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Status Epilepticus Patient Treatment: FERNE Clinical Update

Clinical Question: How are seizure and status epilepticus patients optimally treated based on clinical guideline recommendations?

Seizure and SE Patient Treatment Key Concepts 

These key concepts are derived from the 2014 and 2024 ACEP Clinical Policies and the 2016 and 2020 AES Guidelines on convulsive status epilepticus (CSE) and refractory convulsive status epilepticus (RCSE).

20 Key Clinical Concepts

  1. Policy scope strictly limits application to generalized convulsive adult patients only. The ACEP guidelines intentionally exclude pediatric patients, pregnant patients, complex partial seizures, trauma patients, brain tumors, and out-of-hospital environments.
  2. Provoked seizures require underlying condition treatment, not automatic antiepileptic drug initiation. Precipitating acute medical conditions, like electrolyte abnormalities or toxins, must be identified and treated; prophylactic antiepileptic medication initiation is unnecessary in the ED.
  3. First unprovoked seizure without brain injury history requires no immediate treatment. If a patient has a first unprovoked seizure and lacks evidence of brain disease or injury, the initiation of antiepileptic medication can be appropriately deferred.
  4. Remote brain injury following unprovoked seizure may warrant antiepileptic therapy. Patients with a remote history of central nervous system disease or injury, such as stroke or trauma, may be candidates for antiepileptic medication initiation in the emergency department.
  5. Recovered first unprovoked seizure patients need not be routinely hospitalized for observation. Emergency physicians need not admit patients who have returned to their clinical baseline after a first unprovoked seizure to prevent immediate adverse events.
  6. Resuming chronic antiepileptic medication allows physician discretion in route of administration. There is no evidence supporting one route (IV or oral) over the other for preventing early recurrent seizures when resuming appropriate antiepileptic medications in the ED.
  7. SE treatment protocols use 5 minute duration to minimize adverse outcomes. Status epilepticus treatment should begin when a seizure lasts longer than 5 minutes to minimize the risk of prolonged seizures and associated morbidity and mortality.
  8. IV lorazepam, IM midazolam, IV diazepam are established first-line SE agents. These benzodiazepines are established as efficacious initial therapy for convulsive status epilepticus in both adults and children, demonstrating high efficacy, safety, and tolerability (Level A).
  9. IM midazolam is superior to IV lorazepam without existing intravenous access. In adult patients with CSE where IV access is not yet established, intramuscular (IM) midazolam demonstrates superior effectiveness compared to intravenous (IV) lorazepam (Level A).
  10. Refractory SE requires immediate second-line agent administration to reduce mortality. Emergency physicians should treat seizures refractory to optimal benzodiazepine dosing with an additional antiepileptic agent to achieve cessation and reduce patient morbidity (Level A).
  11. Fosphenytoin, levetiracetam, valproate are therapeutically interchangeable second-line SE options. Based on the ESETT trial, these three agents may be used with similar efficacy to terminate generalized convulsive status epilepticus in adult ED patients (Level A).
  12. Standardized second-line loading doses are LEV 60, FOS 20PE, VAL 40. For benzodiazepine-refractory SE, the recommended IV loading doses are levetiracetam 60 mg/kg, fosphenytoin 20 mgPE/kg, and valproate 40 mg/kg in order to achieve therapeutic concentrations.
  13. Second-line efficacy is similar across patient age groups and home medications. The ability of fosphenytoin, levetiracetam, and valproate to stop SE is not statistically influenced by whether the patient is young adult, older adult, or on a home anticonvulsant.
  14. Second-line SE therapy includes fosphenytoin, valproate, levetiracetam, no clear best. When initial benzodiazepine therapy fails (20–40 minutes), fosphenytoin (Level U), valproic acid (Level B), and levetiracetam (Level U) are all reasonable options, lacking established superiority.
  15. Valproic acid proved equally effective as phenytoin for established status epilepticus. VPA (60 mg/kg) is established as equally effective as fosphenytoin (20 mg PE/kg) for established SE in adults, offering comparable seizure control and fewer adverse effects.
  16. Refractory convulsive SE definition: failure of initial benzodiazepine plus second ASM. RCSE is a serious condition characterized by a high risk of morbidity and death when seizures persist despite two appropriately dosed antiseizure medications.
  17. Lacosamide and levetiracetam efficacy for true RCSE treatment is unproven. While these agents show comparable efficacy for established SE, insufficient evidence exists to support their use as third-line agents for true refractory convulsive status epilepticus (Level U).
  18. Pentobarbital and thiopental infusions are likely favored for refractory SE management. Evidence suggests that the efficacy of pentobarbitahiopental (PTB/THP) infusions is probably favored compared to midazolam (MDZ) and propofol (PRO) in treating children and adults with CRSE (Level C).
  19. Respiratory, cardiac symptoms are major adverse events of IV anticonvulsant therapy. The most frequent serious adverse events associated with IV anticonvulsant drug administration are cardiorespiratory symptoms, but respiratory problems are also a consequence of untreated SE itself.
  20. Anticonvulsant efficacy drops substantially after the first and second sequential therapies. In adults, the second drug administered is less effective than the first “standard” anticonvulsant, and the third is substantially less effective, showing sharply diminishing returns.

