Transcript view his slides

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
Definitions
2.7%
32%
12-43%
10-15%
Shorvon S and Ferlisi M. Brain 2011
NON-CONVULSIVE SEIZURES
AND STATUS EPILEPTICUS
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
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
How to diagnose NCS and NCSE
Sutter R, et al. Epilepsia 2011
How long should the EEG be?
Claassen J, et al. Neurology 2003
Shafi MM, et al. Neurology 2012
What do the EEG findings mean?
Claassen J, et al. Neurology 2003
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
Does changing management have an
effect?
Williams RP, et al. Epilepsia 2016
Does addressing NCSE prevent injury?
REFRACTORY STATUS
EPILEPTICUS
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
RSE basic info
Mayer S, et al. Archives of Neurology 2002
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
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
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
RSE basic info
 Etiology broadly
assigned to one of five
groups
1.
2.
3.
4.
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
RSE basic info
 Etiology broadly
assigned to one of five
groups
1.
2.
3.
4.
5.
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
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
Status epilepticus timeline
Grover EH, et al. Curr Treat Options Neurol 2016
RSE TREATMENT
AED selection in RSE
Levetiracetam
Phenobarbital
Yasiry Z and Shorvon S. Seizure 2014
Valproate
Phenytoin
AED selection criteria
Synowiec A, et al. Epilepsy Research 2012
Aiguabella M, et al. Seizure 2011
Miró J, et al. Seizure 2013
Shorvon S and Ferlisi M. Brain 2012
AED selection
Turnbull D and Singatullina N. Minerva Anestesiol 2013
Zeiler FA, et al. Seizure 2015
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
Comparison of IV anesthetics
Claassen J, et al. Epilepsia 2002
Shorvon S and Ferlisi M. Brain 2012
Claassen meta-analysis (2002)
Claassen J, et al. Epilepsia 2002
Seizure vs background suppression
Rossetti AO, et al. Archives of Neurology 2005
Claassen J, et al. Epilepsia 2002
How to guide your EEG titration
Sutter R, et al. J Clin Neurophysiol 2015
IV anesthesia outcomes
Claassen J, et al. Epilepsia 2002
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
Shorvon meta-analysis (2012)
Shorvon S and Ferlisi M. Brain 2012
Differing end points
Control
Breakthrough Sz
Withdrawal Sz
Barbiturates
Claassen
78%
11%
42%
Midazolam
Propofol
Shorvon Claassen Shorvon Claassen Shorvon
64%
70%
78%
71%
68%
0%
54%
3%
11%
1%
9%
64%
<1%
47%
6%
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
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
Ubogu EE, et al. Epilepsy Behavior 2003
Gaspard N, et al. Epilepsia 2013
Non-anesthesia




Surgery
Hypothermia
Immunotherapy
“Other”







Inhalational anesthesia
Magnesium***
Pyridoxine
Ketogenic diet
ECT
TMS
CSF air-exchange
Surgery
 Primarily considered in focal RSE
 33/36 controlled RSE
 27 with “good” outcomes
Lhatoo SD and Alexopoulos AV. Epilepsia 2007
Ma X, et al. Epilepsy Research 2001
Alexopoulos A, et al. Neurology 2005
Shorvon S and Ferlisi M. Brain 2012
Best outcomes with concordant data
Alexopoulos A, et al. Neurology 2005
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
Kowski AB, et al. Brain Research 2012
Rossetti AO. Epilepsia 2011
Corry JJ, et al. Neurocritical Care 2008
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
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
FACTORS ALTERING
PROGNOSIS AND OUTCOMES
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
Duration of RSE and outcomes
Drislane F, et al. Epilepsia 2009
What happens when they survive?
Cooper A, et al. Archives of Neurology 2009
Possible treatment paradigm
Influences
prognosis most
Shorvon S and Ferlisi M. Brain 2011
Comments or questions?
Works cited

















