Status Epilepticus

Recognition, Definition, and Management

Maksim Parfyonov, MD FRCPC
parfyom@ccf.org

Cleveland Clinic Epilepsy Center

August 4, 2026

Case Scenario

A 6-year-old girl (20 kg) with PCDH19-related epilepsy presents to the ED with witnessed generalized tonic-clonic seizure activity ongoing for 8 minutes. EMS administered midazolam 1 mg IM en route. She is still seizing on arrival.

Discussion questions:

  1. Was the prehospital BZD dose adequate?
  2. What is your next step?
  3. When do you escalate to third-line therapy?

Learning Objectives

After this presentation, learners will be able to:

  1. Define status epilepticus using the current ILAE framework
  2. Recognize convulsive and non-convulsive status epilepticus
  3. Identify common etiologies and risk factors
  4. Apply a stepwise, time-based treatment algorithm
  5. Describe the pathophysiology underlying pharmacoresistance

Why Does This Matter?

Adults

  • 50,000–60,000 new cases annually (US)
  • Incidence 10–41 per 100,000
  • Mortality ~20%, unchanged over 3 decades
  • 54% occur without a prior epilepsy diagnosis
  • Direct inpatient costs >$4 billion per year

Children

  • Incidence 17–23 per 100,000 per year
  • Highest in infants under 1 year
  • Case fatality ~2–11%; 30-day mortality as low as 1.8% in a nationwide cohort
  • Prolonged febrile seizure is the largest single category under 5 years
  • About half have no prior epilepsy diagnosis

(Betjemann & Lowenstein, 2015; Chin et al., 2006; Gettings et al., 2025; Neligan et al., 2019)

Recognition & Definitions

Definition: The ILAE Framework (2015)

Status epilepticus is a condition resulting from the failure of mechanisms responsible for seizure termination or from the initiation of mechanisms leading to abnormally prolonged seizures.

(Trinka et al., 2015)

Two critical time points

  • t₁ = mechanisms of seizure termination failed, once this time has been reached seizure will not stop without treatment
  • t₂ = long-term consequences of prolonged seizure

(Gettings et al., 2025; Trinka et al., 2015)

T₁ and T₂ Definitions

(Gettings et al., 2025)

Stages of Status Epilepticus

(Trinka & Leitinger, 2022)

Classification: Motor vs. Non-Motor

With Prominent Motor Symptoms

  • Tonic-clonic (generalized)
  • Tonic
  • Clonic
  • Myoclonic
  • Focal motor
  • Hyperkinetic

Without Prominent Motor Symptoms (NCSE)

  • Absence SE
  • Focal SE with impaired awareness
  • Subtle SE (comatose patients)

Requires EEG for diagnosis

(Betjemann & Lowenstein, 2015; Trinka et al., 2015)

Recognizing Convulsive SE

Typically obvious at onset:

  • Unresponsiveness + tonic, clonic, or tonic-clonic movements
  • May be generalized or focal with secondary generalization

Key pitfall — evolution over time:

  • Overt convulsions → subtle twitching of extremities/face → saccadic eye movements only
  • After treatment for GCSE, 48% continued to have electrographic seizures and 14% were in NCSE
  • Always maintain a high index of suspicion for ongoing seizures in patients with persistent encephalopathy

(Betjemann & Lowenstein, 2015; DeLorenzo et al., 1998)

Non-Convulsive SE (NCSE)

(Britton et al., 2016)

Recognizing Non-Convulsive SE (NCSE)

Clinical clues:

  • Unexplained altered mental status or encephalopathy
  • Behavioral changes, confusion, aphasia
  • Subtle motor signs: eye deviation, nystagmus, facial twitching
  • Fluctuating level of consciousness
  • Failure to “wake up” after a treated convulsive seizure

Bottom line: Low threshold for continuous EEG (cEEG) monitoring when:

  • Persistent encephalopathy after treated GCSE
  • Unexplained altered consciousness in ICU patients
  • Comatose patients (especially post-cardiac arrest, CNS infection, stroke)

(Betjemann & Lowenstein, 2015; Rossetti et al., 2024)

