Epilepsy & Status Epilepticus

Tan Hui Jan MD, MRCP, Mmed Fellow in Neurology (Melbourne) Universiti Kebangsaan Malaysia Medical Centre

Content
Definition Epidemiology Aetiology Pathophysiology Subtypes Drugs used in status epilepticus Refractory status epilepticus

Introduction
Epilepsy derived from Greek verb epi lambamo to be seized, to be taken hold of Hippocrates in 400 BC: epilepsy is a disease of the brain

Definition

Seizure a stereotyped episode of sudden onset that may manifest as a disturbance of consciousness, behavior, emotion or motor, sensory or autonomic dysfunction

Definition
Epileptic seizure the clinical manifestation that results from abnormal and excessive synchronized discharge of a set of cerebral neurones Epilepsy a chronic condition characterized by a tendency to develop recurrent unprovoked seizures

Definition- status epilepticus

Classical definition (ILAE) 30 mins of continuous sz activity 2 sz in 30 mins without intervening full recovery of consciousness Operational definition proposed 5 minutes of continuous sz activity 2 seizures without intervening full recovery of consciousness

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

Refractory status epilepticus

SE that persists for longer than 60 minutes despite adequate doses of benzodiazepine and a 2nd antiepileptic drug Occurs in 31-43% patients with SE Mortality rate 16-22% Worse outcome than non RSE

Early SE- seizure > 5 minutes Established SE 30 minutes Refractory SE 60 minutes

Classification of status epilepticus

SE confined to early childhood

Neonatal SE SE in specific infantile epilepsy synd

SE confined to later childhood

Febrile SE Non convulsive SE in benign partial epilepsy synd Non convulsive SE in severe childhood epileptic encephalopathies

SE occurring in childhood and adult life

Tonic clonic SE Absence SE Atypical absence SE Non convulsive SE in specific epilepsy synd Myoclonic SE in coma Myoclonic SE Tonic SE Epilepsia partialis continua Simple partial SE Complex partial SE Shorvon SD. Status epilepticus :Its clinical features and treatment in adults and children. Cambridge University Press, Cambridge 1994

Classification of status epilepticus

Content
Definition Epidemiology Aetiology Pathophysiology Subtypes Drugs used in status epilepticus Refractory status epilepticus

Epidemiology

Overall incidence : 10 to 20/100 000/year

Eur J Emer Med 2008;15:187-95

Epidemiology- prognosis
Major consequences:unprovoked sz & death Mortality 17 to 26%1,2 SE increased the risk of unprovoked sz after an acute symptomatic sz 2.9 x Increased risk of death:

Symptomatic SE Initial SE Older pts Presence of epilepsy

1. 2. 3. Classen et al. Neurology 2b;58:139-42 DeLorenzo et al. Neurology 1996;46(4):1029-35 Ristic et al.Epilepsia 2010;51-57-61

Content
Definition Epidemiology Aetiology Pathophysiology Subtypes Drugs used in status epilepticus Refractory status epilepticus

Aetiology
Acute symptomatic causes Stroke Low AED level Alcohol related Toxicity Tumours Hypoxia Metabolic Infection Eclampsia Trauma Remote symptomatic causes Stroke Head injury Brain infections Toxic/metabolic Progressive neurological dis Developmental brain malformation

Postgrad Med J 2006;82:723-32

Content
Definition Epidemiology Aetiology Pathophysiology Subtypes Drugs used in status epilepticus Refractory status epilepticus

Pathophysiology
Glutamate
Glutamate excess
influx of Ca into neurons lead to cell death

GABA
Reduce phosphorylation of GABA receptor
reduced synaptic inhibition

Pathophysiology
Excessive neuronal firing triggers excitotoxic mechanisms loss of inhibition by accelerated internalisation of GABA receptor Decreased neuronal density in hippocampi Increased neuron specific enolase after complex partial SE

