Ednea Simon, MD Swedish Pediatric Neuroscience Center
1 Status Epilepticus
• Status epilepticus (SE) is a condition resulting either from failure of the mechanisms responsible for seizure termination or form the initiation of mechanisms which lead to abnormally prolonged seizures.
• It can have long-term consequences, including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures
• Prolonged seizures lasting over 30 minutes or repeated frequently enough that recover between seizures does not occur.
• Important considerations in treatment
– T1 when a seizure is likely to be prolonged leading to continuous seizure activity and treatment should be established after 5-minute mark for convulsive seizure and 10 minute mark for focal seizure – T2 marks the time at which neuronal damage or self perpetuating alteration of neuronal networks may begin if seizure is not controlled
Trinka E, Cock H, Hesdorffer D at al, Epilepsia 56(10): 1515-23, 2015 Lowenstein et al. Epilepsia 40:120-122, 1999
2 Status Epilepticus
• Goal of therapy: rapid cessation of seizure activity before 30-minute mark when seizure-associated neurologic injury can occur
• Incidence of up to 10-41 cases per 100,000 per year and overall mortality of 20% – Risk factors • Etiology • Higher incidence in ages less than 12 months and over 60 years • Long duration SE
Betjemann JP & Lowenstein DH. Lancet Neurology (6): 615-24, 2015 Kantanen AM et al. Epilepsy Behav, 49 (Aug): 131-4, 2015 Trinka et al., Seizure 44: 65-73, 2017
3 Age-specific incidence of SE Mortality of SE
DeLorenzo et al. Epidemiology of Status Epilepticus, J Clin Neurophys; 12(4):316-25, 1995
4 CLASSIFICATION OF STATUS EPILEPTICUS
• With prominent motor symptoms – Convulsive type comprises 37-70% of all forms of status – Myoclonic – Focal motor – Tonic – Hyperkinectic
• Nonconvulsive status epilepticus: enduring epileptic condition with reduced or altered consciousness, behavioral, and vegetative abnormalities, or merely subjective symptoms without major convulsive movements lasting more than 30 minutes with ictal epileptiform discharges on EEG. – 8-34% of patient with altered mental status in ICU presents NCSE
– With associated coma represents a life threatening condition that requires urgent treatment
– Without coma • Focal • Generalized
Trinka E et al. Epilepsia 53(suppl 4): 127-138, 2012
5 ETIOLOGY OF STATUS EPILEPTICUS
• Symptomatic – Acute symptomatic – Remote symptomatic – Progressive symptomatic
• Unknown
• Most frequent causes – Acute symptomatic 48-63% of cases with stroke present in 14-22% – Preexisting epilepsy -> low level of AED (25% of cases) that has good prognosis with mortality of 4-8.6% – Remote stroke
• Approximately 12% of patients with epilepsy have had at least 1 episode of SE in their lifetime
• Acute symptomatic etiology may account for 40-50% of cases
Trinka E et al. Epilepsia 53(suppl 4): 127-138, 2012 DeLorenzo RJ et al. J Clin Neurophysiol 12:316-25, 1995 Towne AR et at. Epilepsia 35:27-34, 1994
6 ETIOLOGY OF STATUS EPILEPTICUS
Trinka E et al. Epilepsia 53(suppl 4): 127-138, 2012
7 ETIOLOGY OF STATUS EPILEPTICUS
• Hypoxic ischemic encephalopathy • Cerebrovascular diseases • Withdrawal or low AEDs levels • Metabolic
• Intracranial tumors • CNS infections • Neurodegenerative diseases • Cortical dysplasia • Head trauma • Intoxication • Autoimmune • Mitochondrial cytopathy • Genetic • Neurocutaneous syndromes • NORSE – New onset refractory status epilepticus (adults) • FIRES – Febrile infection related epilepsy syndrome
Trinka E et al. Epilepsia 56(10): 1515-23, 2015
8 NORSE NEW ONSET REFRACTORY STATUS EPILEPTICUS
• Condition characterized by the sudden onset of continuous seizures or a flurry of very frequent seizures that can not be controlled with seizure medications
• In many cases there is report of a cold or flu like illness days to weeks prior to the start of seizures
• Affects otherwise healthy young adults, although it can affect people of any age.