Seizures and SE Patient Treatment Protocol

Time Based Seizures and SE Treatment  

  • Status epilepticus (SE) protocols should be initiated when a convulsive seizure lasts for five minutes or longer.
  • Treatment follows a time-based algorithm.

Stabilize the Patient

0–5 Minutes: Stabilization Phase

  • Stabilize the patient by managing their airway, breathing, and circulation (ABCs).
  • Time the seizure from its onset, monitor vital signs, assess oxygenation and provide oxygen.
  • Check blood glucose and treat if low, establish IV access, and collect blood samples.

Provide a First Medication

5–20 Minutes: Initial Therapy Phase

  • Administer a first-line medication to stop the seizure.
  • A benzodiazepine is the initial therapy of choice.
  • First-line options include IM midazolam, IV lorazepam, or IV diazepam.

5–20 Minutes: Initial Therapy Phase Meds

  • A benzodiazepine is the initial therapy of choice for seizures lasting 5-20 minutes.
  • Equivalent first-line options include IM midazolam (10 mg >40kg or 5 mg for 13-40kg), IV lorazepam (0.1 mg/kg, max 4 mg), or IV diazepam (0.15-0.2 mg/kg, max 10 mg).
  • If the primary options are unavailable, alternatives include IV phenobarbital, rectal diazepam, or intranasal/buccal midazolam.

Provide a Second Medication

20–40 Minutes: Second Therapy Phase

  • If the seizure persists despite an optimal benzodiazepine dose, it’s considered refractory status epilepticus, and a second-line medication should be administered.
  • There is no evidence-based preferred second therapy, but options include IV fosphenytoin, IV valproic acid, or IV levetiracetam.
  • ACEP guidelines recommend administering an additional antiepileptic medication.

20–40 Minutes: Second Therapy Phase Meds

  • The Second Therapy Phase begins if seizures continue despite benzodiazepine treatment, typically 20-40 minutes after onset.
  • Fosphenytoin, levetiracetam, and valproate are likely equally effective second-line IV medications.
  • Doses include IV fosphenytoin (20 mg PE/kg, max 1500 mg PE), IV valproic acid (40 mg/kg, max 3000 mg), or IV levetiracetam (60 mg/kg, max 4500 mg).

Provide a Third Therapy

40–60 Minutes: Third Therapy Phase

  • If the seizure continues after a second-line agent, the third therapy phase begins.
  • There is no clear evidence to guide therapy in this phase.
  • Treatment options include repeating a dose of a second-line therapy or administering anesthetic doses of medications.

40–60 Minutes: Third Therapy Phase Meds

  • The Third Therapy Phase begins 40-60 minutes after seizure onset if seizures persist after first- and second-line therapies.
  • There is no clear evidence to guide therapy (Level U), and anticonvulsant effectiveness decreases with each failed therapy.
  • Options include repeating a second-line therapy or initiating anesthetic doses of medications requiring continuous EEG monitoring.

Overall Seizure and Status Epilepticus Patient Care

Overall Resuscitation Recommendations

  • Follow a Time-Based Treatment Protocol: The most effective management of status epilepticus follows a timed protocol with distinct phases: a stabilization phase (0–5 minutes), an initial therapy phase (5–20 minutes), a second therapy phase (20–40 minutes), and a third therapy phase (40-60 minutes). Using a protocol helps ensure rapid, appropriate care and improves patient outcomes. Institutions should consider developing their own protocols based on available resources.
  • Prioritize a Comprehensive Stabilization Phase: In the first five minutes, before administering anticonvulsants, the focus should be on stabilizing the patient and addressing immediate life threats. Beyond airway and blood pressure management, this includes:
    • Timing the seizure from its onset and continuously monitoring vital signs.
    • Assessing oxygenation, providing oxygen, and initiating electrocardiogram (ECG) monitoring.
    • Establishing intravenous (IV) access to facilitate medication administration and blood draws.
  • Immediately Check and Treat Hypoglycemia: A finger stick blood glucose test should be performed during the initial stabilization phase. If the glucose level is low (e.g., < 60 mg/dL), it must be treated immediately with intravenous dextrose.
  • Identify and Treat the Underlying Cause: A critical part of management is to search for and treat the specific condition provoking the seizures. This includes investigating causes such as:
    • Hypoglycemia, hyponatremia, and hypoxia.
    • Drug toxicity or withdrawal syndromes.
    • Systemic or central nervous system (CNS) infections.
    • Ischemic stroke or intracerebral hemorrhage.
  • Administer Adequate Anticonvulsant Doses for Seizure Termination: Therapy should be aimed at the complete termination of seizures, not just a reduction in seizure activity. Initial therapies, such as benzodiazepines, should be administered as a single adequate full dose rather than being broken into multiple smaller doses. It’s important to recognize that anticonvulsant efficacy decreases substantially with each failed medication, making effective first- and second-line treatment critical.
  • Utilize Continuous EEG Monitoring for Anesthetic Infusions: While you mentioned EEG for diagnosing subtle status epilepticus, it is also a required component of care when using anesthetic infusions. If seizures persist into the third therapy phase (after 40 minutes) and require anesthetic doses of medications like propofol, midazolam, or barbiturates, continuous EEG monitoring is mandatory to guide treatment.

