Status Epilepticus - Management, Prognosis, and EEG utilization

Umair Hamid, MD (1), Filzah Faheem, MD (2), Holly J Skinner, DO (3)
1 - University of Health and Sciences, Pakistan
2 - Services Institute of Medical Sciences, Pakistan
3 - AdventHealth Orlando, Department of Neurology, Orlando FL


Introduction

  • Status epilepticus (SE)
    • ≥5 minutes of continuous clinical and/or electrographic seizure activity
    • Recurrent seizure activity without recovery (returning to baseline) between seizures

Emergency Management

  • Non-invasive airway protection and gas exchange with head positioningTiming: Immediate (0-2 minutes)Goals: maintaining airway patency; to avoid snoring; administering O2
  • Intubation
    • Indications
      • Airway/gas exchange compromised
      • Elevated ICP suspected
      • Glasgow coma scale <8
      • If patient fails first- and second-line therapies
    • Timing: Immediate (0-10 minutes)
    • Goals: Establish secure oxygenation and ventilation
  • Initial monitoring: O2, BP, HR, and ECG
    • Timing: Immediate (0-2 minutes)
    • Goals: Establish and support baseline vital signs
  • Vasopressor support
    • Indication - MAP <70 mmHg
    • Timing: Immediate (5-15 minutes)
    • Goals: Support cerebral perfusion pressure
  • Finger stick blood glucose
    • Timing: Immediate (0-2 minutes)
    • Goals: Diagnose hypoglycemia
  • Peripheral IV access
    • Timing: Immediate (0-5 minutes)
    • Goals
      • Emergent initial AED therapy [First AED]
      • Fluid resuscitation
      • Nutrient resuscitation (thiamine + glucose)
  • Urgent SE control therapy with AED [Second AED]
    • Timing: Immediate after initial AED given (5-10 minutes)
  • Neurologic exam
    • Timing: Urgent (5-10 minutes)
    • Goals: Evaluate for mass lesion; acute intracranial process
  • Triage lab test panel
    • Timing: Immediate (5 minutes)
    • Goals: Diagnose life threatening metabolic condition
  • RSE treatment
    • Timing: Urgent (20-60 minutes after 2nd AED)
    • Treatment strategies based on individual patient response and AED concentrations
  • Urinary catheter
    • Timing: Urgent (0-60 minutes)
  • Continuous EEG
    • Timing: Urgent (15-60 minutes)
    • Evaluate for NCSE if not waking up after clinically obvious seizures cease
  • Diagnostic testing: CT, LP, and MRI
    • Selection depends on clinical presentation
    • Timing: Urgent (0-60 minutes)
    • Goals: Evaluate for mass lesions, meningitis, encephalitis
  • Intracranial pressure monitoring
    • Timing: Urgent (0-60 minutes of imaging diagnosis)
    • Goals: Measure and control ICP

