Status Epilepticus

Quick Answer

Status epilepticus (SE) is a seizure lasting ≥5 minutes or ≥2 seizures without full recovery of consciousness between episodes. It represents a neurological emergency requiring immediate treatment to prevent neuronal injury and death. The ILAE 2015 definition identifies two critical time points: t₁ = 5 minutes (when treatment must start) and t₂ = 30 minutes (when long-term brain damage occurs). First-line treatment is benzodiazepines (IV lorazepam 0.1 mg/kg or IM midazolam 10 mg). Second-line agents include levetiracetam 60 mg/kg, phenytoin 20 mg/kg, or valproate 40 mg/kg. Refractory SE (failure of first- and second-line agents) requires general anaesthesia with propofol, midazolam infusion, or thiopentone, titrated to EEG seizure suppression or burst suppression. Non-convulsive status epilepticus (NCSE) affects 10-20% of ICU patients and requires continuous EEG monitoring for diagnosis.

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CICM Exam Focus

What Examiners Expect

For the CICM Second Part Examination, candidates must demonstrate:

1. Definition and Classification: ILAE 2015 two-timepoint definition (t₁ = 5 min, t₂ = 30 min), convulsive vs non-convulsive SE, refractory SE (failure of 2 agents), super-refractory SE (greater than 24 hours despite anaesthesia).

2. Immediate Resuscitation: ABCDE approach, airway protection, high-flow oxygen, IV access, BSL check and treatment of hypoglycaemia (dextrose 50% 50 mL + thiamine 100 mg IV).

3. Tiered Pharmacological Management:

   • First-line: Benzodiazepines (lorazepam 0.1 mg/kg IV, midazolam 10 mg IM if no IV access)
   • Second-line: Levetiracetam 60 mg/kg, phenytoin 20 mg/kg, or valproate 40 mg/kg
   • Third-line: General anaesthesia (propofol, midazolam infusion, thiopentone, ketamine)

4. Continuous EEG Monitoring: Mandatory for NCSE diagnosis, titration of anaesthetic agents to seizure suppression or burst suppression (1:5 ratio).

5. Complications: Rhabdomyolysis, hyperthermia, cerebral oedema, aspiration pneumonia, lactic acidosis, cardiac arrhythmias, propofol infusion syndrome (PRIS).

6. Evidence-Based Practice: RAMPART trial (IM midazolam non-inferior to IV lorazepam), ESETT trial (levetiracetam, phenytoin, and valproate equally effective as second-line agents).

Common CICM SAQ Themes

• Management algorithm for generalised tonic-clonic status epilepticus (tiered approach).
• Diagnosis and management of NCSE in comatose ICU patient.
• Refractory status epilepticus: anaesthetic agents, EEG targets, complications.
• Differential diagnosis of prolonged seizures (e.g., hypoglycaemia, stroke, encephalitis, toxins).
• Neuroimaging findings: MRI DWI/FLAIR hyperintensity, hippocampal swelling, pulvinar sign.

Key Evidence to Cite

• ILAE 2015 Definition (Trinka & Cock, PMID: 26336950): t₁ = 5 min, t₂ = 30 min for GTCS.
• RAMPART Trial (Silbergleit et al., PMID: 22150065): IM midazolam 73.4% vs IV lorazepam 63.4% seizure cessation.
• ESETT Trial (Kapur et al., PMID: 31461640): Levetiracetam, fosphenytoin, and valproate had similar efficacy (47%, 45%, 46% seizure cessation).
• Neurocritical Care Society Guidelines (Brophy et al., PMID: 22522065): Consensus on refractory SE management.
• Salzburg Criteria (Leitinger et al., PMID: 26724103): EEG criteria for NCSE diagnosis.

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Key Points

1. Status epilepticus is defined as a seizure ≥5 minutes or ≥2 seizures without full recovery of consciousness (ILAE 2015, PMID: 26336950).

2. The two critical time points are t₁ = 5 minutes (treatment threshold) and t₂ = 30 minutes (onset of irreversible neuronal injury).

3. First-line treatment is benzodiazepines: IV lorazepam 0.1 mg/kg (4 mg adult dose) or IM midazolam 10 mg if no IV access (RAMPART trial, PMID: 22150065).