• Super-refractory status epilepticus with patients often treated with IV anesthetics for weeks in an intensive care unit
• NORSE is a life-threatening condition, with a death rate of around 30%. Survivors often have lasting brain damage and epilepsy. A minority of people fully recover and return to a normal lifestyle
9 FIRES FEBRILE INFECTION-RELATED EPILEPSY SYNDROME
• Rare epilepsy syndrome of unclear etiology in which children, usually of school age, suddenly develop very frequent seizures (up to hundreds per day) within two weeks after a mild febrile illness.
• Super-refractory status epilepticus despite use of IV anesthetics that can last months
• Immune treatment and the ketogenic diet may help.
• Outcome is poor with cognitive disability and refractory epilepsy.
10 TIME IS BRAIN! CLINICAL COURSE Early phase 5-10 Impending SE MIN
10-30 Established SE MIN
30-60 Refractory SE MIN
Super >24 H Refractory SE PROGNOSIS OF STATUS EPILEPTICUS WORSENS WITH INCREASING DURATION OF SEIZURE ACTIVITY Trinka et al., Seizure 44: 65-73, 2017
11 Treatment Algorithm of Status Epilepticus
• Stabilization phase (0-5 minutes of seizure activity) including standard initial first aid for seizures and initial assessments and monitoring. Maintain airway, respiration, and circulation
EARLY TREATMENT SHOULD BE EMPHASIZED SINCE TREATMENT BECOMES LESS EFFECTIVE THE LONGER THE EPISODE OF STATUS EPILEPTICUS LASTS
• Initial therapy phase (5-20 minutes) when it is clear the seizure requires medical intervention.
• Second therapy phase (20-40 minutes) when response (or lack of response) to the initial therapy should be apparent.
• Third therapy phase (+40 minutes) if second therapy fails to stop the seizures, treatment consideration should include repeating second line therapy or IV anesthetic drugs that require continuous video-EEG monitoring.
Trinka et al., Seizure 44: 65-73, 2017
12 Treatment Algorithm of Status Epilepticus Stabilization phase • Intubation for airway protection if unconscious • Monitor blood pressure, pulse, cardiac rhythm, and oxygen saturation • Intravenous access • Initial labs: toxic screen, ethanol level, complete blood count, comprehensive metabolic panel, antiepileptic drug levels • Neuroimaging investigation • CSF studies, if indicated • Electroencephalogram
13 TREATMENT OF EARLY PHASE SE FIRST LINE TREATMENT: BENZODIAZEPINE
Benzodiazepine is recommended IM or IN midazolam, IV lorazepam, IV diazepam with demonstrated efficacy, safety, and tolerability
• Lorazepam IV – 0.07-0.1 mg/kg at rate 2 mg/min
• Diazepam IV or rectal – 0.2 mg/kg at rate 5 mg/min – 5-10 mg up to 20 mg
• Midazolam IM or IN or buccal – 0.2 mg/kg, dose 10 mg
Benzodiazepine increases channel opening frequency of GABA-A receptors with increased chloride conductance and neuronal hyperpolarization, with increased inhibition
Trinka et al., Seizure 44: 65-73, 2017
14 TREATMENT OF EARLY PHASE SE FIRST LINE TREATMENT: BENZODIAZEPINE • VA cooperative study using IV lorazepam vs IV phenytoin as first line treatment for SE – 64.9% controlled with IV lorazepam – 43.5 % controlled with IV phenytoin
15 IM Midazolam vs IV Lorazepam as first line for treatment of status epilepticus
Double blind study including 893 children and adults treated by paramedics
IM Midazolam IV Lorazepam Seizure control 73.4% 63.4% Time administration 1.2 min 4.8 min Clinical seizure cessation 3.3 min 1.6 min
RAMPART- rapid anticonvulsant medications prior to arrival trial
Silbergleit R et al., N Engl J Med 2012; 366 February (7): 591-600
16 INTRAVENOUS LORAZEPAM VS DIAZEPAM
• Meta analysis of 5 randomized controlled trial including 656 patients – 320 treated with LZP – 336 with DZP
• No statistically significant differences were found between IV LZP and IV DZP regarding – Clinical seizure cessation – Continuation of SE requiring a different drug – Seizure cessation after a single dose of medication – Ventilatory support – Clinically relevant hypotension
Brigo et al., Epilepsy Behav 64 (Oct): 29-36, 2016
17 BENZODIAZEPINES AND ROUTES OF ADMINISTRATION Meta-analysis of 19 studies for efficacy and safety in children and adults using non-intravenous midazolam and rectal or intravenous diazepam.