Pathophysiology

Widespread neuronal death Acute cerebral edema Chronic atrophy Focal atrophy in areas of intense activity SE- induced epileptogenesis (seizures begets seizures)

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

Physiological changes in status epilepticus

Premonitory stage Phase 1 compensation Phase 2 - decompensation

Physiological changes in tonic clonic status epilepticus Phase 1 (compensation)

30-90 minutes Massive release of catecholamines

Increase in HR, BP, glucose Cardiac arrhythmias

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

Physiological changes in tonic clonic status epilepticus Phase 2 (decompensation)

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

Content
Definition Epidemiology Aetiology Pathophysiology Subtypes Drugs used in status epilepticus Refractory status epilepticus

Subtypes
Generalized convulsive SE Focal motor SE Non convulsive SE

Subtypes

Generalised convulsive SE generalised spike waves rhythmic activity

Subtypes

Focal motor SE Continuous motor twitching of a single limb or side of face

Subtypes

Non convulsive SE continuous rhythmic activity episodic generalised attenuation

Role of EEG in status epilepticus

Confirms EEG SE Identify clinical syndrome of SE Helps to prognosticate SE Monitoring of treatment efficacy Detect non convulsive SE

Content
Definition Epidemiology Aetiology Pathophysiology Subtypes Drugs used in status epilepticus Refractory status epilepticus

Principles of management
Termination of seizure Prevention of seizure recurrence Treatment of precipitating causes Treatment of complications Identify 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 Wernickes encephalopathy, consider iv thiamine 100 mg Other additional ix when pt stable- Brain CT/MRI, LP

Drugs used in status epilepticus

Early SE Diazepam Midazolam Lorazepam Clonazepam Established SE

Refractory SE

Phenytoin Fosphenytoin Valproate Phenobarbital Levetiracetam

Midazolam Thiopentone Pentobarbital Propofol

Benzodiazepines
diazepam
route IV/rectal

lorazepam
iv

midazolam
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 neuronal cell membrane & decreased neuronal firing Rectal 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 /min Rapid onset of action, short duration of action High lipid solubility and highly protein bound Rapidly distributed to fat and muscle Side effects: sedation, resp depression, hypotension

Midazolam

Midazolam

GABA receptor agonist Via buccal route in premonitory phase has 75% chance of preventing recurrence sz Iv, im, nasal, buccal, endotracheal, per rectal Water soluble, lipid soluble at physiological pH Side effects: sedation, resp depression, hypotension Recommendations: buccal/nasal/im 0.2 -0.3mg/kg , adults 10 mg iv midazolam 0.1-0.3 mg/kg at 4 mg/min, 0.05 mg/kg/h to 0.4 mg/kg/hr

Lorazepam

Lorazepam
GABA receptor agonist Used as first line treatment during established stage iv lorazepam given at 4 mg (0.1 mg/kg) at 2 mg/minute Termination of SE in 60-90% pts Longer redistribution T1/2 leading to lower recurrence of sz Side effects- sedation, resp depression, hypotension

Drugs used in status epilepticus

Early SE Diazepam Midazolam Lorazepam Clonazepam Established SE

Established SE

Phenytoin Fosphenytoin Valproate Phenobarbital Levetiracetam

Midazolam Thiopentone Pentobarbital Propofol

Phenytoin

Phenytoin

Blocks sodium channel An adjunct to benzodiazepine in established status epilepticus Readily enters the brain with slower redistribution BP and cardiac monitoring during infusions Side effects: sedation, resp depression, hypotension, rash, purple glove syndrome Recommendations: bolus 15-20 mg /kg at 25-50 mg /min

Fosphenytoin
A prodrug of phenytoin, rapidly dephosphorylated to PHT Water soluble Side effects similar to phenytoin but less thrombophlebitis Recommendations: iv 15-20 mg PE/kg at 100 PE/minute