4. Second-line agents (levetiracetam 60 mg/kg, phenytoin 20 mg/kg, valproate 40 mg/kg) are equally effective (ESETT trial, PMID: 31461640).

5. Refractory SE (failure of 2 agents) requires intubation and general anaesthesia: propofol, midazolam infusion, thiopentone, or ketamine, titrated to EEG seizure suppression or burst suppression.

6. Non-convulsive status epilepticus (NCSE) affects 10-20% of ICU patients and is diagnosed using continuous EEG and Salzburg criteria (PMID: 26724103).

7. Super-refractory SE (greater than 24 hours despite anaesthesia) may require ketamine, inhaled anaesthetics (isoflurane), immunotherapy, or ketogenic diet.

8. Complications include rhabdomyolysis, hyperthermia, cerebral oedema, lactic acidosis, aspiration pneumonia, cardiac arrhythmias, and propofol infusion syndrome (PRIS).

9. Continuous EEG monitoring is mandatory for RSE and NCSE to guide anaesthetic titration and detect electrographic seizures.

10. Always check BSL in all seizure patients and treat hypoglycaemia with dextrose 50% (50 mL) + thiamine 100 mg IV.

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Clinical Overview

Definition and Epidemiology

Status epilepticus (SE) is a life-threatening neurological emergency characterised by prolonged seizure activity or recurrent seizures without full recovery of consciousness. The International League Against Epilepsy (ILAE) redefined SE in 2015 to incorporate two critical operational time points¹:

• t₁ (Time to initiate treatment): 5 minutes for generalised tonic-clonic seizures (GTCS), 10 minutes for focal seizures with impaired awareness.
• t₂ (Threshold for long-term consequences): 30 minutes for GTCS, greater than 60 minutes for focal seizures.

This definition reflects the clinical reality that most seizures lasting greater than 5 minutes do not terminate spontaneously and require emergency intervention to prevent neuronal injury and systemic complications.

Epidemiology

• Incidence: 10-40 per 100,000 population per year²
• Mortality: 10-20% overall, higher in elderly (20-38%) and refractory SE (30-50%)²³
• Age distribution: Bimodal peaks in children below 1 year and adults greater than 60 years
• Aetiology:
  • "Adults: Stroke (25%), alcohol withdrawal (15%), AED non-compliance (20%), CNS infection (10%), hypoxic brain injury (10%)⁴"
  • "Children: Acute symptomatic (50%), remote symptomatic (30%), idiopathic (20%)⁵"

Classification

SE is classified along multiple axes¹:

1. Semiology (Clinical Presentation)

2. Response to Treatment

3. Aetiology

• Acute symptomatic: Stroke, CNS infection, trauma, metabolic (hypoglycaemia, hyponatraemia)
• Remote symptomatic: Prior brain injury, structural lesion (tumour, dysplasia)
• Progressive symptomatic: Autoimmune encephalitis, mitochondrial disease
• Unknown/cryptogenic: No identifiable cause despite full investigation

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Pathophysiology

Mechanisms of Seizure Termination Failure

Normal seizures terminate within 1-2 minutes through intrinsic inhibitory mechanisms. SE occurs when these mechanisms fail⁶⁷:

1. GABA Receptor Internalisation

• Prolonged neuronal firing → GABA_A receptors internalised from synaptic membrane to cytoplasm
• Clinical consequence: Benzodiazepines become progressively less effective after 20-30 minutes of seizure activity
• Mechanism: Clathrin-mediated endocytosis triggered by excess glutamate and calcium influx
• Evidence: Animal models show 50% reduction in surface GABA_A receptors after 30 min SE⁸

2. NMDA Receptor Upregulation

• Glutamate receptor trafficking: NMDA receptors translocate to synaptic membrane during SE
• Calcium influx: Excessive Ca²⁺ entry → excitotoxicity, mitochondrial dysfunction, cell death
• Clinical implication: NMDA antagonists (ketamine) become more effective in late/refractory SE
• Evidence: NMDA receptor density increases 3-fold within 60 min of SE onset⁹

3. Metabolic Decompensation

Neuronal Injury Cascade

Prolonged SE (greater than 30 minutes) initiates a cascade of neuronal injury¹⁰¹¹:

