Convulsive Status Epilepticus
Convulsive status epilepticus (CSE) is the most common and dangerous form of status epilepticus, defined as continuous tonic-clonic seizure activity lasting ≥5 minutes or two or more seizures without full return of consciousness between them. It represents a neurologic emergency with a mortality rate of 10–30% in adults and carries substantial risk of permanent neurologic disability. The urgency of treatment cannot be overstated — each minute of ongoing seizure activity increases the probability of pharmacoresistance, systemic complications, and irreversible neuronal injury.
Bottom Line
- Definition: Continuous convulsive seizure activity ≥5 minutes (time point t1) or recurrent tonic-clonic seizures without recovery of consciousness; neuronal injury risk begins at 30 minutes (time point t2)
- Epidemiology: Annual incidence of 10–41 per 100,000; 30-day mortality is ~10% in adults and ~2% in children; 20% of patients present with SE as their first seizure
- First-line therapy: Benzodiazepines — IV lorazepam 4 mg, IM midazolam 10 mg, or IV diazepam 10 mg for adults >40 kg; underdosing is the most common treatment error
- Second-line therapy: ESETT trial showed equivalent efficacy of IV fosphenytoin (20 mg PE/kg), valproate (40 mg/kg), and levetiracetam (60 mg/kg)
- Key principle: Time is brain — delayed or underdosed benzodiazepines increase risk of refractory SE, intubation, and death
- Third-line: No consensus on immediate anesthetic infusion vs. a second non-sedating ASM; individualize based on clinical severity and institutional resources
Definition and Classification
The 2015 International League Against Epilepsy (ILAE) task force established the current definition of status epilepticus as "a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms which lead to abnormally prolonged seizures." The definition introduces two operational time points:
- Time point t1 (5 minutes): The point at which a seizure should be regarded as continuous seizure activity and treatment should begin. For generalized tonic-clonic SE, this threshold is 5 minutes, based on the observation that most self-terminating seizures end within 2–3 minutes.
- Time point t2 (30 minutes): The point of ongoing seizure activity after which there is a risk of long-term neuronal injury, including neuronal death, neuronal network alteration, and hippocampal damage. This is derived from animal experiments and limited clinical data.
Stages of Convulsive Status Epilepticus
| Stage | Time Frame | Definition | Treatment Phase |
|---|---|---|---|
| Developing SE | 0–5 minutes | Seizure activity leading up to SE; most seizures self-terminate within this window | Stabilization — ABCs, glucose, IV access, monitoring |
| Established SE | 5–20 minutes | Ongoing seizure activity ≥5 minutes or recurrent seizures without recovery | First phase — benzodiazepines |
| Established SE (continued) | 20–40 minutes | SE persisting despite adequate first-line therapy | Second phase — non-benzodiazepine IV ASM loading |
| Refractory SE | >40 minutes | SE persisting after failure of two adequately dosed ASMs from different classes | Third phase — anesthetic infusions or additional non-sedating ASM |
| Super-refractory SE | >24 hours | SE persisting despite ≥24 hours of anesthetizing ASM infusions | Escalation — multimodal therapy in ICU |
ILAE Semiologic Classification
The ILAE classifies SE along four axes: semiology (with and without prominent motor signs), etiology (known and unknown), EEG patterns, and age group (neonatal through old age). Convulsive SE encompasses generalized tonic-clonic SE, focal motor SE (formerly epilepsia partialis continua), tonic SE, and myoclonic SE. This topic focuses on generalized convulsive SE, the most common and immediately life-threatening subtype.
