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Refractory Status Epilepticus – NCSE, Challenges, and Unknowns

Refractory Status Epilepticus – NCSE, Challenges, and Unknowns. Patrick Landazuri, M.D. March 18, 2016. Overview. Definitions NCSE RSE clinical characteristics RSE basic pathophysiology RSE Treatment AEDs Anesthesia Non-anesthesia Overall outcome data Suggested treatment paradigm.

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Refractory Status Epilepticus – NCSE, Challenges, and Unknowns

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  1. Refractory Status Epilepticus – NCSE, Challenges, and Unknowns Patrick Landazuri, M.D. March 18, 2016

  2. Overview • Definitions • NCSE • RSE clinical characteristics • RSE basic pathophysiology • RSE Treatment • AEDs • Anesthesia • Non-anesthesia • Overall outcome data • Suggested treatment paradigm

  3. Definitions 12-43% 2.7% 32% 10-15% Shorvon S and Ferlisi M. Brain 2011

  4. Non-convulsive seizures and Status epilepticus

  5. Non-convulsive status epilepticus (NCSE) • Change in behavior and/or mental processes from baseline associated with epileptiform EEG • 20-25% of SE overall • 8% -20% of comatose patients • 14% of GCSE patients after controlling motor movements • 18% mortality and 39% morbidity Meierkord H and Holtkamp M. Lancet Neurol 2007 Schneker BF and Fountain NB. Neurology 2003

  6. NCSE – When to consider • Remote risk factors for epilepsy • Intracranial tumor • Meningitis/encephalitis • MRI evidence of encephalomalacia • Previous stroke • Previous neurosurgery • History of epilepsy • Physical exam • Abnormal ocular movements • Subtle mouth movements • Severely impaired mental status Laccheo I, et al. Neurocrit Care 2014 Husain AM, et al. JNNP 2003 Gilmore EJ, et al. Intensive Care Med 2015

  7. How to diagnose NCS and NCSE Sutter R, et al. Epilepsia 2011

  8. How long should the EEG be? Claassen J, et al. Neurology 2003 Shafi MM, et al. Neurology 2012

  9. What do the EEG findings mean? Claassen J, et al. Neurology 2003

  10. Does continuous EEG result in changed management? • One study from MGH • Changed management in 52% of cases • Started AEDs in 14% • Altered AED regimin in 33% • Stopped AEDs in 5% • One study from CHOP • Initiate or escalate AEDs in 43% • Demonstrate non-ictal behavior in 21% • Obtain urgent neuro-imaging in 3% Kilbride RD, et al. Arch Neurol 2009 Abend NS, et al. Neurocrit Care 2011

  11. Does changing management have an effect? Williams RP, et al. Epilepsia 2016

  12. Does addressing NCSE prevent injury?

  13. Refractory status epilepticus

  14. RSE basic info • RSE mortality rate: 16-48% • 29-33% return to baseline • SRSE has “high morbidity”, but there are “case reports with favorable outcome” • Risk factors for developing RSE • New onset or “incident” SE • Focal motor seizures (epilepsia partialis continua) • Acute CNS disorders Claassen J, et al. Epilepsia 2002 Hocker S, et al. Archives of Neurology 2013 Shorvon S and Ferlisi M. Brain 2011

  15. RSE basic info Mayer S, et al. Archives of Neurology 2002

  16. RSE basic info • Etiology broadly assigned to one of five groups • Drug/toxins Shorvon S and Ferlisi M. Brain 2011 Betjemann JP and Lowenstein DH. Lancet Neurol 2015 Turnbull D and Singatullina N. Minerva Anestesiol 2013

  17. RSE basic info • Etiology broadly assigned to one of five groups • Drug/toxins • Infectious Shorvon S and Ferlisi M. Brain 2011 Betjemann JP and Lowenstein DH. Lancet Neurol 2015 Turnbull D and Singatullina N. Minerva Anestesiol 2013

  18. RSE basic info • Etiology broadly assigned to one of five groups • Drug/toxins • Infectious • Structural Shorvon S and Ferlisi M. Brain 2011 Betjemann JP and Lowenstein DH. Lancet Neurol 2015 Turnbull D and Singatullina N. Minerva Anestesiol 2013

  19. RSE basic info • Etiology broadly assigned to one of five groups • Drug/toxins • Infectious • Structural • Metabolic Shorvon S and Ferlisi M. Brain 2011 Betjemann JP and Lowenstein DH. Lancet Neurol 2015 Turnbull D and Singatullina N. Minerva Anestesiol 2013

  20. RSE basic info • Etiology broadly assigned to one of five groups • Drug/toxins • Infectious • Structural • Metabolic • Uncommon genetic disorders Shorvon S and Ferlisi M. Brain 2011 Betjemann JP and Lowenstein DH. Lancet Neurol 2015 Turnbull D and Singatullina N. Minerva Anestesiol 2013

  21. Why does RSE occur? • Microcellular damage • ↑ glutamate and NMDA receptor expression • ↓ GABA receptors • ↑ BBB permeability  ↑ K+ levels  hyperexcitation • Hyperexcitation  Ca2+ influx  apoptosis • Micro to macro • Enough microcellular damage = macro cerebral damage • Further lowers seizure threshold and increased epileptogenicity Kapur J and Macdonald RL. J Neurosci 1997 Shorvon S and Ferlisi M. Brain 2011, 2012 Rosati M, et al. Neurology 2013