1. Excitotoxicity: Excess glutamate → calcium overload → mitochondrial dysfunction → apoptosis
2. Oxidative stress: Reactive oxygen species (ROS) production → lipid peroxidation → membrane damage
3. Inflammation: Microglial activation → cytokine release (IL-1β, TNF-α) → BBB disruption
4. Cerebral oedema:
   • Cytotoxic oedema (0-24 hours): Neuronal swelling, DWI restriction on MRI
   • Vasogenic oedema (24-72 hours): BBB breakdown, FLAIR hyperintensity
5. Long-term consequences: Hippocampal sclerosis, mesial temporal lobe epilepsy, cognitive impairment

Self-Sustaining Seizure Activity

After 30-60 minutes, SE becomes self-sustaining and may continue even if the initial trigger is removed¹²:

• Molecular changes: Altered ion channel expression, synaptic remodelling
• Network reorganisation: Formation of aberrant excitatory circuits
• Clinical implication: Early aggressive treatment (below 30 min) prevents transition to self-sustaining SE

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Clinical Presentation

Convulsive Status Epilepticus (CSE)

Generalised Tonic-Clonic SE

Early phase (0-20 minutes):

• Continuous tonic-clonic motor activity
• Hypertension (SBP 180-220 mmHg), tachycardia (HR 120-160)
• Hyperglycaemia (BSL 10-20 mmol/L)
• Hypoxia (SpO₂ 80-90%) if airway compromised
• Hyperthermia (38-40°C)

Late phase (greater than 30 minutes):

• Motor activity may become subtle or absent ("subtle generalised convulsive SE")
• Hypotension (SBP below 90 mmHg)
• Hypoglycaemia (BSL below 3.0 mmol/L)
• Severe lactic acidosis (pH 7.0-7.2, lactate 10-20 mmol/L)
• Hyperthermia (greater than 40°C), rhabdomyolysis (CK greater than 10,000 U/L)
• Respiratory failure, aspiration pneumonia

Focal Motor SE (Epilepsia Partialis Continua)

• Continuous focal motor seizures (e.g., hand, face) without impaired consciousness
• May last hours to days
• Causes: Stroke, tumour, Rasmussen's encephalitis, autoimmune encephalitis
• Treatment: AEDs, immunotherapy if autoimmune

Non-Convulsive Status Epilepticus (NCSE)

NCSE accounts for 25-30% of SE cases and is frequently missed without EEG monitoring¹³¹⁴.

Clinical Features

• Altered mental status: Confusion, lethargy, stupor, coma
• Subtle motor signs (20-30% of cases):
  • Nystagmus or eye deviation
  • Facial or limb twitching
  • Automatisms (lip-smacking, fumbling)
• No overt tonic-clonic activity
• Fluctuating level of consciousness

High-Risk Populations for NCSE

Salzburg Consensus Criteria for NCSE Diagnosis

The Salzburg criteria provide EEG-based diagnostic criteria for NCSE¹⁵:

For patients WITHOUT known epileptic encephalopathy, NCSE is diagnosed if:

1. Epileptiform discharges (EDs) greater than 2.5 Hz, OR
2. EDs ≤2.5 Hz or rhythmic delta/theta activity (greater than 0.5 Hz) PLUS one of:
   • EEG improvement after IV benzodiazepine
   • Clinical improvement after IV benzodiazepine
   • Subtle clinical ictal phenomena (e.g., eye twitching)
   • Spatiotemporal evolution (change in frequency greater than 1 Hz, morphology, or location)

For patients WITH known epileptic encephalopathy:

• Increased prominence of baseline EEG abnormalities AND clinical/EEG improvement with IV benzodiazepine

Diagnostic Approach to NCSE

Comatose ICU patient with unexplained altered mental status
            ↓
    Continuous EEG monitoring (minimum 24-48 hours)
            ↓
    Apply Salzburg Criteria
            ↓
    ┌─────────────────┬─────────────────┐
    ↓                 ↓                 ↓
Certain NCSE    Possible NCSE    Not NCSE
(EDs greater than 2.5 Hz)   (EDs ≤2.5 Hz)    (No criteria met)
    ↓                 ↓                 ↓
Treat with      IV benzodiazepine   Continue monitoring
AEDs            "trial"             Investigate other causes
    ↓                 ↓
            Clinical/EEG improvement?
            ↓               ↓
          Yes             No
            ↓               ↓
        Treat NCSE   Unlikely NCSE
                     Consider other DDx