Carefully Resuscitate the Seizure/SE Patient

  • CT Brain Imaging is Recommended Urgently: Perform a CT scan promptly to identify structural abnormalities, hemorrhage, or other intracranial pathology that could influence management.
  • EEG Diagnosis is Critical for Subtle SE: Obtain continuous EEG monitoring when clinical signs are inconclusive, to detect non-convulsive or subtle status epilepticus.
  • Airway Management is Essential for Respiratory Support: Ensure airway patency, provide oxygen, and consider intubation if respiratory compromise or hypoventilation occurs.
  • Blood Pressure Must Be Monitored and Managed Carefully: Maintain adequate perfusion; avoid hypotension with cautious fluid resuscitation and vasopressors if needed.
  • Supplementation with Thiamine is Important: Administer thiamine before dextrose in malnourished or alcohol-dependent patients to prevent Wernicke encephalopathy.

Journal Club Articles Summaries

2014 ACEP Clinical Policy: Critical Issues in the Evaluation and Management of Adult Patients Presenting to the Emergency Department with Seizures

This ACEP clinical policy (a 2014 revision) addresses critical issues in the ED evaluation and management of adult patients with generalized convulsive seizures, necessitated by complex diagnostics and evolving terminology.

Four critical questions guide the policy’s recommendations:

  1. Antiepileptic therapy initiation for a first seizure: For a first generalized convulsive seizure (patient at baseline), physicians need not initiate antiepileptic medication for provoked seizures (treat underlying cause) or unprovoked seizures without brain injury evidence. Treatment may be initiated or deferred only if the unprovoked seizure follows a remote history of brain disease/injury.
  2. Disposition for a first unprovoked seizure: Patients at baseline after a first unprovoked seizure need not be admitted to the hospital to prevent adverse events.
  3. Route of administration for known seizure disorder: When resuming antiepileptic medication for a known seizure disorder, the emergency physician may administer IV or oral medication at their discretion, as efficacy evidence is lacking to favor one route for preventing early recurrence.
  4. Second-line agents for status epilepticus (SE): For refractory generalized convulsive SE (failed benzodiazepines), physicians should administer an additional antiepileptic medication (Level A). Level B options include IV phenytoin, fosphenytoin, or valproate; Level C options are IV levetiracetam, propofol, or barbiturates. Valproate is comparable to phenytoin/fosphenytoin, offering faster administration and potentially fewer adverse effects.
  5. The key clinical concept is that emergency seizure management uses evidence-based stratification to determine disposition and treatment initiation (etiology), allowing flexible administration routes for chronic disorders, and employing stepped, multi-agent therapy for refractory status epilepticus.

