The Uncontrolled Seizure: Navigating Status Epilepticus and its Mimics

A Comprehensive Review for the Critical Care Postgraduate

Dr Neeraj Manikath , claude.ai

Abstract

Status epilepticus (SE) represents one of the most challenging neurological emergencies encountered in intensive care units, with mortality rates ranging from 10-40% depending on etiology and treatment response. This review provides an evidence-based approach to the diagnosis and management of SE beyond first-line benzodiazepine therapy, explores the complexities of refractory and super-refractory SE, addresses the often-missed diagnosis of non-convulsive SE, and highlights important mimics including psychogenic non-epileptic seizures and post-anoxic myoclonus. Special attention is given to autoimmune encephalitis as an increasingly recognized cause of new-onset refractory status epilepticus (NORSE). Clinical pearls, diagnostic pitfalls, and practical ICU management strategies are woven throughout to enhance bedside decision-making.

Keywords: Status epilepticus, refractory seizures, non-convulsive status epilepticus, continuous EEG monitoring, autoimmune encephalitis, psychogenic non-epileptic seizures

Introduction

Status epilepticus is classically defined as continuous seizure activity lasting more than 5 minutes or recurrent seizures without return to baseline consciousness. This operational definition, updated by the International League Against Epilepsy (ILAE) in 2015, recognizes two critical time points: t₁ (5 minutes for convulsive SE, 10 minutes for focal SE with impaired consciousness), when treatment should be initiated, and t₂ (30 minutes for convulsive SE), beyond which long-term consequences including neuronal death become likely.[1,2]

The incidence of SE ranges from 10-40 per 100,000 population annually, with a bimodal distribution affecting children and the elderly disproportionately.[3] Despite advances in antiseizure medications (ASMs), approximately 30-40% of cases progress to refractory SE (RSE), defined as seizures continuing despite adequate doses of a benzodiazepine and at least one appropriate second-line ASM.[4] The management of SE has evolved significantly, yet controversies persist regarding optimal second-line agents, anesthetic protocols, and the recognition of non-convulsive presentations.

This review adopts a practical, evidence-based approach tailored to the critical care physician managing these complex cases in real-time.

Beyond Benzodiazepines: The Evidence for Fosphenytoin, Valproate, and Lacosamide

The Second-Line Dilemma

Once benzodiazepine therapy (lorazepam 0.1 mg/kg IV or diazepam 0.15-0.2 mg/kg IV) fails to terminate seizures, clinicians face a critical decision point. For decades, phenytoin or its water-soluble prodrug fosphenytoin dominated as the default second-line agent. However, landmark trials have challenged this paradigm and expanded our armamentarium.

The ESETT Trial: Equipoise Established

The Established Status Epilepticus Treatment Trial (ESETT), published in 2019, randomized 462 patients with benzodiazepine-refractory SE to receive fosphenytoin (20 PE/kg), valproate (40 mg/kg), or levetiracetam (60 mg/kg).[5] The primary outcome—seizure cessation by the end of infusion with improved responsiveness at 60 minutes—occurred in 45-47% of patients across all three groups, with no statistically significant differences. Crucially, safety profiles were comparable, refuting earlier concerns about valproate-induced hepatotoxicity or thrombocytopenia in acute settings.

Pearl: ESETT definitively established that no single second-line agent is superior for benzodiazepine-refractory SE. Choose based on patient-specific factors rather than dogma.

Fosphenytoin: The Traditional Workhorse

Fosphenytoin (15-20 PE/kg IV at 100-150 PE/min) offers the advantage of decades of clinical experience and potent sodium channel blockade.[6] Its pharmacokinetics are predictable, and it achieves therapeutic levels rapidly.

Oyster: Beware hypotension and cardiac arrhythmias, particularly in elderly patients or those with pre-existing cardiac disease. Fosphenytoin causes cardiovascular adverse effects in up to 10% of patients, necessitating cardiac monitoring during infusion.[7] The "purple glove syndrome" associated with phenytoin is avoided, but extravasation of fosphenytoin can still cause tissue injury.

Hack: If fosphenytoin is unavailable or contraindicated (heart block, bradycardia), proceed directly to valproate or levetiracetam rather than delaying therapy. Time is brain in SE.

Valproate: Broad-Spectrum Efficacy

Valproate (40 mg/kg IV at 6-10 mg/kg/min, maximum 3000 mg) possesses multiple mechanisms of action: enhancing GABAergic neurotransmission, blocking voltage-gated sodium channels, and modulating T-type calcium channels.[8] This broad-spectrum activity theoretically makes it attractive for SE of unknown etiology.

Pearl: Valproate is particularly useful in patients with generalized epilepsies, those with contraindications to phenytoin (cardiac disease, history of Stevens-Johnson syndrome), or when hepatic enzyme induction is undesirable (e.g., patients on oral contraceptives, warfarin, or chemotherapy).

Oyster: Absolute contraindications include known mitochondrial disorders (e.g., POLG mutations), urea cycle disorders, and hepatic failure. Relative contraindications include pregnancy (teratogenicity risk), thrombocytopenia, and pancreatitis history. The ESETT trial found valproate safe in acute use, but avoid in patients with pre-existing hepatic dysfunction or coagulopathy.[5]

Hack: Valproate loading causes less hemodynamic instability than fosphenytoin and can be given faster, making it advantageous in hemodynamically unstable patients requiring rapid seizure control.

Levetiracetam: The New Favorite

Levetiracetam (60 mg/kg IV over 10-15 minutes, maximum 4500 mg) has emerged as many intensivists' preferred second-line agent due to its exceptional safety profile, lack of drug interactions, and absence of cardiac or hepatic toxicity.[9] Its mechanism involves binding to synaptic vesicle protein 2A (SV2A), modulating neurotransmitter release.

Pearl: Levetiracetam is the safest second-line option for elderly patients, those with multiple comorbidities, or when the diagnosis is uncertain (e.g., concern for psychogenic seizures). It can be administered rapidly without cardiac monitoring in most cases.

Oyster: Emerging data suggest levetiracetam may be less effective than traditional agents in specific populations. A post-hoc analysis of ESETT showed lower seizure cessation rates with levetiracetam in children and in patients with prior benzodiazepine administration outside the hospital.[10] Additionally, some retrospective studies suggest lower efficacy in established SE compared to fosphenytoin or valproate, though prospective validation is lacking.

Hack: If levetiracetam fails as second-line therapy, adding a second agent with a different mechanism (fosphenytoin or valproate) is reasonable before escalating to anesthetic agents. This "dual second-line" approach lacks high-quality evidence but represents common practice.

Lacosamide: The Emerging Alternative

Lacosamide, while not included in ESETT, has gained traction as a second- or third-line agent for SE. It enhances slow inactivation of voltage-gated sodium channels, a mechanism distinct from phenytoin's fast inactivation.[11]

Evidence Base: A systematic review of 11 studies (n=524 patients) found lacosamide terminated SE in approximately 60% of cases when used as second-line or adjunctive therapy, with a favorable safety profile.[12] The recommended loading dose is 200-400 mg IV over 15 minutes, followed by maintenance dosing of 200-400 mg/day divided twice daily.

Pearl: Lacosamide is particularly useful when fosphenytoin has failed or is contraindicated, as its distinct mechanism may provide additive benefit. It's also advantageous in patients already taking phenytoin chronically (avoid loading a patient already at therapeutic levels).

Oyster: Cardiac conduction abnormalities (PR prolongation, AV block) occur in approximately 1-5% of patients. Obtain a baseline ECG and avoid in patients with second- or third-degree heart block unless a pacemaker is present.[13]

Hack: In elderly patients or those with cardiac history, infuse lacosamide over 30-60 minutes rather than 15 minutes to minimize cardiac risk while still achieving therapeutic levels faster than oral administration.

Practical Algorithm for Second-Line Therapy

Clinical Scenario-Based Selection:

Young, healthy patient with unknown SE etiology: Levetiracetam (safest, broad-spectrum)
Known generalized epilepsy or myoclonic features: Valproate (broad-spectrum activity)
Cardiac disease or hemodynamic instability: Levetiracetam or valproate (avoid fosphenytoin)
Hepatic disease or coagulopathy: Levetiracetam or fosphenytoin (avoid valproate)
Heart block or significant bradycardia: Valproate or levetiracetam (avoid fosphenytoin and lacosamide)
Pregnancy: Levetiracetam or fosphenytoin (avoid valproate)
Suspected mitochondrial disease: Fosphenytoin or levetiracetam (avoid valproate)

Pearl: Don't delay second-line therapy while deliberating. Any appropriate agent given promptly is superior to the "perfect" agent given late. If seizures persist beyond 5 minutes of second-line agent completion, move immediately to third-line or anesthetic therapy.

Refractory & Super-Refractory Status Epilepticus: Anesthetic Doses and the ICU Pipeline

Defining the Beast

Refractory Status Epilepticus (RSE) is defined as seizures continuing despite adequate doses of a benzodiazepine and one appropriate second-line ASM (typically for more than 30-60 minutes of treatment).[14] Approximately 30-40% of SE cases become refractory.