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Differential Diagnosis

Mimics of Status Epilepticus

Causes of Status Epilepticus

Acute Symptomatic (50%)

• Metabolic: Hypoglycaemia, hyponatraemia (below 120 mmol/L), hypocalcaemia, uraemia, hepatic encephalopathy
• Vascular: Ischaemic stroke, intracerebral haemorrhage, SAH, PRES (posterior reversible encephalopathy syndrome)
• Infection: Meningitis, encephalitis (HSV, VZV, autoimmune), cerebral abscess, malaria
• Toxic: Alcohol withdrawal, cocaine, amphetamines, isoniazid, organophosphates
• Trauma: Traumatic brain injury, subdural haematoma
• Anoxic: Post-cardiac arrest, drowning, asphyxiation

Remote Symptomatic (30%)

• Prior brain injury: Remote stroke, TBI, perinatal injury
• Structural lesion: Brain tumour, cortical dysplasia, hippocampal sclerosis
• Epilepsy: AED non-compliance or withdrawal, subtherapeutic levels

Progressive Symptomatic (10%)

• Autoimmune encephalitis: NMDA receptor, LGI1, GABA_B receptor antibodies
• Mitochondrial disorders: MELAS, Alpers' disease
• Neurodegenerative: Creutzfeldt-Jakob disease (CJD)

Cryptogenic/Unknown (10%)

• No identifiable cause despite full investigation

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Investigations

Initial Urgent Investigations

All patients with SE require the following investigations performed in parallel with initial treatment:

Bedside Tests (0-5 minutes)

• Blood glucose (BSL): Hypoglycaemia (below 3.0 mmol/L) is a common and reversible cause
• ECG: Arrhythmias, prolonged QTc (risk with phenytoin, antipsychotics)
• Capillary blood gas (VBG/ABG): Lactic acidosis, hypoxia, hypercapnia
• Core temperature: Hyperthermia (greater than 40°C) indicates severe SE with rhabdomyolysis risk

Blood Tests (0-10 minutes)

Neuroimaging

CT Brain (Non-Contrast)

Indications:

• All new-onset SE (perform within 1 hour if patient stable)
• Focal neurological signs
• Head trauma
• Anticoagulation (risk of ICH)

Findings:

• Acute stroke (ischaemic or haemorrhagic)
• Intracerebral haemorrhage, SAH
• Brain tumour, abscess
• Normal in 50-70% of SE cases (proceed to MRI if diagnosis unclear)

MRI Brain (with DWI, FLAIR, T2, GRE)

Indications:

• Unexplained SE (cryptogenic)
• Suspected encephalitis
• Focal SE
• Persistent altered mental status after seizure control

Findings in SE¹⁶¹⁷:

Classic patterns:

• Hippocampal swelling: Unilateral or bilateral, predictor of mesial temporal lobe epilepsy
• Cortical hyperintensity: Crosses vascular territories (unlike stroke), involves cortex > white matter
• Crossed cerebellar diaschisis: Contralateral cerebellar hemisphere hypoperfusion/signal change

Electroencephalography (EEG)

Indications for Continuous EEG (cEEG) Monitoring

1. All patients with NCSE or suspected NCSE
2. All patients with RSE or SRSE (to guide anaesthetic titration)
3. Comatose patients post-SE (to detect ongoing electrographic seizures)
4. Post-cardiac arrest patients (25-30% have NCSE)
5. Unexplained coma in ICU (SAH, TBI, stroke with delayed awakening)

Duration of cEEG Monitoring

• Comatose patients: Minimum 24-48 hours (95% of seizures detected within 48 hours)¹⁸
• Awake but confused: Minimum 24 hours
• RSE on anaesthetic agents: Continuous until 24-48 hours post-anaesthetic withdrawal

EEG Patterns and Interpretation

Lumbar Puncture

Indications:

• Fever + altered mental status (meningitis, encephalitis)
• Immunocompromised
• HIV positive
• Suspected autoimmune encephalitis (paraneoplastic, NMDA receptor)

Timing:

• Perform after neuroimaging (CT brain) to exclude mass lesion/elevated ICP
• Do not delay antibiotics if bacterial meningitis suspected (give empiric ceftriaxone + vancomycin before LP if necessary)