Table 1: Drug categorization on the basis of level of evidence available

notion image

American Epilepsy Society (AES) Proposed Algorithm for Convulsive SE

Initial Therapy Phase or Emergent Initial Therapy

  • Benzodiazepines are considered as agent of choice
  • I/V lorazepam through either dose method (Level A)
    • Weight Based: 0.1 mg/kg at maximum rate of 2 mg/minute
      • Wait for one minute
      • Reassess
      • If seizures continue
        • Second IV catheter placement
        • Additional doses of lorazepam can be infused
    • Fixed dose based: Initial loading dose of lorazepam 4mg fixed dose; repeated if still seizing
    • Adverse effects
      • Hypotension
      • Respiratory depression
    • Considerations
      • Dilute 1:1 with saline
      • IV contains propylene glycol
    • Treiman et al.
      • Subgroup of 384 patients with overt generalized convulsive SE (GCSE)
      • Lorazepam was successful in 64.9%
      • Terminated seizures within 20 minutes
      • Maintained seizure-free for first 60 minutes after administration
    • Advantage: Effective duration against seizures is 4-12 hours
  • If lorazepam is not available
    • I/V diazepam: 0.15 mg/kg, up to 10 mg per dose (Level A)
      • Adverse effects
        • Hypotension
        • Respiratory depression
      • Considerations
        • Rapid redistribution (short duration)
        • Active metabolite
        • IV contains propylene glycol
      • Chamberlain et al.
        • 140 patients on diazepam vs 133 patients on lorazepam (all randomized; pediatric patient groups)
        • Absolute efficacy difference was only 0.8%
        • No significant difference between both for convulsive SE treatment in pediatric population
      • Advantage: Stability in liquid form for longer periods at room temperature, hence easy accessibility and availability
  • If no I/V access available
    • I/M midazolam: 10 mg for >40 kg, 5 mg for 13-40 kg; single dose (Level A)
      • Adverse effects
        • Hypotension
        • Respiratory depression
      • Considerations
        • Active metabolite
        • Renal elimination
        • Rapid redistribution (short duration)
    • If neither of the above options are available, either of the following
    • I/V phenobarbital: 15 mg/kg/dose; single dose (Level A)
      • Adverse effects
        • Hypotension
        • Respiratory depression
      • Considerations
        • IV contains propylene glycol
    • Rectal diazepam: 0.2-0.5 mg/kg, max: 20 mg/dose; single dose (Level B)
    • I/N midazolam (Level B)
    • Buccal midazolam (Level B)
  • If seizure control has reached clinically and electrophysiologically (as seen on EEG)
    • Nonbenzodiazepine antiseizure drug loading dose should follow
    • Symptomatic medical care should continue

Second Therapy Phase or Urgent Control Therapy

  • Goals
    • For patients who respond to emergent initial therapy and have complete resolution
      • the goal is rapid attainment of therapeutic levels of an AEDContinued dosing for maintenance therapy
    • For patients who fail emergent initial therapy, the goal is to stop SE
  • If seizure continues, AED’s should be given in combination with benzodiazepines
  • Preferred second therapy of choices (given as single dose)
    • I/V fosphenytoin: 20 mg phenytoin equivalents (PE)/kg, max: 1500 mg PE/dose; single dose (Level U)
      • Adverse effects
      • Hypotension
      • Arrhythmias
    • Considerations
      • Compatible in saline, dextrose, and LR solutions
      • Infusion of fosphenytoin should be done with cardiac monitoring, due to increased risk for QT prolongation and arrhythmias
    • Advantage: Can be infused rapidly as compared to phenytoin due to reduced risk of local irritation at the site of injection
  • I/V levetiracetam: 60 mg/kg, max: 4500 mg/dose; single dose (Level U by AES 2016 and Level C by Brophy et al. 2012)
  • I/V valproic acid: 40 mg/kg, max: 3000 mg/dose; single dose (Level B)
    • Adverse effects
      • Hyperammonemia
      • Pancreatitis
      • Thrombocytopenia
      • Hepatotoxicity
    • Considerations
      • Use with caution in patients with traumatic head injury
      • May be a preferred agent in patients with glioblastoma multiforme
      • Contraindicate in Europe in pregnancy
  • If none of the above are available
  • I/V phenobarbital: 15 mg/kg; single dose (Level B)Adverse effectsHypotensionRespiratory depressionCardiac depressionParalytic ileusAt high doses, complete loss of neurological functionConsiderationsRequires mechanical ventilationIV contains propylene glyco

Table 2: Evidence for choice of AED in second therapy phase

notion image
Legend: LVA: Levetiracetam; VPA: Valproic Acid; PHT: Phenytoin; DZP: Diazepam; PBT: Phenobarbital
Derived from Betjemann, J. P., & Lowenstein, D. H. (2015). Status epilepticus in adults. The Lancet Neurology, 14(6), 615-624

EEG Utilization

  • No data to support a standardized regimen for the intensity and duration of treatment of RSE
  • It is usually dictated by continuous EEG (cEEG) findings
  • Common practice is to achieve electrographic burst suppression
    • 1-2 sec bursts of cerebral activity interspersed by 10 sec intervals of background suppression
    • Pattern should be continued for 24-48 hours before sedation is lightened
    • During burst suppression, continuation of other AED is controversial
    • Stopping other AED to allow for down-regulation of receptors while patient is on pentobarbital may be useful

Table 3: Frequency and mortality associated with acute and chronic causes of SE in adults

notion image
Derived from Betjemann, J. P., & Lowenstein, D. H. (2015). Status epilepticus in adults. The Lancet Neurology, 14(6), 615-624

