Patrick VAN BOGAERT, MD, PhD Clinique de Neurologie P

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Patrick VAN BOGAERT, MD, PhDClinique de
Neurologie PédiatriqueLaboratoire de
Cartographie Fonctionnelle du CerveauUniversité
Libre de BruxellesHôpital Erasme
Status epilepticus in infancy
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What is status epilepticus (SE)?

• ILAE 1993 (guidelines for epidemiologic studies)
• Single epileptic seizure gt 30-min duration
• Or series of epileptic seizures during which
  function is not regained between ictal events in
  a gt 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

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From Raspall-Chaure et al, 2007
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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)

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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

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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

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Absence of hybridation signal on 15q11.2
Angelman syndrome
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Clinical case 2

• F, 4y
• Sz from age 3y (GTCS, absences), refractory to
  AED
• Mental deterioration, progressive ataxia

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Curvilinear intracellular inclusionslate
infantile neuronal ceroid lipofuscinosis
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Epidemiology of SE
Peak age lt 1 year related to febrile SE
From Raspall-Chaure et al, 2007
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Classification of SE according to etiology (ILAE
1993)

• Acute symptomaticin a previously normal child
• Remote symptomaticin the absence of an
  identified acute insult but with a history of a
  pre-existing CNS abnormality
• Idiopathic epilepsy relatedin children with
  prior diagnosis of idiopathic epilepsy
• Cryptogenic epilepsy relatedin children with
  prior diagnosis of cryptogenic epilepsy

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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

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Distribution of etiologies
From Raspall-Chaure et al, 2007
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• 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) 20bacterial
  meningitis 12viral encephalitis 8

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Treatment rationale for early intervention
From Raspall-Chaure et al, 2007
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1. CSE may lead to brain injury

• Animal model Kainate induced SE leading to
  hippocampal sclerosis
• SE-induced MRI changesusually reversible but
  irreversible changes reported (focal atrophy,
  mesial temporal sclerosis, hemispheric damage)

Huang et al, 2009
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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)

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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

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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
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The four phases for CSE management

• Prehospital
• First-line treatment in emergency room
• Second-line treatment after failure of
  benzodiazepine
• General anesthesia

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PrehospitalBuccal MDZ to replace rectal DZ
Authors Design specificities N (ages) EfficacySF at 10m for 1h (MDZ vs DZ) Safety Conclusion
McIntyre Lancet 2005 Emergency room 219 (gt6m) 56 vs 27 plt.01 relapse 8 vs 17 Respiratory depression 5 (12 pts, intubation in 5) MDZPO gt DZIR
Mpimbaza Pediatrics 2008 Emergency room, data for children without malaria 108 (3m-12y) 73.5 vs 44p0.02 Respiratory depression 1 MDZPO gt DZIR
RCT comparing buccal midazolam and rectal
diazepam (both 0.5 mg/kg)
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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)

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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

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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

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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

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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
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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 life-threatening
  causes (e.g. hypoglycemia, meningitis, cerebral
  space-occupying lesion)

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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 gt 60 min.

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Second-line treatment after failure of
benzodiazepine phenytoin

• gt 2 doses BZP associated with
• SE lasting gt 60 min
• respiratory depression
• IV phenytoin 9 times greater likehood of sz
  termination than paraldehyde IR

(Chin et al, 2008)
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Second-line treatment VPA as an alternative to
PHT?

• Phenobarbitalprobably similar efficacy than PHT
  but
• greater incidence of respiratory depression
• same mechanism of action than benzos
• Paraldehydeno 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

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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

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Thiopental (pentothal)

• Ter Maaten et al 1998 n10
• EEG  clean  but death 10/10
• Gestel et al 2005 n34
• propofol efficacy 64 death 2/22
• thiopental efficacy 55 death 6/20
• Rantala et al 1999 n54
• complications during thiopental 50
• seizure relapse after thiopental 53/54
• back to previous seizure frequency 78
• significantly more drugs needed

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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)

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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 (m30mg/kg/d)
• SE stopped in 45 by LVT (m40mg/kg/d)
• Topiramate
• Kahrima, et al 2003
• TPM by tube effective in 3 children

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Ketogenic diet

• Diet resulting in a continuous cetosis
• Low carbohydrates, high fat
• Ratio Lipides / (Protides Glucides) 31 or 41
• 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 (plt.04)
• Nabbout et al, 2010
• FIRES 7/9 were responders within 48 h following
  ketonuria

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Recommendations in different countries
Country 1st line 2nd line 3rd line
Cochrane (UK) MDZPO/IN LRZ VPA, PHT, DZIV
US BZ, PHT VPA, LVT 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
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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
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Outcome seems to be more related to etiology (?)

• Mortality 5, no death in febrile SE
• Morbidity (new deficits)
• Acute symptomatic gt 20
• Febrile and unprovoked lt 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)
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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