NICIS Paris, June Review of Status epilepticus care

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1 NICIS Paris, June Review of Status epilepticus care Andrea O. Rossetti Département des Neurosciences Cliniques Lausanne, Switzerland

2 Disclosure UCB pharma, SAGE Research support Several medications discussed in this presentation are not FDA / EMA approved for status epilepticus 2

3 Summary Background SE prognosis SE Treatment Treatment and prognosis Conclusions 3

4 GCSE Lothman Neurology 1990, Wasterlain Epilepsia 2008 Phase I Convulsions Good EEG correlation GABA A responsiveness Encephalopathogenic coma minutes?! Subtle SE Pase II Pure electrical SE E-M dissociation GABA A resistance NMDA hyperactivity 4

5 Claude Serre, Humour noir et hommes en blanc, 1975 The longer generalized SE lasts, the harder it is to treat! Fountain J Clin Neurophysiol 1995, Treiman NEJM

6 Etiologies Children Infection 52% Remote sympt. 39% AED withdr. 21% DeLorenzo Neurology 1996 Africa CNS infection 36% AED withdr. 18% Idiopathic 17% Amare Epilepsia 2008 Alvarez Epilepsia

7 Summary Background SE prognosis SE Treatment Treatment and prognosis Conclusions 7

8 Mortality Short-term: 7%-39% Long-term: 43% at 10 years (RR=3 vs. controls) Logroscino Neurology

9 Mortality predictors Sutter Nature Rev Neurol

10 Non-convulsive SE and Coma Bauer & Trinka Epilepsia

11 Summary Background SE prognosis SE Treatment Treatment and prognosis Conclusions 11

12 SE treatment in Lausanne (2014) 1 st line 2 nd line RSE 3 rd line SRSE additional lines 12

13 Evidence... 1 st line S. Botticelli, L inferno, ca Manuscript of La Divina Commedia. Kupferstichkabinett, Berlin 13

14 1st-line, adults, GSE : pre-hospital Responders (205 pts.) Alldredge NEJM 2001 LZP (2mg) IV : 59% DZP (5mg) IV : 43% Placebo : 21% significant 1st-line, children&adults, GSE: pre-hosp. Responders (893 pts.) Silbergleit NEJM 2012 MDZ (10mg) IM : 73% LZP (4mg) IV : 63% significant 14

15 1st-line, veterans, GSE : in-hospital Responders Treiman NEJM 1998 subtle (134 pts.) overt (384 pts.) LZP (0.1mg/kg) : 24% 65% PB (15mg/kg) : 18% 58% DZP (0.15mg/kg)+PHT (18mg/kg) : 8% 56% ns significant PHT (18mg/kg) : 8% 44% 15

16 Evidence... 2 nd line S. Botticelli, L inferno, ca Manuscript of La Divina Commedia. Kupferstichkabinett, Berlin 16

17 2nd-line, children&adults, GSE Responders (100 pts., after DZP) Agarwal Seizure 2007 VPA IV (20mg/kg) : 88% PHT IV (20mg/kg) : 84% non-significant 17

18 2nd-line, adults, G and CP SE Responders (187 pts., after BDZ; not RCT) Alvarez Epilepsia 2011 VPA IV (20mg/kg) : 75% PHT IV (20mg/kg) : 59% LEV IV (20mg/kg) : 52% 2nd-line, adults, GCSE significant (LEV < PHT, VPA) Responders (150 pts., after BDZ) Mundlamuri Epilepsy Res 2015 VPA IV (30mg/kg) : 68% PHT IV (20mg/kg) : 68% LEV IV (25mg/kg) : 78% non-significant 18