Epidemiology
Status epilepticus accounts for a significant burden of neurologic critical care. Key epidemiologic data include:
- Incidence: 10–41 per 100,000 per year in the United States, with higher rates in children (<1 year) and the elderly (>60 years), following a bimodal distribution
- First seizure presentation: Approximately 20% of patients present with SE as their first-ever seizure; when the first seizure is SE, mortality risk is substantially higher
- Mortality: A large Korean nationwide study of 33,814 patients found 30-day mortality of 1.8% in children and 10.2% in adults; 1-year mortality was 4.6% in children and 30.3% in adults
- Disability: New neurologic disabilities occurred in 10.7% of patients overall, with children aged 5–9 years having the highest risk (21.3%)
- Refractory SE: Develops in 23–55% of patients; in the Korean cohort, 33.2% of children and 17.6% of adults progressed to refractory SE
Mortality Predictors in Convulsive SE
- Advanced age (≥65 years) — strongest demographic predictor
- Acute symptomatic etiology (especially anoxia, CNS infection, acute stroke)
- Progression to refractory status epilepticus
- Higher Status Epilepticus Severity Score (STESS ≥3)
- Longer duration of SE before treatment initiation
- Presence of peri-ictal MRI abnormalities (associated with 27% vs. 11% in-hospital mortality)
- Postanoxic SE carries the worst prognosis and has been excluded from most treatment trials
Etiologies
Identifying the underlying cause of SE is critical because etiology is the strongest predictor of outcome and directly influences management. Etiologies are broadly classified into four categories:
| Category | Examples | Approximate Frequency | Prognosis |
|---|---|---|---|
| Acute symptomatic | Stroke, CNS infection, traumatic brain injury, metabolic derangement (hyponatremia, hypoglycemia, hepatic failure), drug toxicity, hypoxic-ischemic injury | 25–40% | Worst prognosis; highest mortality |
| Remote symptomatic | Prior stroke, prior TBI, neurodegenerative disease, brain tumor, cortical malformation | 20–30% | Intermediate; depends on lesion and seizure control |
| Breakthrough in known epilepsy | ASM non-adherence (most common), subtherapeutic drug levels, intercurrent illness, sleep deprivation, alcohol use | 20–35% | Best prognosis if rapidly treated; low mortality |
| De novo / Unknown | NORSE/FIRES, autoimmune encephalitis, genetic epilepsy presenting as SE, cryptogenic | 10–20% | Variable; cryptogenic NORSE has 19–22% mortality |
Do Not Forget These Reversible Causes
- Hypoglycemia: Check point-of-care glucose immediately; administer 25–50 mL of D50W (or 1 mL/kg of D25W in children) if glucose <60 mg/dL
- Hyponatremia: Severe (<120 mEq/L) can cause SE; treat with hypertonic saline 3% (100 mL bolus over 10 min, may repeat ×2)
- ASM non-adherence: The most common precipitant in patients with known epilepsy; check drug levels stat
- Drug toxicity: Isoniazid (treat with pyridoxine 5 g IV), theophylline, bupropion, tramadol, synthetic cannabinoids
- Eclampsia: Magnesium sulfate 4–6 g IV is the treatment of choice, not standard ASMs
- CNS infection: Empiric acyclovir and antibiotics should be started immediately if infection is suspected
Pathophysiology of Self-Sustaining Seizures
The transition from a self-terminating seizure to SE involves progressive failure of seizure-termination mechanisms combined with activation of self-perpetuating excitatory circuits:
- GABAA receptor internalization: Within minutes of ongoing seizure activity, GABAA receptors are internalized from the synaptic membrane via clathrin-mediated endocytosis, reducing the inhibitory effect of both endogenous GABA and exogenous benzodiazepines. This explains the declining efficacy of benzodiazepines with prolonged SE.
- NMDA receptor externalization: Simultaneously, excitatory NMDA receptors are trafficked to the synaptic surface, amplifying glutamatergic excitation and promoting further neuronal depolarization.
- Neuropeptide changes: Inhibitory neuropeptides (neuropeptide Y, galanin, dynorphin) are depleted, while excitatory neuropeptides (substance P, neurokinin B) accumulate.
- Excitotoxic cascade: Sustained glutamate release activates calcium influx through NMDA receptors, triggering mitochondrial dysfunction, free radical production, and apoptotic and necrotic cell death, particularly in the hippocampus, cortex, and thalamus.
