Transcript Document

The Practical Management of
Status Epilepticus
David Y. Gosal,
Neuro SpR,
Manchester Neurosciences Centre
Before I commence…
• The following is a synthesis of best available
published information, national and local practice
guidelines amongst Neurologists/Intensivists, and
finally personal practice.
• All criticism welcome.
How To Define Status?
• 1981, ILAE (International League against
Epilepsy)
“a seizure that persists for a sufficient length of
time or is repeated frequently enough that
recovery between attacks does not occur”
How To Define Status?
• More recent publications
“A condition in which epileptic activity persists
for 30 min or more”
• Based on primate models of the estimated duration
necessary to cause neuronal injury.
But
• This is not practical operational definition.
• Longer periods with uncontrolled seizure activity,
more likely to develop a RSE syndrome.
• More practical guidelines needed to draw that
arbitrary ‘line in sand’, beyond which substantial
risk of developing clinical SE exists.
Operational Definition
“Continuous seizures lasting at least 5 minutes
or two or more discrete seizures between which
there is an incomplete recovery of
consciousness.”
Compensated
Decompensation
Premonitory Stage (pre-status)
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Build up of seizure activity
Increasing frequency and / or severity of events.
Commonly 2mg-4mg lorazepam given.
A proportion of cases of early status can be
terminated.
• Confident diagnosis GTC status not always
possible
– Pseudoseizures
– Minor motor features
• Subtle SE (Electromechanical dissociation)
small amplitude twitching movements.
occasionally quiet.
• CPSE
Pseudoseizures
• Genuine and factitious seizures commonly occur
in same individual.
• 80% patients with NEAD are on anticonvulsants.
• 1/3 patients present with ‘status’.
• 2/3 positive motor attacks.
• If treated as per status are highly likely to end up
on anaesthetic agents.
• Can appear focal onset, bite tongue, become
incontinent.
Pseudoseizures: clinical features
• Difficult, share many common characteristics.
• Tremor like asynchronous waxing and waning
asynchronous movement.
• Thrashing limbs.
• Pelvic thrusting.
• Back arching.
• Unresponsive , resists eye opening, versive eye
movement to confrontation, strong stimuli.
• Fever, tachycardia, leucocytosis, acidosis nonspecific and late.
Could this be pseudoseizure activity?
• On balance, where there exists doubt, so long as
possibility of functional attacks have been
considered but felt less likely (and documented as
such), prompt treatment is best.
Basic investigation and general medical
management
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ABC.
Usual bloods.
Serum drug levels: CBZ, Phenytoin, Valproate.
Store 20mls of blood, and urine for toxicology if
no obvious aetiological cause.
Initial treatment (Early Status 10-30min)
• One area where some good class I evidence exists.
• Three RCTs.
Pre-hospital treatment by
paramedics.
2mg lorazepam, or 5mg diazepam
Placebo
Repeated dose after 4min if still
actively seizing
Lorazepam terminated 59.1%
Diazepam 42.6%
Placebo 21%
384 patients
0.1mg/kg lorazepam
15mg/kg phenobarbital
0.15mg/kg diazepam / 18mg/kg
phenytoin
18mg/kg phenytoin
Duration of status and response to initial
therapies
80
70
60
50
40
% patients
responding
30
20
10
0
0.5
<1.0
<1.5
<2.0
>2.0
Lowenstein et al., Neurology 1993;43:483
Initial anti-epileptic drug treatment (0-60min)
• Lorazepam is benzodiazepine of choice.
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Smaller volume of distribution
Longer therapeutic half-life. Anti-seizure effect 12hrs.
Relatively fast onset action
Previous rectal diazepam does not preclude its use
2mg aliquots upto a max dose of 8mg in total
• Diazepam
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?Respiratory compromise
-- Consider lignocaine / valproate
More lipid soluble
Shorter half-life. Anti-seizure effect 15-30min.
Repeated dosing
Faster onset
Initial anti-epileptic drug treatment (0-60min)
• I personally follow on with second-line agent in
any individual with early status, irregardless of
seizure termination with benzodiazepines.
• Phenytoin / Phenobarbitone most logical choices.