19 Evidence... 3 rd line S. Botticelli, L inferno, ca Manuscript of La Divina Commedia. Kupferstichkabinett, Berlin 19

20 3rd-line, adults, G and CP SE Responders (23 pts., after BDZ+ AED) Rossetti Neurocrit Care 2011 PRO IV (EEG guided) : 43% THP/PTB IV (EEG guided) : 22% non-significant 3rd-line, children, GSE Responders (40 pts., after DZP+ PHT) Singhi J Child Neurol 2002 MDZ IV (clinically guided): 86% DZP IV (cllinically guided): 89% non-significant 20

21 3rd line (anesthetics): overview BBT PRO MDZ Mechanisms GABA A (NMDA,Ca) GABA A (NMDA?,Ca) GABA A Loading dose Maintenance THP 2-7mg/kg PTB 5-15 mg/kg THP 3-5 mg/kg/h PTB 1-5 mg/kg/h 2 mg/kg mg/kg 2-5(10) mg/kg/h mg/kg/h Elimination t1/2 THP 36h, PTB 22h 2h h 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

22 Beyond the lines Ketamine ( hypotension, anti-nmda) Synowiec Epilepsy Res 2013, Gaspard Epilepsia 2013 Ketogenic diet Bodenant Rev Neurol 2008, Thakur Neurology 2014 Hypothermia Corry Neurocrit Care 2008 VNS Patwardhan Surg Neurol 2005, De Herdt Eur J Ped Neur 2008 Surgery Lhatoo Epilepsia 2007 Immuno-suppression Sage 547 (allopregnanolone) Broomall Ann Neurol

23 Ketamine 58 adults, retrospective, multi-center Gaspard Epilepsia 2013 permanent RSE control in 7 (12%); 4 with postanoxic SE No response if given <0.9mg/kg/h, after >8 days 11 adults, retrospective, single-center Synowiec Epilepsy Res 2013 RSE control in all (100%) All treated <8 days Ketogenic diet 10 adults, retrospective, multi-center Thakur Neurology 2014 Long RSE duration (2 months) Acidosis reached in 9, achieving SE control (90%) 23

24 EEG targets Brophy Neurocrit Care

25 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 25

26 Summary Background SE prognosis SE Treatment Treatment and prognosis Conclusions 26

27 Does SE treatment influence prognosis? Model Predictors Area 11 Etiology Etiology, STESS Etiology, STESS, Comorbidity Etiology, STESS, Comorbidity, Treatment 0.85 Hospit. cohort, 225 incident episodes Rossetti J Neurol

28 Does SE treatment influence prognosis? ICU-based, 144 episodes Kowalski Crit Care Med 2012 ICU-based, 171 episodes Sutter Neurology

29 Does SE treatment influence prognosis? Adjusted RR of therapeutic coma (new disability: diamonds; mortality: squares) Hospit. cohort, 467 patients Marchi Crit Care Med

30 Summary Background SE prognosis SE Treatment Treatment and prognosis Conclusions 30

31 Induce coma in which SE form? Quickly in gen.-convulsive, deferred in compl.-partial, never in absence! Which agent? MDZ PRO > BBT To which EEG target? Seizure suppression or burst-suppression (1 / 10 sec.) How long? hours, then wean over 6-12 hours, (and again ) Stopping treatment? Only if evidence of permanent brain damage! 31

32 Take home messages... 1 st line has best evidence Biological background is determinant Adapt tt aggressiveness (~ intubation!) Ketamine, ketogenic diet are promising Target the etiology! Auguste Rodin, Le penseur, 1902, Paris 32

33 Acknowledgments Drs J. Novy, V. Alvarez; Chr. Stähli RN; EEG fellows and technicians Service de Neurologie, CHUV/UNIL PD Dr Mauro Oddo, Tamara Suys RN Service de Médecine Intensive Adulte, CHUV/UNIL Prof. B. Burnand, Jean-Marie Januel MPH, Mohamed Faouzi PhD Institut universitaire de médecine sociale et préventive, Lausanne Dr JW Lee, Pr Barbara Dworetzky Pr G. Logroscino Epilepsy/Neuro-ICU, BWH-Harvard, Boston (MA, USA) Università di Bari (I) 33