Journal Club: 10 Key Clinical Concepts, ACEP 2014 Clinical Policy

  1. Policy scope limited strictly to adult generalized convulsive seizures, excluding pediatric patients. This guideline is specifically intended for adult patients aged 18 years and older presenting with generalized convulsive seizures, while intentionally excluding those with acute head trauma, brain tumors, or complex partial seizures.
  2. Provoked seizures require identifying and treating underlying acute medical condition etiologies immediately. Emergency physicians need not initiate long-term antiepileptic medication for patients experiencing a first provoked seizure; instead, the diagnosis and treatment of the precipitating medical condition is the primary clinical goal.
  3. First unprovoked seizure patients without existing brain injury need not start treatment. Emergency physicians need not initiate antiepileptic medication in the ED for a first unprovoked seizure if there is no evidence of underlying brain disease; deferring treatment until a second event is deemed appropriate.
  4. Remote brain injury history suggests potential antiepileptic medication initiation or deferred coordination. For patients experiencing a first unprovoked seizure who have a remote history of brain injury or disease, the physician may initiate antiepileptic medication or coordinate the decision with other providers.
  5. Discharge admission recommendation: recovered first unprovoked seizure patients may be sent home safely. Patients who have had a first unprovoked seizure and have returned to their clinical baseline need not be admitted to the hospital solely to prevent immediate adverse events.
  6. Administering chronic antiepileptic drugs: oral or IV routes are acceptable per discretion. When resuming antiepileptic medication for a known seizure disorder, the emergency physician may administer IV or oral medication because there is currently a lack of evidence supporting one route over the other regarding seizure recurrence.
  7. Status epilepticus failing benzodiazepines requires immediate mandatory administration of additional medication. For ED patients with refractory status epilepticus who have failed optimal benzodiazepine dosing, emergency physicians should administer an additional antiepileptic medication to rapidly achieve seizure control (Level A recommendation).
  8. Phenytoin, fosphenytoin, valproate are Level B options after initial benzodiazepine therapy failure. Emergency physicians may administer intravenous phenytoin, fosphenytoin, or valproate in ED patients with refractory status epilepticus who failed initial benzodiazepine treatment (Level B recommendations).
  9. Valproate compares favorably against phenytoin, potentially faster delivery with fewer adverse effects. Evidence suggests that IV valproate is at least as effective as phenytoin for status epilepticus and offers the advantage of being given more quickly, often with a lower incidence of severe adverse effects.
  10. Levetiracetam, propofol, barbiturates are alternative Level C agents for refractory status epilepticus. Intravenous levetiracetam, propofol, or barbiturates may be administered in ED patients with refractory status epilepticus, though definitive proof of efficacy for these agents awaits future prospective studies.
ACEP 2014 Clinical Policy: Summary of Importance

This clinical policy is essential for emergency physicians because it provides clear, evidence-based management strategies (Levels A, B, and C) for both first-time and refractory seizures, directly addressing critical disposition and treatment decisions. It defines a structured, multi-step approach for managing life-threatening generalized convulsive status epilepticus and clarifies when long-term antiepileptic medication initiation is necessary following a first seizure.

Learn More

2016 AES Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society 

This 2016 publication presents the American Epilepsy Society’s (AES) Evidence-Based Guideline for the treatment of convulsive status epilepticus (CSE) in children and adults, which is critical because rapid pharmacologic intervention is essential to terminate seizures and reduce substantial associated morbidity and mortality (estimated up to 30% in adults).

The guideline, which synthesizes evidence from 38 randomized controlled trials, proposes a treatment algorithm structured in phases. For Initial Therapy (0–20 min), a benzodiazepine (IM midazolam, IV lorazepam, or IV diazepam) is the established treatment of choice (Level A). In adults lacking IV access, IM midazolam is established as superior to IV lorazepam (Level A). IV lorazepam and IV diazepam can be repeated once at full doses (Level A). Alternatives like rectal diazepam, IM midazolam, intranasal midazolam, or buccal midazolam are probably effective in children (Level B). Respiratory and cardiac symptoms are the most common treatment-emergent adverse events associated with IV anticonvulsants (Level A). For Second Therapy (20–40 min) after benzodiazepine failure, reasonable options include fosphenytoin (Level U), valproic acid (Level B), or levetiracetam (Level U), with no established superiority among them. Fosphenytoin is preferred over phenytoin due to better tolerability (Level B). In children, IV valproic acid has similar efficacy but better tolerability than IV phenobarbital as a second therapy (Level B). Importantly, the second agent administered is less effective, and the third is substantially less effective, compared to the first “standard” anticonvulsant (Level A in adults).

The key clinical concept summarized in this guideline is the necessity of a rapid, phased treatment algorithm for CSE across all ages, mandating immediate first-line use of efficacious benzodiazepines and recognizing that pharmacologic efficacy decreases substantially after the initial therapy fails.

