Status epilepticus in
infancy
Patrick VAN BOGAERT, MD, PhD
Clinique de Neurologie Pédiatrique
Laboratoire de Cartographie Fonctionnelle du Cerveau
Université Libre de Bruxelles
Hôpital Erasme
What is status epilepticus (SE)?
• ILAE 1993 (guidelines for epidemiologic studies):
– Single epileptic seizure > 30-min duration
– Or series of epileptic seizures during which function is
not regained between ictal events in a > 30-min period
• ILAE 2001 (glossary of descriptive terminology
for ictal semiology)
– Seizure that shows no clinical signs of arresting after a
duration encompassing the great majority of seizures of
that type in most patients
– Or recurrent seizures without interictal resumption of
baseline central nervous system function
From Raspall-Chaure et al, 2007
So the concept of SE relies on the
occurrence of seizures
• An epileptic seizure is a transient occurrence of
signs and/or symptoms due to abnormal
excessive or synchronous neuronal activity in the
brain (ILAE 2005)
• Different types of SE according to the type of
seizure:
– Convulsive SE (CSE)
– Non-convulsive SE
•
•
•
•
•
Absence SE (typical or atypical)
Myoclonic SE
Focal SE
(Electrical SE during slow-wave sleep)
(Hypsarrhythmia)
Myoclonic SE in infancy
• In the course of a non-progressive
encephalopathy
– Psychomotor retardation from 3-4 m, no
regression
– Myoclonic sz may be confounded with a
movement disorder
– Important etiologies: Angelman, Rett, other
chromosomal deletions
• In the course of a progressive
encephalopathy: progressive myoclonic
epilepsy (PME) of infancy
Clinical case 1
• M, 15 m
• Admitted for febrile
seizure (GTCS)
• Global psychomotor
delay from age 4 m, no
regression
• Exam: jerky
movements, possible
ruptures of contact
Absence of hybridation signal on 15q11.2: Angelman syndrome
Clinical case 2
• F, 4y
• Sz from age
3y (GTCS,
absences),
refractory to
AED
• Mental
deterioration,
progressive
ataxia
Curvilinear intracellular inclusions:
late infantile neuronal ceroid lipofuscinosis
Epidemiology of SE
Peak age < 1 year: related to febrile SE
From Raspall-Chaure et al, 2007
Classification of SE according to
etiology (ILAE 1993)
• Acute symptomatic
in a previously normal child
• Remote symptomatic
in the absence of an identified acute insult but with a
history of a pre-existing CNS abnormality
• Idiopathic epilepsy related
in children with prior diagnosis of idiopathic epilepsy
• Cryptogenic epilepsy related
in children with prior diagnosis of cryptogenic epilepsy
Limits of this classification for CSE,
particularly relevant in infants
• Acute symptomatic = 2 very different
conditions that need to be individualized:
– Febrile (excluding CNS infection)
– Due to an identified neurological insult (infection,
trauma,...) = true acute symptomatic!
• Some children with CSE associated with fever
have pre-existing neurological abnormalities,
including epilepsy, while others are
previously neurologically normal
acute vs acute on remote
Distribution of etiologies
From Raspall-Chaure et al, 2007
• About 1/2 cases occurs without history of
prior seizures
• Fever-associated SE is the most frequent
situation in infants (Chin et al 2005; 95 cases)
– Febrile: 59%
– Previous neurological abnormality (acute on
remote): 21%
– CNS infection (acute symptomatic): 20%
bacterial meningitis: 12%
viral encephalitis: 8%
Treatment: rationale for early
intervention
From Raspall-Chaure et al, 2007
1. CSE may lead to brain injury
• Animal model:
Kainate induced SE
leading to
hippocampal
sclerosis
• SE-induced MRI
changes:
usually reversible but
irreversible changes
reported (focal
atrophy, mesial
temporal sclerosis,
hemispheric damage)
Huang et al, 2009
CSE and hippocampal injury
• Relationship between MTS and prolonged
febrile sz controversial (cause or consequence)
