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% Left numbers are mortality
Right numbers are percentage of the previous stage in which that stage occurs
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?
Two ways to answer this question
Left graph shows that the longer you monitor for, the more likely you are to diagnose a nonconvulsive seizure if present
Right graph shows that if the EEG is normal in the first 30 minutes, there is about a 3% chance of seizure.
So in essence, if you have a high suspicion of NCS, video EEG is the appropriate test. A low pretest probability would probably see a one hour EEG as sufficient.
Claassen J, et al. Neurology 2003
Shafi MM, et al. Neurology 2012

9. What do the EEG findings mean?
Periodic findings lead to seizures in a high rate of patients
PLEDs perhaps warrant a longer monitoring time, as a first seizure can present greater than 24 hours after
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?
Top study establishes some physiological basis for possible injury – surface and intracortical depth electrodes with cerebral microdialysis – Microdialysis showed increased lactate/pyruvate levels during seizures and periodic patterns – this only establishes acute injury and does not
Bottom study shows correlation between NCSE time and 3 month functional outcome – Study comparing length of NCSE in SAH patients and assessing function by telephone interview 3 months later – They found each hour correlated with a 10% higher odds of death/disability at 3 months
These two studies are notable that they address acute, significant neurological injury and not chronic epilepsy

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
The last point is that etiologies that are relatively “easy” to treat have the best outcomes
Some mortality rates may be due to the underlying disease rather than the status as well. In other words, the status is a symptom rather than a cause
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 Micro to macro
↑ 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
There is precious little data on this subject. This meta-analysis from 2014 analyzed 22 studies and found levetiracetam, phenobarbital, and valproate were all similarly efficacious while phenytoin lagged behind.
Levetiracetam – 68.5%
Phenobarbital – 73.6%
Valproate – 75.7%
Phenytoin – 50.2%
The Established status epilepticus treatment trial is underway and will compare PHT, LVT, and VPA in benzodiazepine resistant status epilepticus
Yasiry Z and Shorvon S. Seizure 2014

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

26. AED selection
Lidocaine – 76 patients studied – 70% seizure cessation, the majority with phenytoin having already failed – suggests safety in setting of other sodium channel blockers – did have 23% relapse rate
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. Much of the work we know about comparison between these 3 drugs is from a 2002 meta-analysis of 28 studies from As with all meta-analysis, this one had some difficulties with the heterogeneity of the study designs and definitions. However, a few very useful conclusions were able to be made

30. Claassen meta-analysis (2002)
Two important things to note.
Pentobarb had a relatively low number of continuous monitoring.
Pentobarb also had a higher percentage of their patients tirated to EEG background suppression.
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

35. Only RCT done for RSE. It compared propofol to thiopental, with a goal of burst suppression for treatment.
Stopped prematurely at 24 patients (goal 150 patients) due to low recruitment
Only finding was that there was longer ventilation with barbiturates
There was a trend towards increased efficacy with propofol.
Median dose of propofol required for burst suppression was 5 mg/kg/h
Median dose of thiopental required was 6.7mg/kg/h

36. Shorvon meta-analysis (2012)
54 MDZ  585 MDZ (306 cases from one study), so subtracting that, 54 MDZ  279 MDZ
33  106 PRO
106  192 BARB
This means in the intervening time, there have been an additional 690 patients put into the pool. Again, only 24 of these cases were from a RCT. The quality of data is only as good as what we put in, so we are limited as to stringent data that can be taken away.
Important to note that the breakthrough seizures do not include patients who had a seizure relapse, which was controlled by increasing initial medicine. Those numbers are 7% of MDZ, 12% of PRO, and 6% of BARB.
With regards to withdrawal seizures, it was interesting to note that 93% of those that were reintroduced to MDZ regained control, as compared to only 47% of PRO and 22% of BARB.
Shorvon S and Ferlisi M. Brain 2012

37. Differing end points Barbiturates Midazolam Propofol Claassen Shorvon
Barbiturates
Midazolam
Propofol
Claassen
Shorvon
Control
78%
64%
70%
71%
68%
Breakthrough Sz
11% 0%
54% 3% 1%
Withdrawal Sz
42% 9%
<1%
47% 6%
More clearly illustrates the point of the difficulty in interpreting meta-analyses. Different methadologies were used for these studies, which yielded very different information. Always should use caution when interpreting these results.

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 Sympathomimetic
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 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 Alexopoulos A, et al. Neurology 2005
Ma X, et al. Epilepsy Research 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
Suggested mechanisms of decreased damage include:
Decreased brain metabolism
Inhibition of glutamate release
Reduction of free radical production
Mitigation of reperfusion injury
Decreased damage to BBB with resultant decreased cerebral edema
Decrease of proinflammatory reactions.
Orlowski JP, et al. Critical Care Medicine Rossetti AO. Epilepsia 2011
Kowski AB, et al. Brain Research Corry JJ, et al. Neurocritical Care 2008

45. Hypothermia 3 pediatric patients in 1984 4 adult patients in 2008
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
1 patient who did poorly in 1984 series had Rasmussen’s encephalitis
2 patients who died had limbic encephalitis and hepatic encephalopathy. Limbic encephalitis case died due to pertonitis after G-tube insertion
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 EEG characteristics
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
Retrospective review of 119 patients from BI Deaconess. Only 35% of these patients survived. These patients represented all SE, (both anoxic and non-anoxic status).
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?

53. Works cited
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