CSF studies:

• Cell count, protein, glucose
• Gram stain, bacterial culture
• HSV PCR (if encephalitis suspected)
• Autoimmune panel: NMDA receptor antibodies, LGI1, GABA_B, AMPA, CASPR2
• Cytology (if malignancy suspected)

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Management

Initial Stabilisation (0-5 Minutes)

ABCDE Approach:

A – Airway

• Protect airway: Position patient in recovery position (left lateral) to reduce aspiration risk
• Suction oropharynx if secretions or vomitus present
• Do NOT insert oral airway or bite block during active seizure (risk of dental trauma)
• Intubation indications: Persistent hypoxia (SpO₂ below 90%), respiratory failure, refractory SE requiring general anaesthesia

B – Breathing

• High-flow oxygen (15 L/min via non-rebreather mask) to maintain SpO₂ greater than 94%
• Monitor respiratory rate, SpO₂, ETCO₂ (if available)
• Capillary blood gas (VBG/ABG): Assess for hypoxia, hypercapnia, lactic acidosis

C – Circulation

• Two large-bore IV cannulae (14-16G)
• ECG monitoring: Continuous cardiac monitoring (arrhythmias, prolonged QTc)
• Blood pressure monitoring: Hypertension in early SE, hypotension in late SE
• IV fluid resuscitation: 0.9% NaCl 20 mL/kg bolus if hypotensive (SBP below 90 mmHg)

D – Disability

• Blood glucose (BSL): ALWAYS check BSL in all seizure patients
  • "If BSL below 3.0 mmol/L: Dextrose 50% 50 mL IV + Thiamine 100 mg IV (prevents Wernicke's encephalopathy)"
• GCS score: Assess level of consciousness
• Pupil size and reactivity: Miosis (opiates), mydriasis (anticholinergics, sympathomimetics)
• Focal neurological signs: Suggests structural lesion (stroke, tumour, abscess)

E – Exposure

• Core temperature: Hyperthermia (greater than 40°C) indicates severe SE, risk of rhabdomyolysis
• Active cooling if T greater than 39.5°C: Ice packs to groin/axillae, cooling blanket, paracetamol 1 g IV
• Examine for trauma: Tongue biting (lateral tongue = focal seizure), posterior shoulder dislocation

Tiered Pharmacological Management

The management of SE follows a tiered approach based on time and response to treatment¹⁹²⁰²¹:

Time 0 min ─────────────────────────────────────────────────────────────→
     ↓
 0-5 min: Initial stabilisation (ABCDE, BSL, IV access)
     ↓
 5-20 min: FIRST-LINE (Benzodiazepines)
     ↓
 20-40 min: SECOND-LINE (Levetiracetam, Phenytoin, Valproate)
     ↓
 40-60 min: THIRD-LINE (General anaesthesia: Propofol, Midazolam, Thiopentone, Ketamine)
     ↓
 greater than 24 hours: SUPER-REFRACTORY SE (Ketamine, Isoflurane, Immunotherapy)

First-Line Treatment: Benzodiazepines (5-20 Minutes)

Benzodiazepines are the gold standard first-line treatment for SE. They enhance GABA_A receptor activity, increasing chloride influx and neuronal hyperpolarisation.

Drug Options

Evidence: RAMPART Trial (PMID: 22150065)

The RAMPART trial (2012) compared IM midazolam vs IV lorazepam in prehospital SE²²:

• Design: Multicentre, double-blind RCT, 893 patients
• Intervention: IM midazolam 10 mg vs IV lorazepam 4 mg
• Primary outcome: Seizure cessation on arrival to ED without rescue medication
• Results:
  • "IM midazolam: 73.4% (329/448 patients)"
  • "IV lorazepam: 63.4% (282/445 patients)"
  • p below 0.001 (IM midazolam superior)
• Time to administration: IM midazolam 1.2 min vs IV lorazepam 4.8 min (faster due to no IV access required)
• Conclusion: IM midazolam is at least as effective as IV lorazepam and is preferred in prehospital setting.

