AET Symposium Management of Refractory Status
Epilepticus December 1, 2012
Aristea S. Galanopoulou, MD PhD
Albert Einstein College of Medicine, Bronx NY USA
American Epilepsy Society | Annual Meeting
Disclosure
Novartis
Morgan & Claypool Publishers,
John Libbey Eurotext Limited,
Elsevier
NINDS NS078333, NS020253
Autism Speaks
American Epilepsy Society | Annual Meeting 2012
Speaker’s honorarium
Royalties for publications
Research Grants
Overall Learning Objectives
Recognize and initiate appropriate treatment algorithms for RSE for adults and pediatric patient populations.
Learn current theories on the basic mechanisms of RSE and apply this information in patient care.
Recognize when autoimmune and inflammatory pathogenic processes may underlie RSE and implement etiology-specific treatment protocols in patient care.
Recognize when emerging treatments for RSE may be helpful in the management of RSE patients.
American Epilepsy Society | Annual Meeting 2012
Case 1 30 year old man (70kg) with no prior history of illness or seizures:
- 6 pm: noted to have generalized tonic clonic seizure (GTC) activity, EMS was called
- 6:10 pm: EMS arrival: afebrile, normal BP, unresponsive with continuous seizure activity 4 mg lorazepam IV given no effect
- 6:25pm: arrival to the ER, continuous seizure activity repeat 4 mg lorazepam IV given no effect
- 6:30 pm: fosphenytoin 20 mg PE/kg IV infusion started
- 6:50 pm: still unresponsive, normal BP, with persisting seizure activity
American Epilepsy Society | Annual Meeting 2012
Management of refractory status epilepticus (RSE)
•Introduction Aristea S. Galanopoulou, MD PhD •Management of RSE in adults Andrea Rossetti, MD •Management of RSE in the pediatric population Tobias Loddenkemper, MD •Pathophysiology and treatment of RSE: lessons from animal models Claude Wasterlain, MD American Epilepsy Society | Annual Meeting 2012
Case 2 12 year old girl:
2 weeks prior to admission: fever, headache and upper respiratory symptoms
1 week later: progressive anxiety, insomnia, delusions and paranoia, and episodes of catatonia
On admission: temperature of 390C, oro-lingual-facial dyskinesias and right hand twitching were noted
EEG: continuous seizure activity maximal at the left hemisphere
CSF: lymphocytic pleocytosis, mildly increased protein, and negative bacterial cultures
Benzodiazepines and phenytoin load did not have any effect on abnormal movements and seizures
American Epilepsy Society | Annual Meeting 2012
Management of refractory status epilepticus (RSE)
•Paraneoplastic and autooimmune encephalitis resulting in RSE Josep Dalmau, MD PhD •The role of immune system in RSE: preclinical perspectives Annamaria Vezzani PhD •Future perspectives in the management of RSE Eugen Trinka, MD MSc •Conclusions Angus A. Wilfong, MD
American Epilepsy Society | Annual Meeting 2012
Management of Refractory
Status Epilepticus in Adults December 1st 2012
Andrea O. Rossetti, MD
Service de Neurologie, CHUV
Lausanne, Switzerland
American Epilepsy Society | Annual Meeting
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Disclosure
Pfizer, UCB, Astra-Zeneca,
Eisai, Sandoz, GSK
American Epilepsy Society | Annual Meeting 2012
Research support
Several medications discussed in this presentation
are not FDA approved for status epilepticus
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Learning Objectives
• To understand definition, frequency and prognosis of
refractory SE
•To tailor pharmacological treatment according to the
clinical situation
American Epilepsy Society | Annual Meeting 2012 10
Background
Prognosis
Treatment
Conclusion
Summary
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Background
Prognosis
Treatment
Conclusion
Summary
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Refractory SE: definition
SE resistant to 1st + 2nd line AED Holtkamp Lancet Neurol 2007
23%-43% of SE Mayer Arch Neur 2002, Novy Epilepsia 2010, Kellinghaus Epil Behav 2012
Most (17/29) RSE patients not in the ICU! Novy Epilepsia 2010
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RSE etiologies
Novy Epilepsia 2010
• Up to 50% without previous seizures
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Background
Prognosis
Treatment
Conclusion
Summary
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Prognosis after RSE
Novy Epilepsia 2010
• But: reasonable prognosis after long RSE (15%-40%)! Cooper Arch Neurol 2009, Bausell Neurology 2011, Drislane Epil Behav 2011
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Mortality predictors
• Age Towne Epilepsia 1994, Logroscino Epilepsia 1997, Rossetti JNNP 2006
• Acute etiology Towne Epilepsia 1994, Logroscino Epilepsia 1997
• Consciousness impairment Shneker Neurology 2003, Rossetti JNNP 2006
• Treatment delay >1h Towne Epilepsia 1994 ( but Logroscino Epilepsia 1997,
Rossetti JNNP 2006, Drislane Epilepsia 2009, Kellinghaus Epil Behav 2012 )