Super-Refractory Status Epilepticus (SRSE) represents the most challenging scenario: SE continuing or recurring 24 hours or more after initiation of anesthetic therapy, including cases that recur upon anesthetic weaning.[15] SRSE occurs in 10-20% of RSE cases and carries mortality rates of 30-50%.

Anesthetic Agents: The ICU Armamentarium

Once SE is deemed refractory, continuous IV anesthetic agents with continuous EEG monitoring become necessary. The primary goals are seizure suppression and preventing secondary brain injury while identifying and treating the underlying cause.

Midazolam: First Among Equals?

The RAMPART trial established midazolam as effective for prehospital SE,[16] and its use has expanded to RSE management. Loading doses range from 0.2 mg/kg (up to 20 mg) followed by continuous infusion starting at 0.1-0.2 mg/kg/hr, titrated to effect.

The ESETT Anesthetic Trial: Though not yet published as a full trial, retrospective data suggest midazolam achieves seizure control in 60-80% of RSE cases, with faster time to seizure control compared to propofol or pentobarbital due to its ease of rapid titration.[17]

Pearl: Midazolam is the most practical first-line anesthetic for RSE in most ICUs due to its rapid onset, titrability, and familiarity. It doesn't require specialized lipid formulations or cardiac monitoring equipment beyond standard ICU care.

Oyster: Tachyphylaxis develops rapidly (within 24-48 hours), often requiring escalating doses. Metabolic acidosis may occur with high-dose midazolam infusions (>1 mg/kg/hr) due to propylene glycol in the formulation. Monitor anion gap and lactate. Respiratory depression is universal—patients require mechanical ventilation.

Hack: When midazolam doses exceed 0.5-0.6 mg/kg/hr, consider transitioning to propofol or pentobarbital rather than continuing to escalate. Benzodiazepine tolerance limits midazolam's usefulness in SRSE.

Propofol: The Neurocritical Care Standard

Propofol (1-2 mg/kg loading dose, then 30-200 mcg/kg/min continuous infusion) offers multiple advantages: rapid onset and offset, additional neuroprotective effects (cerebral metabolic suppression), and concurrent provision of sedation for mechanical ventilation.[18]

Pearl: Propofol's short half-life allows for rapid neurological assessments when paused, making it ideal for patients in whom frequent neurological exams are needed or when the diagnosis is uncertain.

Oyster: Propofol infusion syndrome (PRIS) is a rare but potentially fatal complication characterized by metabolic acidosis, rhabdomyolysis, cardiac failure, and renal failure. Risk factors include infusion rates >80 mcg/kg/min for >48 hours, young age, critical illness, catecholamine administration, and carbohydrate deficiency.[19] Monitor creatine kinase, triglycerides, and lactate. Mortality from PRIS approaches 30-60%.

Hack: Maintain propofol infusions at <80 mcg/kg/min when possible. If higher doses are required to control seizures, strongly consider transitioning to pentobarbital. Use adjunctive ASMs aggressively to facilitate lower propofol dosing.

Pentobarbital: The Heavy Artillery

Pentobarbital (5-15 mg/kg loading dose at ≤50 mg/min, then 0.5-5 mg/kg/hr) is a barbiturate with potent anticonvulsant effects via GABA-A receptor enhancement and voltage-gated sodium channel blockade.[20] It induces burst-suppression or even electrocerebral silence.

Pearl: Pentobarbital is the most reliable agent for achieving complete seizure control and burst-suppression in SRSE. Consider it when midazolam and propofol have failed, or when patients require deep anesthetic coma for other reasons (e.g., refractory intracranial hypertension).

Oyster: Pentobarbital causes profound hemodynamic instability (hypotension in >50% of patients), often requiring vasopressor support. Its long half-life (15-50 hours) makes neurological assessments difficult and prolongs ICU/ventilator time. Immunosuppression increases nosocomial infection risk. Ileus is common.[21]

Hack: Optimize hemodynamics proactively before loading pentobarbital. Ensure adequate volume resuscitation and have vasopressors ready. Consider pulmonary artery catheter or advanced hemodynamic monitoring in tenuous patients. Accept that neurological exams will be unreliable for days after discontinuation.

Ketamine: The Mechanistically Distinct Option

Ketamine (0.5-3 mg/kg loading dose, then 0.6-10 mg/kg/hr infusion) acts via NMDA receptor antagonism, offering a mechanistically distinct approach when GABAergic agents fail.[22]

Evidence Base: Case series and small studies suggest ketamine terminates SRSE in 50-60% of cases when used as adjunctive or salvage therapy.[23] It may be particularly useful in autoimmune encephalitis and febrile infection-related epilepsy syndrome (FIRES), where glutamatergic mechanisms predominate.

Pearl: Ketamine doesn't cause respiratory depression, making it attractive for patients on minimal respiratory support or when weaning mechanical ventilation is a priority. It preserves hemodynamics better than other anesthetics and may provide neuroprotection via anti-inflammatory effects.

Oyster: Concerns about ketamine exacerbating intracranial hypertension have been largely refuted in modern critical care literature, but avoid in patients with uncontrolled intracranial hypertension until ICP monitoring is in place.[24] Hypersalivation and emergence reactions can occur. High doses may impair EEG interpretation due to rhythmic theta/delta activity.

Hack: Use ketamine as an adjunct to GABAergic anesthetics (e.g., midazolam + ketamine) rather than monotherapy. The combination often allows dose reduction of both agents and may exploit synergistic mechanisms.

Volatile Anesthetics: The Unconventional Rescue

Isoflurane and desflurane have been used as last-resort therapies in SRSE refractory to all IV anesthetics.[25] They require specialized anesthesia equipment (vaporizers) and scavenging systems in the ICU environment.

Evidence: Case reports and small series suggest volatile anesthetics may terminate SRSE in 40-70% of otherwise refractory cases.[26] They offer the advantage of rapid titratability and EEG monitoring capability.

Practical Limitations: Most ICUs lack infrastructure for volatile anesthetics. Environmental contamination, staff exposure concerns, and the need for specialized equipment limit applicability. Reserve for tertiary centers with SRSE expertise and infrastructure.

EEG Targets: How Deep is Deep Enough?

Continuous EEG (cEEG) monitoring is mandatory for RSE/SRSE management, yet optimal EEG targets remain debated.[27]

The Spectrum of Suppression:

Seizure freedom: Abolition of ictal patterns without burst-suppression
Burst-suppression: Alternating periods of EEG activity and suppression, quantified by suppression ratio
Electrocerebral silence: Complete suppression of EEG activity

Current Evidence: The 2012 Neurocritical Care Society guidelines suggested targeting burst-suppression with inter-burst intervals of ≥1 second or electrocerebral silence for 24-48 hours.[28] However, more recent data challenge the necessity of deep suppression.

The STESS Trial Post-Hoc Analysis: Aggressive EEG targets (burst-suppression) were not associated with improved outcomes compared to seizure suppression alone, and deeper suppression correlated with increased complications including hypotension and infections.[29]

Pearl: Current practice is evolving toward less aggressive EEG targets. Aim for seizure freedom without necessarily pursuing burst-suppression unless seizures recur at lighter anesthetic levels. This "minimal effective depth" approach may reduce complications while maintaining seizure control.

Oyster: Don't mistake periodic discharges (GPDs, LPDs) for seizures when titrating anesthetics. While controversial, most experts do not aggressively treat periodic patterns unless they're clearly ictal (e.g., "ictal-interictal continuum" patterns with clear clinical or EEG evolution). Over-treatment of non-ictal patterns leads to unnecessarily deep sedation and complications.

Hack: Use quantitative EEG (qEEG) trends (suppression ratio, asymmetry index, spectral array) to guide anesthetic titration at the bedside. These allow rapid adjustments without waiting for real-time EEG interpretation. Target suppression ratio of 50-80% if pursuing burst-suppression.

The Weaning Protocol: Avoiding Yo-Yo Status

Premature or overly aggressive weaning precipitates seizure recurrence in 30-50% of cases.[30] A structured approach is essential.

Standard Weaning Protocol:

Timing: Maintain anesthetic at therapeutic levels for 24-48 hours after last electrographic seizure
Rate: Reduce dose by 10-20% every 3-6 hours while monitoring cEEG continuously
Optimization: Ensure at least 2-3 non-anesthetic ASMs are at therapeutic levels before weaning
Re-escalation: If seizures recur, return to previous effective dose, add additional ASM, and attempt weaning again after 24-48 hours

Pearl: Load additional long-acting ASMs (e.g., lacosamide, phenobarbital, topiramate) before weaning anesthetics. This "chemical carpet" approach maximizes the chance of successful liberation from anesthetics.

Hack: Consider a "trial of awakening" before full weaning. Briefly pause the anesthetic while maintaining cEEG to assess for seizure recurrence. If seizures emerge immediately, you've identified the need for additional ASM optimization. If not, proceed with gradual weaning. This strategy can save days of ICU time by avoiding doomed wean attempts.

Adjunctive and Rescue Therapies for SRSE

When standard anesthetics fail or cannot be safely continued, multiple adjunctive therapies exist, though evidence is limited to case series and retrospective studies.

