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