Journal Club: 10 Key Clinical Concepts from 2016 AES Guideline

  1. IV lorazepam diazepam phenobarbital midazolam established efficacious initial adult SE therapy. In adults, intravenous lorazepam, intravenous diazepam (with or without phenytoin), intramuscular midazolam, and intravenous phenobarbital are all established as effective first-line agents for stopping seizures lasting at least five minutes (Level A).
  2. IM midazolam superior to IV lorazepam when intravenous access is unavailable in adults. For adults with convulsive status epilepticus lacking established intravenous access (IV), intramuscular (IM) midazolam is established as having superior effectiveness compared to intravenous lorazepam (Level A).
  3. No significant difference found between intravenous lorazepam and intravenous diazepam effectiveness. Studies comparing IV lorazepam and IV diazepam demonstrated no significant difference in overall effectiveness for controlling status epilepticus in both adult and pediatric populations (Level A).
  4. Rectal, buccal, intranasal midazolam diazepam probably effective first-line therapy children. In pediatric patients, non-intravenous routes, including rectal diazepam, IM midazolam, intranasal midazolam, and buccal midazolam, are probably effective alternatives for initial seizure control (Level B).
  5. Second-line therapy options fosphenytoin valproic acid levetiracetam lack established superiority currently. When initial benzodiazepine therapy fails (20–40 minutes), reasonable second-line agents include fosphenytoin (Level U), valproic acid (Level B), or levetiracetam (Level U), but there is no clear evidence favoring one.
  6. Fosphenytoin preferred over phenytoin based on tolerability, but efficacy data are insufficient. Fosphenytoin is better tolerated compared with phenytoin (Level B), making it the preferred choice when available, although data remain insufficient to establish a difference in comparative efficacy (Level U).
  7. Anticonvulsant efficacy diminishes significantly with each sequential drug administered after initial therapy. In adults, the second anticonvulsant administered is less effective than the first “standard” anticonvulsant, and the third is substantially less effective than the first (Level A).
  8. Cardio respiratory symptoms are most common treatment adverse events with IV anticonvulsants. Respiratory and cardiac symptoms, such as hypoventilation, hypotension, and cardiac rhythm disturbance, are the most commonly encountered treatment-emergent adverse events associated with IV anticonvulsant drug administration in adults (Level A).
  9. Respiratory depression is also important consequence of prolonged untreated convulsive status epilepticus itself. The guideline noted that the rate of respiratory depression in patients treated with benzodiazepines is lower than in those receiving placebo, indicating that respiratory problems are an important consequence of the untreated convulsive status epilepticus (Level A).
  10. Evidence is inadequate or insufficient to guide treatment decisions for third therapy phase. The third therapy phase, which begins when the seizure duration reaches 40 minutes, currently has inadequate or insufficient data (Level U) to guide specific pharmacologic treatment choices.

AES 2016 Guideline: Summary of Importance

This guideline is vital for clinical practice because it represents an essential, evidence-based algorithm derived from 38 randomized controlled trials, unifying the treatment approach for convulsive status epilepticus across all age groups beyond neonates. It provides crucial Level A and Level B recommendations detailing preferred initial benzodiazepines (especially IM midazolam when IV access is unavailable) and defining subsequent therapy options, thereby minimizing variations in care and reducing substantial morbidity and mortality associated with delayed treatment.

2020 AES Treatment of Refractory Convulsive Status Epilepticus: A Comprehensive Review by the American Epilepsy Society Treatments Committee 

This 2020 publication provides a comprehensive review of the treatment of Refractory Convulsive Status Epilepticus (RCSE), defined as convulsive SE that does not stop after an intravenous (IV) benzodiazepine and a second antiseizure medication (ASM). This is crucial because RCSE carries a high risk of morbidity and death.

The review examined the evidence strength for eight parenteral ASMs used as third-line agents, finding that evidence remains inconclusive or low-level for most third-line options. For established SE (a precursor to RCSE), IV valproic acid (VPA) is equally effective as fosphenytoin (Level B) and as lacosamide (LCM) and levetiracetam (LEV) (Level C) in adults. However, insufficient evidence supports the effectiveness of LCM and LEV in treating true CRSE. For continuous IV infusions used in CRSE, the efficacy of pentobarbital (PTB)/thiopental (THP) is probably favored compared to midazolam (MDZ) and propofol (PRO) (Level C). Newer agents like brivaracetam (BRV) and ketamine (KET), and specialized immune therapies (ACTH, corticosteroids, IVIg), currently have insufficient evidence (Level U) to guide their use in RCSE.

The key clinical concept is that while certain ASMs are comparable for established SE, the pharmacologic treatment of true RCSE lacks high-level comparative evidence for determining superiority among continuous IV infusions or newer agents.

Journal Club: 10 Key Clinical Concepts from AES 2020 Guideline

This comprehensive response draws on the American Epilepsy Society (AES) review, “Treatment of Refractory Convulsive Status Epilepticus: A Comprehensive Review”.