Abend NS, et al. “Impact of Continuous EEG Monitoring on Clinical Management in Critically Ill Children”. Neurocrit Care 2011
Aug;15(1):70-5
Alexopoulos, A., et al. “Resective surgery to treat refractory status epilepticus in children with focal epileptogenesis.” Neurology, v. 64 issue 3,
2005, p. 567-70.
Claassen, J.; Hirsch, LJ.; Emerson, RG.; Mayer, SA. “Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a
systematic review.” Epilepsia (Series 4), v. 43 issue 2, 2002, p. 146-53.
Claassen, J, et al. “Detection of electrographic seizures with continuous EEG monitoring in critically ill patients”. Neurology 2004;62:1743-1748
Cooper, AD.; Britton, JW.; Rabinstein, AA. “Functional and cognitive outcome in prolonged refractory status epilepticus.” Archives of
Neurology, v. 66 issue 12, 2009, p. 1505-9.
Corry, JJ.; Dhar, R.; Murphy, T.; Diringer, MN. “Hypothermia for refractory status epilepticus.” Neurocritical Care, v. 9 issue 2, 2008, p. 189-97.
De Marchis GM, et al. “Seizure burden in subarachnoid hemorrhage associated with functional and cognitive decline”. Neurology 2016;86:25360
Drislane, FW., et al. “Duration of refractory status epilepticus and outcome: loss of prognostic utility after several hours.” Epilepsia (Series 4),
v. 50 issue 6, 2009, p. 1566-71.
Gall, CR.; Jumma, O.; Mohanraj, R. “Five cases of new onset refractory status epilepticus (NORSE) syndrome: outcomes with early
immunotherapy.” Seizure : the journal of the British Epilepsy Association, v. 22 issue 3, 2013, p. 217-20.
Gaspard N, et al. “Intravenous ketamine for the treatment of refractory status epilepticus: A retrospective multicenter study”. Epilepsia,
54(8);1498-1503
Gilmore EJ, et al. “Acute brain failure in severe sepsis: a prospective study in the medical intensive care unit utilizing continuous EEG
monitoring”. Intensive Care Med 2015 APR;41(4):686-94
Grover EH, Nazzal Y, and Hirsch LJ. “Treatment of Convulsive Status Epilepticus”. Curr Treat Options Neurol. 2016 Mar;18(3):11
Hocker, SE., et al. “Predictors of outcome in refractory status epilepticus.” JAMA Neurology, v. 70 issue 1, 2013, p. 72-7.
Husain Am, Horn GJ, Jacobson MP. “Non-convulsive status epilepticus: usefulness of clinical feature sin selecting patients for urgent EEG”
JNNP 2003;74:189-91
Kapur, J.; Macdonald, RL. “Rapid seizure-induced reduction of benzodiazepine and Zn2+ sensitivity of hippocampal dentate granule cell
GABAA receptors.” Journal of Neuroscience, 17 (19), 1997;7532-40
Kilbride RD, et al. “How Seizure Detection by Continuous Electroencephalographic Monitoring Affects the Prescribing of Antiepileptic
Drugs”. Arch Neurol 2009;66(6):723-8
Köhrmann, et al. “CSF-air-exchange for pharmacorefractory status epilepticus.” Journal of Neurology, v. 253 issue 8, 2006, p. 1100-1.
Works cited

