Study included 1,933 seizures in 1,602 patients
• For seizure cessation, non-IV midazolam was as effective as IV or rectal diazepam
• Time interval between arrival and seizure cessation was shorter with non-IV midazolam
• Time from time interval from drug administration to clinical seizure cessation as shorter for diazepam by any route
• Non difference in side effects found with midazolam or with any route of diazepam
• Non-intravenous midazolam routes represents a practical, rapid, reasonably safe and effective alternative as first-line treatment in out of hospital setting
Brigo et al., Epilepsy Behav 2015; 49(August): 325-36; Brigo et al., CNS drugs 2015 A(August)
18 TREATMENT OF ESTABLISHED SE SECOND THERAPY PHASE
Approximately 40% of patients with generalized convulsive SE are refractory to benzodiazepine treatment Options:
• Fosphenytoin/Phenytoin • Valproic acid • Levetiracetam • Phenobarbital • Lacosamide
There is no class I evidence for choosing one AED over the other. Drug choice should take into consideration comorbidities and side effect profile
Trinka et al., Seizure 44: 65-73, 2017
19 TREATMENT OF ESTABLISHED SE SECOND THERAPY PHASE • Fosphenytoin/Phenytoin – Fosphenytoin: 20 mg/kg IV at 150 mg PE/min – Phenytoin: 20 mg/kg IV at 50 mg /min – Effect noted within 20 minutes of administration – If seizure persist after 30 minutes, give additional 10 mg/kg IV – Fosphenytoin is preferable due to increased risk for site reactions with phenytoin (purple glove syndrome). Cardiac arrhythmia may also occur with both drugs
20 TREATMENT OF ESTABLISHED SE SECOND THERAPY PHASE • Levetiracetam – 2000-4000g IV bolus
• Valproic acid – 20-40 mg/kg IV bolus – Contraindicated in mitochondrial disease
• Phenobarbital – 20 mg/kg IV bolus
• Lacosamide – 200-400 mg IV bolus
21 TREATMENT OF ESTABLISHED SE INTRAVENOUS SECOND THERAPY PHASE • Meta-analysis found higher rates of seizure cessation with valproic acid 75.7%, and phenobarbital 73.6 % than with levetiracetam 68.5% or phenytoin 50.2%
• Favorable tolerability profile for levetiracetam and valproate as compared to phenobarbital and phenytoin
Trinka E et al. Curr Opin Neurol 29(April):189-98, 2016 Trinka E. Expert Opin Pharmacother 17(March): 513-34, 2016
22 TREATMENT OF ESTABLISHED SE INTRAVENOUS LACOSAMIDE
• Review of 136 patients with refractory SE (convulsive and nonconvulsive) obtained seizure control in 56% of cases and adverse effects in 25%, mostly mild sedation
• Retrospective study of 98 patients showed seizure control in 76.5% with seizure cessation < 24 h in 57.1%
• Dose: IV bolus 400 mg, infusion over 5-10 min. – Higher response with high loading dose (400 mg) with 50% response as compared to low dose (200 mg) with 18% response • Maintenance dose: 200-400 mg
• Adverse events: somnolence, nausea, dizziness, diplopia, blurred vision, vomiting, increased PR interval on ECG, AV block
• Lacosamide enhances slow inactivation of voltage-gated sodium channels
Garces M et al. Epilepsy Behav 2014, 36(July): 144-52 Hofler J & Trinka E. Epilepsia 2013: 54(3): 393-404. Legros et al. Neurocrit Care 2013
23 TREATMENT OF REFRACTORY SE CHALLENGES OF SECOND THERAPY PHASE
• VA cooperative study showed that 55% response to benzodiazepine followed by phenytoin or phenobarbital (Treiman et al., 1998).
