Emergency Management of Paediatric Status Epilepticus. Dr. Maggie Yau Department of Paediatrics Prince of Wales Hospital

Transcription

1 Emergency Management of Paediatric Status Epilepticus Dr. Maggie Yau Department of Paediatrics Prince of Wales Hospital

2 Definition (ILAE 2015) After t1 failure of the mechanisms responsible for seizure termination OR initiation of mechanisms which lead to abnormally prolonged seizures Beyond t1 -> continuous seizure activity After t2, long-term consequences (including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures. Epilepsia, 56(10): , 2015

3 Definition ILAE 2015

4 How long do new-onset seizures in children last? Shinnar S., et al. 2001;49(5): % mean duration 3.6 minutes 24 % mean 31 minutes

5 Physiological change in SE Shorvon S. Handbook of epilepsy treatment. 2001

6 Objectives Background - Epidemiology/ Aetiology Why do we treat? When do we treat? How do we treat?

7 Epidemiology (UK) North London SE study per 100,000 children per year Chin RF. Lancet 2006;368(9531):

8 Aetiology of first-ever episodes of CSE in North London Prolonged febrile seizures 32% Acute symptomatic 17% Remote symptomatic 16% Acute on remote symptomatic 16% Idiopathic epilepsy related 10% Cryptogenic epilepsy related 2% Unclassified 7% Chin RF. Lancet 2006;368(9531):

9 Why treat? Risk of brain injury Generalized status epilepticus Neuron loss Evidence of cytotoxic injury FEBSTAT study: 117 patients with MRI within 72 hours of FS 22 (11.5%) with T2 signal in hippocampi Shinnar et al 2012 Neurology

10 Treatment of SE Treat aetiology Prevent complications Control seizures

11 How do we treat? STOP SEIZURE Seizure airway and administer oxygen Assess cardiorespiratory function Measure glucose Intravenous access Establish aetiology

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13 5.4% 22% Chin RFM et al. Lancet Neurology 2008;7:

14 Chin RFM et al. Lancet Neurology 2008;7: >2 doses associated with increased likelihood seizure > 60min (odds ratio 3.1) & respiratory depression (odds ration 3.2)

15 postulated to contribute to cognitive deficits associated with schizophrenia 104. In vivo analysis of animal models will help to determine the extent to which aberrant GABAergic plasticity contributes to the pathophysiology of schizophrenia. For example, mice lacking the 3 GABA A R subunit ished ability to process sensorimotor information 140. There was a dramatic loss of synaptic GABA A Rs and gephyrin clusters in the thalamic reticular nucleus 141 (one of the main regions in the brain where the 3 subunit is normally expressed 142 ) of 3-subunit-knockout mice and a resultant absence of functional inhibitory a 3 3 Repeated seizures (status epilepticus) 3 3 AP2 clathrin complex P P AP2 PKC 3 Endocyt osis CCV Enhanced internalization of synaptic GABA A receptors b Jacob TC, et. Al. Nature Review Neurology 2008

16 Benzodiazepines available Diazepam Lorazepam Midazolam route IV/ PR IV IV/IM/Buc onset 1-3 min 2-3min 1-5min duration 5-15min 12-48hrs 1-5hrs Half-life 30hrs 15hrs 2-4hrs Receptor binding

17 Cochrane review Drug management for acute tonic clonic convulsion in children, including status epilepticus Appleton, Macleod, Martland 2009 Results 1. IV lorazepam is as effective as IV diazepam, fewer adverse effect. RR1.09 Appleton et al Intranasal midazolam as effective as IV diazepam. RR Lahat et al Buccal midazolam more effective than rectal diazepam. RR Mclntyre et al, 2005

18 RAMPART study Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART)

19 RAMPART Neurological Emergencies Treatment Trials (NETT) network 4314 paramedics, 33 EMS agencies, and 79 receiving hospitals Estimated body weight of 13 kg or more and adults requiring treatment with benzodiazepines for status epilepticus in the prehospital setting.

20 RAMPART IM midazolam + IV placebo IM Placebo + IV lorazepam

21 RAMPART- results Seizures were absent without rescue therapy 73.4% in the im-midazolam group vs 63.4% in the ivlorazepam (P<0.001: non-inferiority and superiority). The two treatment groups were similar with respect to need for endotracheal intubation and recurrence of seizures Seizures ceased before arrival in the emergency department: median times to active treatment minutes in the immidazolam group vs 4.8 minutes in the iv lorazepam group, Adverse-event rates similar

22 RAMPART - conclusion IM midazolam is at least as safe and effective as IV lorazepam for prehospital seizure cessation

23 Buccal midazolam The time for drug administration and drug effect was significantly less with buccal midazolam than with rectal diazepam (p value<0.001). In the buccal midazolam group, 46 (94%) parents were satisfied with their child s treatment and route of drug administration while in the rectal diazepam group, 7 (14%) parents were satisfied. Buccal midazolam was significantly more acceptable than rectal diazepam (p value < 0.001).

