This document provides an overview and discussion of refractory status epilepticus (RSE) and non-convulsive status epilepticus (NCSE). It defines these conditions and reviews their clinical characteristics, pathophysiology, treatment options including antiepileptic drugs, anesthesia, surgery, hypothermia and immunotherapy. It examines factors that influence prognosis and outcomes such as etiology, age, seizure duration and EEG findings. It suggests RSE treatment should be guided by etiology, duration of seizures and EEG characteristics as these most influence patient prognosis and recovery.

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%
10-15%
2.7%
32%
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
1. 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
1. Drug/toxins
2. 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
1. Drug/toxins
2. Infectious
3. 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
1. Drug/toxins
2. Infectious
3. Structural
4. 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
1. Drug/toxins
2. Infectious
3. Structural
4. Metabolic
5. 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
Phenobarbital
Phenytoin
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

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

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

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

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

34. 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

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

37. Differing end points
Barbiturates Midazolam Propofol
Claassen Shorvon Claassen Shorvon Claassen Shorvon
Control 78% 64% 70% 78% 71% 68%
Breakthrough Sz 11% 0% 54% 3% 11% 1%
Withdrawal Sz 42% 9% 64% <1% 47% 6%

38. 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

39. 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

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

41. 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

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

44. 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

45. 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

46. 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

47. FACTORS ALTERING
PROGNOSIS AND OUTCOMES

48. 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

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

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

51. Possible treatment paradigm
Influences
prognosis most
Shorvon S and Ferlisi M. Brain 2011

52. Comments or questions?

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