Common Etiologies in Children

Acute Symptomatic

  • Prolonged febrile seizure (largest single category under 5 years)
  • CNS infection: meningitis, encephalitis
  • Acute metabolic: hyponatremia, hypoglycemia, hypocalcemia
  • Traumatic brain injury, including non-accidental
  • Hypoxic-ischemic injury
  • Toxic ingestion

Established Epilepsy / Remote

  • Subtherapeutic ASM levels or nonadherence
  • Genetic epilepsies with an SE phenotype: Dravet, PCDH19, ring 20
  • Remote structural: prior stroke, TBI, malformations of cortical development
  • Autoimmune encephalitis
  • FIRES after a febrile illness in a previously well child

(Betjemann & Lowenstein, 2015; Chin et al., 2006; Gettings et al., 2025)

Pathophysiology

GABA Receptors

(Burman et al., 2022)

SE causes disruptions to GABA receptor function and composition

(Burman et al., 2022)

GABA Receptor Trafficking: The Key Mechanism

  • During prolonged seizures, GABA-A receptors are internalized from the synaptic surface
  • Simultaneously, NMDA (excitatory) receptors increase on the cell surface
  • Intracellular chloride accumulates → GABAergic signaling shifts from inhibitory to excitatory
  • This explains why benzodiazepines lose efficacy with prolonged SE
  • Rationale for early, aggressive treatment and polytherapy targeting multiple mechanisms

Net effect over time:

Early SE Late SE
GABA-A (inhibitory) Normal ↓↓↓
NMDA (excitatory) Normal ↑↑↑
Benzodiazepine efficacy High Low

(Aroniadou-Anderjaska et al., 2024; Gettings et al., 2025; Walker, 2018)

Systemic Consequences: What Else Is Happening

Cardiovascular and respiratory

  • Catecholamine surge: tachycardia, hypertension, arrhythmia
  • Hypoxia, aspiration, neurogenic pulmonary edema

Metabolic

  • Lactic acidosis, often profound early
  • Hyperglycemia then hypoglycemia
  • Hyperkalemia, hyponatremia

Muscular and renal

  • Rhabdomyolysis → myoglobinuria → acute tubular necrosis
  • Follow CK, renal function, urine output

Thermal

  • Hyperthermia from motor activity alone, independent of infection
  • Temperatures above 40°C recorded in prolonged SE

(Betjemann & Lowenstein, 2015; Gettings et al., 2025)

Pathophysiology: Why Time Matters

(Sarria-Estrada & Toledo, 2019)

The longer SE persists, the harder it is to treat. Every minute counts.

Treatment

Treatment Overview: The Stepwise Approach

(Trinka & Leitinger, 2022)

Don’t Forget: Stabilization & Workup

Concurrent with pharmacotherapy

Stabilization

  • ABCs — airway, breathing, circulation
  • Supplemental O₂; low threshold for intubation
  • IV access (×2 if possible); consider IO early in a seizing child
  • Fingerstick glucose → treat hypoglycemia
  • Cardiac monitoring
  • Temperature management
  • Consider pyridoxine in infants with refractory SE of unknown cause

Diagnostic Workup

  • Labs: BMP, CBC, LFTs, lactate, ammonia, CK, ASM levels, toxicology screen, VBG
  • Neuroimaging: CT head if trauma or focal deficit; MRI when stable
  • LP: if infection or autoimmune etiology suspected
  • EEG: continuous monitoring for refractory SE, NCSE, or persistent encephalopathy
  • Genetic and metabolic workup if unexplained SE in a young child

(Betjemann & Lowenstein, 2015; Rossetti et al., 2024)

First-Line: Benzodiazepines

Drug Route Pediatric dose Adult dose
Midazolam IM Fixed dose: 5 mg (13–40 kg); 10 mg (>40 kg). No established recommendation <13 kg 10 mg
Midazolam IN / buccal 0.2 mg/kg IN; 0.5 mg/kg buccal (max 10 mg) 10 mg
Lorazepam IV 0.1 mg/kg (max 4 mg/dose) 0.1 mg/kg (max 4 mg/dose)
Diazepam IV 0.15 mg/kg (max 10 mg); FDA label states 0.2 mg/kg (max 8 mg), ages 3 mo–17 y 0.15 mg/kg (max 10 mg)
Diazepam PR 0.5 mg/kg (2–5 y), 0.3 mg/kg (6–11 y), 0.2 mg/kg (≥12 y); max 20 mg —
  • Administer within 5–10 min of seizure onset
  • Repeat dosing: AES says give a single full dose, and repeat only IV lorazepam or IV diazepam, once. Broader reviews advise a second dose of any benzodiazepine if seizing persists at 5–10 min. Know which your protocol follows.
  • Account for any pre-hospital doses already given
  • BZDs terminate SE in ~70% of cases