  22. Status epilepticus timeline Grover EH, et al. Curr Treat Options Neurol 2016

  23. Rse treatment

  24. AED selection in RSE Levetiracetam Valproate Phenytoin Phenobarbital Yasiry Z and Shorvon S. Seizure 2014

  25. AED selection criteria Synowiec A, et al. Epilepsy Research 2012 Miró J, et al. Seizure 2013 Aiguabella M, et al. Seizure 2011 Shorvon S and Ferlisi M. Brain 2012

  26. AED selection Turnbull D and Singatullina N. Minerva Anestesiol 2013 Zeiler FA, et al. Seizure 2015

  27. IV Anesthesia for RSE • John Hughlings Jackson in 1888 • “Chloral is the best drug; and if the fits are very frequent, ehterisation will help” • Three main drugs studied • Barbiturates • Midazolam • Propofol • Ketamine* Claassen J, et al. Epilepsia 2002 Shorvon S and Ferlisi M. Brain 2011

  28. Comparison of IV anesthetics Claassen J, et al. Epilepsia 2002 Shorvon S and Ferlisi M. Brain 2012

  29. Claassen meta-analysis (2002) Claassen J, et al. Epilepsia 2002

  30. Seizure vs background suppression Rossetti AO, et al. Archives of Neurology 2005 Claassen J, et al. Epilepsia 2002

  31. How to guide your EEG titration Sutter R, et al. J Clin Neurophysiol 2015

  32. IV anesthesia outcomes Claassen J, et al. Epilepsia 2002

  33. Claassen meta-analysis conclusions • Barbiturates show better efficacy** • Burst suppression has fewer breakthrough seizures • Mortality is NOT dependent on: • Drug selection • EEG characteristics • Authors suggested a RCT be done

  34. Shorvon meta-analysis (2012) Shorvon S and Ferlisi M. Brain 2012

  35. Differing end points

  36. IV anesthesia meta-analyses summary • No agent is “better” than the other • Treating to background suppression • Leads to fewer breakthrough seizures • Trends towards lower treatment failure • Trends towards lower withdrawal seizure rate • Does not lower mortality • Increases hypotension

  37. Ketamine • NMDA antagonist • Neuroprotective? • Sympathomimetic • Less sedating compared to other IV anesthesia • Meta-analysis through 2012 had 20/24 responders • Small 2013 retrospective study had 6/9 responders • Mostly patients with epilepsy • “Large” multicenter retrospective study had 19/60 responders • Mostly patients with NORSE • Only 2/46 had MRS<2 • Concern for cerebellar atrophy • This case study confounded by long term PHT usage Rosati R, et al. Neurology 2013 Gaspard N, et al. Epilepsia 2013 Ubogu EE, et al. Epilepsy Behavior 2003

  38. Non-anesthesia • Surgery • Hypothermia • Immunotherapy • “Other” • Inhalational anesthesia • Magnesium*** • Pyridoxine • Ketogenic diet • ECT • TMS • CSF air-exchange

  39. Surgery • Primarily considered in focal RSE • 33/36 controlled RSE • 27 with “good” outcomes Lhatoo SD and Alexopoulos AV. Epilepsia 2007 Alexopoulos A, et al. Neurology 2005 Ma X, et al. Epilepsy Research 2001 Shorvon S and Ferlisi M. Brain 2012

  40. Best outcomes with concordant data Alexopoulos A, et al. Neurology 2005

  41. Hypothermia • First 3 cases reported in 1984 • Grew out of intraoperative experience of putting cold water on seizing brain • Rat data demonstrates decreased cerebral damage compared to normothermic and hyperthermic groups • Suggested exclusion criteria • Immunosuppression • Hemodynamically unstable • Coagulopathy • Active infection Orlowski JP, et al. Critical Care Medicine 1984 Rossetti AO. Epilepsia 2011 Kowski AB, et al. Brain Research 2012 Corry JJ, et al. Neurocritical Care 2008

  42. Hypothermia • 3 pediatric patients in 1984 • Thiopental to burst suppression • 2/3 patients recovered • 4 adult patients in 2008 • Target temp of 31 – 33°C • 24 hour hypothermic period • 2/4 seizure free Orlowski JP, et al. Critical Care Medicine 1984 Corry JJ, et al. Neurocritical Care 2008

  43. Immunotherapy • Considered in NORSE • One series with plasmapheresis, one with IVIG • 8 patients total • 5/8 responder rate • 2 died (underlying disease) • Beneficial independent effect? Li J, et al. Seizure 2013 Gall C, et al. Seizure 2013 Shorvon S and Ferlisi M. Brain 2011

  44. Factors altering prognosis and outcomes

  45. RSE Outcomes • Factors affecting outcome • Etiology • Age? • Seizure duration • Non-convulsive SE • EEG characteristics • Isoelectric EEG  poor prognosis (4/4) • Burst suppression  poor functional outcome (22/27) • Inversely, seizure control without BS or isoelectric correlates with good functional outcome • Increased CSF protein and WBC associated with poor outcome (associated with inflammatory etiology?) Hocker S, et al. JAMA Neurology 2013 Alexopoulos A, et al. Neurology 2005 Shorvon S and Ferlisi M. Brain 2011

  46. Duration of RSE and outcomes Drislane F, et al. Epilepsia 2009

  47. What happens when they survive? Cooper A, et al. Archives of Neurology 2009

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