Status Epileptic Us

Epilepsy & Status Epilepticus

Tan Hui JanTan Hui JanMD, MRCP, MmedMD, MRCP, Mmed

Fellow in Neurology (Melbourne)Fellow in Neurology (Melbourne)Universiti Kebangsaan Malaysia Universiti Kebangsaan Malaysia

Medical CentreMedical Centre

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DefinitionDefinition EpidemiologyEpidemiology AetiologyAetiology PathophysiologyPathophysiology SubtypesSubtypes Drugs used in status epilepticusDrugs used in status epilepticus Refractory status epilepticusRefractory status epilepticus

Introduction

‘‘Epilepsy’ derived from Greek verb Epilepsy’ derived from Greek verb epi epi lambamolambamo

‘‘to be seized’, ‘to be taken hold of’to be seized’, ‘to be taken hold of’ Hippocrates in 400 BC: epilepsy is a Hippocrates in 400 BC: epilepsy is a

disease of the braindisease of the brain

Definition

Seizure Seizure – a – a stereotypedstereotyped episode of sudden episode of sudden onset that may manifest as a onset that may manifest as a disturbance of disturbance of consciousnessconsciousness, behavior, emotion or motor, , behavior, emotion or motor, sensory or autonomic dysfunctionsensory or autonomic dysfunction

Definition

Epileptic seizureEpileptic seizure – the clinical – the clinical manifestation that results from manifestation that results from abnormal abnormal and excessive synchronized dischargeand excessive synchronized discharge of a of a set of cerebral neuronesset of cerebral neurones

EpilepsyEpilepsy – a chronic condition – a chronic condition characterized by a tendency to develop characterized by a tendency to develop recurrent unprovoked seizuresrecurrent unprovoked seizures

Definition- status epilepticus Classical definition (ILAE)Classical definition (ILAE)

≥ ≥ 30 mins of continuous sz activity30 mins of continuous sz activity ≥ ≥ 2 sz in 30 mins without intervening full 2 sz in 30 mins without intervening full

recovery of consciousnessrecovery of consciousness Operational definition proposedOperational definition proposed

≥ ≥ 5 minutes of continuous sz activity5 minutes of continuous sz activity ≥ ≥ 2 seizures without intervening full recovery 2 seizures without intervening full recovery

of consciousnessof consciousness

Nandhagopal R. Postgrad Med J 2006;82:723-32

Refractory status epilepticus

SE that persists for longer than 60 minutes SE that persists for longer than 60 minutes despite adequate doses of benzodiazepine despite adequate doses of benzodiazepine and a 2and a 2ndnd antiepileptic drug antiepileptic drug

Occurs in 31-43% patients with SEOccurs in 31-43% patients with SE Mortality rate 16-22%Mortality rate 16-22% Worse outcome than non RSEWorse outcome than non RSE

Early SE- seizure > 5 minutesEarly SE- seizure > 5 minutes Established SE ≥ 30 minutesEstablished SE ≥ 30 minutes Refractory SE ≥ 60 minutesRefractory SE ≥ 60 minutes

Classification of status epilepticus SE confined to early childhoodSE confined to early childhood

Neonatal SENeonatal SE SE in specific infantile epilepsy syndSE in specific infantile epilepsy synd

SE confined to later childhoodSE confined to later childhood Febrile SEFebrile SE Non convulsive SE in benign partial epilepsy syndNon convulsive SE in benign partial epilepsy synd Non convulsive SE in severe childhood epileptic encephalopathiesNon convulsive SE in severe childhood epileptic encephalopathies

SE occurring in childhood and adult lifeSE occurring in childhood and adult life Tonic clonic SETonic clonic SE Absence SEAbsence SE Atypical absence SEAtypical absence SE Non convulsive SE in specific epilepsy syndNon convulsive SE in specific epilepsy synd Myoclonic SE in comaMyoclonic SE in coma Myoclonic SEMyoclonic SE Tonic SETonic SE Epilepsia partialis continuaEpilepsia partialis continua Simple partial SESimple partial SE Complex partial SEComplex partial SE