IM midazolam is a fixed dose, not weight-based. A 20 kg child gets 5 mg IM. Underdosing is the most common error: after 1 mg of prehospital midazolam, 32.3% needed rescue therapy, versus 4.5% after 10 mg.

(Gettings et al., 2025; Guterman et al., 2020; Silbergleit et al., 2012)

Back to the Case: Question 1

6-year-old, 20 kg, given midazolam 1 mg IM prehospital, still seizing at 8 minutes.

The correct dose was 5 mg IM. She received one-fifth of it.

  • This is not a refractory patient yet, this is an underdosed patient
  • Next step is a full-dose benzodiazepine, not escalation to second-line
  • Every additional milligram of prehospital midazolam lowered the odds of needing rescue therapy (OR 0.8, 95% CI 0.7–0.9)
  • Escalating past an inadequate first-line dose is the most common protocol deviation

(Gettings et al., 2025; Guterman et al., 2020; Silbergleit et al., 2012)

The RAMPART Trial: IM Midazolam Works

Silbergleit et al. — 893 patients, prehospital SE

Outcome IM Midazolam IV Lorazepam
Seizure cessation at ED arrival 73.4% 63.4%
Time to drug administration 1.2 min 4.8 min
Time from drug to seizure cessation 3.3 min 1.6 min
Endotracheal intubation 14.1% 14.4%
Recurrent seizures 11.4% 10.6%
Admitted to hospital 57.6% 65.6% (P=0.01)
  • Enrolled patients 13 kg and above, so this includes school-age children
  • Dosing was 5 mg IM for 13–40 kg, 10 mg above 40 kg

Take-home: IM midazolam was non-inferior and statistically superior to IV lorazepam — largely because it was given faster.

(Silbergleit et al., 2012; Silbergleit et al., 2013)

Second-Line: The ESETT Trial

Kapur et al. — 384 patients with BZD-refractory SE

Drug Dose Success at 60 min
Levetiracetam 60 mg/kg (max 4500 mg) 47%
Fosphenytoin 20 mg PE/kg 45%
Valproate 40 mg/kg (max 3000 mg) 46%
  • Trial stopped for futility — no drug was superior
  • In the 225 children analyzed by age group: LEV 52%, fosphenytoin 49%, valproate 52%. Same conclusion
  • Any of the three is a reasonable first-choice second-line agent
  • Overall: numerically more hypotension and intubation with fosphenytoin, more deaths with levetiracetam, none significant
  • In children specifically, intubation was significantly higher with fosphenytoin. Isolated finding, not seen in EcLiPSE or ConSEPT
  • 10% of enrolled patients were later adjudicated as psychogenic seizures

(Chamberlain et al., 2020; Kapur et al., 2019)

Second-Line Agents: Practical Considerations

Drug Dose Infusion Rate Watch For
Fosphenytoin 20 mg PE/kg (max 1500 mg PE) 150 mg PE/min Hypotension, arrhythmia, purple glove syndrome (less with fos-)
Levetiracetam 60 mg/kg (max 4500 mg) Over 10 min in ESETT Somnolence, agitation; fewest drug interactions
Valproate 40 mg/kg (max 3000 mg) 3 mg/kg/min, or full dose over 10 min Hepatotoxicity, pancreatitis, thrombocytopenia; avoid under 2 years, in suspected mitochondrial disease, and in pregnancy
Lacosamide 200–400 mg (adult); pediatric dosing extrapolated Over 15 min PR prolongation; small underpowered trial vs fosphenytoin (TRENdS), used as an alternative
Phenobarbital 20 mg/kg (AES lists 15 mg/kg as initial therapy) 50–75 mg/min Respiratory depression, hypotension, sedation

Important

All second-line dosing is weight-based, unlike IM midazolam. Check the maximum, but start from the kilogram.

