Lieven Lagae Department of Paediatric Neurology Leuven University Leuven, Belgium. Management of acute seizure settings from infancy to adolescence

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1 Lieven Lagae Department of Paediatric Neurology Leuven University Leuven, Belgium Management of acute seizure settings from infancy to adolescence

2 Consequences of prolonged seizures Acute morbidity and mortality Trauma Accidents Systemic effects e.g. Rhabdomyolysis Evolution towards SE Brain oedema & damage Influence on epileptogenesis (?) Lagae, 2011

3 Time is brain???

4 Percent cases with duration >t How long do new onset seizures in children last? Data (N=407) Model Type equation here. Two populations Group 1: Mean 3.6 minutes (76%) Group 2: Mean 31 minutes (24%) Duration of first unprovoked seizure (min) 60 Shinnar et al, 2001

5 Higher risk for prolonged seizures after the first prolonged seizure Percent cases with duration t Duration of recurrent seizure as function of duration of initial seizure (N=182) First seizure 30 min, n=25 First seizure 6 29 min, n=42 First seizure 5 min, n= Duration of recurrent seizure (min) Shinnar et al, 2001

6 Intensity function Risk for prolonged seizures 0.30 Probability of spontaneous ending of an ongoing seizure Duration of seizure (min) Shinnar et al, 2001

7 Predicted hazard Cumulative percent Duration of febrile SE in the FEBSTAT cohort Weibull predicted Kaplan-Meier curve Duration of febrile SE (min) N= [S(t)=e (t/95.9)1.68) ] Duration of febrile SE (min) FEBSTAT, Consequences of Prolonged Febrile Seizures in Childhood study Shinnar et al, 2008

8 Aetiology of childhood convulsive SE Aetiology Patients (%) Prolonged febrile seizures 32 Acute symptomatic 17 Remote symptomatic 16 Acute or remote symptomatic 16 Idiopathic epilepsy related 10 Cryptogenic epilepsy related 2 Unclassified 7 Neville et al, 2007

9 Treatment

10 Ideal first line medication outside the hospital Effective : fast action Short hangover Safe (hypotension, respiratory depression) No need for medical setting to administer Easy to administer also by parents, teachers, Simplified dosing Preservable for longer periods Socially acceptable : not rectal anymore Risk of a prolonged seizure versus side effects

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12 Hyperpolarization through Chloride influx (GABA receptor)

13 Chen and Wasterlain, Lancet Neurology 2006

14 If a seizure lasts for more than 5 minutes : Evolution towards prolonged seizure and status epilepticus Time window for intervention : 0-5 minutes Identification of children at risk for prolonged seizures : Convulsive seizures worse than non convulsive

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16 Home setting: rectal diazepam Dreifuss F et al, N Eng J Med 1998

17 Buccal midazolam and rectal diazepam Hospital emergency department setting: long lasting seizures Rectal diazepam or buccal midazolam 0.5mg/kg/dose Outcome : number of patients with stop seizures at 10 minutes Subsequent need for intravenous lorazepam Need for respiratory support McIntyre et al, Lancet 2005

18 Buccal midazolam and rectal diazepam Therapeutic success (%) Buccal midazolam (109 episodes) Rectal diazepam (110 episodes) Percentage difference (95% confidence interval [CI]) All episodes 61 (56%) 30 (27%) 29 (16, 41) Initial episodes 49 (53%) 24 (28%) 25 (11, 39) Time (min) to stop seizing after treatment (median, interquartile range [IQR]) All episodes 8 (5 20) 15 (5 31) Initial episodes 10 (5 22) 15 (6 32) Stopped seizing within 10 min (%) All episodes 71 (65%) 45 (41%) 24 (11, 37) Initial episodes 56 (60%) 36 (42%) 18 (4, 33) Given IV lorazepam (%) All episodes 36 (33%) 63 (57%) 24 (12, 37) Initial episodes 33 (36%) 47 (55%) 19 (5, 35) Seizure stopped, then further seizure All episodes 10 (14%) (n=71) 15 (33%) (n=45) 19 (4, 36) Initial episodes 7 (13%) (n=56) 12 (34%) (n=31) 22 (4, 40) Respiratory depression (%) All episodes 5 (5%) 7 (6%) 2 (-4, 8) Initial episodes 4 (4%) 6 (7%) 3 (-4, 10) McIntyre et al, 2005

