Status Epilepticus -

Management, Prognosis, and EEG utilization

Umair Hamid, MD 1, Holly J Skinner, DO 2

1University of Health and Sciences, Pakistan

2AdventHealth 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 seizure
  • Refractory status epilepticus (RSE)
    • Patients who do not respond to standard treatment regimens for SE
    • RSE is considered when patients fail first line therapy which is sufficient dose of benzodiazepines and at least one AED as second line therapy, irrespective of time
    • 26.6% to 36.6% of patients with SE fail to respond to administration of first-line agents
    • Out of all patients who fail first-line agents, 23-48% of the patients fail second line-agents and termed as RSE
  • Super-refractory status epilepticus (SRSE)
    • SRSE is considered when Se continues for 24 hours or more after the use of 3rd line therapies or anesthetic therapy (continuous IV infusions), including cases that recur on weaning of the anesthetic agent
    • SRSE occurs in 22% of patients with SE

Emergency Management

    • Non-invasive airway protection and gas exchange with head positioning
    • Timing: 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

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 AED
          • Continued 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
      • If none of the above are available
        • I/V phenobarbital: 15 mg/kg; single dose (Level B)
          • Adverse effects
            • Hypotension
            • Respiratory depression
            • Cardiac depression
            • Paralytic ileus
            • At high doses, complete loss of neurological function
          • Considerations
            • Requires mechanical ventilation
            • IV contains propylene glycol

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

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

Treatment of Refractory Status Epilepticus (RSE)

  • Estimates of the frequency of RSE in patients with SE have ranged from 9% to 40%
  • There is no clear evidence, according to AES protocol, to guide therapy in RSE
  • Treatment for RSE should be carried out with continuous EEG monitoring
  • According to many authors, treatment should be started immediately
  • Main decision lies between repeating bolus of urgent control AED or to immediately initiate additional agents
  • Following are RSE dosing recommendations; initial doses and continuous infusion (CI) dosing recommendations-titrated to EEG
    • Midazolam
      • Initial dose: 0.2 mg/kg; administer at an infusion rate of 2 mg/min
      • CI: 0.05-2 mg/kg/hr
      • Breakthrough status epilepticus (SE): 0.1-0.2 mg/kg bolus, increase CI rate by 0.05-0.1 mg/kg/hr every 3-4 hours
      • Adverse effects
        • Respiratory depression
        • Hypotension
      • Considerations
        • Tachyphylaxis occurs after prolonged use
        • Active metabolite, renally eliminated, rapid redistribution (short duration)
        • Does not contain propylene glycol
    • Propofol
      • Initial dose: start at 20 mcg/kg/min, with 1-2 mg/kg loading dose
      • CI: 30-200 mcg/kg/min
      • Breakthrough SE: Increase CI rate by 5-10 mcg/kg/min every 5 min or 1 mg/kg bolus plus CI titration
      • Use caution:
        • When administering high doses (>80 mcg/kg/min) for extended periods of time (i.e. >48h)
        • Peds: with doses >65 mcg/kg/min; contraindicated in young children
      • Adverse effects
        • Hypotension (especially with loading dose in critically ill patients)
        • Respiratory depression
        • Cardiac failure
        • Rhabdomyolysis
        • Metabolic acidosis
        • Renal failure (propofol related infusion syndrome)
      • Considerations
        • Requires mechanical ventilation
        • Must adjust daily caloric intake (1.1 kcal/ml)
      • Metabolized to pentobarbital
    • Ketamine (a propofol sparing agent)
      • See below in SRSE protocol

Management of Super-Refractory Status Epilepticus (MGH SRSE Protocol)

  • Repeat burst suppression for 24-48 hours
  • Add other AEDs like carbamazepine or topiramate
  • IV magnesium (bolus 4g, then infuse 2-6 g/hr)
  • Pentobarbital
      • Initial dose: 5-15 mg/kg, may give additional 5-10 mg/kg; administer at an infusion rate ≤50 mg/min
      • CI: 0.5-5 mg/kg/h
      • Breakthrough SE: 5 mg/kg bolus, increase CI by 0.5-1 mg/kg/h every 12 h
  • Ketamine
    • Initial dose: 1-2 mg/kg IV slow push
    • CI: 0.5-7.5 mg/kg/hr
    • Titrate by 0.5 mg/kg/hr every 10 minutes
    • Considerations
      • Maximal effect in 1 minute
      • Hepatic metabolism to active metabolite - norketamine
    • Advantages
      • Favorable hemodynamic effects
      • Minimal respiratory effects
    • Adverse effects
      • Agitation with auditory and visual hallucinations
      • Conscious vivid dreams
      • Increased intracranial pressure
      • Tachyarrhythmias
      • Hypersalivation
  • IV pyridoxine 200 mg/day
  • Thiopental
    • Initial dose: 2-7 mg/kg, administer at an infusion rate ≤50 mg/min
    • CI: 0.5-5 mg/kg/h
    • Breakthrough SE: 1-2 mg/kg bolus, increase CI rate by 0.5-1 mg/kg/h every 12h
    • Adverse effects
      • Hypotension
      • Respiratory depression
      • Cardiac depression
    • Considerations
      • Requires mechanical ventilation

Table 3: Alternative Therapy Options for Super-Refractory Status Epilepticus

Alternative Therapy Options

    • Brivaracetam
      • 10-30 fold higher affinity than levetiracetam
      • Initial dose range between 50-400 mg/day
      • Titrated to daily dose of 100-400 mg
    • Brexanolone
      • Initial dose: 286.6 μg/kg for 1 hour
      • CI: 86-156 μg/kg/h for four days
    • Immune modulation
      • Methylprednisolone 1 g IV qd x 3-5 days
      • IVIG 0.4 g/kg/day x 5 days
      • Plasma exchange every other day x 5-7 days
    • Isoflurane
      • MAC ranging from 0.5-5.0%
      • Seizure control was seen in 43 out of 47 patients
      • Seizure activity often returned upon discontinuation
    • Emergency neurosurgery
      • Suggested that patients who fail three courses of cerebral suppressant therapy for 2 weeks be considered for surgical treatment
      • Preferred for intractable partial SE with focal electrographic changes
    • Ketogenic diet
      • 4:1 ratio of fat (g) to protein plys carbohydrates (g)
      • Studies show improvements and cessation of seizures in 1-2 weeks
      • Benefits
        • Easy to start, maintain, and monitor in the ICU
        • Synergism with other AEDs
        • Minimal side effects
    • Electroconvulsive therapy
      • There is evidence that cases of SRSE may benefit from ECT
      • ECT consisted of a 504-mC (≈99.4 J)
      • Improvement in seizures in ⅝ patients
      • Need for further research
    • Transcranial magnetic stimulation
      • Had dismal results in epilepsy, although recent promising reports of use in epilepsia partialis continua have been published.
    • Vagal nerve stimulation
      • Four published cases reporting benefit from VNS
    • Therapeutic hypothermia
      • Review of studies include a total of 40 patients
      • Target temperature of 33 degree Celsius, sustained for a median 48 hours
      • 62.5% patients displayed seizure cessation
      • 15% had seizure reduction
      • 22.5% had failure of treatment

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

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
  • RSE
    • Prognosis for RSE treated with prolonged courses of pentobarbital, propofol, or midazolam is very poor
    • Outcome of new-onset RSE by Gaspard et al.
      • Retrospective review of patients with RSE etiology within 48 hours of admission

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

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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