• No evidence currently to choose between agents in
terms of efficacy, although in general
phenobarbitone is quicker in onset.
• Phenytoin more widely accepted and used than
phenobarbitone possibly because historically, oral
phenytoin was preferred to phenobarbitone as
maintenance therapy.
Initial anti-epileptic drug treatment: Sodium
Valproate
• If worried re arrhythmias, hypotension, sedation,
can use valproate.
• Has been reported to be effective in GTCSE.
• Efficacy rates 63% in one study.
• Loading dose 25-45mg/kg. Rate 200-500mg/min.
• Continuous infusion rate upto 6mg/min.
384 patients
0.1mg/kg lorazepam
15mg/kg phenobarbital
0.15mg/kg diazepam / 18mg/kg
phenytoin
18mg/kg phenytoin
Initial anti-epileptic drug treatment: Sodium
Valproate
• If worried re arrhythmias, hypotension, sedation,
can use valproate.
• Has been reported to be effective in GTCSE.
• Efficacy rates 63% in one study.
• Loading dose 25-45mg/kg. Rate 200-500mg/min.
• Continuous infusion rate upto 6mg/min.
Phenytoin
• Common problem is that about 70% patients
admitted to ITU are given an inadequate loading
dose.
• I normally give a dose of 15mg/kg at a rate of
50mg/min in young, 20-30mg/min in elderly.
• Risk bradycardia secondary to drug, and
hypotension secondary to glycol additives.
• A further 5mg/kg given almost immediately
afterwards if no response to initial dose.
• Can give upto 30mg/kg., before consideration
anaesthesia.
• Cardiac monitoring necessary..unnecessary delays.
• 15-20minutes at least to take effect.
Phenytoin
• If already on phenytoin, give 10mg/kg, and
request urgent levels.
• Must be aggressive with dosing, and even if
responds to initial dose, should aim for high
normal levels. Range 40-80 micromoles/litre.
• Request serum phenytoin level 1/2hr to 1 hr after
loading dose, and keep giving iv aliquots, with
levels after each dose until desired range.
• In general for micromoles/l, for every 4
micromoles/l off desired target, give 1mg/kg.
Phenytoin
• Non-linear elimination kinetics because capable of
saturating metabolising enzyme.
• In general 20mg/kg usually saturates.
• Predominately protein bound. In
hypoalbuminaemic states can be clinically toxic
with apparently normal total serum levels.
Adjusted Phenytoin = Measured total conc.
(0.2 x albumin) + 0.1
Refractory Status (60min onwards)
• No accepted definition.
• 30-50% patients fail initial benzo / phenytoin Rx.
• Expert consensus and all current guidelines
advise that by this stage patient should be
transferred to ITU for general anaesthesia.
– Urgently suppress seizures (Time is brain)
– Manage systemic adverse effects
– Find possible aetiology
– SE becomes more refractory with time
– RSE Mortality 20%
Mortality
30%
Compensated
Decompensation
Refractory Status (60min onwards)
• No accepted definition.
• 30-50% patients fail initial benzo / phenytoin Rx.
• Expert consensus and all current guidelines
advise that by this stage patient should be
transferred to ITU for general anaesthesia.
– Suppress seizures
– Manage systemic adverse effects
– Find possible aetiology
– SE becomes more refractory with time
– RSE Mortality 20%
But, in practice
–60% European Neurologists, epileptologists,
intensivists use third anti-epileptic agent.
–(43% US)
–Some evidence to show that 50% refractory
cases successfully treated.
–?but at what cost.
Anaesthetic agents
• Choice of agent
• What depth of anaesthesia
Treatment of Refractory Status Epilepticus with Pentobarbital,
Propofol, or Midazolam: A Systematic review
Jan Claassen et al., Epilepsia, 43(2);146-153, 2002
193 patients, 28 trials.
Propofol in the treatment of refractory status epilepticus
Parviainen I et al., Intensive Care Med (2006) 32:1075
•10 patients with refractory SE.
•Terminated seizure activity in all initially.
•Quality of burst suppression unsatisfactory.
•Incremental doses of propofol needed.
•Most needed noradrenaline.
•Need continuous EEG monitoring.