24 Buccal midazolam

25 Buccal midazolam

26 **Take home message ** 1. The earlier the better 1. Don t give >2 doses of benzodiazepine Usually not useful and May be harmful

27 Median time for 1 st AED: 28 min 2 nd AED 40 min 3 rd AED: 57 min DELAY!!

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29 ESTABLISHED SE

30 Established SE All AED doses are based on observational studies and expert opinion Phenytoin Phenobarbitone Valproate Levetiracetam (Lacosamide)

31 Phenytoin IV route Give slowly with ECG monitoring Half-life= hours Very alkalotic Side Effects Purple glove syndrome Hypotension Arrhythmia

32 Phenobarbitone GABA agonist Routinely used for treatment of neonatal seizures More widely used in developing countries Similar anticonvulsant activity to PHT and BZP

33 Established SE: Sodium Valproate Risk in children? Rule out metabolic diseases IV VPA has a better tolerability than PHT in treatment of GCSE, without any statistically significant differences in terms of efficacy. More rigorous RCTs of VPA versus an appropriate comparator, are required

34 Levetiracetam (Keppra ) Pyrrolidine derivative which act through binding to and modulation of the synaptic vesicle protein SV2A Good oral bioavailability Not affected by drug-drug interaction Low protein binding ability (< 10%) Not cytochrome p450 metaboliser Side Effects Mild sedation/ nausea Transient asymptomatic thrombocytopenia Transient elevation in liver function tests

35 Established SE: Levetiracetam Overall 707 patients with various forms of SE were treated with intravenous LEV. The success rate of was ~70%. The most often used initial dose was 2,000 3,000 mg per day over 15 min. Adverse events were reported in <10% and were mild and transient. Epilepsia, 52(Suppl. 8):35 38, 2011

36 Efficacy of levetiracetam was 68.5% phenobarbital 73.6% valproate 75.7% phenytoin 50.2% Lacosamide: insufficient data.

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38 REFRACTORY SE

39 Occurrence: % of SE Mortality ranges from 3 9% in children Up to 15% with neurological sequalae Lack of high-quality evidence to guide care Use of anaesthetic agents No evidence which one is superior to others Mayer SA et al.2002, Novy J et al., 2010, Holtkamp M et al., 2005

40 Refractory SE: ICU complications Manifestations of SE Lactic acidosis Shoulder dislocation Rhabdomyolysis Medication side effect Hypotension Apnea intubation Ileus Immunocompromised Expected medical complications Critical illness polyneuropathy

41 Refractory SE? Bolus of the urgent control AED? Immediately initiate additional agents No well defined period of observation that has been determined to be safe No data to suggest that watchful waiting is safer than proceeding with more aggressive treatment

42 Treatment NOT without risk!! Neurology2014;82:

43 Refractory SE Midazolam Propofol Pentobarbital / thiopental No data to suggest which is preferred agent

44 Refractory SE: midazolam Binds to GABA receptors and augments GABAergic transmission Advantages Only benzodiazepine with pharmacokinetic properties suitable for prolonged infusion without accumulation Disadvantages May be less effective than other anesthetics Hypotension, cardiorespiratory depression Risk of hepatic and renal impairment Risk of tolerance and breakthrough seizures (? Overestimated)

45 Refractory SE: propofol Inhibits NMDA and modulates Ca influx

46 Refractory SE: propofol Advantages Excellent pharmacokinetic properties including very rapid onset and recovery even after prolonged infusion allowing ease of control of anesthesia No drug interactions Less hypotension and cardiorespiratory depression than barbiturate or midazolam anesthesia

47 Refractory SE: propofol Disadvantages Propofol infusion syndrome, especially in children CPK>2000U/L Triglycerides> 500mg/dL Progressive lactic acidosis > 48hour use Pain at the injection site Difficulty in differentiating drug-induced involuntary movements and seizures

48 Refractory SE: thiopental GABA receptor (different from benzodiazepines)

49 Refractory SE: thiopental Advantages: strong antiepileptic action long clinical experience tendency to lower core temperature theoretical neuroprotective effects. Disadvantages: problematic pharmacokinetics zero-order kinetics profound tendency to accumulation, long recovery time, hepatic metabolism, autoinduction, drug-drug interactions hypotension, cardio and respiratory depression pancreatic and hepatic toxicity.