• In refractory cases, only 7% responded to a second agent. Those who did not respond had dose limiting adverse effects – Hypotension – Cardiac and respiratory depression
24 TREATMENT OF REFRACTORY SE THIRD THERAPY PHASE • Lack of seizure control in 31-43% of patients
• Use of intravenous anesthetic drugs in 488 episodes of refractory status epilepticus used – Midazolam 59% – Propofol 32% – Pentobarbital 8% – Similar efficacy among those agents
• Requires continuous video-EEG monitoring with suppression of electrographic seizures or presence of burst suppression for at least 24 hours
Mayer et al. Arch Neurol 59(2):205-10, 2002 Holtkamp M et al. J Neurol Neurosurg Psychiatry 76(4):534-9, 2005 Ferlisi Mt al. Epilepsy Behav, 48(Aug): 318-24, 2015 Classen J et al. Epilepsia 43(2): 146-53, 2002 Ferlisi M et al. Brain 2012 135(Aug): 2314-28, 2012
25 TREATMENT OF REFRACTORY SE THIRD THERAPY PHASE
• Meta analysis of 193 patients with RSE using pentobarbital (n=106), midazolam (n=54), and propofol (n=33) – 48% death, independent of AED choice or titration goal – Pentobarbital titrated to background suppression and midazolam and propofol titrated to seizure suppression – Pentobarbital compared to midazolam and propofol was associated with a lower frequency of short-term treatment failure (8 vs. 23%; p < 0.01), breakthrough seizures (12 vs. 42%; p < 0.001), and changes to a different cIV- AED (3 vs. 21%; p < 0.001) – Pentobarbital showed a higher frequency of hypotension (77 vs. 34%; p < 0.001). – Compared with seizure suppression (n = 59), titration of treatment to EEG background suppression (n = 87) was associated with a lower frequency of breakthrough seizures (4 vs. 53%; p < 0.001
• Second line therapy should be maintained in addition to anesthetic medications
Claasen et al. Epilepsia 43(2): 146-53, 2002
26 TREATMENT OF REFRACTORY SE PROPOFOL
• NMDA antagonist and potentiated GABA receptor binding • Lipid soluble and accumulates in lipid stores causing delayed offset effects • Dose: 1-2 mg/kg loading dose; maintenance 2-10 mg/kg/h • Rapid distribution 2-4 min, half-life 3-12 hours • Side effects – Hypotension and bradycardia – Propofol infusion syndrome • Metabolic acidosis • Rhabdomyolysis • Renal failure • Heart failure • Hypertriglyceridemia • Risk factors: – Infusion over 48 hours – Doses above 5 mg/kg/h (monitoring of triglycerides, lactate and CK levels)
Niermeijer JM et al. J Neurol 250(10: 1237-40, 2003
27 TREATMENT OF REFRACTORY SE MIDAZOLAM • Safest drug with lowest rate of cardiovascular and metabolic complications
• Dose: 0.2 mg/kg loading dose; maintenance 0.1-0.4 mg/kg/h, half-life 2-6 hours
• Midazolam is less effective with prolonged use and requires an increase in dose for the same effect
• Often weaned after 48-72 hours or transitioned to pentobarbital
28 TREATMENT OF REFRACTORY SE PENTOBARBITAL
• Pentobarbital has a long half-life and very reliable in its ability to achieve burst-suppression pattern on EEG
• Pugin et al., in 31 patients who had failed midazolam, showed seizure control in 90% with EEG in BS but 48% had withdrawal seizures. Addition of phenobarbital helped with successful pentobarbital wean.