•Stepwise weaning, risk of emergent seizure activity.
Reduction 5% infusion rate/hr over 24hours.
•Weaning time from ventilator 50% quicker than
thiopentone.
•Similar to propofol, effectively terminated seizures.
•Easier to attain and keep burst suppression.
•Doses needed higher than generally recommended.
•Recovery from anaesthesia prolonged
---most had co-morbid conditions.
•Most ended up with RTI.
•Theoretical advantage of being neuroprotective by dosedependently reducing cerebral metabolic rate and 02
comsumption.
•127 patients with status epilepticus.
•47 patients with RSE of various aetiologies.
•2/3 “burst suppression”.
•Incidence of potentially serious / fatal aetiologies
same in both groups.
•“Outcome was independent of the specific comainducing agents used and the extent of EEG burst
suppression, suggesting that the underlying cause
represents the main determinant”.
•Mortality 23% RSE, 8% SE
•Baseline 31% RSE, 50% SE
Conclusions in RSE
• Evidence for treatment poor and based on retrospective
studies.
• More important to initiate anaesthesia with undue delay,
rather than argue over pros and cons of any particular
treatment.
• Continuous monitoring until electrographic seizures
abolished, and at least daily monitoring is required in all
cases of RSE is a minimum.
• Is burst suppression really necessary? Prospective trial
• How long anaesthesia should be administered is unclear,
and probably depends on underlying aetiology.
• Barbituates have someadvantages over other agents, but at
expense of respiratory complications and prolonged ITU
stay.
• Prognosis ultimately depends on aetiology.
What if nothing works?
• Repeated failed attempts at withdrawal anaesthesia.
• Even with known epilepsy, should have MRI and CSF as a
minimum.
• Serum amticonvulsant levels.
• Alternative anti-epileptics…
– iv valproate worth a go
– Leviteracetam
– Topiramate
• Anoxic / metabolic brain damage..Post-anoxic myoclonus?
• Longer and deeper anaesthesia.
Prognosis
• Mortality and morbidity severely influenced by
underlying aetiology. Cannot give reliable figures
for condition itself.
• Mortality 20%
• Morbidity; high risk recurrent seizures, cognitive
deficits, and future episodes
• Many aetiological causes, useful to divide into
acute and chronic processes.
Acute processes
Chronic processes
Stroke
Pre-existing epilepsy
Metabolic disturbances
Ethanol abuse
CNS infection
Old CVA
Trauma
Relatively long-standing
tumours
Drug Toxicity
Hypoxia
Difficult to manage
Higher mortality
Other forms of status
• Non-convulsive status epilepticus (NCSE).
• Myoclonic status.
• Focal motor status
Non-convulsive status epilepticus
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Absense Status
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Rare
Primary generalised epilepsy
Learning disabled
Profound stupor
Occur after tonic-clonic seizure / GTCSstatus
Eyelid / facial myoclonia
Little evidence that it is harmful in itself
Iv valproate, or iv benzodiazepines
Non-convulsive status epilepticus
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Complex partial status epilepticus
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Much more prevalent
Elderly
Vastly under-diagnosed
Confused…profound stupor
Focal motor phenomenon
Fluctuating symptoms
Level of consciousness can be occasionally
significantly impaired…iv phenytoin, and
occasionally will need anaesthesia
Quite refractory to treatment.
Unsure how aggressively to treat..individualistic.
Non-convulsive status epilepticus
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Husain et al, 2003, JNNP,74,189-91
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Altered consciouness / mental state
Remote risk factor seizure eg previous stroke
Ocular movement abnormality
100% predictive value
Myoclonic status
• Usually seen with the primary epilepsy
syndromes.
• Can be a sign of impending tonic-clonic status.
• IV benzodiazepine
• IV valproate
Focal motor status
• Epilepsia partialis continua (EPC).
Conclusions
• Serious medical condition with high mortality
rate.
• Relative dearth of evidence on how to treat
condition.
• Despite this, good practical guidelines exist.
• Pick your drugs, know them well, and use enough.
• Ask for specialist help early.
• Prognosis depends on aetiology, delay in initiation
of appropriate treatment, and usual co-morbid
factors.