• MRI after CSE (Provenzale et al, 2008)
– Acute hypersignal in hippocampus: 7/11
– Subsequent hippocampal atrophy: 5/7 (with sz in 4)
HHE syndrome: hemiconvulsions-hemiplegia-epilepsy
Clinical case: M, 10 years
-Age 2 years: Febrile convulsive status epilepticus
-Refractory epilepsy since age 4 years, R hemiparesis,
severe mental retardation
-Sz-free after hemispherotomy
2. GABAergic mechanisms fail and
seizures become self-sustaining and
pharmacoresistant
Miniature IPSCs from
dentate gyrus granule
cells of SE (dotted
line) and controls
(solid line)
demonstrating smaller
amplitude and
prolonged decay in SE
The change of mIPSCs with SE reflects a decrease in the
number of functional postsynaptic GABA-A receptors
Naylor, 2005
The four phases for CSE
management
• Prehospital
• First-line treatment in emergency room
• Second-line treatment after failure of
benzodiazepine
• General anesthesia
Prehospital:
Buccal MDZ to replace rectal DZ
Authors
McIntyre
Lancet 2005
Design
specificities
N
(ages)
Emergency
room
219
(>6m)
Mpimbaza Emergency room, 108 (3mPediatrics
2008
data for children
without malaria
12y)
Efficacy
Safety
Conclusion
56 vs 27% p<.01
relapse 8 vs 17%
Respiratory
depression 5%
(12 pts,
intubation in 5)
MDZPO > DZIR
73.5 vs 44%
p=0.02
Respiratory
depression 1%
MDZPO > DZIR
SF at 10m for 1h
(MDZ vs DZ)
RCT comparing buccal midazolam and rectal
diazepam (both 0.5 mg/kg)
Administration
• Following time frames
in care plan
• Ensure patients head is
upright and in the
midline to ensure
solution is given (and
stays in the buccal
space)
L Herd April 2007 Reviewed A
Harrison Sept 2007 Review Date Nov
2009
Administration 2
• It is accepted best
practice that the
medicine dose should
be split equally
between both spaces
• If it is a very small
dose this may not be
practical
Administration 3
• Carefully insert the syringe
between the lower jaw and
the cheek
• Ensure it is in the buccal
space by pointing it
downwards
• Give half of medicine in one
space then transfer the
syringe to other buccal
space and complete dose
Administration tips
• Do not massage gums
as you are likely to
move the solution out
of the buccal space
• Keep patient wherever
possible in that
position for 5-10
minutes
• If medicine is lost or
swallowed –do not
repeat
• Always remember to
Time seizure
• Note any differences
from normal
• Keep patient safe
throughout
• All guidelines say not
to put anything in
patients mouth – this
is the exception
Who is at risk for SE?
• In children with epilepsy (2 unprovoked sz):
– Risk = 9.5%
– Risk factors: history of SE, younger age ar
onset, symptomatic etiology
Berg et al, 2004
First-line treatment in emergency
room: generalities
• Maintenance of adequate airways,
breathing and circulation (ABC)
IV access with saline, not glucose
• Termination of seizure and prevention of
recurrence
• Diagnosis and initial therapy of lifethreatening causes (e.g. hypoglycemia,
meningitis, cerebral space-occupying
lesion)
First-line treatment in emergency
room: benzo IV
• 2 RCT, MDZ nasal against DZ IV, both at 0.2 mg/kg
(Lahat 2000, Mahmoudian, 2004)
– NS in terms of safety and efficacy
– Sz controlled more quickly with IV DZ
• Prospective population-based treatment of CSE
(Chin et al, 2008)
– Prehospital treatment (DZ IR) efficient in 22%
– IV lorazepam 3.7 times greater likehood of sz termination
than DZ IR
– for each minute delay from onset of CSE to arrival at
emergency room, 5% cumulative increase in the risk of
the episode lasting > 60 min.
Second-line treatment after failure
of benzodiazepine: phenytoin
• > 2 doses BZP
associated with
– SE lasting > 60 min
– respiratory
depression
• IV phenytoin 9
times greater
likehood of sz
termination than
paraldehyde IR
(Chin et al, 2008)
Second-line treatment: VPA as an
alternative to PHT?
