Transcript Slide 1

Status Epilepticus
Karim Rafaat, MD
Definition
• Single seizure lasting greater than 30
minutes OR
• Series of seizures lasting 30 minutes or
longer without full return of consciousness
between seizures
Pathophysiology
• Status occurs because of failure of the
normal mechanisms that limit the spread
and recurrence of isolated seizures
– Excitation is excessive and/or inhibition is
ineffective
Pathophysiology
• Excitatory
– Glutamate
• Major amino acid excitatory neurotransmitter in
the brain
• Role in the pathogenesis of SE was suggested by
an outbreak of illness caused by eating mussels
contaminated with domoic acid, an analogue of
glutamate
– Aspartate
– Acetylcholine
Pathophysiology
• Inhibitory
– Gamma-aminobutyric acid (GABA)
• Main inhibitory neurotransmitter in the brain
• Antagonists to its effects or alterations in its
metabolism in the substantia nigra may contribute
to SE
– Calcium ion-dependent potassium ion current
– Blockage of NMDA channels by magnesium
Subtypes of Status
• Convulsive
– Primary generalized
– Simple of complex partial
– Secondary generalized
• Nonconvulsive
– Absence status
– Complex partial status
– Atonia (electromechanical dissociation)
• “Give Me a Break”
– Pseudoseizures
Epidemiology
• Status epilepticus occurs in 5-15% of patients
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with epilepsy
Status is more common in childhood than
adulthood
Approximately 10% of children with epilepsy
have status on initial presentation
In children the seizure is usually generalized
from the onset (often a partial seizure with
secondary generalization in adults)
Causes of Status
• Reactive
• Fever
• Metabolic Alterations (hyponatremia, hypocalcemia,
hypoglycemia)
• Symptomatic
– Acute
• Infection
• Hypoxia
• Trauma
• Hemorrhage/Stroke
– Remote
• Perinatal Hypoxic-Ischemic Injury
• Trauma
• Infection
• Congenital Brain Malformation
• Idiopathic or Cryptogenic
Physiological Changes During
Status Epilepticus
• Hypoxia
– Responsible for the majority of morbidity and
mortality in patients with status
– Results from:
• impaired mechanical ventilation by muscle spasms
• increased salivation and secretions in lungs
• increased oxygen consumption with the increased
demands from muscle and brain tissue
Physiological Changes During
Status Epilepticus
• Respiratory Acidosis
– Results from impaired ventilation and
increased metabolic production of carbon
dioxide
• Metabolic Acidosis
– Predominantly lactic acidosis from impaired
tissue oxygenation and perfusion
Physiological Changes During
Status Epilepticus
• Elevated WBC
– Peripheral leukocytosis in 50-60%
– CSF pleocytosis in 10-15%
• Hyperkalemia
• Increased muscle enzymes
– Rhabdomyolysis results in myoglobinuria
– May result in ATN/acute renal failure
Physiological Changes During
Status Epilepticus
• Hyperglycemia
– Associated with sympathetic discharge and
increased hepatic gluconeogenesis
• Hypoglycemia
– Develops after approximately 60 minutes of
seizure activity
– Associated with increased consumption by
brain and muscles during seizures
Neurological Changes During
Status Epilepticus
• Most frequent neurological changes
– Pupillary changes
– Increased or decreased tone
– Positive Babinski sign
• Result from electrical activity, underlying
neurological disease, or metabolic
disturbance
• May be bilateral or asymmetrical
EEG Changes During Status
Epilepticus
• Attenuation of background activity
• Generalized low voltage fast activity
• Epileptic recruiting rhythm with increased
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amplitude and decreased frequency
Generalized polyspike and slow discharges with
repetition rate of 1-4Hz
Diffuse depression of background activity after
cessation of seizure
Systemic Changes During Early
Status Epilepticus
• Hypertension, tachycardia
– Caused by massive catecholamine release and
autonomic discharge
• Cardiac output increases
• Mean arterial pressure increases
• Hyperpyrexia
– Caused by excessive muscle activity
Cerebral Changes During Early
Status Epilepticus
• Increased ICP
– Cerebral blood flow increases 5-7 times
• Results from both cerebral vasodilatation and
systemic hypertension
– Metabolic rate increases 2-5 times