Shorvon SD. Status epilepticus :Its clinical features and treatment in adults and children. Cambridge University Press, Cambridge 1994

Classification of status epilepticus

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Epidemiology

Eur J Emer Med 2008;15:187-95

Overall incidence : 10 to 20/100 000/year

Epidemiology- prognosis Major consequences:unprovoked sz & deathMajor consequences:unprovoked sz & death Mortality 17 to 26%Mortality 17 to 26%1,21,2

SE increased the risk of unprovoked sz after SE increased the risk of unprovoked sz after an acute symptomatic sz 2.9 xan acute symptomatic sz 2.9 x

Increased risk of death:Increased risk of death: Symptomatic SESymptomatic SE Initial SE Initial SE Older ptsOlder pts Presence of epilepsyPresence of epilepsy

1. Classen et al. Neurology 2b;58:139-422. DeLorenzo et al. Neurology 1996;46(4):1029-353. Ristic et al.Epilepsia 2010;51-57-61

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Aetiology

Acute symptomatic causesAcute symptomatic causes StrokeStroke Low AED levelLow AED level Alcohol relatedAlcohol related ToxicityToxicity TumoursTumours HypoxiaHypoxia MetabolicMetabolic InfectionInfection EclampsiaEclampsia TraumaTrauma

Remote symptomatic causesRemote symptomatic causes StrokeStroke Head injuryHead injury Brain infectionsBrain infections Toxic/metabolicToxic/metabolic Progressive neurological Progressive neurological

disdis Developmental brain Developmental brain

malformationmalformation

Postgrad Med J 2006;82:723-32

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Pathophysiology

GlutamateGlutamate GABAGABA

Glutamate excess

influx of Ca into neurons lead tocell death

Reduce phosphorylation of GABA receptor

reduced synaptic inhibition

Pathophysiology

Excessive neuronal firing Excessive neuronal firing triggers excitotoxic mechanismstriggers excitotoxic mechanisms loss of inhibition by accelerated loss of inhibition by accelerated

internalisation of GABA receptorinternalisation of GABA receptor Decreased neuronal density in hippocampi Decreased neuronal density in hippocampi Increased neuron specific enolase after Increased neuron specific enolase after

complex partial SEcomplex partial SE

Pathophysiology

Widespread neuronal deathWidespread neuronal death Acute cerebral edema Acute cerebral edema Chronic atrophyChronic atrophy Focal atrophy in areas of Focal atrophy in areas of

intense activityintense activity SE- induced epileptogenesis SE- induced epileptogenesis

(seizures begets seizures)(seizures begets seizures)

Common precipitants of SE (Epilepsia 1994;35:27-34)

Physiological changes in status epilepticus Premonitory stagePremonitory stage Phase 1 – compensationPhase 1 – compensation Phase 2 - decompensationPhase 2 - decompensation

Physiological changes in tonic clonic status epilepticus

Phase 1 (compensation)

30-90 minutes30-90 minutes Massive release of catecholaminesMassive release of catecholamines

Increase in HR, BP, glucoseIncrease in HR, BP, glucose Cardiac arrhythmiasCardiac arrhythmias

Increase in core body temperatureIncrease in core body temperature Acidosis – lactate production, rise in CO2Acidosis – lactate production, rise in CO2 Autonomic activity Autonomic activity Massive increase in cerebral blood flowMassive increase in cerebral blood flow

Physiological changes in tonic clonic status epilepticus

Phase 2 (decompensation)

> 90 minutes> 90 minutes Hypotension –autonomic & cardioresp changesHypotension –autonomic & cardioresp changes Progressive hypoxiaProgressive hypoxia Loss of cerebral autoregulation Loss of cerebral autoregulation Failure of cerebral perfusionFailure of cerebral perfusion Raised intracranial hypertensionRaised intracranial hypertension Rhabdomyolysis, renal & hepatic failure, DIVCRhabdomyolysis, renal & hepatic failure, DIVC