(Betjemann & Lowenstein, 2015; Gettings et al., 2025; Husain et al., 2018; Vossler et al., 2020)

Third-Line: Refractory SE

Definition: SE persisting despite a benzodiazepine plus a second appropriately selected and adequately dosed ASM. Develops in roughly 23–43% of SE patients.

  • Continuous IV anesthetic infusion — requires intubation + ICU + cEEG
  • Options:
Agent Advantages Disadvantages
Midazolam gtt Fewer hemodynamic effects Tachyphylaxis
Propofol gtt Rapid onset/offset Propofol infusion syndrome; avoid prolonged use in children
Pentobarbital gtt Greatest seizure suppression Significant hypotension, immunosuppression, ileus
  • Titrate to electrographic seizure cessation; burst suppression is a common target but is a convention, not a proven endpoint
  • Case series have not shown that depth of suppression or choice of agent predicts outcome
  • Mortality rises stepwise from responsive to refractory to super-refractory SE, but published series vary widely (adult refractory SE: 17–39%) and etiology dominates

(Gettings et al., 2025; Rossetti et al., 2024)

Anesthetic Infusions: Monitoring and Weaning

Propofol infusion syndrome

  • Risk rises with >5 mg/kg/h beyond 24–48 h
  • Children are at higher risk than adults
  • Monitor CK, lactate, ABG, triglycerides, amylase/lipase, renal function
  • Higher acidosis risk with carbonic anhydrase inhibitors (topiramate, zonisamide)

Coming off the drip

  • Relapse during weaning is common, roughly half in published series
  • Load a maintenance ASM before weaning, not during
  • Adding phenobarbital before weaning pentobarbital reduces relapse
  • Wean slowly with cEEG running; relapse after withdrawal predicts worse outcome

(Gettings et al., 2025; Rossetti et al., 2024)

Super-Refractory SE

Definition: SE that continues or recurs ≥24 hours after onset of anesthetic therapy, or on reduction/withdrawal of anesthesia.

Additional options to consider:

  • Ketamine — NMDA antagonist; mechanistically rational given NMDA receptor upregulation, and relatively favorable hemodynamically. No proven outcome benefit: an individual-patient meta-analysis found no difference in disability at discharge, as with phenobarbital and the ketogenic diet
  • Additional non-sedating ASMs — topiramate, perampanel, zonisamide, phenobarbital
  • Immunotherapy — if autoimmune etiology suspected (IVIG, steroids, plasma exchange)
  • Ketogenic diet — more experience in children than adults, particularly in FIRES
  • Hypothermia has not been shown to confer benefit

(Cornwall et al., 2023; Gettings et al., 2025)

CCF Pocket Card

CCF Pocket Card

Outcomes

Poll: Which patient with non-convulsive SE is at highest risk of a poor outcome?

  1. Awake, focal NCSE, recognized within an hour
  2. Awake, focal NCSE, recognized on day 2
  3. Comatose, NCSE, recognized within an hour
  4. Duration doesn’t matter once NCSE is established

How Long Is Too Long?

There is no clean threshold. What the data support:

  • Duration is one of the few prognostic variables we influence. In focal NCSE without impaired consciousness, duration beyond 100 hours independently predicted poor outcome at discharge, 1 year, and 4 years
  • NCSE in coma is independently associated with higher in-hospital and 30-day mortality across all etiology groups
  • Duration, age, and NCSE in coma together predict new neurologic deficits, which in turn predict 2-year mortality (OR 5.1, 95% CI 2.2–11.8)
  • Older ICU series suggested inflection points around 10 and 20 hours; treat these as historical, not as a safe window

The practical message is not “you have ten hours.” It is that unrecognized NCSE accumulates injury and that recognition depends on someone ordering the EEG.

(Gettings et al., 2025; Young et al., 1996)

Prognosis

Stage Mortality (children) Mortality (adults)
Responsive to BZDs ~2% ~10%
Refractory SE Lower than adults 17–39% across series
Super-refractory SE Higher, etiology-driven ~4× the risk of uncomplicated SE

Series vary widely and cohorts are not comparable. Etiology dominates every one of these numbers.

