Status Epilepticus - Management, Prognosis, and EEG utilization

Primary Category

Epilepsy

P-Category

Secondary Category

Neurocritical Care

S-Category

Authors:

Umair Hamid MD,
Filzah Faheem MD,
Holly J Skinner DO

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 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

Level A	Definition: ≥1 class I studies or ≥2 class II studies Conclusion: Established as effective, ineffective, or harmful for the given condition in the specified population.
Level B	Definition: ≥1 class II studies or ≥3 class III studies Conclusion: Probably Effective, ineffective, or harmful for the given condition in the specified population
Level C	Definition: ≥2 consistent class III studies Conclusion: Probably effective, ineffective, or harmful for the given condition ion the specified condition
Level U	Definition: Lack of Studies meeting level A, B, or C designation Conclusion: Data inadequate or insufficient

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 effects Hypotension Respiratory depression Cardiac depression Paralytic ileus At high doses, complete loss of neurological function Considerations Requires mechanical ventilation IV contains propylene glyco

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

Study	AED’s	Results
Dalziel et al. (2019)	LVA vs PHT	Levetiracetam is not superior
Misra et al. (2012)	LVA vs lorazepam	Both are equivalent
Alvarez et al. (2011)	Phenytoin vs VPA vs LVA	LVA less effective than VPA; no significant difference between VPA and PHT
Gilad et al. (2008)	PHT vs VPA	Both are equivalent
Misra et al. (2006)	PT vs VPA	VPA are more effective than PHT
Shaner et al. (1998)	DZP + PHT vs PBT	Both equally effective

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

Etiologies	Frequency (%)	Mortality (%)
Acute	ㅤ	ㅤ
Stroke	22%	33%
Metabolic abnormalities	15%	30%
Hypoxia	13%	53%
Systemic infection	7%	10%
Anoxia	5%	71%
Trauma	3%	25%
Chronic	ㅤ	ㅤ
Low concentration of AED	245	4%
Remote symptomatic (eg tumor)	25%	14%
Alcohol misuse	13%	20%
Tumor	7%	30%
Idiopathic*	3%	25%

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)

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