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Subtypes

Generalized convulsive SEGeneralized convulsive SE Focal motor SEFocal motor SE Non convulsive SENon convulsive SE

Subtypes Generalised Generalised

convulsive SEconvulsive SEgeneralised spike generalised spike waveswaves

rhythmic activityrhythmic activity

Subtypes Focal motor SEFocal motor SE Continuous motor Continuous motor

twitching of a single twitching of a single limb or side of facelimb or side of face

Subtypes Non convulsive SENon convulsive SE continuous rhythmic continuous rhythmic

activityactivityepisodic generalised episodic generalised attenuationattenuation

Role of EEG in status epilepticus

Confirms EEG SEConfirms EEG SE Identify clinical syndrome of SEIdentify clinical syndrome of SE Helps to prognosticate SEHelps to prognosticate SE Monitoring of treatment efficacyMonitoring of treatment efficacy Detect non convulsive SEDetect non convulsive SE

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Principles of management

Termination of seizureTermination of seizure Prevention of seizure recurrencePrevention of seizure recurrence Treatment of precipitating causesTreatment of precipitating causes Treatment of complicationsTreatment of complications Identify the underlying causeIdentify the underlying cause

Initial management of SE Assess cardiorespiratory status, consider endotracheal intubation Monitor vital parameters- BP, HR, Oxygen sats Left lateral positioning Ensure intravenous access is established. Oxygen via a high flow mask. Take blood for FBC, Calcium, MG, RBS, renal profile. drug

levels (AEDs and toxicology), arterial blood gas, ECG If hypoglycemia, give 50mls of 50% dextrose If suspect Wernicke’s encephalopathy, consider iv thiamine 100

mg Other additional ix when pt stable- Brain CT/MRI, LP

Drugs used in status epilepticus

Early SE Early SE DiazepamDiazepam MidazolamMidazolam LorazepamLorazepam ClonazepamClonazepam

Established SEEstablished SE PhenytoinPhenytoin FosphenytoinFosphenytoin ValproateValproate PhenobarbitalPhenobarbital LevetiracetamLevetiracetam

Refractory SERefractory SE PhenytoinPhenytoin FosphenytoinFosphenytoin ValproateValproate PhenobarbitalPhenobarbital LevetiracetamLevetiracetam

PhenytoinPhenytoin FosphenytoinFosphenytoin ValproateValproate PhenobarbitalPhenobarbital LevetiracetamLevetiracetam

MidazolamMidazolam ThiopentoneThiopentone PentobarbitalPentobarbital PropofolPropofol

Benzodiazepinesdiazepam lorazepam midazolam

route IV/rectal iv Iv/im/buccal

onset 1-3min 2-3 min 1-5 min

duration 5-15 min 12-48 hrs 1-5 hrs

Half -life 30 hrs 15 hrs 2-4hrs

Diazepam

Diazepam GABA receptor agonist-hyperpolarization of GABA receptor agonist-hyperpolarization of

neuronal cell membrane & decreased neuronal firingneuronal cell membrane & decreased neuronal firing Rectal route 10-20 mg, 0.2-0.5 mg/kgRectal route 10-20 mg, 0.2-0.5 mg/kg Iv route 5-10 mg (0.25- 0.5 mg/kg) at 2-5 mg /minIv route 5-10 mg (0.25- 0.5 mg/kg) at 2-5 mg /min Rapid onset of action, short duration of actionRapid onset of action, short duration of action High lipid solubility and highly protein boundHigh lipid solubility and highly protein bound Rapidly distributed to fat and muscleRapidly distributed to fat and muscle Side effects: sedation, resp depression, hypotensionSide effects: sedation, resp depression, hypotension