Dosing Protocol

If IV access available:

1. Lorazepam 0.1 mg/kg IV (4 mg adult dose) over 2 minutes
2. Repeat after 5 minutes if seizures continue (max 2 doses)

If NO IV access:

1. Midazolam 10 mg IM (deltoid or vastus lateralis)
2. Repeat after 10 minutes if seizures continue (max 2 doses)

Alternative: Diazepam 10-20 mg IV or 10-20 mg PR (rectal)

Adverse Effects

• Respiratory depression (10-20%): Risk increases with multiple doses or co-administration of opiates
• Hypotension (5-10%): More common with rapid IV bolus
• Management: Monitor SpO₂, consider intubation if persistent hypoxia (SpO₂ below 90%)

Second-Line Treatment: Non-Sedating AEDs (20-40 Minutes)

If seizures continue despite benzodiazepines (established SE), administer a non-sedating AED. The ESETT trial (2019) showed that levetiracetam, phenytoin, and valproate are equally effective as second-line agents²³.

Drug Options

Evidence: ESETT Trial (PMID: 31461640)

The Established Status Epilepticus Treatment Trial (ESETT) (2019) compared three second-line agents²³:

• Design: Multicentre, double-blind RCT, 384 patients
• Population: Benzodiazepine-refractory SE (established SE)
• Intervention:
  • Levetiracetam 60 mg/kg (max 4,500 mg)
  • Fosphenytoin 20 mg PE/kg (max 1,500 mg PE)
  • Valproate 40 mg/kg (max 3,000 mg)
• Primary outcome: Clinical seizure cessation by 60 minutes, no further seizures by 60 minutes, no rescue medication required
• Results:
  • "Levetiracetam: 47% (52/118 patients)"
  • "Fosphenytoin: 45% (56/125 patients)"
  • "Valproate: 46% (56/121 patients)"
  • No significant difference (p = 0.90)
• Conclusion: All three agents are equally effective for benzodiazepine-refractory SE. Choice depends on patient factors (cardiac disease, pregnancy, hepatic dysfunction).

Recommended Protocol

Levetiracetam (preferred in most patients due to safety profile):

• Dose: 60 mg/kg IV (max 4,500 mg)
• Infusion: Over 10 minutes
• Monitoring: No cardiac monitoring required
• Contraindications: None (renally excreted, dose reduction in renal impairment)

Phenytoin/Fosphenytoin (if cardiac history, focal SE):

• Dose: Phenytoin 20 mg/kg (max 1,500 mg) OR Fosphenytoin 20 mg PE/kg (max 1,500 mg PE)
• Infusion: Phenytoin 50 mg/min, Fosphenytoin 100-150 mg PE/min
• Monitoring: Continuous ECG, BP monitoring (risk of bradycardia, AV block, hypotension)
• Contraindications: 2nd/3rd degree AV block, sick sinus syndrome, pregnancy
• Adverse effects: Purple glove syndrome (phenytoin), hypotension (infusion rate greater than 50 mg/min)

Valproate (if generalised epilepsy, absence SE):

• Dose: 40 mg/kg IV (max 3,000 mg)
• Infusion: Over 10 minutes
• Monitoring: LFTs, platelets
• Contraindications: Pregnancy (teratogenic), hepatic failure, mitochondrial disorders
• Adverse effects: Hepatotoxicity, thrombocytopenia, hyperammonaemia

Additional Second-Line Agents

Phenobarbital:

• Dose: 20 mg/kg IV at 50-100 mg/min
• Indication: Neonatal SE, alcohol withdrawal seizures
• Adverse effects: Respiratory depression, hypotension (requires intubation in 50% of cases)

Lacosamide:

• Dose: 200-400 mg IV over 15 minutes
• Evidence: Retrospective studies show 50-60% efficacy in established SE
• Adverse effects: PR prolongation (avoid in AV block), hypotension

Third-Line Treatment: General Anaesthesia (40-60 Minutes)

If seizures continue despite benzodiazepines + one second-line AED, the patient has refractory status epilepticus (RSE) and requires intubation and general anaesthesia²⁴²⁵.