19 Time to adequate BZP treatment in prolonged seizures Pellock et al, Epilepsy and Behaviour, 2004

20 Treatment Delay Pellock, J Child Neurol, 2007

21 Management of refractory SE in adults: still more questions than answers Impending and early SE (5 30 min) IV BZP Lorazepam 0.1 mg/kg, clonazepam mg/kg or midazolam 0.2 mg/kg IV AED Phenytoin 20 mg/kg, valproate mg/kg or levetiracetam mg/kg Generalised-convulsive (or subtle) SE Focal-complex, myoclonic, or absence SE Established and early refractory SE (30 min 48 h) IV midazolam 0.2 mg/kg mg/kg/h and/or IV propofol 2 mg/kg 2 10 mg/kg/h Further IV or oral AED Valproate, levetiracetam, lacosamide, topiramate, pregabalin or other Late refractory SE (>48 h) Other drugs Lidocaine, verapamil, magnesium, immunomodulation Phenobarbital (thiopental) 5 mg/kg (1 mg/kg) 1 5 mg/kg/h Other anaesthetics Isoflurane, desflurane, ketamine Other approaches Surgery, vagal nerve stimulation (VNS), repetitive transcranial magnetic stimulation (rtms), electroconvulsive therapy (ECT), hypothermia, ketogenic diet Rossetti and Lowenstein, 2011

22 What happens in the emergency room? Community-onset prolonged seizures First-line community treatment: rectal diazepam Seizure termination was defined as termination of overt clinical seizure activity within 10 minutes of completion of the administration of antiepileptic drugs (AEDs) Chin et al, 2008

23 Treatment of childhood convulsive status epilepticus (CSE) in the emergency room 240 episodes of CSE 93 episodes not treated before reaching hospital 147 episodes treated before reaching hospital 5 seizure terminations 32 seizure terminations 203 episodes treated on arrival at accident and emergency department 187 treated with first-line AEDs: n=107 intravenous (IV) lorazepam n=80 rectal diazepam 121 seizure terminations after first-line AEDs: 63 after IV lorazepam 56 after rectal diazepam 82 episodes treated with second-line AEDs: n=42 rectal paraldehyde n=32 IV phenytoin n=5 IV phenobarbitone n=3 thiopentone 82/240 (30%) episodes treated with second-line AEDs 41 seizure terminations after second-line AEDs 41 episodes treated with thiopentone 1 in 6 children needed admission to the ICU Chin et al, 2008

24 Buccal midazolam and rectal diazepam 35 59% Therapeutic success (%) Buccal midazolam (109 episodes) Rectal diazepam (110 episodes) Percentage difference (95% confidence interval [CI]) All episodes 61 (56%) 30 (27%) 29 (16, 41) Initial episodes 49 (53%) 24 (28%) 25 (11, 39) Time (min) to stop seizing after treatment (median, interquartile range [IQR]) All episodes 8 (5 20) 15 (5 31) Initial episodes 10 (5 22) 15 (6 32) Stopped seizing within 10 min (%) All episodes 71 (65%) 45 (41%) 24 (11, 37) Initial episodes 56 (60%) 36 (42%) 18 (4, 33) Given IV lorazepam (%) All episodes 36 (33%) 63 (57%) 24 (12, 37) Initial episodes 33 (36%) 47 (55%) 19 (5, 35) Seizure stopped, then further seizure All episodes 10 (14%) (n=71) 15 (33%) (n=45) 19 (4, 36) Initial episodes 7 (13%) (n=56) 12 (34%) (n=31) 22 (4, 40) Respiratory depression (%) All episodes 5 (5%) 7 (6%) 2 (-4, 8) Initial episodes 4 (4%) 6 (7%) 3 (-4, 10) McIntyre et al, 2005

25 What about paediatric patients? Post-BZP IV treatment options Phenytoin (20 mg/kg) Need to replace with another AED after the SE episode is resolved Pharmacokinetic/dynamic problems with other AEDs Need for IV line with physiological serum Acute cardiovascular side effects, hypotension Phenobarbital (20 mg/kg) Need to replace with another AED after the SE episode is resolved Valproate (20 mg/kg) Caution for use in metabolic diseases and young children Levetiracetam (30 mg/kg) Few controlled studies Lacosamide Two case reports

