The Practical Management of Status Epilepticus

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The Practical Management of Status Epilepticus

• David Y. Gosal,
• Neuro SpR,
• Manchester Neurosciences Centre

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Before I commence

• The following is a synthesis of best available
  published information, national and local
  practice guidelines amongst Neurologists/Intensivi
  sts, and finally personal practice.
• All criticism welcome.

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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

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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.

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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.

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• Operational Definition
• Continuous seizures lasting at least 5
  minutes or two or more discrete seizures between
  which there is an incomplete recovery of
  consciousness.

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Compensated
Decompensation
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Premonitory Stage (pre-status)

• 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.

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• Confident diagnosis GTC status not always
  possible
• Pseudoseizures
• Minor motor features
• Subtle SE (Electromechanical dissociation)
• small amplitude twitching movements.
• occasionally quiet.
• CPSE

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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.

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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
  non-specific and late.

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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.

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Basic investigation and general medical management

• ABC.
• Usual bloods.
• Serum drug levels CBZ, Phenytoin, Valproate.
• Store 20mls of blood, and urine for toxicology if
  no obvious aetiological cause.

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Initial treatment (Early Status 10-30min)

• One area where some good class I evidence exists.
• Three RCTs.

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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
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384 patients 0.1mg/kg lorazepam 15mg/kg
phenobarbital 0.15mg/kg diazepam / 18mg/kg
phenytoin 18mg/kg phenytoin
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Duration of status and response to initial
therapies
Lowenstein et al., Neurology 199343483
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Initial anti-epileptic drug treatment (0-60min)

• Lorazepam is benzodiazepine of choice.
• 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
• More lipid soluble
• Shorter half-life. Anti-seizure effect 15-30min.
• Repeated dosing
• Faster onset

?Respiratory compromise -- Consider lignocaine /
valproate
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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.

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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.

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384 patients 0.1mg/kg lorazepam 15mg/kg
phenobarbital 0.15mg/kg diazepam / 18mg/kg
phenytoin 18mg/kg phenytoin
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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.

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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.

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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.

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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

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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

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Mortality
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Compensated
Decompensation
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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

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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.

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Anaesthetic agents

• Choice of agent
• What depth of anaesthesia

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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.
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Propofol in the treatment of refractory status
epilepticus
Parviainen I et al., Intensive Care Med (2006)
321075

• 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.

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• 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
  dose-dependently reducing cerebral metabolic rate
  and 02 comsumption.

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• 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
  coma-inducing 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

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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.

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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.

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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.

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Acute processes Stroke Metabolic disturbances CNS
infection Trauma Drug Toxicity Hypoxia Difficult
to manage Higher mortality
Chronic processes Pre-existing epilepsy Ethanol
abuse Old CVA Relatively long-standing tumours
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Other forms of status

• Non-convulsive status epilepticus (NCSE).
• Myoclonic status.
• Focal motor status

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Non-convulsive status epilepticus

• Absense Status
• 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

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Non-convulsive status epilepticus

• Complex partial status epilepticus
• Much more prevalent
• Elderly
• Vastly under-diagnosed
• Confusedprofound stupor
• Focal motor phenomenon
• Fluctuating symptoms
• Level of consciousness can be occasionally
  significantly impairediv phenytoin, and
  occasionally will need anaesthesia
• Quite refractory to treatment.
• Unsure how aggressively to treat..individualistic.
  

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Non-convulsive status epilepticus

• Husain et al, 2003, JNNP,74,189-91
• Altered consciouness / mental state
• Remote risk factor seizure eg previous stroke
• Ocular movement abnormality
• 100 predictive value

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Myoclonic status

• Usually seen with the primary epilepsy syndromes.
• Can be a sign of impending tonic-clonic status.
• IV benzodiazepine
• IV valproate

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Focal motor status

• Epilepsia partialis continua (EPC).

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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.

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