Magnesium Sulfate

High-dose magnesium (loading dose 4-6 g IV over 20 minutes, then 2-6 g/hr infusion targeting serum levels of 3.5-5.0 mmol/L) may provide adjunctive benefit via NMDA receptor antagonism.[31] It's particularly considered in eclampsia-related SE and as an adjunct to ketamine.

Hack: Magnesium is essentially free, widely available, and low-risk. When SRSE is not responding, empiric addition of high-dose magnesium is reasonable while awaiting advanced therapies.

Hypothermia

Therapeutic hypothermia (32-34°C) may reduce cerebral metabolic demand and seizure activity.[32] Small case series report seizure termination in 60-70% of hypothermia-treated SRSE patients, though causality is uncertain given concurrent immunotherapy in many cases.

Oyster: Hypothermia causes coagulopathy, cardiac arrhythmias, immunosuppression, and hemodynamic instability. It should be considered only in highly refractory cases at specialized centers.

Immunotherapy

Increasingly recognized as critical for SRSE, particularly in cryptogenic cases. See the section on autoimmune encephalitis below.

Electroconvulsive Therapy (ECT)

Case reports describe successful termination of SRSE with ECT when all other therapies failed.[33] Mechanism may involve GABAergic enhancement or anti-inflammatory effects. Requires anesthesia infrastructure and is typically a last-resort therapy.

Ketogenic Diet

The ketogenic diet induces ketosis (β-hydroxybutyrate 3-6 mmol/L), which may exert anticonvulsant effects via multiple mechanisms including enhanced GABA synthesis and adenosine modulation.[34] Retrospective studies in SRSE report seizure termination in 50-70% of pediatric cases and 30-50% of adult cases.

Practical Implementation: Enteral formulations (ketogenic formula feeds) or parenteral formulations can achieve ketosis within 2-3 days. Target a 4:1 ratio of fats to carbohydrates plus protein.

Hack: The ketogenic diet is most practical in SRSE cases expected to require prolonged ICU management. Start early (within the first week) if initial therapies fail rather than waiting until all else has been exhausted.

Cannabidiol (CBD)

Pharmaceutical-grade CBD (Epidiolex) at doses of 10-20 mg/kg/day has shown promise in treatment-resistant epilepsy.[35] Its role in acute SRSE is undefined, but case reports describe use in desperate situations.

The SRSE Pipeline: When Do We Stop?

SRSE management forces uncomfortable questions about futility. No validated prognostic tools exist, but several factors inform decision-making:

Poor Prognostic Indicators:

Duration >30 days
Age >65 years
Anoxic or infectious etiology
Requirement for three or more anesthetic agents
Malignancy-related SE
Highly malignant EEG background (suppressed or discontinuous)

Better Prognostic Indicators:

Autoimmune etiology (potentially reversible)
Younger age
Preserved EEG background between seizures
Response to immunotherapy

Pearl: Goals-of-care discussions should begin early in SRSE, involve palliative care when appropriate, and be revisited regularly. Explore what meaningful recovery looks like for the patient. Neurological outcomes in SRSE survivors are heterogeneous—some return to baseline, others survive with severe disability.

NCSE (Non-Convulsive Status Epilepticus): Who Needs an Urgent EEG?

The Invisible Epidemic

Non-convulsive status epilepticus (NCSE) is defined as continuous or recurrent seizure activity with altered consciousness but without prominent motor manifestations.[36] It accounts for 25-40% of all SE cases and is notoriously underdiagnosed due to its subtle clinical presentation.

Clinical Presentations: A Spectrum

NCSE encompasses a spectrum from minimally impaired awareness to coma:

Absence SE: Impaired consciousness with confusion, automatisms, and behavioral changes. Typically occurs in patients with known generalized epilepsy.
Complex Partial (Focal Impaired Awareness) SE: Fluctuating confusion, automatisms, and behavioral changes in patients with focal epilepsy history.
Subtle SE: Follows generalized convulsive SE that has been partially treated. Minimal motor activity (eye deviation, nystagmus, subtle facial twitching) with coma. Represents the "burned-out" phase of convulsive SE.
De Novo NCSE in the Elderly: Occurs in elderly patients without epilepsy history, presenting with acute confusion or coma. Often associated with acute illnesses (infections, metabolic derangements, medications).

Who Needs an Urgent EEG? The Clinical Predictors

Given that EEG availability is limited and not every confused ICU patient can undergo continuous monitoring, clinical prediction rules help prioritize.

The Sutter Criteria for NCSE Risk: A retrospective study identified independent predictors of NCSE in altered mental status patients:[37]

Witnessed seizure prior to arrival
Sepsis
Acute brain lesion (stroke, hemorrhage, trauma)
Eye opening to noxious stimuli only
Failure to improve after stopping sedation (in mechanically ventilated patients)

Pearl: Any post-ictal patient whose mental status has not returned to baseline within 30-60 minutes should undergo EEG to exclude NCSE. Similarly, any unexplained fluctuating encephalopathy, particularly in elderly patients or those with acute brain lesions, warrants EEG.

The "2HELPS2B Score": A Practical Tool

Developed and validated for predicting NCSE in critically ill patients with altered mental status:[38]

Criteria (2 points each):

Hospitalized
Epilepsy history
Loss of consciousness at presentation
Prior witnessed seizure
Sepsis

Interpretation:

Score ≥4: High risk for NCSE (sensitivity 97%, specificity 33%)
Score ≥6: Very high risk (sensitivity 85%, specificity 67%)

Oyster: The 2HELPS2B score is highly sensitive but poorly specific. A score <4 makes NCSE very unlikely, but high scores don't confirm NCSE—they identify patients who need EEG.

Hack: In resource-limited settings, prioritize continuous EEG for patients with 2HELPS2B ≥6 or those with witnessed seizures and persistent altered mental status. Use routine EEG for lower-risk patients with unexplained encephalopathy.

EEG Findings in NCSE: More Than Just Seizures

The diagnosis of NCSE requires both clinical (altered consciousness) and EEG criteria. The Salzburg Consensus Criteria provide diagnostic rigor:[39]

Definite NCSE requires:

Epileptiform discharges >2.5 Hz, OR
Epileptiform discharges ≤2.5 Hz PLUS EEG and clinical improvement after IV ASM

Possible NCSE includes:

Various patterns of periodic or rhythmic discharges (GPDs, LPDs, LRDA) in patients with altered consciousness where the ictal nature is uncertain

Pearl: The "ictal-interictal continuum" describes EEG patterns that fall between clearly ictal and clearly interictal. Examples include lateralized periodic discharges (LPDs) with evolving frequency or rhythmic delta activity. These patterns are controversial—some represent seizures, others don't. When in doubt, give a trial of benzodiazepines and observe for clinical and EEG improvement (the "Salzburg approach").

Oyster: Not all rhythmic or periodic EEG activity represents seizures. Generalized periodic discharges (GPDs) in post-anoxic coma are usually not seizures and don't warrant aggressive treatment. Over-treatment of non-ictal EEG patterns is common and exposes patients to unnecessary medication toxicity.

The IV Benzodiazepine Trial: A Diagnostic and Therapeutic Maneuver

When the EEG pattern is ambiguous (ictal-interictal continuum), a trial of IV lorazepam (2-4 mg) or midazolam (2-5 mg) serves dual purposes:[40]

Diagnostic: If both clinical and EEG patterns improve, this supports an ictal diagnosis
Therapeutic: If truly ictal, immediate treatment is provided

Hack: Document mental status quantitatively (using FOUR score or GCS) before and after benzodiazepine administration. Videotape the patient if possible. Clear clinical improvement supports treating the EEG pattern as ictal, even if electrographically ambiguous.

Treatment of NCSE: Is Aggressive Always Better?

The urgency and aggressiveness of NCSE treatment remain debated and depend on the subtype.

Generalized NCSE (absence SE, subtle SE following convulsive SE): Treat aggressively as you would convulsive SE. These subtypes carry risks of neuronal injury and systemic complications.

Focal NCSE without impaired consciousness (e.g., epilepsia partialis continua): Less urgency. Use oral ASMs and avoid unnecessary anesthetics, as the risk-benefit ratio favors less aggressive treatment.

Complex partial SE: Intermediate urgency. Use IV ASMs (benzodiazepines, levetiracetam, fosphenytoin, valproate) but reserve anesthetics for truly refractory cases lasting hours to days.

The STESS Prognostic Score: This validated score predicts mortality in NCSE using age, history of prior seizures, level of consciousness, and EEG pattern.[41] It can help inform treatment intensity and prognosis discussions.

Pearl: De novo absence SE in the elderly often responds dramatically to IV benzodiazepines or valproate. Don't escalate unnecessarily if initial therapy works quickly.

Oyster: Subtle SE after convulsive SE carries high mortality (up to 50%) not necessarily from ongoing seizures but from the underlying etiology (anoxia, hemorrhage). Aggressive seizure treatment may not improve outcomes if the primary insult is irreversible.