Midazolam

Midazolam GABA receptor agonistGABA receptor agonist Via buccal route in premonitory phase has 75% Via buccal route in premonitory phase has 75%

chance of preventing recurrence szchance of preventing recurrence sz Iv, im, nasal, buccal, endotracheal, per rectalIv, im, nasal, buccal, endotracheal, per rectal Water soluble, lipid soluble at physiological pHWater soluble, lipid soluble at physiological pH Side effects: sedation, resp depression, hypotensionSide effects: sedation, resp depression, hypotension Recommendations: Recommendations:

buccal/nasal/im 0.2 -0.3mg/kg , adults 10 mg buccal/nasal/im 0.2 -0.3mg/kg , adults 10 mg iv midazolam 0.1-0.3 mg/kg at 4 iv midazolam 0.1-0.3 mg/kg at 4 mg/min, 0.05 mg/kg/h to 0.4 mg/kg/hrmg/min, 0.05 mg/kg/h to 0.4 mg/kg/hr

Lorazepam

Lorazepam GABA receptor agonistGABA receptor agonist Used as first line treatment during established stageUsed as first line treatment during established stage iv lorazepam given at 4 mg (0.1 mg/kg) at 2 iv lorazepam given at 4 mg (0.1 mg/kg) at 2

mg/minutemg/minute Termination of SE in 60-90% ptsTermination of SE in 60-90% pts Longer redistribution T1/2 leading to lower Longer redistribution T1/2 leading to lower

recurrence of szrecurrence of sz Side effects- sedation, resp depression, hypotensionSide effects- sedation, resp depression, hypotension

Drugs used in status epilepticus

Early SE Early SE DiazepamDiazepam MidazolamMidazolam LorazepamLorazepam ClonazepamClonazepam



PhenytoinPhenytoin FosphenytoinFosphenytoin ValproateValproate PhenobarbitalPhenobarbital LevetiracetamLevetiracetam

MidazolamMidazolam ThiopentoneThiopentone PentobarbitalPentobarbital PropofolPropofol

Phenytoin

Phenytoin Blocks sodium channelBlocks sodium channel An adjunct to benzodiazepine in established status An adjunct to benzodiazepine in established status

epilepticus epilepticus Readily enters the brain with slower redistributionReadily enters the brain with slower redistribution BP and cardiac monitoring during infusionsBP and cardiac monitoring during infusions Side effects: sedation, resp depression, hypotension, Side effects: sedation, resp depression, hypotension,

rash, purple glove syndrome rash, purple glove syndrome Recommendations: bolus 15-20 mg /kg at 25-50 Recommendations: bolus 15-20 mg /kg at 25-50

mg /minmg /min

Fosphenytoin

A prodrug of phenytoin, rapidly A prodrug of phenytoin, rapidly dephosphorylated to PHTdephosphorylated to PHT

Water solubleWater soluble Side effects similar to phenytoin but less Side effects similar to phenytoin but less

thrombophlebitisthrombophlebitis Recommendations: iv 15-20 mg PE/kg at Recommendations: iv 15-20 mg PE/kg at

100 PE/minute100 PE/minute

Phenobarbitone

Phenobarbitone Reduces Na & K conductance, Ca influx, Reduces Na & K conductance, Ca influx,

glutamate. Enhances GABAglutamate. Enhances GABA Terminates 60-70% sz in established status Terminates 60-70% sz in established status

epilepticusepilepticus Side effects: sedation, resp depression, Side effects: sedation, resp depression,

hypotension, rashhypotension, rash Used only after failure of BZD and PHTUsed only after failure of BZD and PHT Recommendations: loading iv 15-20 mg/kg, Recommendations: loading iv 15-20 mg/kg,

maximum infusion rate 50 -100 mg/minmaximum infusion rate 50 -100 mg/min

Valproate

Valproate Reduces Na, Ca, glutamate. Enhances Reduces Na, Ca, glutamate. Enhances

GABAGABA Water solubleWater soluble Low risk of hypotension, cardioresp or Low risk of hypotension, cardioresp or

cerebral depressioncerebral depression Recommendations: Recommendations:

iv 15-30 mg/kg at 3 mg/min iv 15-30 mg/kg at 3 mg/min infusion 1 mg/kg/hr for 6 hrsinfusion 1 mg/kg/hr for 6 hrs