Complications and Prognosis

  • Generalized convulsive SE (GCSE)
    • Complications include cardiac arrhythmias, hypoventilation, hypoxia, fever, and leukocytosis in patients with
    • Risk factors leading to increase in complications include aspiration pneumonitis, pulmonary edema, and respiratory failure
    • Important predictors of outcome
      • Etiology
      • Older age
      • Medical comorbidity
      • High APACHE-II scores
    • Increased duration of SE in the setting of acute neurological insult are risk factors for long-term neurologic disability
    • SE recurs in about one-third of patients with a first episode of SE
    • 40% of patients with first episode of SE develop subsequent epilepsy
  • Focal motor SE
    • Prognosis depends on prognosis of underlying lesion
    • Long-term morbidity in terms of weakness, sensory, and visual loss, and language dysfunction can be substantial, and many patients have severe cognitive problems
    • Cortical laminar necrosis (CLN) can be a sequela; based on case reports derived from Donaire et al.
      • Radiologically defined as high intensity cortical lesions on T1 weighted MRI images following a gyral distribution
      • Histopathologically characterized by pan-necrosis of the cortex involving neurons, glial cells, and blood vessels
      • Two patients with SE discussed in the case reports
        • Both patients displayed permanent brain imaging abnormalities consistent with CLN after prolonged focal SE
        • No metabolic or significant decreases in blood pressure during the episodes of focal SE
        • The authors hypothesized that necrosis in these patients is primarily a consequence of repeated seizures
        • The hypothesis is supported by the fact that CLN is seen in the same areas as those displaying acute cortical edema and hyperperfusion during the acute phase of SE
  • Myoclonic SE (MSE)
    • Prognosis depends on form of MSE
    • Benign primary epilepsy syndromes leading to MSE have best prognosis
    • Secondary myoclonic epilepsy syndromes leading to MSE are more refractory to AED’s
    • Poorest prognosis in patients with MSE due to an acute new illness
    • Presence of myoclonic seizures early after anoxia has been identified as a poor prognostic factor
      • 89% of patients died in a review study of 134 cases of post-anoxic MSE
Mortality
  • According to Vignatelli et al., 30-day case fatality was 39% (33% excluding postanoxic patients) in Italians
  • From a systemic review on 61 studies by Neligan et al.
    • The main outcome measure was in-hospital mortality or 30-day case fatality expressed as proportional mortality
    • SE in adults
      • Estimated pooled proportional mortality of 15.9%
      • Studies before year 2000 had higher pooled mortality of 24%
    • All-age population pooled mortality ratio of 13%
    • Pediatrics: Pooled mortality of 3.6%
    • RSE: Pooled mortality was at 17.3%
  • Mortality was 15.6% among 96 patients with a first SE episode in study by Rossetti et al.
  • Seizures lasting more than 30 minutes are less likely to terminate spontaneously and are associated with a higher mortality than seizures lasting less than 30 minutes
  • Case mortality rate in patients with RSE was recorded as 38% by Sutter et al.
  • Chronic epilepsy and low AED levels are the most common causes of SE among chronic or acute causes and are associated with a relatively low mortality
  • Rosetti et al. developed “Status Epilepticus Severity Score” (STESS) to predict in-hospital mortality
    • Outcome predictors are determined before treatment institution, which are
      • Age
      • History of seizures
      • Seizure type
      • Extent of consciousness impairment
    • Maximum score of 6; optimal cut-off value at ≥3 with sensitivity of 0.94, specificity of 0.60, NPV of 0.97, and PPV of 0.39
    • Predictive value of STESS was assessed by Aukland et al.
      • STESS correlated significantly with overall mortality though with lower odds ratios
      • STESS was reliable for in-hospital mortality
      • STESS did not allow correct estimation of mortality after discharge

      Refractory Status Epilepticus (RSE)

Further Reading

Dubey, D., Kalita, J., & Misra, U. K. (2017). Status epilepticus: Refractory and super-refractory. Neurology India, 65(7), 12.
Betjemann, J. P., & Lowenstein, D. H. (2015). Status epilepticus in adults. The Lancet Neurology, 14(6), 615-624.

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