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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. Status epilepticus in infancy. What is status epilepticus (SE)?. ILAE 1993 (guidelines for epidemiologic studies):

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Status epilepticus in infancy

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  1. Patrick VAN BOGAERT, MD, PhDClinique de Neurologie PédiatriqueLaboratoire de Cartographie Fonctionnelle du CerveauUniversité Libre de BruxellesHôpital Erasme Status epilepticus in infancy

  2. 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

  3. From Raspall-Chaure et al, 2007

  4. 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)

  5. 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

  6. 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

  7. Absence of hybridation signal on 15q11.2: Angelman syndrome

  8. Clinical case 2 • F, 4y • Sz from age 3y (GTCS, absences), refractory to AED • Mental deterioration, progressive ataxia

  9. Curvilinear intracellular inclusions:late infantile neuronal ceroid lipofuscinosis

  10. Epidemiology of SE Peak age < 1 year: related to febrile SE From Raspall-Chaure et al, 2007

  11. 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

  12. 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

  13. Distribution of etiologies From Raspall-Chaure et al, 2007

  14. 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%

  15. Treatment: rationale for early intervention From Raspall-Chaure et al, 2007

  16. 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

  17. 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)

  18. 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

  19. 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

  20. The four phases for CSE management • Prehospital • First-line treatment in emergency room • Second-line treatment after failure of benzodiazepine • General anesthesia

  21. Prehospital:Buccal MDZ to replace rectal DZ RCT comparing buccal midazolam and rectal diazepam (both 0.5 mg/kg)

  22. 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

  23. 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

  24. 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

  25. 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 Administration tips

  26. 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

  27. 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)

  28. 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 lorazepam3.7 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.

  29. 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)

  30. 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 AEor recurrences

  31. 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 • Benzocontinuous infusion • Barbiturates: thiopental or pentobarbital • Propofol • New AEDs: levetiracetam, topiramate • Ketogenicdiet

  32. Thiopental (pentothal°) • Ter Maaten et al 1998 n=10 • EEG « clean » but death 10/10 • Gestel et al 2005 n=34 • propofol efficacy 64% death 2/22 • thiopental efficacy 55% death 6/20 • Rantala et al 1999 n=54 • complications during thiopental : 50% • seizure relapse after thiopental : 53/54 • back to previous seizure frequency : 78% • significantly more drugs needed

  33. Thiopental & cerebral blood flow • Wada et al 1996 • decreasefrom 123 to 84ml/mn (19%) for regional CBF in rat • De Bray et al 1993 • significantdecrease 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: • isbeneficial if infarct or oedema (occasionnal SE, trauma) • isdeleterious if epilepsy (CBF increaseisneeded if SE)

  34. 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

  35. 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

  36. Recommendations in different countries * Clonazepam IV non available, ** Lorazepam non available, *** Midazolam and Lorazepam non available

  37. 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 5min 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

  38. 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)

  39. 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

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