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 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

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? 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

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

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? 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

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 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 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

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

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

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

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

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

Rse treatment

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

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

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

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

Much of the work we know about comparison between these 3 drugs is from a 2002 meta-analysis of 28 studies from 1980-2001. 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

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

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

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

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

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.

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 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 2013 Gaspard N, et al. Epilepsia 2013 Ubogu EE, et al. Epilepsy Behavior 2003

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 Alexopoulos A, et al. Neurology 2005 Ma X, et al. Epilepsy Research 2001 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 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 1984 Rossetti AO. Epilepsia 2011 Kowski AB, et al. Brain Research 2012 Corry JJ, et al. Neurocritical Care 2008

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

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 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

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

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?

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