• Oxygen and glucose utilization increase
Cerebral Changes as Status
Epilepticus Progresses
Cerebral blood flow decreases
– Cerebral autoregulation is compromised
– Brain oxygenation decreases
• Brain glucose levels decrease
– Metabolic demands are higher than supply
• Brain damage generally starts to occur after 3060 minutes of status
– Occurs earlier/more profound with persistent hypoxia
Pharmacotherapy for Status
Epilepticus
• Ideal medication
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Effective against all seizures
Several routes of administration
Potent so small volumes can be given rapidly
Cross blood brain barrier rapidly for fast onset
Long half life for long activity
Safe
• No cardiorespiratory depression
• No systemic side effects
• Remember to treat the underlying cause
Lorazepam (Ativan)
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Benzodiazepene/GABA agonist
Dose: 0.05-0.1mg/kg (max 4mg)
Route: IV, ET
Onset of action: 2-3 minutes
Duration of Action: 4-14 hours
Low lipid solubility/small area of distribution
Metabolized by the liver; no active metabolites
Respiratory depression occurs in 10% of pts
Tolerance develops with repeated doses
Diazepam (Valium)
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Benzodiazepene/GABA agonist
Dose: 0.2-0.5mg/kg (max 10mg)
Route: IV, ET, IM, PR
Onset of action: 1-3 minutes
Duration of action: 20 minutes
Highly lipophilic/large volume of distribution
Metabolized by the liver/metabolite is Ndesmethydiazepam which accumulates
Respiratory depression develops in 10%
Midazolam (Versed)
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Benzodiazepene/GABA agonist
Dose: 0.05-0.2mg/kg
Route: IV, IM
Onset of action: 1-5 minutes
Duration of action: 1-2 hours
Continuous drip more effective long-term than
bolus doses
Highly lipophilic/large volume of distribution
Metabolized by the liver
Side effects: bradycardia, hypotension
Phenytoin (Dilantin)
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Dose: 18-20mg/kg
Route: IV
Onset of action: 10-30 minutes
Duration of action: 12-24 hours
Maximal infusion rate: 50mg/min
Cardiac arrythmias and hypotension can result
from rapid administration
Risk of thrombophlebitis and tissue necrosis with
infiltration
Highly lipid soluble, but not water soluble
Metabolized by the liver
Fosphenytoin (Cerebyx)
• Prodrug of phenytoin
– Phosphate ester group is removed from drug once in
enters bloodstream
• Same dose, onset of action, duration of action
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as phenytoin
Route: IV, IM
Maximal infusion rate: 150mg/min
Water soluble
Less risk of thrombophlebitis, tissue necrosis
with extravasation
10 times more expensive than phenytoin
Phenobarbital (Luminal)
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Loading dose: 10-20mg/kg
Route: IV, IM, PO
Onset of action: 15-60 minutes
Duration of action: 24-96 hours
Maximal infusion rate: 100mg/min
Side effects: sedation, hypotension, respiratory
suppression
Dose needs to be adjusted in renal or hepatic
failure
Thiopental (Pentathol)
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Loading dose: 12mg/kg
Continuous dose: 3-5mg/kg/hr
Onset of action: 20-60 minutes
Hypotension is common/pressors often needed
Infiltrate can cause tissue necrosis
Tolerance develops
Intermittent EEG should be followed
Metabolized to pentobarbital by the liver
– Thiopental and pentobarb levels are followed
Pentobarbital (Nembutal)
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Barbiturate/GABA agonist
Loading dose: 5-12mg/kg
Continuous dose: 0.5-1mg/kg/hr
Onset of action: 10-20 minutes
Hypotension is common/pressors often required
Ileus/feeding intolerance is common
Requires intermittent EEG monitoring to assess
sedation
Isoflorane (Forane)
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Liquid anesthetic agent
Route: inhaled
Onset of action: 1-2 minutes
Eliminated by exhalation/little to no risk of
hepatotoxicity (unlike halothane)
May cause hypotension requiring pressors
Impractical in ICU setting since it requires
facilities for administration of continuous inhaled
anesthetic
Etomidate (Adimate)
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IV anesthetic agent
Dose: 0.3mg/kg
Route: IV continuous infusion