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Mortality and semiology
Non-Convulsive SE Thomas Epilepsia 2007
1. Absence SE (also elderly) : excellent (BDZ)
2. CPSE : usually good, but not always (…etiology!)
3. In coma (« subtle ») : very poor (ominous etiologies)
Generalized-convulsive-SE
• Variable (depends on etiology, complications)
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Complications of long ICU stay Cereda Neurocrit Care 2009, Cooper Arch Neurol 2009, Sutter Epilepsia 2012
• Infections
• ICU myopathy, neuropathy
• Thrombosis, embolism
• Ileus
• AED side effects
• …
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Background
Prognosis
Treatment
Conclusion
Summary
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The longer generalized SE lasts, the harder it is to treat! Fountain J Clin Neurophysiol 1995, Treiman NEJM 1998
Claude Serre, Humour noir et hommes en blanc, 1975
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SE treatment: overview
Rossetti & Lowenstein Lancet Neurol 2011 22
Anesthetics: overview
BBT PRO MDZ
Mechanisms GABAA (NMDA,Ca)
GABAA (NMDA ?,Ca)
GABAA
Loading dose THP 2-7mg/kg
PTB 5-15 mg/kg
2 mg/kg 0.1-0.3 mg/kg
Maintenance THP 3-5 mg/kg/h
PTB 1-5 mg/kg/h
2-5(10) mg/kg/h 0.05-0.6
mg/kg/h
Elimination t1/2 THP 36h, PTB 22h 2h 0.5-50h
Drawbacks Long wash-out PRIS: check lactate, add BDZ
Habituation
Kress 1987, Van Ness 1990, Parke 1992, Orser 1995, Cremer 2001, Zhan 2001, Claassen 2001
& 2002, Walder 2002, Vasile 2003, Charlesworth 2004, Marik 2004, Rogawsky 2004, Rossetti
2004, Parviainen 2006, Zarovnaya 2007, Iyer 2009
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No clear 1st choice
Claassen Epilepsia 2002, Rossetti Arch Neurol 2005, Shorvon Brain 2012
Rossetti Neurocrit Care 2011
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EEG Targets
Brophy Neurocrit Care 2012
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Resistant RSE
Non-pharmacological
approach
Pharmacological
approach
Nonsedating Sedating Electrical Other…
Shorvon Brain 2012
And then?!
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3rd-line : other approaches
•Isoflurane ( hypotension) Mirsattari Arch Neurol 2004
•Ketamine ( hypotension, anti-NMDA) Sheth Neurology 1998, Prüss Epilepsy Res 2008, Hsieh Clin Neurophys 2010
•Ketogenic diet Bodenant Rev Neurol 2008, Wusthoff Epilepsia 2010
•Immunological suppression Robakis Neurocrit Care 2006
•Hypothermia (neuroprotection) Corry Neurocrit Care 2008
•VNS Patwardhan Surg Neurol 2005, De Herdt Eur J Ped Neur 2008
•Surgery Lhatoo Epilepsia 2007
•…
•Music Miranda Epilepsy Behav 2010
Does SE treatment influence prognosis?
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Yes ! Aranda Epilepsia 2010
!? 36%(USA) vs. 12%(CH) intubated, same prognosis Rossetti J Neurol 2008
Hospit. cohort, 225 incident
episodes Rossetti J Neurol 2012
ICU-based, 144 episodes
Kowalski Crit Care Med 2012
Model Predictors Area
11 Etiology 0.72
12 Etiology, STESS 0.80
13 Etiology, STESS, Comorbidity 0.85
14 Etiology, STESS, Comorbidity, Treatment 0.85
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How to use coma-induction?
Hieronymus Bosch, Antonius temptations, 1495-1515, Museu Nacional de Arte Antiga, Lisbon
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Quickly in gen.-convulsive, deferred in compl.-partial, never in absence!
When (in which SE form)?
Which agent?
To which EEG target?
How long?
Stopping treatment?
MDZ PRO > BBT
Burst-suppression (1 / 10 sec.)
24 hours, then wean over 12-24 hours, (and again…)
Only if evidence of permanent brain damage!
Background
Prognosis
Treatment
Conclusion
Summary
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“Strategic” considerations
• Biological background seems (far) more important
• Target the etiology!
• New pharmacodynamic approaches (inflammation)?
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Impact on clinical practice Meierkord & Holtkamp Lancet Neurology 2007, Rossetti&Lowenstein Lancet Neurol 2011
Auguste Rodin, Le penseur, 1902, Paris
1. Primum non nocere
2. Prognosticators to orient treatment
3. Think trice before giving up
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Merci ! Unité d’épileptologie et électroéncéphalographie, Dépt. Neurosciences, CHUV
Drs J. Novy, V. Alvarez, M. Maeder-Ingvar; EEG technologists
Institut universitaire de médecine sociale et préventive, Lausanne
Prof. B. Burnand, Jean-Marie Januel MPH
Dipartimento di Neuroscienze, Bari
Prof. G. Logroscino
Dept. of Neurology, BWH, Harvard Medical School, Boston (MA)
Prof. E.B. Bromfield +, Dr J.W. Lee, Dr T. Milligan, Prof. B. Dworetzky
Dept. of Neurology, Johns Hopkins BMC, Baltimore (MD)
Prof. P.W. Kaplan
