Status Epilepticus

OVERVIEW

Status epilepticus is defined as:

• continuous seizure activity for 5 minutes or more without return of consciousness, or
• recurrent seizures (2 or more) without an intervening period of neurological recovery

Refractory status epilepticus

• definitions vary
• seizure activity which fails to respond to first-line anticonvulsant therapies (see below)
• accounts for about a third of status epilepticus patients

Note that:

• older definitions required seizure activity to continue for 30 minutes to be considered status epilepticus
  • most seizures terminate within 5 minutes and those that don’t are often prolonged
  • significant neuronal injury occurs well before 30 minutes
• rapid seizure control is important because:
  • limits seizure-induced neuronal injury (animal studies; also associated with better outcomes in humans)
  • benzodiazepine effectiveness decreases over time (likely to changes in GABA subunits with ongoing seizure activity)
  • prevent ‘duration-dependent kindling’ and cytokine-mediated effects (experimental models)
• seizures account for about 1% of all ED presentations and about 30% of neurological presentations

CAUSES

• epilepsy
• infective
• hypoxic
• vascular
• metabolic
• structural
• physical (hyperthermia)
• drug-induced or related to withdrawal

Pseudoseizures are an important differential diagnosis characterised by:

• volitional or non-volitional
• preserved consciousness or purposeful movements
• asymmetric movements
• poorly coordinated thrashing
• back arching
• eyes held shut
• head rolling
• pelvic thrusting
• bicycling/ pedalling movements of legs

PATHOPHYSIOLOGICAL EFFECTS

Neurological

• excitotoxic neuronal injury
• secondary injury from systemic complications (hypotension, hypoxia, hyperthermia)
• excessive intracellular calcium influx -> intracellular neurochemical medicated cell damage/death.
• intracranial hypertension
• increased cerebrospinal fluid protein

Respiratory

• hypoxia
• respiratory acidosis
• neurogenic pulmonary oedema
• aspiration pneumonitis

Cardiovascular

• hypertension -> hypotension
• tachycardia
• dysrhythmias

Metabolic

• lactic acidosis
• hyperpyrexia
• hyperglycaemia -> hypoglycaemia

Other

• rhabdomyolysis
• blood leukocytosis

CLINICAL FEATURES

History

• description of seizure activity
  • time of onset and offset
  • warning signs
  • parts of body involved in motor activity, and sequence of involvement
• history of epilepsy
• family history
• compliance
• precipitants
  • drug withdrawal
  • intercurrent illness
  • new medications (e.g. antipsychotics, antidepressants, isoniazid)
  • recreational drug use (e.g. sympathomimetics)
  • traumatic brain injury

Examination

• observation of seizure activity if persists
• temperature
• meningism
• focal neurology
• pupils (response to light is ‘poor man’s EEG’)
• general examination
• lateral tongue biting
• incontinence

INVESTIGATIONS

Bedside

• glucose
• blood gas/ lactate

Laboratory

• UEC, CMP (Na+, glucose, Ca2+, renal function)
• toxins (TCA, theophylline, amphetamines, other recreational drugs, salicylates, glycols, alcohols, hydrocarbons)
• Prolactin levels (peak at 20 minutes after seizure, return to baseline in 60 minutes)
• TFTs
• porphyrins
• LP (can have over 100 WBCs following prolonged seizure without meningoencephalitis; relative contra-indication soon after seizure)

Imaging

• CT Brain
• MRI Brain

MANAGEMENT

Goals

1. Resuscitation to prevent secondary brain injury and maintain cerebral perfusion pressure
2. Terminate seizure
3. Decrease cerebral metabolic rate
4. Diagnose and treat cause
5. Treat complications

Resuscitation

• Attend to ABCS and address life threats
• Manage airway with recovery position, airway adjuncts and intubation if required
• Optimise oxygenation and provide ventilatory support as needed (prone to hypercapnia)
• Early IV or IO access, optimise cerebral perfusion pressure
• Treat hypoglycaemia and life-threatening electrolyte disturbance if present
• Maintain normothermia
• Give relevant antidote if due to toxic agent (e.g. pyridoxine for isoniazid)

Terminate seizure

• First line therapies
  • Bolus dose benzodiazepines
    • Midazolam 0.1mg/kg IV – also buccal or IM (IM not inferior to IV lorazepam)
    • Lorazepam 0.1mg/kg IV (onset in 3-5 minutes and last hours; preferred for longer acting effects)
    • Diazepam 5mg IV/PR (avoid IM as painful) (onset in ~1 minute but lasts only about ~20 min for anticonvulsant activity)
    • Clonazepam