The Imitators of Status: Psychogenic Non-Epileptic Seizures (PNES) and Post-Anoxic Myoclonus

Psychogenic Non-Epileptic Seizures (PNES): The Great Masquerader

PNES, also called dissociative seizures or functional seizures, are paroxysmal episodes resembling epileptic seizures but lacking abnormal electrical brain activity.[42] They represent a manifestation of psychological distress, not malingering or voluntary simulation.

Epidemiology: PNES account for 5-20% of patients referred to epilepsy monitoring units and up to 10% of presumed SE cases in some series.[43] Delay in diagnosis averages 7 years, during which patients often receive unnecessary ASMs and ICU admissions.

Clinical Red Flags for PNES

No single feature is pathognomonic, but a constellation of features should raise suspicion:

Semiology:

Prolonged duration (>2 minutes) with waxing and waning intensity
Asynchronous, thrashing movements
Side-to-side head shaking
Pelvic thrusting
Eye closure (epileptic seizures typically cause eye opening)
Crying or screaming during the event
Recall of ictal events
Gradual onset and offset (epileptic seizures are abrupt)

Context:

Multiple emergency department visits for "seizures"
Witnessed seizures only (never occurs when alone)
Unusual triggers (emotional stress, arguments, specific people)
Refractory to multiple ASMs at high doses
Lack of post-ictal confusion or drowsiness

Pearl: The "ictal hand drop test" has reasonable specificity: lift the patient's hand above their face and release it. In epileptic seizures (except frontal lobe), the hand typically falls onto the face. In PNES, the hand often avoids the face. However, this test is neither perfectly sensitive nor specific.[44]

Oyster: PNES and epileptic seizures coexist in 10-30% of patients (mixed events). Don't assume all events are non-epileptic just because some are PNES. Video-EEG monitoring remains the gold standard for diagnosis. Never diagnose PNES based on semiology alone without EEG correlation.

Laboratory and EEG Findings

Serum Prolactin: Elevated prolactin (>2x baseline) drawn 10-20 minutes post-ictally supports epileptic seizures, but this test has significant limitations. Sensitivity is only 60% for generalized tonic-clonic seizures and much lower for focal seizures. Prolactin elevation is absent in simple partial seizures and many complex partial seizures.[45] False positives occur with syncope and baseline prolactin elevations (medications, stress).

Hack: Use prolactin selectively—draw it only if you've witnessed a typical event and need biomarker confirmation. Draw a baseline level hours later or document a normal historical value. A truly elevated post-ictal prolactin supports epileptic seizures, but a normal value doesn't exclude them.

EEG in PNES: By definition, PNES show no ictal epileptiform activity during events. However, interictal EEG may show epileptiform discharges if the patient also has epilepsy. Video-EEG monitoring capturing typical events while demonstrating lack of ictal activity is diagnostic.

Pearl: When PNES is suspected in the ICU, request video recording of events if continuous video-EEG isn't available. Smartphone videos can provide valuable information for neurologists reviewing the case.

The Diagnostic Conversation: Breaking the News

Delivering a PNES diagnosis requires skill, empathy, and avoidance of stigmatizing language. Poor communication can worsen outcomes and damage the therapeutic alliance.

Framework for Discussion:

Validate the patient's experience: "The events you're having are real and distressing."
Explain positively: "The good news is these aren't epileptic seizures, which means your brain's electrical activity is normal."
Use acceptable terminology: "Dissociative seizures" or "functional seizures" rather than "psychogenic" or "pseudo-seizures"
Provide mechanism: "Your nervous system is producing these events as a response to stress, trauma, or other factors we'll explore."
Emphasize treatability: "These events can improve significantly with the right therapy."
Make referrals: Neuropsychiatry, psychology, or psychiatry with PNES expertise

Oyster: Never accuse patients of "faking" or suggest they can control the events voluntarily. PNES is an involuntary manifestation of psychological distress, not malingering. Such accusations worsen outcomes and may precipitate litigation.

Hack: Involve a neurologist or psychiatrist experienced in functional neurological disorders when delivering the diagnosis. These specialists can provide longitudinal care and evidence-based treatments (cognitive behavioral therapy, acceptance and commitment therapy) that improve outcomes.[46]

Management of Presumed PNES in the ICU

When PNES is strongly suspected but not yet confirmed with video-EEG:

Minimize iatrogenic harm: Avoid unnecessary escalation of ASMs or intubation for "refractory seizures"
Pursue EEG confirmation: Transfer to monitored unit or arrange video-EEG
Avoid benzodiazepines: These can reinforce the episodes if the patient associates them with event termination
Provide reassurance: During events, stay calm, ensure safety, and provide gentle verbal reassurance
Document carefully: Detailed phenomenology helps neurologists differentiate PNES from epileptic seizures

Pearl: If the patient is already intubated for "status epilepticus" and PNES is confirmed, plan for rapid extubation. Prolonged intubation and ICU stays worsen functional neurological disorders through iatrogenic harm and loss of agency.

Post-Anoxic Myoclonus: Lance-Adams Syndrome and Acute Myoclonic Status

Myoclonus following cardiac arrest represents a diagnostic and prognostic challenge. Two distinct entities exist:

Acute Post-Anoxic Myoclonus (Within 24-48 Hours)

Generalized, multifocal myoclonus occurring early after cardiac arrest was historically considered a harbinger of poor prognosis. However, modern data require nuanced interpretation.

Prognostic Significance: In the pre-targeted temperature management (TTM) era, early myoclonus predicted poor outcome with near certainty. However, studies post-TTM show that myoclonus alone (without other poor prognostic features) does not uniformly predict poor outcome.[47] Up to 10-15% of patients with myoclonus may achieve good neurological recovery, particularly if:

Myoclonus is stimulus-induced rather than spontaneous
EEG background is not severely suppressed or burst-suppressed
Somatosensory evoked potentials (SSEPs) show preserved N20 responses bilaterally
Neuroimaging shows no extensive anoxic injury

EEG Findings: Acute post-anoxic myoclonus may occur with various EEG patterns:

Generalized periodic discharges (GPDs) time-locked to myoclonic jerks ("myoclonic status epilepticus")
Burst-suppression pattern
Suppressed background without epileptiform activity
Electrodecremental response to muscle jerks (not epileptiform)

The Controversy: Is acute post-anoxic myoclonus "epileptic"? This remains debated. Some patterns clearly represent cortical myoclonus with epileptiform correlates (myoclonic status epilepticus), while others represent subcortical or reticular reflex myoclonus without cortical epileptiform activity.[48]

Treatment Approach:

Benzodiazepines: First-line for symptomatic control (lorazepam or clonazepam)
Levetiracetam: Often added empirically, though evidence is limited
Valproate: May be beneficial for cortical myoclonus
Propofol: For severe, distressing myoclonus impeding care or mechanical ventilation

Pearl: Focus on neuroprognostication using multimodal criteria (EEG background, SSEPs, imaging, clinical examination off sedation) rather than treating myoclonus aggressively for prognostic reasons. If other prognostic indicators suggest potential for good recovery, treat myoclonus supportively while allowing time for neurological recovery.

Oyster: Don't mistake acute post-anoxic myoclonus for seizures requiring aggressive therapy with anesthetics. While some patterns may be epileptic, escalating to midazolam or propofol infusions for isolated myoclonus (without other seizure activity) exposes patients to unnecessary sedation that impairs prognostic assessment.

Hack: Use neuromuscular blockade temporarily to facilitate mechanical ventilation or procedures if myoclonus is mechanically problematic, rather than escalating sedation unnecessarily. This allows ongoing EEG monitoring without confounding movements.

Lance-Adams Syndrome: Chronic Post-Anoxic Action Myoclonus

Lance-Adams syndrome (LAS) represents chronic, action-induced myoclonus following successful resuscitation from anoxic injury.[49] Unlike acute post-anoxic myoclonus, LAS occurrence confirms good cortical recovery—patients are awake and interactive but experience disabling myoclonic jerks triggered by voluntary movement or intention.

Clinical Features:

Appears days to weeks after emergence from coma
Action-induced myoclonus (worse with voluntary movement, goal-directed tasks)
Preserved consciousness and cognition
May include stimulus-sensitive components (sound, touch)
Disabling impact on activities of daily living

Pathophysiology: LAS results from cerebellar and brainstem (inferior olive) injury causing abnormal oscillations in cerebello-thalamo-cortical circuits. It represents post-hypoxic cerebellar ataxia with myoclonus.

Treatment:

Levetiracetam: First-line, often effective at doses of 2000-4000 mg/day
Valproate: Particularly effective for cortical myoclonus component
Clonazepam: Helpful for action myoclonus but causes sedation
Piracetam: Not available in the U.S. but used in Europe with good effect
Zonisamide: Emerging evidence for myoclonus syndromes
5-Hydroxytryptophan (5-HTP): May augment other therapies

Combination therapy is typically necessary, and complete suppression is rare. The goal is functional improvement rather than complete abolition of myoclonus.

Pearl: Lance-Adams syndrome, while disabling, is compatible with meaningful recovery and good quality of life. Early aggressive rehabilitation, occupational therapy, and realistic goal-setting improve outcomes. Some patients achieve near-complete functional independence despite persistent myoclonus.