Clinical Implication: Why Time Matters
- The progressive internalization of GABAA receptors explains why benzodiazepines lose efficacy with each passing minute — creating a "treatment window" that narrows rapidly
- The US VA Cooperative Trial demonstrated a stepwise decline in treatment efficacy: the first ASM controlled seizures in 55.5% of patients, the second in an additional 7.0%, and the third in only 2.3%
- This pharmacodynamic shift from benzodiazepine-responsive to benzodiazepine-resistant SE is the fundamental rationale for aggressive, protocol-driven early treatment
Stabilization Phase (0–5 Minutes)
The initial assessment and stabilization should occur simultaneously with preparation for pharmacologic treatment. The stabilization phase follows standard resuscitation principles adapted to the seizure patient:
Immediate Actions
- Airway: Position the patient on their side (recovery position) if not already intubated; suction secretions; place a nasopharyngeal airway if tolerated; do NOT place anything in the mouth (risk of dental injury and aspiration)
- Breathing: Apply supplemental oxygen via non-rebreather mask; monitor SpO2; prepare for possible intubation
- Circulation: Establish two large-bore IV lines; obtain point-of-care glucose, BMP, CBC, hepatic panel, ASM levels, toxicology screen, blood gas
- Dextrose: Administer 25–50 mL of 50% dextrose (D50W) IV if hypoglycemia is confirmed or suspected; give thiamine 100 mg IV first if alcohol use or malnutrition is suspected
- Monitoring: Continuous cardiac telemetry, pulse oximetry, automated blood pressure; prepare for continuous EEG (cEEG) as soon as available
- Safety: Pad side rails; remove constrictive clothing; note seizure onset time (critical for staging treatment)
First-Line Therapy: Benzodiazepines (5–20 Minutes)
Benzodiazepines remain the unquestioned first-line treatment for established convulsive SE. They act by enhancing GABAA receptor-mediated chloride influx, providing rapid anticonvulsant activity. Three agents are recommended by the 2016 American Epilepsy Society (AES) guideline:
| Agent | Route | Adult Dose (>40 kg) | Pediatric Dose | Onset | May Repeat | Evidence Level |
|---|---|---|---|---|---|---|
| Lorazepam | IV | 4 mg (0.1 mg/kg) | 0.1 mg/kg, max 4 mg | 2–3 min | Yes, once | Highly likely effective |
| Midazolam | IM | 10 mg (>40 kg); 5 mg (13–40 kg) | 0.2 mg/kg, max 10 mg | 3–5 min (IM) | Single dose | Highly likely effective |
| Diazepam | IV | 10 mg (0.15–0.2 mg/kg) | 0.15–0.2 mg/kg, max 10 mg | 1–2 min | Yes, once | Highly likely effective |
Alternative Routes When IV Access Is Not Available
- Rectal diazepam: 0.2–0.5 mg/kg, max 20 mg single dose (likely effective)
- Intranasal midazolam: 5 mg (FDA-approved device) (likely effective)
- Intranasal diazepam: 5–20 mg weight-based dosing (FDA-approved)
- Buccal midazolam: Likely effective; widely used in Europe
- IV phenobarbital: 15 mg/kg single dose if no benzodiazepine is available (highly likely effective)
The RAMPART Trial
The Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART, 2012) was a landmark Phase III, double-blind, randomized clinical trial that compared IM midazolam 10 mg with IV lorazepam 4 mg administered by paramedics to 893 patients with prehospital SE lasting >5 minutes. Key findings:
- IM midazolam was noninferior and statistically superior to IV lorazepam for terminating convulsions before ED arrival (73.4% vs. 63.4%, p < 0.001)
- The advantage of IM midazolam was attributed to faster drug delivery — IM injection is immediate, whereas establishing IV access in a seizing patient causes significant delays
- Rates of endotracheal intubation and recurrent seizures were similar between groups
- IM midazolam had a higher rate of ED discharge than IV lorazepam
- These results established IM midazolam as the preferred agent when IV access is not immediately available
The Critical Problem of Benzodiazepine Underdosing
- Multiple studies demonstrate that the majority of children and adults with SE receive subtherapeutic benzodiazepine doses in clinical practice
- In the ESETT trial, >75% of 460 subjects received prehospital benzodiazepine doses lower than guideline recommendations
- The SENSE registry found suboptimal benzodiazepine dosing in >75% of adults with SE; underdosing was even more pronounced in NCSE
- Consequences of underdosing: Higher rates of progression to refractory SE, longer SE duration, more frequent intubation, and increased mortality