• Pentobarbital has increased morbidity due to prolonged duration of pentobarbital associated coma
• Dose: 5-10 mg/kg load, maintenance 0.5-5 mg/kg/h, half-life 15-50 hours
• Side effects – Cardiovascular complications with need for vasopressors in 29% – Immunosuppression – Infections with pneumonia in 1/3 of patients – Other: DVT and ileus in 10%
29 TREATMENT OF SUPER-REFRACTORY SE
• Status epilepticus that continues beyond 24 hours following initiation of an anesthetic agent
• The use of anesthetics in refractory and super- refractory SE was associated with more infections and a 2.9-fold relative risk for death
• Patients are weaned off the third-line agent after 24-48 hours. If seizures recur, patient is placed back on IV anesthetic for seizure suppression for 3-7 days with intermittent weaning of medication to assess seizure control
Trinka et al., Seizure 44: 65-73, 2017
30 TREATMENT OF SUPER-REFRACTORY SE
• Search for other options – Ketamine – Other AEDs – Ketogenic diet – Emergency Epilepsy Surgery – VNS – Deep Brain Stimulation – Steroids – IVIG – Allopregnenolone (positive modulator GABA-A receptor) – Hypothermia 32-34 C – Topiramate – Electroconvulsive therapy
31 TREATMENT OF SUPER-REFRACTORY SE KETAMINE • Decreases excitatory glutamate activity via NMDA receptor antagonism
• Used in super-refractory status epilepticus
• Gaspard et al. in a retrospective series of 42 patients showed seizure control of 64% and no significant adverse effects
• Dose: 1.5 mg/kg repeated every 5 min up to 4.5 mg/kg, maintenance 2-5 mg/kg/h, half life 10 min-2.5 hours
32 KETOGENIC DIET TREATMENT FOR STATUS EPILEPTICUS
Kossoff E, Epilepsy Curr 11(3): 88-89
33 KETOGENIC DIET TREATMENT FOR STATUS EPILEPTICUS
KD initiation KD contraindications • Fasting lipid profile, CMP, CBC, • Unstable metabolic condition amylase, lipase, selenium, • Hemodynamic or cardiorespiratory vitamin D, urine HCG instability • Coagulopathy • Baseline weight and height • Pancreatitis • Nutrition consult • Liver failure • Remove dextrose from IV • Severe hyperlipidemia fluids and medications • Inability to tolerate enteral feeds, including ileus • Switch enteral formula to • Pregnancy ketocal • Received propofol infusion within • Begin multivitamin and 24 hours • Known fatty acid oxidation disorder calcium or pyruvate carboxylase deficiency
34 KETOGENIC DIET TREATMENT FOR SUPER REFRACTORY STATUS EPILEPTICUS
• Ketosis achieved in a median of 2 days • 73% controlled SRSE • Side effects – Metabolic acidosis – Hyperlipidemia – Constipation – Hypoglycemia – Hyponatremia – Weight loss • 33% death
Cervenka et al. Neurology 2017;88:938-43
35 SUPER REFRACTORY STATUS EPILEPTICUS COMPLICATIONS
• Increased risk for a – Acute organ failure – Critical illness polyneuropathy and myopathy in 30-50% – Sepsis – Deep venous thrombosis/pulmonary embolism – Persistence of prolonged coma, even if seizures are suppressed
36 STATUS EPILEPTICUS PROGNOSIS • Pugin et al. – 1-year follow-up 31 patients with super-refractory SE • 74% died or were unresponsive • 16% with moderate disability • 10% no or minimal disability
• Marchi et al. – 467 adults with SE • 35% developed new disability • 14% died • Poor prognosis in patients requiring therapeutic coma
37 Sutter et al., 2017 CNS drugs 31:65-74
38 STATUS EPILEPTICUS PROGNOSIS • Therapeutic coma should be used cautiously
• Consensus that therapeutic coma is indicated in refractory convulsive SE and nonconvulsive SE with coma
• Early seizure control will avoid early changes in the brain that lead to refractoriness and prevent need for therapeutic coma that may lead to complications and guarded prognosis
39 CONCLUSION
• Status epilepticus is a major neurologic emergency
• Early prehospital treatment should be emphasized and shows highest efficacy
• Established status epilepticus tend to be refractory and associated with increased morbidity and mortality
40