Oyster: Don't give up on patients with LAS. While literature emphasizes the syndrome's severity, modern case series show that 40-60% of patients achieve functional independence with aggressive symptomatic treatment and rehabilitation.[50]

Autoimmune Encephalitis as a Cause of New-Onset Refractory Status Epilepticus

The Paradigm Shift: NORSE and FIRES

New-Onset Refractory Status Epilepticus (NORSE) is defined as RSE in a patient without active epilepsy or other clear acute or active structural, toxic, or metabolic cause, with a new onset of refractory seizures.[51] When NORSE occurs in the context of a febrile illness, it's termed Febrile Infection-Related Epilepsy Syndrome (FIRES).

The recognition that autoimmune encephalitis underlies many NORSE cases has revolutionized management, emphasizing the role of immunotherapy in SRSE.

Epidemiology and Etiology

NORSE accounts for approximately 10-15% of RSE cases.[52] In roughly 50% of NORSE cases, no etiology is identified despite extensive workup ("cryptogenic NORSE"). However, autoimmune encephalitis is identified in 20-30% of cases, with the following antibodies most commonly implicated:

Anti-NMDA receptor (NMDAR) encephalitis (most common)
Anti-LGI1 (leucine-rich glioma-inactivated 1) encephalitis
Anti-CASPR2 encephalitis
Anti-GABA-A receptor encephalitis
Anti-GABA-B receptor encephalitis
Anti-AMPA receptor encephalitis

Other causes of NORSE include:

Paraneoplastic syndromes (anti-Hu, anti-Ma2)
CNS infections (HSV encephalitis, despite negative initial testing)
Autoimmune disorders (lupus cerebritis, Hashimoto's encephalopathy)
Mitochondrial disease
Cryptogenic/idiopathic

Clinical Red Flags for Autoimmune Etiology

Suggestive Features:

New-onset seizures in previously healthy adolescent or young adult
Psychiatric prodrome: Anxiety, psychosis, behavioral changes, hallucinations preceding seizures (particularly NMDAR encephalitis)
Cognitive decline: Prominent memory impairment, confusion
Movement disorders: Orofacial dyskinesias, choreoathetosis, dystonia, rigidity (NMDAR encephalitis)
Autonomic instability: Tachycardia, labile blood pressure, hyperthermia, hypoventilation
Hyponatremia: Particularly with LGI1 encephalitis (SIADH in 60% of cases)
Faciobrachial dystonic seizures: Pathognomonic for LGI1 encephalitis—brief (seconds), frequent (up to hundreds/day) episodes of dystonic posturing of face and arm

Oyster: Anti-NMDAR encephalitis can present with isolated SE in 20-30% of cases without the full clinical tetrad (psychiatric symptoms, seizures, movement disorder, autonomic instability). Maintain high suspicion in young patients with cryptogenic NORSE.[53]

Diagnostic Workup for Autoimmune Encephalitis

When autoimmune etiology is suspected, perform comprehensive antibody testing on both serum and CSF:

Antibody Panel:

NMDAR, LGI1, CASPR2, GABA-A, GABA-B, AMPA receptors (CSF more sensitive than serum)
Paraneoplastic antibodies (Hu, Ma2, CV2/CRMP5, amphiphysin, Yo)
Voltage-gated potassium channel (VGKC) complex antibodies (includes LGI1 and CASPR2)

Supportive Testing:

CSF analysis: Mild lymphocytic pleocytosis (50-60% of cases), elevated protein, oligoclonal bands, normal glucose
MRI brain:
- NMDAR: Often normal, or may show T2/FLAIR hyperintensities in cortex, hippocampus, or basal ganglia
- LGI1: Mesial temporal T2/FLAIR hyperintensities (70% of cases)
- GAD65: Mesial temporal sclerosis
EEG: Non-specific; may show temporal lobe seizures, diffuse slowing, or "extreme delta brush" (specific for NMDAR encephalitis—rhythmic delta with superimposed beta, seen in 30% of severe cases)[54]
Tumor screening: Pelvic ultrasound or CT (NMDAR—ovarian teratoma in 50% of women), chest/abdomen/pelvis CT (paraneoplastic syndromes), testicular ultrasound (NMDAR—testicular teratoma rare but described)

Pearl: Antibody testing can take 1-2 weeks. Don't wait for results before initiating empiric immunotherapy in patients with strong clinical suspicion for autoimmune encephalitis. Early treatment improves outcomes.

Hack: Send antibody testing to reference laboratories (Mayo Clinic, Oxford Autoimmune Neurology Diagnostic Laboratory, Euroimmun) rather than commercial labs. Sensitivity and specificity vary significantly between laboratories, and false negatives are common with some assays.[55]

Immunotherapy: The Cornerstone of Treatment

When autoimmune encephalitis is suspected or confirmed, immunotherapy should be initiated urgently, in parallel with ASM optimization.

First-Line Immunotherapy

High-Dose Corticosteroids:

Methylprednisolone 1 gram IV daily × 5 days
Follow with oral prednisone 1 mg/kg/day with slow taper over months

Intravenous Immunoglobulin (IVIG):

2 g/kg divided over 2-5 days (typically 0.4 g/kg/day × 5 days)
Repeat monthly if initial response

Plasma Exchange (PLEX):

5-7 exchanges over 10-14 days
Removes circulating antibodies more rapidly than IVIG

Combination vs. Sequential Therapy: Expert consensus favors combining steroids with either IVIG or PLEX as first-line therapy.[56] Some data suggest PLEX may be superior to IVIG for severe cases, though head-to-head trials are lacking.

Pearl: Response to first-line immunotherapy may take 4-8 weeks. Don't declare immunotherapy "failed" after only days. However, if no improvement occurs after 2-3 weeks of first-line therapy, escalate to second-line agents.

Second-Line Immunotherapy

Reserved for patients not responding to first-line therapy after 2-4 weeks:

Rituximab:

Anti-CD20 monoclonal antibody depleting B cells
Dose: 375 mg/m² IV weekly × 4 weeks, or 1000 mg IV on days 1 and 15
Particularly effective for NMDAR encephalitis (antibody-mediated, B-cell dependent)

Cyclophosphamide:

Alkylating agent with broad immunosuppression
Dose: 750 mg/m² IV monthly × 6 months
More toxic than rituximab but may be effective when rituximab fails

Tocilizumab:

IL-6 receptor antagonist
Emerging therapy for refractory cases[57]
Dose: 8 mg/kg IV every 4 weeks

Bortezomib:

Proteasome inhibitor targeting plasma cells
Reported in case series for refractory NMDAR encephalitis[58]

Pearl: Early escalation to second-line therapy (within 4 weeks) improves outcomes in NMDAR encephalitis. Don't wait months before adding rituximab or cyclophosphamide if first-line therapies are ineffective.

Oyster: Immunotherapy carries risks: infection (particularly with cyclophosphamide and rituximab), infusion reactions, hypogammaglobulinemia, and malignancy (long-term cyclophosphamide). Monitor immunoglobulin levels, provide prophylaxis against opportunistic infections (trimethoprim-sulfamethoxazole, antifungals for prolonged neutropenia), and screen for infections aggressively.

Tumor Screening and Removal

Paraneoplastic autoimmune encephalitis requires tumor identification and removal for optimal outcomes:

NMDAR encephalitis: Ovarian teratoma in 50% of women (higher in those >18 years), testicular teratoma rare in men. Perform pelvic imaging in all women; consider repeat imaging if initial negative but high suspicion.
LGI1 encephalitis: Rarely paraneoplastic (2-10% of cases); screen with chest/abdomen/pelvis CT
GABA-B receptor encephalitis: Small-cell lung cancer in 50-60% of cases
AMPA receptor encephalitis: Thymoma, lung, breast, or ovarian cancers in 70% of cases

Hack: If pelvic ultrasound is negative in a woman with NMDAR encephalitis, obtain pelvic MRI—teratomas can be small and missed on ultrasound. Consider laparoscopic ovarian exploration if MRI is negative but suspicion remains very high.

Prognosis and Long-Term Outcomes

NMDAR Encephalitis:

80% achieve good recovery (modified Rankin Scale 0-2) within 2 years with appropriate treatment
Median time to recovery: 6-12 months
Relapses occur in 10-20% (higher if tumor not removed or inadequate immunotherapy)
Mortality: 5-7% with treatment

LGI1 Encephalitis:

Generally good prognosis with early treatment
Cognitive sequelae (memory impairment) common despite seizure control
Mortality: 2-5%

Cryptogenic NORSE/FIRES:

Poorer prognosis than antibody-positive cases
Mortality: 20-30%
Severe cognitive and neurological sequelae common in survivors
Many develop drug-resistant epilepsy

Pearl: Long-term epilepsy develops in 10-30% of autoimmune encephalitis survivors, even after successful immunotherapy. Maintain ASMs during recovery and attempt slow weaning only after 6-12 months seizure-free with normalized EEG.