• Phenobarbital:
probably similar efficacy than PHT but:
– greater incidence of respiratory depression
– same mechanism of action than benzos
• Paraldehyde:
no experience, interesting if no IV access
• Valproate: one randomized trial against PHT
(Agarwal et al, 2007)
– Same success rate (88% VPA vs 84% DHT)
– No difference for AE or recurrences
Refractory CSE
• Definition: SE refractory to 2 drugs
(usually benzo and PHT, or benzo and VPA)
• Alternatives (no RCT in children!):
–
–
–
–
–
–
VPA or PB if not used previously
Benzo continuous infusion
Barbiturates: thiopental or pentobarbital
Propofol
New AEDs: levetiracetam, topiramate
Ketogenic diet
Thiopental (pentothal°)
• Ter Maaten et al 1998
n=10
– EEG « clean » but death 10/10
• Gestel et al 2005
– propofol
– thiopental
• Rantala et al 1999
–
–
–
–
n=34
efficacy 64%
efficacy 55%
death 2/22
death 6/20
n=54
complications during thiopental : 50%
seizure relapse after thiopental : 53/54
back to previous seizure frequency : 78%
significantly more drugs needed
Thiopental & cerebral blood flow
• Wada et al 1996
– decrease from 123 to 84ml/mn (19%) for regional CBF in rat
• De Bray et al 1993
– significant decrease for CBF (Doppler) in children
– more important for brain trauma than for controls
• Drummond et al 1995, Guo et al 1995.
– Anesthesia : protection of brain and brainstem in a context of
ischemia
Thiopental-induced CBF decrease:
– is beneficial if infarct or oedema (occasionnal SE, trauma)
– is deleterious if epilepsy (CBF increase is needed if SE)
Refractory SE : new AEDs
• Levetiracetam IV
– Gamez-Leyva et al 2009
• 34 (11-90y), no response to PHT/VPA
• SE stopped in 71% by LVT
– Gallentine et al 2009
• 11 (2d-9y), 15-70mg/kg/d (m=30mg/kg/d)
• SE stopped in 45% by LVT (m=40mg/kg/d)
• Topiramate
– Kahrima, et al 2003
• TPM by tube effective in 3 children
Ketogenic diet
• Diet resulting in a continuous cetosis
– Low carbohydrates, high fat
– Ratio Lipides / (Protides + Glucides)= 3:1 or 4:1
– Now ready to give (Ketocal°)
• Encouraging preliminary data in children
– Francois et al 2003
• SE stopped in 3/6 RSE, maintained for 2 y
– Villeneuve et al 2009
• 11/22 children with RPE were responders
• Better response in patients with SE (p<.04)
– Nabbout et al, 2010
• FIRES: 7/9 were responders within 48 h following ketonuria
Recommendations in different countries
Country
1st line
2nd line
3rd line
Cochrane
(UK)
US*
MDZPO/IN
LRZ
BZ, PHT
VPA, LVT
VPA, PHT,
DZIV
anesthesia
Denmark**
DZIR
DZIV, VPA
FosPHT,
MDZIV,
anesthesia
France***
DZIR
DZIV, CNZIV
PHT, PB
* Clonazepam IV non available, ** Lorazepam non available,
*** Midazolam and Lorazepam non available
Protocol of CSE proposed by the Canadian
Paediatric Society
•
•
•
•
First-line: MDZ 0.5 mg/kg IB, or LRZ 0.1 mg/kg IV
After 5 min, repeat 1 time benzo
After 10 min: PHT 20 mg/kg IV over 20 min
After 20 min: PB 20 mg/kg IV over 20 min (but VPA
20 mg/kg IV over 5 min probably better alternative!)
• After 40 min: intubation and midazolam continuous
infusion
–
–
–
–
–
0.15 mg/kg bolus then 2 mg/kg/min infusion
Increase as needed by 2 mg/kg/min q5 min
Bolus 0.15 mg/kg with each increase in infusion rate
Maximum infusion rate: 24 mg/kg/min
Taper after 24 hours
• After 1 hour and 40 min: thiopental/pentobarbital
Friedman 2011, http://www.cps.ca
Outcome: seems to be more
related to etiology (?)
• Mortality 5%, no death in febrile SE
• Morbidity (new deficits):
– Acute symptomatic: > 20%
– Febrile and unprovoked: < 15%
• In the epilepsy related group, occurrence of SE
does not affect social and educational outcomes
• The relationship of CSE with mesial temporal
sclerosis or subtle neurocognitive dysfunction,
and the effect of age at CSE, seizure duration, or
treatment on outcome have not yet been clarified.
From Sillanpää et al (2002) and Raspall-Chaure et al (2007)
Conclusions
• Establish your protocol according to
drugs available in your country
• Among benzos, MDZ should be
encouraged both for prehospital (buccal)
and refractory SE (continuous infusion)
because half-life short (1-3 h)
• PB should be avoided
• Monitor EEG in continuous if possible in
each case of refractory CSE