurology 2005
Limbdi N et al Epilepsia 2007 48(3):478-483
Morton L et al Pediatr Neurol 2007;36:81-83
Metha V et al J Child Neuro 2007; 22:1191
IV Levetiracetam
 FDA approved adults over 16 yrs since 2006
 Limited data in children (most retrospective
case reviews – n=10 and n=32)
 Loaded with 25-50mg/kg at level 3
 Effective
 Safe
 Larger comparison studies needed
Kirmani et al Ped Neurol 2009
Abend et al Pediatr Crit Care Med 2009
Gamez-Leyva et al CND Drugs 2009
Mx of status epilepticus in SA
 Most centres policy of repeated IV PB boluses
 Resulted (anecdotally) dramatic reduction in
admissions to PICU and complications of status
epilepticus
 IV Pb: WHO / IMCI guidelines first line for neonates;
2nd line for infants / children in Mx status
Why is IV phenobarbitone so good
for resource poor countries?
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Highly effective at controlling status
Safe
Cheap
It can be given by rapid IV bolus
It can be repeated
It can be given by IM route
 No need for syringe driver
 If control not attained at 1 hour time to arrange transfer to tertiary
unit – exceptional situation
Crawford et al; Neurol 1988;
Wilmshurst & Newton; DMCN 2005
Lee et al;Pediatr Neurol 2005
Overall
 Still do not have the ideal solution
 Still do not know what this is
 Need effective, rapidly acting, easy to
administer, cheap agent ..
 Watch this space!
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Prospective comparison study underway
relevant for RLC
Final recommendations
2 targets
 Rapid identification of the underlying aetiology
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Affects treatment
Affects prognosis
 Early initiation towards terminating SE
 Decreases morbidity and mortality
Recommend
 Level 1 – benzodiazepines
 Level 2 – phenytoin, phenobarbitone, sodium
valproate
 Level 3 – “other medications” e.g. levetiracetam and
pharmacologic coma induction
Abend and Marsh. Curr Treat Options Neurol 2009