10 Key Clinical Concepts

  1. Refractory convulsive status epilepticus persists after first benzodiazepine and second antiseizure medication. RCSE is defined as established SE that does not stop when patients are treated with an intravenous (IV) benzodiazepine bolus followed by a loading dose of a second antiseizure medication (ASM).
  2. RCSE carries substantial morbidity and mortality risk, especially with delayed treatment. Patients diagnosed with convulsive refractory status epilepticus (CRSE) have a high risk of morbidity and death, reflecting the severity of this condition which causes prolonged hospitalization.
  3. Third-line treatment efficacy for refractory status epilepticus remains inconclusive, based on low evidence. Conclusions regarding the effectiveness of most second or third antiseizure medications (ASMs) in CRSE are inconclusive or based heavily on low-level, non-randomized evidence.
  4. Valproic acid and fosphenytoin are equally effective for established status epilepticus treatment. For adults with established SE, IV valproic acid (60 mg/kg) and fosphenytoin (20 mg PE/kg) are established as equally effective at achieving seizure cessation (Level B, based on one Class I study).
  5. Lacosamide and levetiracetam lack sufficient evidence to support use in CRSE. While these agents show effectiveness equal to others for established SE (Level C), insufficient evidence exists to support the effectiveness of LCM and LEV for refractory status epilepticus (Level U).
  6. Pentobarbital and thiopental infusions are likely favored over propofol and midazolam. Evidence suggests the efficacy of pentobarbital (PTB)/thiopental (THP) continuous infusions is probably favored compared to midazolam (MDZ) and propofol (PRO) in treating children and adults with CRSE (Level C).
  7. Midazolam and propofol continuous infusions lack evidence proving equal efficacy. There is currently insufficient evidence (Level U) to support that MDZ infusion and PRO infusion are equally effective for adults with CRSE, or that low-dose versus high-dose MDZ are equivalent.
  8. Brivaracetam and ketamine effectiveness in RCSE cannot currently be determined. Newer antiseizure medications like brivaracetam (BRV) and ketamine (KET) currently have insufficient evidence (Level U) to establish their effectiveness in refractory convulsive status epilepticus across different populations.
  9. Immune therapies like ACTH, corticosteroids, IVIg lack efficacy studies for RCSE. No studies exist on the efficacy of adrenocorticotropic hormone (ACTH), corticosteroids, or IVIg for treating CRSE, even in cases suspected of having an underlying immune etiology.
  10. Specific loading doses defined for levetiracetam and fosphenytoin established seizures. The guideline reports that if initial benzodiazepines fail in children and adults with established SE, appropriate loading doses are LEV 60 mg/kg and fosphenytoin 20 mg PE/kg (Level B).

2020 AES Guideline Summary of Importance

This review is essential as it transparently summarizes the extremely limited high-level evidence supporting third-line pharmacologic agents used for refractory convulsive status epilepticus (RCSE), a condition associated with high morbidity and mortality. It guides practitioners by identifying where some agents show comparable efficacy for established SE while emphasizing that most continuous IV infusion choices still rely heavily on lower-level evidence or consensus rather than robust comparative data.

2024 ACEP Clinical Policy: Critical Issues in the Management of Adult Patients Presenting to the Emergency Department with Seizures

The 2024 American College of Emergency Physicians (ACEP) Clinical Policy addresses second-line agents for adult ED patients with generalized convulsive status epilepticus (SE), which is vital because early seizure cessation is associated with a reduction in morbidity and mortality.

Based primarily on the Established Status Epilepticus Treatment Trial (ESETT), the policy issues a Level A recommendation that emergency physicians should treat benzodiazepine-refractory seizures with a second-line agent. The policy states that fosphenytoin (20 mgPE/kg), levetiracetam (60 mg/kg), or valproate (40 mg/kg) may be used with similar efficacy. These three agents achieved seizure cessation in approximately 45% to 47% of patients. Efficacy was similar regardless of patient age (>18 years) or whether the agent matched the patient’s home anticonvulsant medication. Safety outcomes, including continued convulsions and respiratory distress, were not significantly different among the three medications. Other critical questions were considered adequately addressed by the 2014 policy. Future research is necessary for agents like lacosamide or ketamine and seizures due to toxins or alcohol withdrawal.

The key clinical concept is the Level A recommendation supporting therapeutic interchangeability among fosphenytoin, levetiracetam, and valproate as equally effective second-line agents for generalized convulsive status epilepticus refractory to benzodiazepines.