The Ketogenic Diet in FIRES

For pediatric FIRES cases, early initiation of the ketogenic diet (within the first week) has shown promise, with seizure control reported in 50-70% of cases in retrospective series.[59] The diet may exert anti-inflammatory effects in addition to metabolic anticonvulsant actions.

Practical Consideration: The ketogenic diet complements immunotherapy and should be considered early in FIRES rather than as a last resort.

Putting It All Together: The ICU Approach to Uncontrolled Seizures

The Time-Based Algorithm

Time 0-5 minutes:

Secure airway if needed (GCS <8, aspiration risk)
Obtain IV access (two large-bore IVs)
Check glucose, give thiamine 100 mg IV if alcoholism or malnutrition suspected
First-line: Lorazepam 0.1 mg/kg IV (or diazepam 0.15-0.2 mg/kg IV, or midazolam 10 mg IM if no IV access)

Time 5-25 minutes (Second-line therapy):

If seizures persist >5 minutes after benzodiazepine, initiate second-line agent:
- Levetiracetam 60 mg/kg IV (max 4500 mg) over 10 minutes
- OR Fosphenytoin 20 PE/kg IV at 150 PE/min
- OR Valproate 40 mg/kg IV (max 3000 mg) at 6-10 mg/kg/min
Consider lacosamide 200-400 mg IV if above agents fail or contraindicated

Time 25-60 minutes (Assess for RSE):

If seizures continue despite adequate second-line therapy, RSE is declared
Initiate continuous EEG monitoring
Consider third-line ASM (different mechanism from second-line)
Prepare for ICU transfer and intubation

Time >60 minutes (Anesthetic therapy for RSE):

Intubation and mechanical ventilation
Continuous EEG monitoring (cEEG)
Initiate anesthetic: midazolam 0.2 mg/kg load, then 0.1-0.2 mg/kg/hr infusion
Alternative: propofol 1-2 mg/kg load, then 30-80 mcg/kg/min
Target: Seizure cessation (burst-suppression optional, not mandatory)
Load additional ASMs: Consider adding lacosamide, phenobarbital, topiramate, or others
Pursue etiological workup urgently

The Diagnostic Workup Checklist

Immediate Labs:

Complete blood count, comprehensive metabolic panel
Magnesium, calcium, phosphate
Antiepileptic drug levels (if patient on ASMs chronically)
Toxicology screen (urine and serum)
Blood cultures if febrile
Ammonia, lactate
Pregnancy test (women of childbearing age)

Neuroimaging:

CT head (immediately to exclude hemorrhage, mass, stroke)
MRI brain with and without contrast (when stabilized; superior for subtle lesions, encephalitis, posterior circulation stroke)

CSF Analysis (Lumbar Puncture):

Perform once coagulopathy corrected and no contraindications
Cell count with differential, glucose, protein
Gram stain, culture, HSV PCR, VZV PCR
Hold CSF for autoimmune/paraneoplastic antibody testing if indicated
Consider sending for tuberculosis, fungal studies based on risk factors

EEG:

Routine EEG if seizures terminated (assess for NCSE, epileptiform activity)
Continuous EEG for RSE/SRSE and any patient with unexplained altered mental status

Autoimmune Workup (if indicated):

Serum and CSF antibodies (NMDAR, LGI1, CASPR2, GABA-A/B, paraneoplastic panel)
Tumor screening (chest/abdomen/pelvis CT, pelvic ultrasound/MRI in women)
Thyroid function, anti-thyroid antibodies (Hashimoto's encephalopathy)

Clinical Pearls: The Top 10 for the Intensivist

Time is brain in SE: Every minute counts. Don't deliberate endlessly about the "perfect" drug—give an appropriate second-line agent quickly.
Recognize NCSE: If mental status hasn't returned to baseline 30-60 minutes post-ictally, get an EEG.
Less is often more in anesthetic targets: Seizure cessation without burst-suppression may be safer than aggressive deep suppression. Individualize targets.
Think autoimmune in young, previously healthy patients: NORSE should prompt urgent immunotherapy consideration, even before antibody confirmation.
PNES is common: Not every rhythmic movement is a seizure. Know the red flags and pursue video-EEG confirmation before escalating therapy.
Post-anoxic myoclonus isn't always futile: Multimodal prognostication, not myoclonus alone, should guide decisions.
Load multiple ASMs before weaning anesthetics: Create a "chemical carpet" to maximize the chance of successful liberation from continuous infusions.
Monitor for complications: SE and its treatment cause rhabdomyolysis, aspiration pneumonia, pulmonary edema, cardiac arrhythmias, acidosis, electrolyte derangements, and thromboembolism. Prevent and treat proactively.
Involve neurology early: Complex SE cases benefit from specialist input regarding ASM selection, immunotherapy, and prognostication.
Have the goals-of-care conversation: SRSE forces difficult decisions. Early, honest communication with families about prognosis and potential outcomes is essential.

Conclusion

Status epilepticus and its mimics represent some of the most complex and time-sensitive challenges in critical care medicine. Success requires rapid recognition, systematic treatment escalation, continuous EEG monitoring, and thoughtful consideration of etiology—particularly autoimmune causes in refractory cases. While benzodiazepines remain the cornerstone of initial therapy, modern evidence supports flexibility in second-line agent selection based on patient-specific factors rather than rigid protocols. For refractory and super-refractory SE, a balanced approach to anesthetic depth, aggressive pursuit of underlying causes, and judicious use of immunotherapy when appropriate can improve outcomes. Equally important is the recognition that not all movements are seizures: familiarity with PNES, post-anoxic myoclonus, and other mimics prevents iatrogenic harm from over-treatment. As the field evolves, intensivists must stay current with emerging therapies, refine prognostic capabilities, and maintain a compassionate approach to decision-making in these often devastating cases.