  • Etiology is the most important prognostic factor at every stage
  • BZD treatment terminates SE in ~70% of cases; second-line agents work in ~50% of the remainder
  • In children, neurologic morbidity in survivors matters more than mortality
  • Recovery in early stages is excellent — most children have no long-term sequelae
  • 5-year seizure recurrence: 9% to 66%

(Chin et al., 2006; Choi et al., 2022; Cornwall et al., 2023; Gettings et al., 2025)

Key Takeaways

Five Things to Remember

  1. Time is brain — treat at 5 minutes, don’t wait for the “old” 30-minute definition
  2. Give the full first dose — underdosing is the most common error. IM midazolam is fixed (5 mg / 10 mg); everything else is weight-based
  3. All three second-line agents are equivalent (ESETT) — pick based on patient factors
  4. Think about NCSE — get EEG if the patient doesn’t wake up
  5. Protocols save lives — know your institution’s SE algorithm

Back to our case

A 6-year-old girl (20 kg) with PCDH19-related epilepsy, seizing for 8 minutes, given midazolam 1 mg IM prehospital.

  1. Was the dose adequate? No. IM midazolam is fixed dosing: 5 mg for 13–40 kg. She got 1 mg.
  2. Next step? Full-dose benzodiazepine now, then second-line therapy in the 20–40 minute window per the AES algorithm. Many institutional protocols move faster than that.
  3. When to escalate? Third therapy from 40 minutes, after adequate first- and second-line agents have failed. Get cEEG running before assuming the drip worked.