50 Burst suppression/ Flat background/ Neither did not affect seizure control No need to suppress all epileptiform discharges

51 No seizure Burst suppression Flat

52 On thiopentone- subclinical sz

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56 SUPER-REFRACTORY SE

57 Super-refractory SE First appeared in 2011 in the summary of the Third London-Innsbruck Colloquium on status epilepticus A stage of refractory SE characterized by unresponsiveness to initial anesthetic therapy SE that continues or recurs 24 hours or more after the onset of general anesthesia, including those cases in which SE recurs on the reduction or withdrawal of anesthesia

58 Super-refractory SE- treatment aims Control seizures Neuroprotection an attempt to block the progression over time of the secondary processes triggered by initial excitotoxicity. Avoid or treat the systemic complications of prolonged unconsciousness and of prolonged anaesthesia.

59 Causes Autoimmune Encephalitis Neural antibody-mediated CNS disorders Anti-NMDAR encephalitis Anti-VGKC encephalitis Glycine receptor encephalitis Anti-GAD Ab associated encephalitis Encephalitis complicated by seizures e.g. Rasmussen encephalitis Limbic encephalitis - both paraneoplastic and non-paraneoplastic Mitochondrial disorders Alpers disease, MELAS, Leigh syndrome, MERRF Genetic Disease POLG Uncommon infectious diseases Drugs or toxins De novo NORSE, FIRES

60 Autoimmune encephalitis Anti-NMDAR encephalitis VGKC complex encephalitis Glycine receptor encephalitis Anti-GAD Ab associated encephalitis Clues for autoimmune/inflammatory etiology High seizure frequency Subacute onset Neuropsychiatric symptoms

61 Anti-NMDA receptor encephalitis Initially described in 2007 Syndrome of memory deficits, psychiatric symptoms, decreased consciousness, and hypoventilation in 4 women with teratomas 1 Antibodies to NR1 subunit of NMDAR Prevalence: 1 % in ICU admission in young adults (18 35 y.o.) 2 2 nd most common immune mediated cause after ADEM Associated with ovarian teratoma in young women Detected in 42% patients (N=500) with 55% in women > 11 years old

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63 Not evidence- based!!! Case series only.

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65 Super-refractory SE: ketamine antagonistic action at the N-methyl-D-aspartate receptor Glutamate blockade becomes more effective than GABA agonism in later stages of SE no cardiac depressant properties and does not cause hypotension potentially neuroprotective, because of its strong N-methyl-D-aspartate antagonist action

66 Super-refractory SE Cycling of anaesthetics Reverse anaesthesia initially every 24 48h, and if seizures recur, then to re-establish it Over time, the duration of individual cycles is increased, After a few weeks, anaesthesia is often continued for 5 days before attempts to reverse it

67 Super-refractory SE Maintenance AEDs High doses for 2-3 AEDs, preferably 2 Avoid frequent changes Favour AED with low interaction potential Favour AED with predictable pharmacokinetics Avoid GABAergic AED

68 KETOGENIC DIET Used in epilepsy since 1920s 4:1 ratio (lipid: protein + carbohydrate) 90% calories from lipid Mechanism Possible anti-inflammatory action Conclusive experimental action is lacking

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70 5 cases ranging from 10 months 10 years old Started mean 12.8 days after seizure onset Age 9 years old 10 months 5 years old 10 y.o 9 years old Seminology focal status EPC Multifocal NCSE myoclonic Concomitant AED 8 + IvIg + pentobarbi tal 7 + MDZ drip + pentobarbita l 7 + barbiturate coma 4 + pentobarbital 4 Seizure abate 5 days 5 days 8 days (improve) 36 hours 48 hours Etiology Unknown Alpers- Huttenlocher syndrome Unknown Known epilepsy Mitochondrial Flu A

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72 Super-refractory SE: prognosis The longer the status epilepticus continues, the worse the outcome (Neligan and Shorvon, 2010) BUT.. Good recovery can occur even after weeks or months of status epilepticus, especially in status epilepticus where no cause was found

73 29 years old boy with NORSE had 2.5 months of status epilepticus and over 4 months of cycling anaesthesia with satisfactory recovery of gait and cognition