Levetiracetam

IV levetiracetam: a new treatment alternative for refractory status epilepticus

(JNNP 2009;80:689-92)

A retrospective review of use of iv LEV in pts who had A retrospective review of use of iv LEV in pts who had failed at least 1other AEDfailed at least 1other AED

36 pts with SE 36 pts with SE Median dose 3000 mg /d, range 1000-9000Median dose 3000 mg /d, range 1000-9000 Bolus infusions 500-2000mg per 30-60 min or continuous Bolus infusions 500-2000mg per 30-60 min or continuous

infusioninfusion 25 (69%) responders, 11 (31%) non responders25 (69%) responders, 11 (31%) non responders No cardiocirculatory side effects or worsening of SE. 2 had No cardiocirculatory side effects or worsening of SE. 2 had

nausea/vomitingnausea/vomiting Study suggests iv LEV may be safe and efficacious for SEStudy suggests iv LEV may be safe and efficacious for SE

IV LEV in the treatment of benzodiazepine refractory SE(JNNP 2008;79:588-9)

A retrospective review of 16 pts with SE treated with A retrospective review of 16 pts with SE treated with iv LEViv LEV

All pts received at least a BDZ (94%) before iv LEVAll pts received at least a BDZ (94%) before iv LEV Mean loading dose 944 mgMean loading dose 944 mg Mean maintenance dose 2166 mg over 24hMean maintenance dose 2166 mg over 24h No severe adverse side effectsNo severe adverse side effects exp 2 had sedation exp 2 had sedation Study suggests iv LEV as an alternative for Study suggests iv LEV as an alternative for

treatment of SEtreatment of SE

Intravenous levetiracetam as treatment for status epilepticus(J Neurol 2009;256:1634-42)

A retrospective review of 35 pts treated A retrospective review of 35 pts treated with iv LEVwith iv LEV

4 groups of pts4 groups of pts No first line AEDNo first line AED Low first line AEDLow first line AED High first line AEDHigh first line AED Full first line AEDFull first line AED

Assess effectiveness of Rx and safety profileAssess effectiveness of Rx and safety profile

¾ pts, SE could be terminated with LEV in ¾ pts, SE could be terminated with LEV in combination with BDZcombination with BDZ

Only mild, transient adverse effects have Only mild, transient adverse effects have been observed-no resp/cardiac been observed-no resp/cardiac insufficiency, drug interactions or insufficiency, drug interactions or encephalopathyencephalopathy

Well tolerated even in critically ill ptsWell tolerated even in critically ill pts

Levetiracetam Targets synaptic vesicle protein (SV2A) in presynaptic terminals, Targets synaptic vesicle protein (SV2A) in presynaptic terminals,

reduces intracellular Ca releasereduces intracellular Ca release Partly extrahepatic hydrolyzation bypasses the cytochrome P450Partly extrahepatic hydrolyzation bypasses the cytochrome P450

60-70% unchanged, renal excretion (dose adjustment)60-70% unchanged, renal excretion (dose adjustment) Easy and rapid titrationEasy and rapid titration Few drug interactionFew drug interaction No effect on respiration, liver, kidney function & blood systemNo effect on respiration, liver, kidney function & blood system Almost 100% oral bioavailability with a bioequivalent iv Almost 100% oral bioavailability with a bioequivalent iv

formulationformulation 15 min infusion 1500 mg15 min infusion 1500 mg 500-1500 mg bd500-1500 mg bd

Lacosamide Initially developed as iv formulation for use in Initially developed as iv formulation for use in

status epilepticusstatus epilepticus Also licensed as oral therapy for partial onset Also licensed as oral therapy for partial onset

seizuresseizures Selectively enhances slow inactivation of voltage Selectively enhances slow inactivation of voltage

gated sodium channelsgated sodium channels Interacts with collapsing response mediator protein-Interacts with collapsing response mediator protein-