- Uncontrolled SE is more dangerous than benzodiazepines: The PHTSE trial showed that patients randomized to placebo had >2× the rate of respiratory dysfunction compared with those receiving lorazepam or diazepam
- A multicenter pediatric study found that two-thirds of children receiving delayed first-stage benzodiazepines had increased odds of death and need for anesthetic infusions
- Clinical mandate: Use full guideline-recommended doses; do not reduce doses out of unfounded fear of respiratory depression
Second-Line Therapy: Non-Benzodiazepine ASMs (20–40 Minutes)
If convulsive SE persists after adequate first-line benzodiazepine therapy, the second treatment phase should begin promptly. The 2016 AES guideline and subsequent trial data support three equivalent options:
| Agent | IV Loading Dose | Max Dose | Infusion Rate | Key Considerations | Evidence Level |
|---|---|---|---|---|---|
| Fosphenytoin | 20 mg PE/kg | 1500 mg PE | ≤150 mg PE/min | Cardiac monitoring required; risk of hypotension, arrhythmia; Purple Glove Syndrome with phenytoin (not fosphenytoin); avoid in known cardiac conduction disorders | Insufficient evidence (pre-ESETT); Likely effective (post-ESETT) |
| Valproic acid | 40 mg/kg | 3000 mg | Up to 10 mg/kg/min | Avoid in pregnancy (teratogenicity), mitochondrial disease, hepatic failure, acute pancreatitis, thrombocytopenia; relatively safe hemodynamic profile | Likely effective |
| Levetiracetam | 60 mg/kg | 4500 mg | Over 15 minutes | Favorable side effect profile; no significant drug interactions; no cardiac or hepatic toxicity; minimal sedation; may cause behavioral changes | Insufficient evidence (pre-ESETT); Likely effective (post-ESETT) |
The ESETT Trial
The Established Status Epilepticus Treatment Trial (ESETT) was a landmark Class I, multicenter, randomized, double-blind, comparative effectiveness trial that enrolled 384 patients aged 2–95 years with benzodiazepine-resistant established convulsive SE. Key findings:
- Primary outcome: Cessation of SE and improvement in consciousness at 60 minutes was achieved by levetiracetam in 47%, fosphenytoin in 45%, and valproic acid in 46% — no significant differences
- Safety: No significant differences in the level of consciousness, endotracheal intubation, recurrence of SE, or other major safety events across groups
- Implication: All three agents are equivalent options for second-line therapy; selection should be guided by individual patient factors (comorbidities, concurrent medications, contraindications)
Supporting Trials
- SAMUKeppra trial: Class I study showing that after initial IV clonazepam 1–2 mg, prehospital adults with CSE had equal seizure control whether given levetiracetam 2500 mg or placebo — suggesting that when first-line benzodiazepines are adequate, second-line agents may not add benefit in the prehospital setting
- EcLiPSE and ConSEPT: Two Class III open-label pediatric RCTs found that IV levetiracetam 40 mg/kg and IV phenytoin 20 mg/kg were possibly equally effective in children
- VA Cooperative Trial: Seminal 1998 trial establishing benzodiazepines as first-line; showed stepwise efficacy decline: first ASM 55.5%, second ASM an additional 7.0%, third ASM only 2.3%
Choosing a Second-Line Agent
- Per ESETT, all three are equivalent in efficacy — the choice depends on the clinical context
- Favor fosphenytoin: When the patient is already on valproate or levetiracetam; when a known therapeutic level can be targeted (10–20 μg/mL); historical familiarity in many centers
- Favor valproic acid: Generalized epilepsies (especially idiopathic generalized epilepsy), no cardiac conduction concerns, hemodynamically unstable patients (less hypotension than fosphenytoin)
- Favor levetiracetam: Hepatic dysfunction, pregnancy (relative — less teratogenic than valproate), unknown epilepsy type, minimal drug interactions, no cardiac monitoring required
- Avoid valproate: Pregnancy, known/suspected mitochondrial disease, active hepatic disease, acute pancreatitis, urea cycle disorders
- Avoid fosphenytoin: Known cardiac conduction abnormalities (second- or third-degree AV block, Brugada syndrome), concurrent use of strong CYP inducers/inhibitors, porphyria
Third-Line Therapy: Refractory SE (>40 Minutes)
Refractory convulsive SE is diagnosed when seizures persist after failure of two adequately dosed ASMs from different classes (typically a benzodiazepine plus one of the second-line agents). It develops in approximately 23–55% of SE patients and carries a mortality rate of 15–39% in adults.