10 Key Clinical Concepts from 2024 ACEP Clinical Policy

  1. Policy targets adult patients only, specifically generalized convulsive seizures exclusively. This guideline is intentionally limited to patients aged 18 years and older who present to the ED with generalized convulsive seizures, while specifically excluding pediatric patients and those with acute trauma.
  2. Primary policy question focuses only on second-line treatment for refractory status epilepticus. The current ACEP update readdressed the critical question of which agent should be administered next when seizures persist despite receiving optimal benzodiazepine dosing in the emergency department.
  3. Refractory seizures must be treated immediately using a second-line agent decisively. Emergency physicians should treat seizures refractory to appropriately dosed benzodiazepines with a second-line agent, as failure to treat promptly is associated with increased morbidity and mortality (Level A).
  4. Fosphenytoin, levetiracetam, valproate demonstrated similar efficacy terminating benzodiazepine resistant status epilepticus. The ESETT trial (Class I) found no statistical difference in the primary outcome of seizure cessation and improved consciousness at 60 minutes among these three second-line agents (Level A).
  5. These three second-line agents stop seizures in approximately half of patients. Studies included in the review found that the use of levetiracetam, fosphenytoin, or valproate resulted in the cessation of status epilepticus in roughly 44% to 47% of all patients assessed.
  6. Recommended loading doses are standardized: LEV 60, FOS 20PE, VAL 40. The policy outlines specific loading doses for status epilepticus treatment: levetiracetam (60 mg/kg), fosphenytoin (20 mgPE/kg), and valproate (40 mg/kg) in order to achieve therapeutic concentrations.
  7. Medication efficacy for status epilepticus termination is not influenced by patient age category. Subgroup analyses confirmed that the cessation rate achieved by the second-line agents was similar across children, adults (18–65 years), and older adults (>65 years), despite some numerical differences.
  8. Receiving home medication as second-line therapy did not improve cessation probability. A tertiary analysis (Class III study) concluded that using a patient’s home anticonvulsant as the second-line agent did not affect the probability of stopping status epilepticus compared to using a non-home agent.
  9. Continued convulsions, altered consciousness, and respiratory distress are frequent serious adverse events. Continued convulsions, altered level of consciousness, and respiratory distress were the most frequent serious adverse events, occurring in 42% of the trial subjects, though safety outcomes were not statistically different between agents.
  10. Future research should focus on other agents and specific seizure etiologies. Additional prospective studies are warranted for second-line agents like lacosamide, ketamine, propofol, and barbiturates, as well as seizures specifically resulting from toxins or alcohol withdrawal.

2024 ACEP Guideline: Summary of Importance

This clinical policy is critical for emergency physicians because it provides clear, Level A, evidence-based guidance directly comparing the three most common second-line agents for benzodiazepine-refractory generalized convulsive status epilepticus. By standardizing the approach and confirming that all three agents (levetiracetam, fosphenytoin, and valproate) have similar efficacy regardless of patient age or home medication status, the policy supports rapid, effective decision-making crucial for reducing associated morbidity and mortality.

Methodology

Four clinical policy and guideline references chosen based on their focus on the management of patients with seizures and status epilepticus. PubMed search for similar articles was also utilized, without additional sources identified.  Notebook LM used to summarize the information from these three references.

Please verify the correctness of these recommendations based on review of these sources and comparison with up to date best clinical practices.

References

  1. Huff JS, Melnick ER, Tomaszewski CA, Thiessen MEW, Jagoda AS, Fesmire FM. Clinical Policy: Critical Issues in the Evaluation and Management of Adult Patients Presenting to the Emergency Department With Seizures. Ann Emerg Med. 2014;63(4):437-447. doi:10.1016/j.annemergmed.2014.01.018.
  2. Glauser T, Shinnar S, Gloss D, et al. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr. 2016;16(1):48-61.
  3. Vossler DG, Bainbridge JL, Boggs JG, et al. Treatment of Refractory Convulsive Status Epilepticus: A Comprehensive Review by the American Epilepsy Society Treatments Committee. Epilepsy Curr. 2020;20(5):245-264. doi:10.1177/1535759720928269.
  4. Smith MD, Sampson CS, Wall SP, et al. Clinical Policy: Critical Issues in the Management of Adult Patients Presenting to the Emergency Department With Seizures. Ann Emerg Med. 2024;84:1-6. doi:10.1016/j.annemergmed.2024.02.018.

Background SE Patient Information

Five Most Common Causes of Prolonged Seizures and SE

  • Sudden Withdrawal or Non-compliance with Antiepileptic Drugs: Discontinuation or missed doses of antiepileptic medications can precipitate prolonged seizures in epileptic patients.
  • Acute Structural Brain Lesions or Injury: Trauma, stroke, intracranial hemorrhage, or tumors can disrupt normal brain activity, leading to status epilepticus.
  • Infections such as Meningitis or Encephalitis: Central nervous system infections can cause inflammation and neuronal excitability, triggering prolonged seizures.
  • Metabolic Disturbances (e.g., Hypoglycemia, Hyponatremia): Electrolyte imbalances and metabolic derangements alter neuronal function, increasing seizure risk and persistence.
  • Substance Abuse or Toxicity: Intoxication with alcohol, drugs, or exposure to neurotoxins can provoke seizures and hinder seizure control.