2 which is aberrantly regulated in epileptic brain2 which is aberrantly regulated in epileptic brain

Topiramate

Evidence in SE limited to case seriesEvidence in SE limited to case series Multiple mechanisms of actionMultiple mechanisms of action

Na channel blockadeNa channel blockade Potentiates GABAPotentiates GABA Glutamate antagonistGlutamate antagonist Carbonic anhydrase inhibitorCarbonic anhydrase inhibitor

Dosage: 300-1600 mg/dayDosage: 300-1600 mg/day

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Anaesthetics used in refractory status epilepticus

BarbituratesBarbiturates ThiopentoneThiopentone PentobarbitonePentobarbitone

Non barbituratesNon barbiturates MidazolamMidazolam PropofolPropofol

DrugDrug DoseDose CommentsCommentsmidazolammidazolam 0.1-0.3 mg/kg at 4 mg min bolus fb 0.1-0.3 mg/kg at 4 mg min bolus fb

infusion 0.05-0.4 mg/kg/hinfusion 0.05-0.4 mg/kg/hLow risk of accumulation- safe Low risk of accumulation- safe for prolonged periods.for prolonged periods. SE:Hypotension,tachyphylaxisSE:Hypotension,tachyphylaxis

propofolpropofol 1-2 mg/kg @ 10mg/min then 1-2 mg/kg @ 10mg/min then infusion of 5-10 mg/kg/hinfusion of 5-10 mg/kg/h

Enhances GABA. Large vol of Enhances GABA. Large vol of distribution and very short half distribution and very short half life. Rapid onset, short life. Rapid onset, short duration of action and rapid duration of action and rapid recovery on drug withdrawalrecovery on drug withdrawal. . SE: Lipaemia, acidosis, SE: Lipaemia, acidosis, rhabdomyolysis (children). rhabdomyolysis (children). Rebound sz on withdrawalRebound sz on withdrawal

thiopentalthiopental 100-250 mg bolus over 20 sec then 100-250 mg bolus over 20 sec then 50 mg boluses every 2-3 min until sz 50 mg boluses every 2-3 min until sz ceased. Infusion 3-5 mg/kg/hceased. Infusion 3-5 mg/kg/h

Saturable pharmacokinetics, Saturable pharmacokinetics, metabolized to pentobarbital metabolized to pentobarbital and strong tendency to accumand strong tendency to accum. . SE:Hypotension, cardioresp SE:Hypotension, cardioresp depression, pancreatitis, depression, pancreatitis, hepatic disturbance, hepatic disturbance, hypersensitivity reactionhypersensitivity reaction

pentobarbitalpentobarbital 10-20 mg/kg bolus at 25 mg/kg then 10-20 mg/kg bolus at 25 mg/kg then infusion of 0.5-1 mg/kg/h increasing infusion of 0.5-1 mg/kg/h increasing to 1-3 mg/kg/hto 1-3 mg/kg/h

As for thiopentalAs for thiopental

Other modalities of treatment in refractory status epilepticus

Ketamine-NMDA antagonistKetamine-NMDA antagonist Inhalational anesthetic agents- isoflurane, Inhalational anesthetic agents- isoflurane,

desfluranedesflurane LidocaineLidocaine Deep brain stimulationDeep brain stimulation Transcranial magnetic stimulationTranscranial magnetic stimulation Immunological therapyImmunological therapy

Other modalities of treatment in refractory status epilepticus (surgery)

Focal resection Hemispherectomy

Corpus callostomy vagal nerve stimulator

Conclusion Status epilepticus is a neurologic emergency Status epilepticus is a neurologic emergency Early recognition of status epilepticus is Early recognition of status epilepticus is

criticalcritical Requires immediate evaluation and rapid Requires immediate evaluation and rapid

treatment treatment Early termination of status epilepticus is the Early termination of status epilepticus is the

key to limit patient morbidity and prevention key to limit patient morbidity and prevention of complicationsof complications

Thank you

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