Phenobarbitone

Phenobarbitone
Reduces Na & K conductance, Ca influx, glutamate. Enhances GABA Terminates 60-70% sz in established status epilepticus Side effects: sedation, resp depression, hypotension, rash Used only after failure of BZD and PHT Recommendations: loading iv 15-20 mg/kg, maximum infusion rate 50 -100 mg/min

Valproate

Valproate
Reduces Na, Ca, glutamate. Enhances GABA Water soluble Low risk of hypotension, cardioresp or cerebral depression Recommendations: iv 15-30 mg/kg at 3 mg/min infusion 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 failed at least 1other AED 36 pts with SE Median dose 3000 mg /d, range 1000-9000 Bolus infusions 500-2000mg per 30-60 min or continuous infusion 25 (69%) responders, 11 (31%) non responders No cardiocirculatory side effects or worsening of SE. 2 had nausea/vomiting Study 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 iv LEV All pts received at least a BDZ (94%) before iv LEV Mean loading dose 944 mg Mean maintenance dose 2166 mg over 24h No severe adverse side effects exp 2 had sedation Study suggests iv LEV as an alternative for treatment of SE

Intravenous levetiracetam as treatment for status epilepticus

(J Neurol 2009;256:1634-42)

A retrospective review of 35 pts treated with iv LEV 4 groups of pts

No first line AED Low first line AED High first line AED Full first line AED

Assess effectiveness of Rx and safety profile

 pts, SE could be terminated with LEV in combination with BDZ Only mild, transient adverse effects have been observed-no resp/cardiac insufficiency, drug interactions or encephalopathy Well tolerated even in critically ill pts

Levetiracetam

Targets synaptic vesicle protein (SV2A) in presynaptic terminals, reduces intracellular Ca release Partly extrahepatic hydrolyzation bypasses the cytochrome P450 60-70% unchanged, renal excretion (dose adjustment) Easy and rapid titration Few drug interaction No effect on respiration, liver, kidney function & blood system Almost 100% oral bioavailability with a bioequivalent iv formulation 15 min infusion 1500 mg 500-1500 mg bd

Lacosamide
Initially developed as iv formulation for use in status epilepticus Also licensed as oral therapy for partial onset seizures Selectively enhances slow inactivation of voltage gated sodium channels Interacts with collapsing response mediator protein-2 which is aberrantly regulated in epileptic brain

Topiramate
Evidence in SE limited to case series Multiple mechanisms of action Na channel blockade Potentiates GABA Glutamate antagonist Carbonic anhydrase inhibitor Dosage: 300-1600 mg/day

Content
Definition Epidemiology Aetiology Pathophysiology Subtypes Drugs used in status epilepticus Refractory status epilepticus

Anaesthetics used in refractory status epilepticus

Barbiturates Thiopentone Pentobarbitone

Non barbiturates Midazolam Propofol

Drug midazolam propofol

Dose
0.1-0.3 mg/kg at 4 mg min bolus fb infusion 0.05-0.4 mg/kg/h
1-2 mg/kg @ 10mg/min then infusion of 5-10 mg/kg/h

Comments
Low risk of accumulation- safe for prolonged periods. SE:Hypotension,tachyphylaxis
Enhances GABA. Large vol of distribution and very short half life. Rapid onset, short duration of action and rapid recovery on drug withdrawal. SE: Lipaemia, acidosis, rhabdomyolysis (children). Rebound sz on withdrawal Saturable pharmacokinetics, metabolized to pentobarbital and strong tendency to accum. SE:Hypotension, cardioresp depression, pancreatitis, hepatic disturbance, hypersensitivity reaction As for thiopental

thiopental

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

pentobarbital

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

Other modalities of treatment in refractory status epilepticus

Ketamine-NMDA antagonist Inhalational anesthetic agents- isoflurane, desflurane Lidocaine Deep brain stimulation Transcranial magnetic stimulation Immunological 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 Early recognition of status epilepticus is critical Requires immediate evaluation and rapid treatment Early termination of status epilepticus is the key to limit patient morbidity and prevention of complications

Thank you