Laccheo I, et al. “Non-convulsive Status Epilepticus and Non-convulsive Seizures in Neurological ICU Patients”. 2015 Apr;22(2):202-11
Lambrecq, V., et al. “Refractory status epilepticus: electroconvulsive therapy as a possible therapeutic strategy.” Seizure, v. 21 issue 9, 2012, p.
661-4.
Lhatoo, SD.; Alexopoulos, AV. “The surgical treatment of status epilepticus.” Epilepsia (Series 4), v. 48 Suppl 8, 2007, p. 61-5.
Li, J.; Saldivar, C.; Maganti, RK. “Plasma exchange in cryptogenic new onset refractory status epilepticus.” Seizure : the journal of the British
Epilepsy Association, v. 22 issue 1, 2013, p. 70-3.
Ma, X.; Liporace, J.; O'Connor, MJ.; Sperling, MR. “Neurosurgical treatment of medically intractable status epilepticus.” Epilepsy Research, v. 46
issue 1, 2001, p. 33-8.
Mayer, SA., et al. “Refractory status epilepticus: frequency, risk factors, and impact on outcome.” Archives of Neurology, v. 59 issue 2, 2002, p.
205-10.
Meierkord H and Holtkamp M. “Non-convulsive status epilepticus in adults: clinical forms and treatment”. Lancet Neurol 2007; 6:329-39
Mirsattari, SM.; Sharpe, MD.; Young, GB. “Treatment of refractory status epilepticus with inhalational anesthetic agents isoflurane and
desflurane.” Archives of Neurology, v. 61 issue 8, 2004, p. 1254-9.
Quek, AM., et al. “Autoimmune epilepsy: clinical characteristics and response to immunotherapy.” Archives of Neurology, v. 69 issue 5, 2012, p.
582-93.
Rosati, A., et al. “Efficacy and safety of ketamine in refractory status epilepticus in children.” Neurology, v. 79 issue 24, 2012, p. 2355-8.
Rossetti, AO.; Logroscino, G.; Bromfield, EB. “Refractory status epilepticus: effect of treatment aggressiveness on prognosis.” Archives of
Neurology, v. 62 issue 11, 2005, p. 1698-702.
Rossetti, AO. “What is the value of hypothermia in acute neurologic diseases and status epilepticus?.” Epilepsia (Series 4), v. 52 Suppl 8, 2011,
p. 64-6.
Rossetti, AO., et al. “A randomized trial for the treatment of refractory status epilepticus.” Neurocritical Care, v. 14 issue 1, 2011, p. 4-10.
Shafi MM, et al. “Absence of early epileptiform abnormalities predicts lack of seizures on continuous EEG”. Neurology 2012;79:1796-1801
Shneker BF and Fountain NB. “Assessment of acute morbidity and mortality in nonconvulsive status epilepticus”. Neurology 2003;61:1066-73
Shorvon, S.; Ferlisi, M. “The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment
protocol.” Brain: A Journal of Neurology, v. 134 issue Pt 10, 2011, p. 2802-18.
Shorvon, S.; Ferlisi, M. “The outcome of therapies in refractory and super-refractory convulsive status epilepticus and recommendations for
therapy.” Brain: A Journal of Neurology, v. 135 issue Pt 8, 2012, p. 2314-28.
Works cited








Smith, M. “Anesthestic agents and status epilepticus.” Epilepsia (Series 4), v. 52 Suppl 8, 2011, p. 42-4.
Sutter R, et al. “Continuous video-EEG monitoring increases detection rate of nonconvulsive status epilepticus in the ICU”. Epilepsia
2011;52(3):453-457
Sutter R, et al. “EEG for Diagnosis and Prognosis of Acute Nonhypoxic Encephalopathy: History and Current Evidence”. J Clin Neurophysiol
2015;32: 456–464
Turnbull, D.; Singatullina, N. “Manuscript title: Super Refractory Status Epilepticus: The development of a paradigm for critical care
management.” Minerva Anestesiologica, 2013 Feb 18 [Epub ahead of print]
Vespa P, et al. “Metabolic Crisis Occurs with Seizures and Periodic Discharges after Brain Trauma”. Ann Neurol 2016 [Epub ahead of print]
Williams RP, et al. “Impat of an ICU EEG monitoring pathway on timeliness of therapeutic intervention and electrographic seizure
termination”. Epilepsia 2016 [Epub ahead of print]
Yasiry Z and Shorvon SD. “The relative effectiveness of five antiepileptic drugs in treatment of benzodiazepine-resistant convulsive status
epilepticus: A meta-analysis of published studies”. Seizure 23 (2014) 167-174
Zeiler FA, et al. “Lidocaine for status epilepticus in adults”. Seizure 31 (2015) 41-48