References

Aroniadou-Anderjaska, V., Figueiredo, T. H., De Araujo Furtado, M., Pidoplichko, V. I., Lumley, L. A., & Braga, M. F. M. (2024). Alterations in GABA-A receptor-mediated inhibition triggered by status epilepticus and their role in epileptogenesis and increased anxiety. Neurobiology of Disease, 200, 106633.
Betjemann, J. P., & Lowenstein, D. H. (2015). Status epilepticus in adults. The Lancet Neurology, 14(6), 615–624.
Britton, J. W., Frey, L. C., Hopp, J. L., Korb, P., Koubeissi, M. Z., Lievens, W. E., Pestana-Knight, E. M., & St. Louis, E. K. (2016). Electroencephalography (EEG): An introductory text and atlas of normal and abnormal findings in adults, children, and infants (E. K. St. Louis & L. C. Frey, Eds.). American Epilepsy Society. https://www.ncbi.nlm.nih.gov/books/NBK390349/figure/f79/
Burman, R. J., Rosch, R. E., Wilmshurst, J. M., Sen, A., Ramantani, G., Akerman, C. J., & Raimondo, J. V. (2022). Why won’t it stop? The dynamics of benzodiazepine resistance in status epilepticus. Nature Reviews Neurology, 18(7), 428–441. https://doi.org/10.1038/s41582-022-00664-3
Chamberlain, J. M., Kapur, J., Shinnar, S., Elm, J., Holsti, M., Babcock, L., Rogers, A., Barsan, W., Cloyd, J., Lowenstein, D., Bleck, T. P., Conwit, R., Meinzer, C., Cock, H., Fountain, N., Underwood, E., Connor, J. T., & Silbergleit, R. (2020). Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): A double-blind, responsive-adaptive, randomised controlled trial. The Lancet, 395(10231), 1217–1224.
Chin, R. F. M., Neville, B. G. R., Peckham, C., Bedford, H., Wade, A., & Scott, R. C. (2006). Incidence, cause, and short-term outcome of convulsive status epilepticus in childhood: Prospective population-based study. The Lancet, 368(9531), 222–229. https://doi.org/10.1016/S0140-6736(06)69043-0
Choi, S.-A., Lee, H., Kim, K., et al. (2022). Mortality, disability, and prognostic factors of status epilepticus: A nationwide population-based retrospective cohort study. Neurology, 99, e1393–e1401.
Cornwall, C. D., Krøigård, T., Kristensen, J. S. S., Callesen, H. E., & Beier, C. P. (2023). Outcomes and treatment approaches for super-refractory status epilepticus: A systematic review and meta-analysis. JAMA Neurology, 80(9), 959–968.
DeLorenzo, R. J., Waterhouse, E. J., Towne, A. R., Boggs, J. G., Ko, D., DeLorenzo, G. A., Brown, A., & Garnett, L. (1998). Persistent nonconvulsive status epilepticus after the control of convulsive status epilepticus. Epilepsia, 39(8), 833–840. https://doi.org/10.1111/j.1528-1157.1998.tb01177.x
Gettings, J. V., Mohammad Alizadeh Chafjiri, F., Patel, A. A., Shorvon, S., Goodkin, H. P., & Loddenkemper, T. (2025). Diagnosis and management of status epilepticus: Improving the status quo. The Lancet Neurology, 24(1), 65–76. https://doi.org/10.1016/S1474-4422(24)00430-7
Guterman, E. L., Sanford, J. K., Betjemann, J. P., Merck, L. H., Groff, J. M., Dixon, A., Fahrenbruch, C., Neumar, R. W., Sporer, K. A., & Josephson, S. A. (2020). Prehospital midazolam use and outcomes among patients with out-of-hospital status epilepticus. Neurology, 95(23), e3203–e3212.
Husain, A. M., Lee, J. W., Kolls, B. J., et al. (2018). Randomized trial of lacosamide versus fosphenytoin for nonconvulsive seizures. Annals of Neurology, 83(6), 1174–1185.
Kapur, J., Elm, J., Chamberlain, J. M., Barsan, W., Cloyd, J., Lowenstein, D., Shinnar, S., Conwit, R., Meinzer, C., Cock, H., Fountain, N., Connor, J. T., & Silbergleit, R. (2019). Randomized trial of three anticonvulsant medications for status epilepticus. New England Journal of Medicine, 381(22), 2103–2113.
Neligan, A., Noyce, A. J., Gosavi, T. D., Shorvon, S. D., Köhler, S., & Walker, M. C. (2019). Change in mortality of generalized convulsive status epilepticus in high-income countries over time: A systematic review and meta-analysis. JAMA Neurology, 76(8), 897–905.
Rossetti, A. O., Claassen, J., & Gaspard, N. (2024). Status epilepticus in the ICU. Intensive Care Medicine, 50(1), 1–16.
Sarria-Estrada, S., & Toledo, M. (2019). Status epilepticus. In F. Barkhof, H. R. Jäger, M. M. Thurnher, & À. Rovira (Eds.), Clinical neuroradiology: The ESNR textbook (pp. 965–989). Springer International Publishing. https://doi.org/10.1007/978-3-319-68536-6_54
Silbergleit, R., Durkalski, V., Lowenstein, D., Conwit, R., Pancioli, A., Palesch, Y., & Barsan, W. (2012). Intramuscular versus intravenous therapy for prehospital status epilepticus. New England Journal of Medicine, 366(7), 591–600.
Silbergleit, R., Lowenstein, D., Durkalski, V., & Conwit, R. (2013). Lessons from the RAMPART study – and which is the best route of administration of benzodiazepines in status epilepticus. Epilepsia, 54, 74–77.
Trinka, E., Cock, H., Hesdorffer, D., Rossetti, A. O., Scheffer, I. E., Shinnar, S., Shorvon, S., & Lowenstein, D. H. (2015). A definition and classification of status epilepticus – report of the ILAE Task Force on classification of status epilepticus. Epilepsia, 56(10), 1515–1523.
Trinka, E., & Leitinger, M. (2022). Management of status epilepticus, refractory status epilepticus, and super-refractory status epilepticus. Continuum, 28(2), 559–602. https://doi.org/10.1212/CON.0000000000001103
Vossler, D. G., Bainbridge, J. L., Boggs, J. G., Novotny, E. J., Loddenkemper, T., Faught, E., Amengual-Gual, M., Fischer, S. N., Gloss, D. S., Olson, D. M., Towne, A. R., Naritoku, D., & Welty, T. E. (2020). Treatment of refractory convulsive status epilepticus: A comprehensive review by the American Epilepsy Society Treatments Committee. Epilepsy Currents, 20(5), 245–264.
Walker, M. C. (2018). Pathophysiology of status epilepticus. Neuroscience Letters, 667, 84–91.
Young, G. B., Jordan, K. G., & Doig, G. S. (1996). An assessment of nonconvulsive seizures in the intensive care unit using continuous EEG monitoring: An investigation of variables associated with mortality. Neurology, 47(1), 83–89. https://doi.org/10.1212/WNL.47.1.83

Questions?

Thank you!