Third-Line Options
There is no Class I evidence and no consensus on the optimal third-line approach. Two strategies exist:
- Strategy 1 — Additional non-sedating ASM: A second non-anesthetizing agent (e.g., lacosamide, valproate, or levetiracetam if not already used) may terminate SE in up to 50% of patients and avoids the complications of anesthetic coma. One study using sequential lorazepam → phenytoin → levetiracetam → valproic acid controlled SE in 92% of patients.
- Strategy 2 — Anesthetic infusion (therapeutic coma): Continuous IV infusion of midazolam, propofol, or pentobarbital, titrated to EEG burst suppression. This is traditionally the default approach based on expert opinion but is associated with significant complications.
| Anesthetic Agent | Loading Dose (IV) | Maintenance Infusion | t1/2 | Key Risks |
|---|---|---|---|---|
| Midazolam | 0.2–0.5 mg/kg | 0.1–2.0 mg/kg/h | 1–4.5 h (child); 2–7 h (adult); up to 24 h with prolonged use | Tachyphylaxis, respiratory depression, hypotension; least hemodynamic compromise of the three |
| Propofol | 1–2 mg/kg bolus, may repeat q3–5 min (max 10 mg/kg) | 1–15 mg/kg/h initially; max 5 mg/kg/h long-term | 0.67 h initially; 4–7 h prolonged; >24 h after 10+ days | Propofol infusion syndrome (PRIS) — metabolic acidosis, rhabdomyolysis, hyperkalemia, cardiac failure; risk increases with doses >5 mg/kg/h for >48 h; avoid prolonged use in children |
| Pentobarbital | 5–15 mg/kg at ≤50 mg/min | 0.5–5 mg/kg/h | 15–22 h | Profound hypotension (often requires vasopressors), immunosuppression, ileus, prolonged sedation; most potent seizure suppressor |
Risks of Anesthetic Infusions
- A Class III study found that continuous IV anesthetic infusions were associated with a 3-fold increased risk of death and 4-fold increased incidence of infection, even after correcting for age and SE severity
- Another Class III study reported a 7-fold relative increase in new disability, 9-fold increase in death, 4-fold increase in infection, and prolongation of hospital stays by one week
- A 2024 systematic review concluded that data are too heterogeneous to determine the optimal first anesthetic agent for refractory SE
- However, two retrospective studies reported that shorter duration, yet deeper, therapeutic coma was associated with fewer complications and better outcomes
- In a 2024 Swiss study, dose escalation of anesthetic infusions was needed in 57% of 111 adults with RSE; despite higher morbidity, survivors who required dose escalation had decreased odds of in-hospital death and similar functional outcomes
Practical Approach to Third-Line Therapy
- If seizures are subtle or intermittent and the patient is not in immediate danger: Consider a second non-sedating IV ASM (e.g., lacosamide 5–10 mg/kg IV, or whichever second-line agent was not used) before proceeding to anesthetic infusions
- If seizures are continuous, generalized tonic-clonic, and the patient is deteriorating: Intubation and anesthetic infusion (midazolam or propofol as first choice in most centers) with continuous EEG monitoring
- EEG target: Titrate to burst suppression (interburst intervals of 5–15 seconds) for 24–48 hours before attempting to wean
- Concurrent therapy: Load additional non-sedating ASMs (lacosamide, levetiracetam, valproate, phenobarbital) during anesthetic infusion to provide a therapeutic "safety net" for weaning
Systemic Complications
Convulsive SE produces a stereotyped cascade of systemic physiologic derangements that contribute independently to morbidity and mortality:
| System | Early Phase (0–30 min) | Late Phase (>30 min) |
|---|---|---|
| Cardiovascular | Hypertension, tachycardia (sympathetic surge) | Hypotension, arrhythmias (including cardiac arrest), heart failure |
| Respiratory | Tachypnea, apneic episodes during tonic phase | Hypoxemia, pulmonary edema (neurogenic), aspiration pneumonia, respiratory failure |