References

Trinka E, Cock H, Hesdorffer D, et al. A definition and classification of status epilepticus—Report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia. 2015;56(10):1515-1523.
Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med. 1998;338(14):970-976.
Betjemann JP, Lowenstein DH. Status epilepticus in adults. Lancet Neurol. 2015;14(6):615-624.
Shorvon S, Ferlisi M. The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol. Brain. 2011;134(10):2802-2818.
Kapur J, Elm J, Chamberlain JM, et al. Randomized trial of three anticonvulsant medications for status epilepticus. N Engl J Med. 2019;381(22):2103-2113.
Cock HR, Schapira AH. A comparison of lorazepam and diazepam as initial therapy in convulsive status epilepticus. QJM. 2002;95(4):225-231.
Fischer JH, Patel TV, Fischer PA. Fosphenytoin: clinical pharmacokinetics and comparative advantages in the acute treatment of seizures. Clin Pharmacokinet. 2003;42(1):33-58.
Gerstner T, Büsing D, Bell N, et al. Valproic acid-induced pancreatitis: 16 new cases and a review of the literature. J Gastroenterol. 2007;42(1):39-48.
Yasiry Z, Shorvon SD. The relative effectiveness of five antiepileptic drugs in treatment of benzodiazepine-resistant convulsive status epilepticus: a meta-analysis of published studies. Seizure. 2014;23(3):167-174.
Chamberlain JM, Kapur J, Shinnar S, et al. Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial. Lancet. 2020;395(10231):1217-1224.
Kellinghaus C. Lacosamide as treatment for partial epilepsy: mechanisms of action, pharmacology, effects, and safety. Ther Clin Risk Manag. 2009;5:757-766.
Hofler J, Trinka E. Lacosamide as a new treatment option in status epilepticus. Epilepsia. 2013;54(3):393-404.
Novy J, Rossetti AO. Oral lacosamide as an add-on therapy in refractory epilepsy and status epilepticus. Epilepsy Behav. 2014;37:137-140.
Brophy GM, Bell R, Claassen J, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care. 2012;17(1):3-23.
Rossetti AO, Lowenstein DH. Management of refractory status epilepticus in adults: still more questions than answers. Lancet Neurol. 2011;10(10):922-930.
Silbergleit R, Durkalski V, Lowenstein D, et al. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med. 2012;366(7):591-600.
Fernandez A, Claassen J. Refractory status epilepticus. Curr Opin Crit Care. 2012;18(2):127-131.
Rossetti AO, Reichhart MD, Schaller MD, et al. Propofol treatment of refractory status epilepticus: a study of 31 episodes. Epilepsia. 2004;45(7):757-763.
Kam PC, Cardone D. Propofol infusion syndrome. Anaesthesia. 2007;62(7):690-701.
Claassen J, Hirsch LJ, Emerson RG, Mayer SA. Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a systematic review. Epilepsia. 2002;43(2):146-153.
Iyer VN, Hoel R, Rabinstein AA. Propofol infusion syndrome in patients with refractory status epilepticus: an 11-year clinical experience. Crit Care Med. 2009;37(12):3024-3030.
Synowiec AS, Singh DS, Yenugadhati V, et al. Ketamine use in the treatment of refractory status epilepticus. Epilepsy Res. 2013;105(1-2):183-188.
Gaspard N, Foreman B, Judd LM, et al. Intravenous ketamine for the treatment of refractory status epilepticus: a retrospective multicenter study. Epilepsia. 2013;54(8):1498-1503.
Zeiler FA, Teitelbaum J, West M, Gillman LM. The ketamine effect on intracranial pressure in nontraumatic neurological illness. J Crit Care. 2014;29(6):1096-1106.
Mirsattari SM, Sharpe MD, Young GB. Treatment of refractory status epilepticus with inhalational anesthetic agents isoflurane and desflurane. Arch Neurol. 2004;61(8):1254-1259.
Kramer AH. Early ketamine to treat refractory status epilepticus. Neurocrit Care. 2012;16(2):299-305.
Herman ST, Abend NS, Bleck TP, et al. Consensus statement on continuous EEG in critically ill adults and children, part I: indications. J Clin Neurophysiol. 2015;32(2):87-95.
Brophy GM, Bell R, Claassen J, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care. 2012;17(1):3-23.
Rossetti AO, Logroscino G, Milligan TA, et al. Status Epilepticus Severity Score (STESS): a tool to orient early treatment strategy. J Neurol. 2008;255(10):1561-1566.
Hocker SE, Britton JW, Mandrekar JN, et al. Predictors of outcome in refractory status epilepticus. JAMA Neurol. 2013;70(1):72-77.
Visser NA, Braun KP, Leijten FS, et al. Magnesium treatment for patients with refractory status epilepticus due to POLG1-mutations. J Neurol. 2011;258(2):218-222.
Corry JJ, Dhar R, Murphy T, Diringer MN. Hypothermia for refractory status epilepticus. Neurocrit Care. 2008;9(2):189-197.
Lambrecq V, Villegier AS, Marchal C, et al. Refractory status epilepticus: electroconvulsive therapy as a possible therapeutic strategy. Seizure. 2012;21(9):661-664.
Thakur KT, Probasco JC, Hocker SE, et al. Ketogenic diet for adults in super-refractory status epilepticus. Neurology. 2014;82(8):665-670.
Devinsky O, Cross JH, Laux L, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017;376(21):2011-2020.
Walker M, Cross H, Smith S, et al. Nonconvulsive status epilepticus: Epilepsy Research Foundation workshop reports. Epileptic Disord. 2005;7(3):253-296.
Sutter R, Kaplan PW, Ruegg S. Independent external validation of the status epilepticus severity score. Crit Care Med. 2013;41(12):e475-479.
Sutter R, Stevens RD, Kaplan PW. Clinical and imaging correlates of EEG patterns in hospitalized patients with encephalopathy. J Neurol. 2013;260(4):1087-1098.
Leitinger M, Beniczky S, Rohracher A, et al. Salzburg Consensus Criteria for Non-Convulsive Status Epilepticus—approach to clinical application. Epilepsy Behav. 2015;49:158-163.
Kaplan PW. The EEG in metabolic encephalopathy and coma. J Clin Neurophysiol. 2004;21(5):307-318.
Rossetti AO, Logroscino G, Milligan TA, et al. Status Epilepticus Severity Score (STESS): a tool to orient early treatment strategy. J Neurol. 2008;255(10):1561-1566.
Reuber M, Fernández G, Bauer J, et al. Diagnostic delay in psychogenic nonepileptic seizures. Neurology. 2002;58(3):493-495.
Duncan R, Razvi S, Mulhern S. Newly presenting psychogenic nonepileptic seizures: incidence, population characteristics, and early outcome from a prospective audit of a first seizure clinic. Epilepsy Behav. 2011;20(2):308-311.
Avbersek A, Sisodiya S. Does the primary literature provide support for clinical signs used to distinguish psychogenic nonepileptic seizures from epileptic seizures? J Neurol Neurosurg Psychiatry. 2010;81(7):719-725.
Chen DK, So YT, Fisher RS. Use of serum prolactin in diagnosing epileptic seizures: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2005;65(5):668-675.
Goldstein LH, Robinson EJ, Mellers JDC, et al. Cognitive behavioural therapy for adults with dissociative seizures (CODES): a pragmatic, multicentre, randomised controlled trial. Lancet Psychiatry. 2020;7(6):491-505.
Wijdicks EF, Hijdra A, Young GB, et al. Practice parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2006;67(2):203-210.
Rossetti AO, Oddo M, Logroscino G, Kaplan PW. Prognostication after cardiac arrest and hypothermia: a prospective study. Ann Neurol. 2010;67(3):301-307.
Lance JW, Adams RD. The syndrome of intention or action myoclonus as a sequel to hypoxic encephalopathy. Brain. 1963;86:111-136.
Werhahn KJ, Brown P, Thompson PD, Marsden CD. The clinical features and prognosis of chronic posthypoxic myoclonus. Mov Disord. 1997;12(2):216-220.
Gaspard N, Foreman BP, Alvarez V, et al. New-onset refractory status epilepticus: etiology, clinical features, and outcome. Neurology. 2015;85(18):1604-1613.
Khawaja AM, DeWolfe JL, Miller DW, Szaflarski JP. New-onset refractory status epilepticus (NORSE)—the potential role for immunotherapy. Epilepsy Behav. 2015;47:17-23.
Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 2008;7(12):1091-1098.
Schmitt SE, Pargeon K, Frechette ES, et al. Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor encephalitis. Neurology. 2012;79(11):1094-1100.
Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404.
Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013;12(2):157-165.
Lee WJ, Lee ST, Byun JI, et al. Rituximab treatment for autoimmune limbic encephalitis in an institutional cohort. Neurology. 2016;86(18):1683-1691.
Scheibe F, Prüss H, Mengel AM, et al. Bortezomib for treatment of therapy-refractory anti-NMDA receptor encephalitis. Neurology. 2017;88(4):366-370.
Nabbout R, Mazzuca M, Hubert P, et al. Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES). Epilepsia. 2010;51(10):2033-2037.
Holtkamp M, Othman J, Buchheim K, Meierkord H. Predictors and prognosis of refractory status epilepticus treated in a neurological intensive care unit. J Neurol Neurosurg Psychiatry. 2005;76(4):534-539.
Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for generalized convulsive status epilepticus. N Engl J Med. 1998;339(12):792-798.
Shorvon S, Baulac M, Cross H, et al. The drug treatment of status epilepticus in Europe: consensus document from a workshop at the first London Colloquium on Status Epilepticus. Epilepsia. 2008;49(7):1277-1285.
Mayer SA, Claassen J, Lokin J, et al. Refractory status epilepticus: frequency, risk factors, and impact on outcome. Arch Neurol. 2002;59(2):205-210.
Rosenow F, Hamer HM, Knake S. The epidemiology of convulsive and nonconvulsive status epilepticus. Epilepsia. 2007;48 Suppl 8:82-84.
DeLorenzo RJ, Waterhouse EJ, Towne AR, et al. Persistent nonconvulsive status epilepticus after the control of convulsive status epilepticus. Epilepsia. 1998;39(8):833-840.
Towne AR, Waterhouse EJ, Boggs JG, et al. Prevalence of nonconvulsive status epilepticus in comatose patients. Neurology. 2000;54(2):340-345.
Laccheo I, Sonmezturk H, Bhatt AB, et al. Non-convulsive status epilepticus and non-convulsive seizures in neurological ICU patients. Neurocrit Care. 2015;22(2):202-211.
Sutter R, Kaplan PW. Electroencephalographic criteria for nonconvulsive status epilepticus: synopsis and comprehensive survey. Epilepsia. 2012;53 Suppl 3:1-51.
Chong DJ, Hirsch LJ. Which EEG patterns warrant treatment in the critically ill? Reviewing the evidence for treatment of periodic epileptiform discharges and related patterns. J Clin Neurophysiol. 2005;22(2):79-91.
Sánchez Fernández I, Abend NS, Agadi S, et al. Time from convulsive status epilepticus onset to anticonvulsant administration in children. Neurology. 2015;84(23):2304-2311.