• Second line therapies (typically requires intubation and mechanical ventilation)
  • Phenytoin 15-20 mg/kg IV over 30 minutes or longer
    • should not be used to terminate seizures as a sole agent, always with benzodiazepines
    • some regard phenytoin as a first line therapy, however not all seizures require therapy in addition to termination with benzodiazepines
    • avoid  if usually on phenytoin
    • avoid rapid push to risk of cardiovascular toxicity from the propylene glycol diluent
    • fosphenytoin is not available in Australia
  • Valproic acid — 40 mg/kg IV over 10 min (may give additional 20 mg/kg over 5 min if still seizing)
  • Leviteracetam (off label use for status epilepticus)
• Third line therapies (for refractory status epilepticus; typically require intubation and ventilation and cEEG monitoring)
  • propofol 2-3mg/kg IV then <4mg/kg/hr
  • midazolam IV infusion
  • Barbiturates
    • Phenobarbitone infusion 10mg/kg IV boluses -> 0.2-0.4mg/kg/min
    • Thiopentone 4mg/kg IV (then repeat boluses or infusion targetting burst suppression)
  • Clonazepam IV infusion
• Fourth line therapies
  • Thiopentone (if not already started)
  •  Volatile anaesthetic agent (e.g. isoflurane)
  • Ketamine infusion
  • Magnesium
  • Lignocaine
• Other seizure therapies of uncertain efficacy
  • steroids
  • immunomodulation (IV IgG or plasmapheresis)
  • ketogenic diet
  • hypothermia
  • deep brain stimulation
  • surgical interventions
• Monitor for ongoing seizures
  • Avoid neuromuscular blockade, consider using suxamethonium for intubation due to short duration of effect (~10 minutes)
  • Observe for muscular activity
  • cEEG to exclude non-convulsive status epilepticus in patients who do not return to normal conscious state
  • A period of 24–48 h of electrographic control is recommended prior to slow withdrawal of continuous infusion AEDs for RSE

Treat underlying cause

• Antibiotics – bacterial infection
• Antivirals – viral infection
• Abscess – surgery
• Increased ICP – neurosurgical decompression
• Eclampsia – Mg2+ and BP management (early delivery of baby and placenta)
• Isoniazid OD or pyridoxine-dependent seizures (e.g. neonates) – pyridoxine
• Cholinergic syndrome – atropine, palidoxime if organophosphate poisoning)
• Sodium channel blocker overdose – sodiu bicarbonate, intralipid

Restore

• Ensure patient receives normal therapeutic prophylaxis
• Check levels
• Consider adding a new generation in difficult cases

Prevent and treat complications

• aspiration
• neurogenic pulmonary oedema
• rhabdomyolysis
• hyperthermia
• trauma (e.g. head injury due to fall, posterior shoulder dislocation)
• Todd’s paralysis (may last 24h)

Disposition

• Patients with status epilepticus generally require HDU/ ICU admission
• Neurology consult

PROGNOSIS

• prolonged seizures have higher mortality and worse outcomes
• mortality of status epilepticus ranges from ~ 10-30% in different studies, depending on the definition used

OTHER INFORMATION

• non-IV benzodiazepines (e.g. IM midazolam) are often preferred first-line therapy in prehospital settings
• respiratory decompensation is more commonly encountered in untreated status epilepticus than in status epilepticus treated with benzodiazepines
• Titrate AEDs to therapeutic levels. When checking post-load drug levels, on should wait at least 2 hours post infusion for fosphenytoin and phenytoin, or immediately post infusion of valproate
• Phenytoin is typically avoided in drug-induced seizures, barbiturates are widely recommended following first line benzodiazepine therapy

References and Links

Journal articles

• Brophy, Gretchen M., et al. Guidelines for the evaluation and management of status epilepticus. Neurocritical care 17.1 (2012): 3-23 PMID: 22528274 [free full text]
• Claassen J, Riviello JJ, Silbergleit R. Emergency Neurological Life Support: Status Epilepticus. Neurocritical care. 23 Suppl 2:S136-42. 2015. [pubmed]
• Holtkamp M. Treatment strategies for refractory status epilepticus. Curr Opin Crit Care. 2011 Apr;17(2):94-100. doi: 10.1097/MCC.0b013e328342fab5. Review. PMID: 21178612.
• Nair PP, Kalita J, Misra UK. Status epilepticus: why, what, and how. J Postgrad Med. 2011 Jul-Sep;57(3):242-52. doi: 10.4103/0022-3859.81807. Review. PubMed PMID: 21941070. [Free Fulltext]
• Rossetti AO, Lowenstein DH. Management of refractory status epilepticus in adults: still more questions than answers. Lancet Neurol. 2011 Oct;10(10):922-30. doi: 10.1016/S1474-4422(11)70187-9. Review. PubMed PMID: 21939901; PubMed Central PMCID: PMC3202016.
• Shorvon S, Ferlisi M. The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol. Brain. 2011 Oct;134(Pt 10):2802-18. doi: 10.1093/brain/awr215. Epub 2011 Sep 13. Review. PubMed PMID: 21914716. [Free fulltext]
• Special Issue: Proceedings of the 3rd London-Innsbruck Colloquium on Acute Seizures and Status Epilepticus. Epilepsia. October 2011. Volume 52, Issue Supplement s8. Pages 1–85 [Free Fulltext]