| Metabolic | Lactic acidosis, hyperglycemia (catecholamine-driven) | Hypoglycemia (glucose depletion), mixed metabolic and respiratory acidosis, hyperkalemia |
| Musculoskeletal | Intense tonic-clonic contractions | Rhabdomyolysis → myoglobinuria → acute kidney injury; vertebral compression fractures; posterior shoulder dislocations |
| Thermoregulatory | Core temperature rising | Hyperthermia (≥40°C) from sustained muscle contraction; worsens neuronal injury |
| Hematologic | Leukocytosis, catecholamine-driven | DIC (rare), thrombocytopenia |
| Neurologic | Excitotoxic injury begins | Cerebral edema, hippocampal sclerosis, cortical laminar necrosis, permanent epileptogenesis |
Outcome Prediction
Status Epilepticus Severity Score (STESS)
The STESS is the most widely validated pretreatment prognostic tool for predicting survival at hospital discharge. It uses four clinical variables assessed before treatment initiation:
| Predictor | Features | Score |
|---|---|---|
| Consciousness | Alert, somnolent, or confused | 0 |
| Stupor or coma | 1 | |
| Worst seizure type | Focal aware, focal impaired awareness, absence, or myoclonic | 0 |
| Tonic-clonic convulsive | 1 | |
| Nonconvulsive SE in coma | 2 | |
| Age | <65 years | 0 |
| ≥65 years | 2 | |
| Prior seizure history | Yes | 0 |
| No or unknown | 1 |
The total STESS ranges from 0 to 6. A score of 0–2 is favorable and associated with a high probability of survival to hospital discharge. A score ≥3 is associated with progressively worse outcomes. Additional predictors of poor outcome include longer SE duration, acute symptomatic etiology, need for anesthetic infusions, and the presence of peri-ictal MRI abnormalities.
Peri-ictal MRI Abnormalities
MRI serves as both a diagnostic and prognostic biomarker in SE. In a study of 307 adults, peri-ictal MRI abnormalities (DWI hyperintensities, FLAIR hyperintensities, ADC changes) were found in 26% of patients. Anatomic distribution included cerebral cortex (75%), thalamus (61%), and hippocampus/amygdala (43%). Patients with peri-ictal MRI abnormalities had significantly higher in-hospital mortality (27% vs. 11%), higher rates of refractory SE (71% vs. 33%), and more frequent delayed-onset epilepsy (40% vs. 21%). Hippocampal and pulvinar thalamic abnormalities were found to be highly specific for SE compared with controls.
Summary: Staged Treatment Protocol
| Phase | Time | Intervention | Key Points |
|---|---|---|---|
| Stabilization | 0–5 min | ABCs, O2, IV access, glucose check, labs, cardiac monitoring | Note seizure onset time; position safely; prepare medications |
| First-line | 5–20 min | IV lorazepam 4 mg (may repeat ×1) OR IM midazolam 10 mg OR IV diazepam 10 mg (may repeat ×1) | Use FULL doses; do not underdose; IM midazolam if no IV access (RAMPART trial) |
| Second-line | 20–40 min | IV fosphenytoin 20 mg PE/kg OR IV valproate 40 mg/kg OR IV levetiracetam 60 mg/kg | All equivalent per ESETT; choose based on patient factors; begin while seizures are ongoing, do not wait |
| Third-line | >40 min | Consider a second non-sedating ASM (lacosamide, brivaracetam) OR anesthetic infusion (midazolam, propofol, or pentobarbital) | Intubate if using anesthetics; continuous EEG required; titrate to burst suppression |
Quality Improvement
Quality improvement initiatives have been demonstrated to successfully reduce time to first benzodiazepine treatment and second-phase ASM administration. Standardized protocols, weight-based dosing tools, SE order sets in the electronic health record, and simulation-based team training are effective interventions. Despite these efforts, a 2025 study of National Association of Epilepsy Centers found that only 66% of SE protocols detailed treatment times, and doses below AES recommendations occurred in 4% of protocols for initial benzodiazepines and 14% for the first non-benzodiazepine ASM.
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