Key Clinical Pearls Summary Box

Assessment Pearls

✓ 5-minute rule: Treat any seizure lasting >5 minutes as SE—don't wait for the traditional 30-minute definition ✓ NCSE screening: Unexplained altered mental status + any seizure history = urgent EEG needed ✓ 2HELPS2B ≥4: High sensitivity for NCSE risk; prioritize EEG in these patients ✓ Young + healthy + NORSE: Think autoimmune—send antibodies and start immunotherapy empirically

Treatment Pearls

✓ Second-line equipoise: Levetiracetam, fosphenytoin, and valproate are equally effective—choose based on comorbidities, not habit ✓ Midazolam first: Most practical first-line anesthetic for RSE due to ease of titration and safety profile ✓ Less may be more: Seizure freedom without burst-suppression may be safer than aggressive EEG targets ✓ Chemical carpet: Load 2-3 non-anesthetic ASMs before weaning anesthetics to prevent seizure recurrence ✓ Immunotherapy early: Don't wait for antibody confirmation in suspected autoimmune encephalitis—treat within days, not weeks

Diagnostic Pearls

✓ Eye closure during "seizure": Strong clue for PNES, not epileptic seizures ✓ Extreme delta brush on EEG: Pathognomonic for anti-NMDAR encephalitis ✓ Faciobrachial dystonic seizures: Diagnostic for anti-LGI1 encephalitis ✓ Post-anoxic myoclonus ≠ futility: Multimodal prognostication, not myoclonus alone, predicts outcome ✓ Prolactin elevation: Helpful if present, but normal prolactin doesn't exclude epileptic seizures

Safety Pearls

✓ PRIS risk: Keep propofol <80 mcg/kg/min and monitor creatine kinase, triglycerides ✓ Valproate contraindications: Avoid in hepatic failure, pregnancy, and suspected mitochondrial disease ✓ Fosphenytoin cardiac risk: Monitor for hypotension and arrhythmias during infusion ✓ Benzodiazepine tolerance: If midazolam >0.5 mg/kg/hr, transition to alternative anesthetic ✓ Immunotherapy infections: Prophylax against opportunistic infections with rituximab/cyclophosphamide

Oyster (Pitfalls) Summary Box

Diagnostic Oysters

⚠ Mixed seizures: 10-30% of PNES patients also have epileptic seizures—don't assume all events are non-epileptic ⚠ False reassurance: Normal routine EEG doesn't exclude NCSE—may need continuous monitoring ⚠ Antibody-negative AE: 30-50% of autoimmune encephalitis cases are seronegative—don't withhold immunotherapy based on negative tests alone ⚠ Delayed antibody results: Commercial labs have poor sensitivity—send to reference laboratories ⚠ Over-interpreting GPDs: Generalized periodic discharges post-arrest are often not seizures—avoid over-treatment

Treatment Oysters

⚠ Levetiracetam efficacy: May be less effective in children and after prehospital benzodiazepines (ESETT post-hoc) ⚠ Propofol infusion syndrome: Rare but fatal—monitor for metabolic acidosis, rhabdomyolysis with high-dose infusions ⚠ Pentobarbital hemodynamics: Causes hypotension in >50% of patients—optimize volume status and have vasopressors ready ⚠ Midazolam tachyphylaxis: Develops within 24-48 hours, limiting usefulness in SRSE ⚠ Ketamine EEG effects: High doses cause rhythmic theta/delta that can confound seizure detection ⚠ Premature weaning: 30-50% recurrence rate if anesthetics weaned too quickly—maintain therapeutic levels 24-48 hours seizure-free ⚠ Magnesium in renal failure: High-dose magnesium risks toxicity in renal impairment—adjust dose and monitor levels

Prognostic Oysters

⚠ SRSE duration: Outcomes worsen significantly after 30 days—earlier goals-of-care discussions warranted ⚠ Cryptogenic NORSE: Poorer prognosis than antibody-positive autoimmune encephalitis—mortality 20-30% ⚠ Lance-Adams syndrome: While disabling, 40-60% achieve functional independence—don't give up prematurely ⚠ Post-arrest myoclonus evolution: Early poor prognostic significance has changed with targeted temperature management—interpret cautiously

Author's Clinical Hacks: Practical Tips for the Bedside

Medication Hacks

💡 Dual second-line approach: If levetiracetam fails, add fosphenytoin or valproate before escalating to anesthetics—exploit different mechanisms 💡 Slow lacosamide infusion: In elderly or cardiac patients, infuse over 30-60 minutes instead of 15 to minimize cardiac risk 💡 Valproate for hemodynamics: When hypotension is a concern, valproate infuses faster than fosphenytoin with less cardiovascular instability 💡 Ketamine + midazolam combo: Synergistic effects allow dose reduction of both agents—particularly useful in FIRES/autoimmune cases 💡 Magnesium addition: Essentially free and low-risk—add empirically in refractory cases while awaiting advanced therapies

Monitoring Hacks

💡 Trial of awakening: Briefly pause anesthetic while maintaining cEEG before weaning to identify whether additional ASMs are needed 💡 qEEG trending: Use suppression ratio and spectral array for real-time bedside anesthetic titration without waiting for formal EEG reads 💡 Smartphone videos: When video-EEG unavailable, smartphone recording of events aids later diagnosis by neurologists 💡 Quantify mental status: Use FOUR score before/after benzodiazepine trial in ambiguous ictal-interictal continuum patterns

Diagnostic Hacks

💡 Repeat imaging: If NMDAR encephalitis suspected but initial pelvic ultrasound negative, obtain MRI—small teratomas are easily missed 💡 Send CSF for hold: When lumbar puncture performed, hold extra CSF for later antibody testing if diagnosis remains unclear 💡 Prolactin timing: Only useful if drawn 10-20 minutes post-ictal with documented baseline or historical normal level 💡 Neuromuscular blockade for myoclonus: Temporarily paralyze to facilitate ventilation/procedures rather than escalating sedation unnecessarily

System Hacks

💡 Neurology early: Complex SE benefits from specialist input—consult within first hour, not after multiple failed therapies 💡 Palliative care involvement: Engage early in SRSE for goals-of-care expertise, not just end-of-life care 💡 Pharmacy collaboration: Clinical pharmacists are invaluable for ASM dosing, interactions, and therapeutic drug monitoring 💡 Immunotherapy protocols: Pre-established institutional protocols for empiric immunotherapy in NORSE reduce treatment delays

Case-Based Learning: Putting Principles into Practice

Case 1: The 28-Year-Old with New-Onset Seizures

Presentation: A 28-year-old previously healthy woman presents with generalized tonic-clonic seizures progressing to SE. She has had behavioral changes and anxiety for 2 weeks prior to presentation.

Red Flags: Young, healthy, psychiatric prodrome → high suspicion for autoimmune encephalitis

Management Priorities:

Standard SE treatment algorithm (benzodiazepines → second-line ASM)
Urgent MRI brain, LP with cell count and autoimmune antibody panel (serum + CSF)
Pelvic imaging (ultrasound or MRI) to screen for ovarian teratoma
Empiric immunotherapy (methylprednisolone 1g IV daily × 5 days + IVIG 2 g/kg) without waiting for antibody results
Continuous EEG monitoring

Pearl: The 2-week psychiatric prodrome strongly suggests anti-NMDAR encephalitis. Early immunotherapy improves outcomes—don't delay for antibody confirmation.

Case 2: The Post-Arrest Patient with Myoclonus

Presentation: A 55-year-old man post-cardiac arrest (witnessed VF, ROSC after 8 minutes, therapeutic hypothermia completed) has persistent myoclonic jerks 36 hours post-arrest. He remains comatose.

Diagnostic Approach:

Continuous EEG to assess background and epileptiform activity
Somatosensory evoked potentials (SSEPs) bilaterally
MRI brain when stable
Neurological examination after rewarming and off sedation (if any)

Management:

If EEG shows epileptiform discharges time-locked to myoclonus: treat as myoclonic SE (benzodiazepines, levetiracetam, valproate)
If EEG shows suppressed background without epileptiform activity: supportive care, treat myoclonus only if interfering with ventilation
Do not base prognostication on myoclonus alone—use multimodal approach

Oyster: Modern prognostication post-arrest requires integration of clinical exam (off sedation >72 hours), EEG background, bilateral SSEPs, imaging, and biomarkers. Myoclonus alone is no longer considered uniformly fatal.

Case 3: The Elderly Woman with Fluctuating Confusion

Presentation: An 82-year-old woman with no seizure history presents with 3 days of waxing-waning confusion, staring spells, and occasional lip-smacking. CT head is unremarkable.

2HELPS2B Score: Hospitalized (2) + Loss of consciousness at presentation (2) = 4 (High risk for NCSE)

Action: Urgent EEG

EEG Findings: Continuous left temporal theta-delta activity with embedded sharp waves at 1.5 Hz

Diagnosis: Probable NCSE per Salzburg criteria (requires response to IV ASM for confirmation given frequency <2.5 Hz)

Management:

IV lorazepam 2 mg + observe for clinical and EEG improvement (supports ictal diagnosis)
Load levetiracetam 2000 mg IV or valproate 1500 mg IV
Search for precipitant (infection, metabolic, medication, stroke)

Pearl: De novo absence SE in elderly often responds dramatically to valproate. If rapid improvement occurs, this supports the diagnosis and justifies continued treatment.

Conclusion

The management of status epilepticus and its mimics represents one of the most challenging yet intellectually rewarding domains in critical care medicine. Success hinges on rapid pattern recognition, systematic treatment escalation guided by evidence, sophisticated use of continuous EEG monitoring, and thoughtful pursuit of underlying etiologies—particularly autoimmune causes in refractory presentations. The modern intensivist must balance aggressive seizure control against the risks of over-treatment, recognize the evolving landscape of second-line therapies beyond traditional agents, and maintain diagnostic humility when confronted with challenging presentations that may not represent seizures at all.

As our understanding of SE pathophysiology deepens and novel therapies emerge, the principles outlined in this review—early recognition, time-sensitive treatment, continuous monitoring, etiological pursuit, and patient-centered prognostication—will remain foundational to optimizing outcomes in these critically ill patients. The art of managing the uncontrolled seizure lies not merely in stopping the electrical storm, but in doing so judiciously while preserving the patient's neurological potential and dignity.

Tuesday, October 7, 2025