26 UZ Leuven protocol Standing order hospital setting for CONVULSIVE seizures Step 1. Benzodiazepines: buccal lorazepam 1mg or 2.5 mg (buccal midazolam 2013) Step 2. IV Benzodiazepines: lorazepam 0,1 mg/kg Step 3. IV loading dose Phenytoin 20 mg/kg Levetiracetam 30 mg/kg Valproate 20 mg/kg

27 IV valproate and phenobarbital for convulsive SE and acute prolonged convulsive seizures in children IV valproate Phenobarbital p-value Response in <20 min after infusion of medication Yes 27/30 (90%) 23/30 (77%) No 3/30 (10%) 7/30 (23%) Seizure recurrence within 24 h after termination of seizures Yes No Malamiri et al, 2012

28 Patients without seizure recurrence after levetiracetam (%) IV levetiracetam for acute seizures in children Single seizure Serial seizures SE * * * * * (n=73) 12 (n=58) 24 (n=54) 48 (n=43) 72 (n=42) *p<0.05 Hours after levetiracetam loading dose (n = number of valid cases analysed at given time interval) Reiter et al, 2010

29 IV levetiracetam in acute repetitive seizures and SE in children: experience from a children s hospital 2-year observational study in patients receiving IV levetiracetam to treat acute repetitive seizures (ARS) or convulsive and non-convulsive SE Results N=51; mean age: 7.1 years (range: years) n=45 patients with ARS or SE Median initial levetiracetam dose: 14.4 mg/kg (range: 5 30 mg/kg) 23/39 (59%) patients with ARS became and remained seizure-free SE terminated in 3/4 (75%) patients with convulsive and 2/2 (100%) patients with non-convulsive SE 34/45 (76%) patients with ARS or SE remained on levetiracetam at final follow-up (2 18 months after receiving drug)

30 Outcomes in children

31 SE in children treated in intensive care: outcome Outcome N % Unchanged neurologic status Neurologic consequences Lethal outcome Total Aetiology of lethal outcome N % Underlying disorder Underlying disorder + respiratory impairment Prolonged coma acute respiratory distress syndrome (ARDS) Total Kravljanac et al, 2011

32 Age as protective factor? Predictive factors for neurologic consequences after SE Variable Coefficient ( ) Standard error Wald 2 p-value Hazard ratio 95% CI Age , 0.96 Duration of SE >24 h , 1.60 Progressive encephalopathy , 1.78 Predictive factors for recurrence after the first episode of SE Variable Coefficient ( ) Standard error Wald 2 p-value Hazard ratio 95% CI Progressive encephalopathy , 1.91 Pre-existing neurologic deficit , Kravljanac et al, 2011

33 Long-term prognosis after status epilepticus SE (n=39) No SE (n=149) At onset Normal intelligence 39 (100%) 149 (100%) Learning disorder 9 (23%) 35 (23%) At follow-up Learning disorder 11 (28%) 49 (33%) Formal psychometric testing School grade repeated 14 (36%) 70 (47%) Extra help at school, resource 15 (39%) 73 (49%) Work/study programme at school 4 (10%) 13 (9%) Stimulant medication 4 (10%) 16 (11%) High school graduation 28 (72%) 104 (70%) University education 12 (31%) 36 (24%) Technical school or community college 13 (33%) 46 (31%) Camfield and Camfield, 2012

34 Rescue plan: keep it simple Familiarize with one product Show how to apply Explain basics about normal protective actions during a seizure Explain when to give the rescue medication: acute convulsive seizure not stopping at 3-5 minutes If no success within 5-10 minutes, call emergency service Discuss the use of a second, similar dosage of the rescue medication (preferentially given by medical professional) Discuss who else can give the rescue medication (teacher, grandparents, )

35 Concluding remarks Acute prolonged seizures remain a medical urgency, also in childhood epilepsy Second-line treatment after BZP: more evidence-based data necessary Loading doses are possible for acute prolonged seizures (phenytoin, phenobarbital, levetiracetam, valproate and lacosamide) Special considerations for specific childhood epilepsy syndromes