Onset of action: 1-2 minutes
Metabolized by the liver
Patients may develop myoclonus or muscle
twitches unassociated with epileptic activity
Long term infusion results in adrenal
suppression
– Corticosteroids are required
Propofol (Diprivate)
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IV anesthetic agent
Loading dose: 1.5mg/kg/hr
Maintenance dose: 6-10mg/kg/hr
Onset of action: 1-2 minutes
Rapidly metabolized by the liver
Patients may develop involuntary muscle
twitches unassociated with EEG activity
Marked lipidemia occurs with prolonged use
No adrenal side effects
Treatment Protocol for Status
Epilepticus
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Establish airway
Assess respirations and blood pressure
Establish IV access
Draw labs
• Chem 7, divalents, CBC, accucheck in all
• AED drug levels, tox screen, cultures when appropriate
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– Lorazepam 0.05-0.1mg/kg IV (ET if n
– Diazepam PR, midazolam IM if needed
Treatment Protocol for Status
Epilepticus
• <15 minutes
– Phenytoin or fosphenytoin load
• Slow infusion rate if hypotensive, arrythmias
– Phenobarbital load if allergic to phenytoin
• <60 minutes
– Midazolam load/drip if seizures persist
• Titrate to seizure cessation or burst suppression on EEG
– Correct any metabolic disturbances found
• >60 minutes
– Pentobarbital load/drip if seizures persist
• Titrate to burst-suppression on EEG
Complications
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Neuronal cell damage/death
Aspiration pneumonia
Neurologic pulmonary edema
Rhabdomyolysis
Hyperthermia
Cardiac arrythmias
Medication complications:
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Respiratory depression
Hypotension
Bradycardia
Ileus
Recurrent Seizures
• Risk factors for recurrent seizures:
– 1st seizure is status epilepticus
– Remote symptomatic etiology
– Abnormal EEG
– Seizure during sleep
– History of prior febrile seizure
– Todd’s paresis
Neurologic Sequelae
• Variable rates of neurologic sequelae
• Neurologic outcome depends primarily on
the underlying condition
• One review demostrated 6 to 15 percent
rate of encephalopathy and neurologic
deficits
Age and Prognosis
• Overall children have better outcomes than
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adults
Poorer prognosis at extremes of age
– Adult mortality rate 25%
– Pediatric mortality rate 5%
• Age under 1 year: 25%
• Age 1-3 years: 10%
• Differences in outcomes thought to be based on
different etiologies in these age groups
Outcomes in Status Epilepticus
• Mortality is related to underlying cause
– 90% of patients with status from AED withdrawal,
alcohol abuse, or trauma do well
– 33% of patients with status from stroke, anoxia, or
major metabolic disturbance do well
• Majority of morbidity results from hypoxia
– More closely related to duration of hypoxia rather
than duration of seizure activity
• But patients who seize for more than 60 minutes have worse
outcomes than those who seize for less
Refractory Status Epilepticus
• Persistent seizure activity despite appropriate
therapy
– Associated with high mortality and morbidity
– Retrospective review of 22 pts tx’d 1992-2000 with
high-dose anesthetic agents for 2 to 146 days
(median 16.5 days)
• Mortality was 32%
• Greater in younger patients and in those with multifocal or
generalized abnormalities on EEG
• All except one survivor developed active epilepsy and none
with a normal neurologic status prior to the event returned
to their baseline
Adjunctive Therapy: the
Ketogenic Diet
• High fat (80-90% of calories), low protein, very
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low carb diet developed in 1900’s
Ketosis is induced by starvation for 1-2 days,
then perpetuated by ketogenic diet
Diet alters metabolism to replace glucose with
fats as the body’s main energy source
Ketone bodies may have an antiepileptic effect
(mechanism not understood)
Many observation studies report good results
– 1/3 sz resolution; 1/3 sz improved; 1/3 unchanged
• No randomized clinical trials in the literature
Future Potential Therapy
• NMDA antagonists and other calcium entry
channel blockers
• Glutamine antagonists
– Limited secondary to psychiatric effects