Morbidity Due to Prolonged Seizures and SE

Observed Morbidities

  • Permanent neuronal injury: Status epilepticus lasting longer than 30 minutes may lead to permanent neuronal injury by itself.
  • Neurological disability: Patients with refractory convulsive status epilepticus (prolonged seizures that do not respond to initial treatment) have a high risk of morbidity and death. This can result in a worsened neurological status that necessitates longer hospital stays and an increased need for rehabilitation. One study found that using anesthetic infusions for refractory SE was associated with a seven-fold increased risk of new disability.
  • Respiratory complications: Respiratory issues are a significant consequence of both untreated status epilepticus and its treatment. These complications include:
    • Hypoventilation
    • Respiratory depression
    • Aspiration pneumonia
    • Need for assisted ventilation
  • Cardiovascular complications: Cardiac symptoms are common adverse events associated with anticonvulsant administration for status epilepticus. These include:
    • Hypotension
    • Cardiac rhythm disturbance or dysrhythmia
  • Increased infection risk and hospitalization: Convulsive status epilepticus can lead to longer hospital stays. In cases of refractory SE, studies have found a two-fold increased risk of infection and hospital stays that are one week longer.

Mortality Rate Associated with Prolonged Seizures and SE

SE Patient Mortality Rate

  • The mortality rate for status epilepticus is estimated to be up to 30% in adults, while it is less than 3% in children. Another source states that convulsive status epilepticus leads to death in 17% to 39% of adults, with a lower rate in children.
  • The prognosis, including mortality risk, is strongly related to the underlying cause of the seizure, the duration of the status epilepticus, and the patient’s age.
  • Appropriate and timely medical therapy is crucial, as it reduces the associated mortality and morbidity.
  • In cases of refractory status epilepticus, the use of anesthetic infusions has been associated with a three-fold to nine-fold increased risk of death.

References Used to Generate Morbidity and Mortality Information

  1. Alldredge BK, Gelb AM, Isaacs SM, et al. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N Engl J Med. 2001;345:631-637.
  2. DeLorenzo RJ, Hauser WA, Towne AR, et al. A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia. Neurology. 1996;46:1029-1035.
  3. DeLorenzo RJ, Towne AR, Pellock JM, Ko D. Status epilepticus in children, adults, and the elderly. Epilepsia. 1992;33(suppl 4):S15-S25.
  4. Glauser T, Shinnar S, Gloss D, et al. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr. 2016;16(1):48-61.
  5. Jagoda A, Riggio S. Refractory status epilepticus in adults. Ann Emerg Med. 1993;22:1337-1348.
  6. Leppik IE, Derivan AT, Homan RW, et al. Double-blind study of lorazepam and diazepam in status epilepticus. JAMA. 1983;249:1452-1454.
  7. Logroscino G, Hesdorffer DC, Cascino GD, et al. Long-term mortality after a first episode of status epilepticus. Neurology. 2002;58:537-541.
  8. Maytal J, Shinnar S, Moshe SL, Alvarez LA. Low morbidity and mortality of status epilepticus in children. Pediatrics. 1989;83:323-331.
  9. Mundlamuri RC, Sinha S, Subbakrishna DK, et al. Management of generalised convulsive status epilepticus (SE): a prospective randomised controlled study of combined treatment with lorazepam and low-dose valproate versus lorazepam and phenytoin in status epilepticus. J Neurol Neurosurg Psychiatry. 2005;76(12):1700-1704.
  10. Neligan A, Shorvon SD. Prognostic factors, morbidity and mortality in tonic-clonic status epilepticus: A review. Epilepsy Res. 2011;93:1-10.
  11. Silbergleit R, Durkalski V, Lowenstein D, et al; NETT Investigators. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med. 2012;366:591-600.
  12. Sutter R, Marsch S, Fuhr P, Kaplan PW, Ruegg S. Anesthetic drugs in status epilepticus: risk or rescue? A 6-year cohort study. Neurology. 2013;81(4):356-364.
  13. Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med. 1998;339:792-798.
  14. Treatment of convulsive status epilepticus. Recommendations of the Epilepsy Foundation of America’s Working Group on Status Epilepticus. JAMA. 1993;270:854-859.
  15. Vossler DG, Bainbridge JL, Boggs JG, et al. Treatment of Refractory Convulsive Status Epilepticus: A Comprehensive Review by the American Epilepsy Society Treatments Committee. Epilepsy Curr. 2020;20(5):245-264.
  16. Wu YW, Shek DW, Garcia PA, et al. Incidence and mortality of generalized convulsive status epilepticus in California. Neurology. 2002;58:1070-1076.

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Edward Sloan, MD, MPH, FACEP                                                             FERNE

FERNE 2025 Clinical Update Optimal Seizure and SE Patient Treatment Oct 30, 2025

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