Indications for Intubation and Anaesthesia

1. Refractory SE: Failure of benzodiazepine + 1 AED (≥2 agents total)
2. Respiratory failure: Persistent hypoxia (SpO₂ below 90%), hypercapnia (PaCO₂ greater than 60 mmHg)
3. Severe lactic acidosis: pH below 7.1, lactate greater than 10 mmol/L
4. Haemodynamic instability: Hypotension (SBP below 90 mmHg) despite fluids

Pre-Intubation Checklist

• Large-bore IV access (14-16G x 2)
• Arterial line for continuous BP monitoring
• Central venous access (for anaesthetic infusions, vasopressors)
• Prepare vasopressors: Noradrenaline infusion ready (anaesthetic agents cause hypotension)
• Continuous EEG monitoring: Mandatory for titration to burst suppression or seizure suppression

Anaesthetic Agent Options

Continuous EEG Targets

The optimal EEG target for anaesthetic titration is debated. Two strategies exist:

1. Seizure suppression: Complete cessation of electrographic seizures (no burst suppression required)

   • Evidence: Adequate for most RSE cases, fewer haemodynamic side effects
   • Monitoring: Continuous EEG, titrate to absence of seizures

2. Burst suppression: Periods of electrical silence (suppression) alternating with bursts of activity

   • Target ratio: 1:5 (1 second burst : 5 seconds suppression)
   • Evidence: Traditional approach, may not improve outcomes but used for refractory cases
   • Monitoring: Quantitative EEG (qEEG) to measure suppression ratio

Current recommendation (Neurocritical Care Society)²⁴:

• Initial target: Seizure suppression
• If seizures recur on weaning: Escalate to burst suppression (1:5 ratio)

Midazolam Protocol

Indication: First-line anaesthetic agent for RSE (preferred in many ICUs)²⁶

Dosing:

1. Loading dose: 0.2 mg/kg IV over 2 minutes (repeat every 5 min until seizures stop, max 2 mg/kg total)
2. Initial infusion: 0.05-0.1 mg/kg/hr
3. Titration: Increase by 0.05-0.1 mg/kg/hr every 15-30 min until EEG target reached
4. Maintenance: 0.05-2.0 mg/kg/hr (range, often requires escalation due to tachyphylaxis)

Monitoring:

• Continuous EEG (target: seizure suppression or BS 1:5)
• Continuous BP (prepare noradrenaline infusion)
• Daily sedation hold to assess neurological status

Weaning:

• Maintain EEG target for 24-48 hours
• Reduce infusion rate by 20-25% every 4-6 hours
• If seizures recur, re-bolus and increase infusion rate

Adverse effects:

• Tachyphylaxis: Tolerance develops after 24-48 hours, requiring dose escalation
• Hypotension: 30-50% of patients require vasopressors
• Metabolic acidosis: Propylene glycol toxicity (rare with modern formulations)

Propofol Protocol

Indication: Alternative to midazolam, familiar to ICU staff

Dosing:

1. Loading dose: 1-2 mg/kg IV over 5 minutes
2. Initial infusion: 2-5 mg/kg/hr
3. Titration: Increase by 1-2 mg/kg/hr every 15-30 min until EEG target reached
4. Maintenance: 2-10 mg/kg/hr (max 4 mg/kg/hr if used greater than 48 hours to reduce PRIS risk)

Monitoring:

• Continuous EEG
• Continuous BP (hypotension common)
• Daily triglycerides, CK, lactate (PRIS monitoring)
• Limit infusion to 48-72 hours (switch to midazolam or thiopentone if longer duration needed)

Propofol Infusion Syndrome (PRIS)²⁷:

• Definition: Severe metabolic acidosis, rhabdomyolysis, cardiac failure, renal failure
• Risk factors: Dose greater than 4 mg/kg/hr, duration greater than 48 hours, young age, mitochondrial disorders
• Mortality: 30-60%
• Prevention: Limit dose to below 4 mg/kg/hr, duration below 48-72 hours, monitor CK/lactate daily

PRIS diagnostic criteria:

• Metabolic acidosis (pH below 7.2, BE <-10)
• Rhabdomyolysis (CK greater than 5,000 U/L)
• Cardiac arrhythmia or failure
• Renal failure
• Management: STOP propofol immediately, switch to alternative agent, supportive care

Thiopentone Protocol

Indication: Most effective agent for super-refractory SE (SRSE), second-line after midazolam/propofol failure²⁸

Dosing:

1. Loading dose: 3-5 mg/kg IV over 5-10 minutes (repeat 50-100 mg boluses until seizures stop or BS achieved)
2. Initial infusion: 3-5 mg/kg/hr
3. Titration: Increase by 1 mg/kg/hr every 4-6 hours to achieve burst suppression (1:5 ratio)
4. Maintenance: 3-7 mg/kg/hr

Monitoring:

• Continuous EEG (target: burst suppression 1:5 ratio)
• Continuous BP (severe hypotension in 80-90% of cases)
• Vasopressor support (noradrenaline, vasopressin)
• Daily levels if prolonged use (therapeutic range 30-50 mg/L)

Weaning:

• Maintain burst suppression for 48-72 hours
• Reduce infusion by 0.5-1 mg/kg/hr every 6-12 hours
• Very slow weaning (thiopentone has long half-life, 10-20 hours)

Adverse effects:

• Severe hypotension: 80-90% require vasopressors (noradrenaline, vasopressin)
• Myocardial depression: Negative inotrope, may require inotropic support
• Ileus: Prolonged recovery, enteral feeding intolerance
• Immunosuppression: Risk of nosocomial pneumonia, sepsis
• Prolonged sedation: Accumulation with long-term use, delayed awakening

Ketamine Protocol

Indication: Super-refractory SE (SRSE) when midazolam/propofol/thiopentone fail, NMDA receptor antagonist²⁹³⁰

Rationale: In prolonged SE, GABA_A receptors internalise (benzodiazepines become ineffective) while NMDA receptors upregulate. Ketamine is a non-competitive NMDA antagonist and becomes more effective in late SE.

Dosing:

1. Loading dose: 1-2 mg/kg IV over 5 minutes
2. Initial infusion: 1-2 mg/kg/hr
3. Titration: Increase by 0.5-1 mg/kg/hr every 4-6 hours (max 5-10 mg/kg/hr)
4. Maintenance: 1-5 mg/kg/hr

Monitoring:

• Continuous EEG (target: seizure suppression)
• Continuous BP (ketamine is sympathomimetic, usually haemodynamically stable)
• Manage secretions (anticholinergic agent if needed)

Evidence:

• Gaspard et al. (2013): Retrospective multicentre study, 64% seizure control with ketamine in RSE (PMID: 23731110)²⁹
• Zeiler et al. (2014): Systematic review, 56.5% clinical response, earlier initiation more effective (PMID: 24823933)³⁰

Advantages:

• Haemodynamically stable (sympathomimetic, raises BP)
• Neuroprotective (blocks glutamate excitotoxicity)
• Effective in SRSE when GABA agonists fail

Adverse effects:

• Emergence phenomena: Hallucinations, agitation (minimised with concurrent sedation)
• Hypertension: Usually beneficial in SE (avoids hypotension)
• Increased secretions: Manage with anticholinergic (glycopyrrolate)

Super-Refractory Status Epilepticus (greater than 24 Hours Despite Anaesthesia)

Definition: SE that continues for greater than 24 hours despite adequate doses of anaesthetic agents, OR recurs on weaning of anaesthesia³¹.

Incidence: 10-15% of all RSE cases Mortality: 30-50%

Management Strategies

1. Optimise existing anaesthetic agents:

   • Ensure adequate dosing (EEG-guided)
   • Combine agents (e.g., midazolam + ketamine)
   • Ensure therapeutic levels of background AEDs

2. Add ketamine (if not already used):

   • Dosing: 1-5 mg/kg/hr infusion
   • Rationale: NMDA antagonism, effective when GABA agonists fail

3. Inhaled anaesthetics (Isoflurane, Desflurane):

   • Indication: SRSE refractory to IV agents
   • Dosing: Isoflurane 0.8-2.0% via ventilator, titrate to burst suppression
   • Evidence: Case series show 60-70% seizure control
   • Challenges: Requires ICU ventilator with anaesthetic gas delivery, scavenging system
   • Adverse effects: Hypotension, hepatotoxicity (rare)

4. Immunotherapy (if autoimmune encephalitis suspected):

   • Indications: Cryptogenic SE, CSF pleocytosis, MRI limbic encephalitis pattern
   • First-line:
     • Methylprednisolone 1 g IV daily x 3-5 days
     • IVIg 0.4 g/kg daily x 5 days
   • Second-line:
     • Plasma exchange (PLEX): 5-7 exchanges over 10-14 days
     • Rituximab: 375 mg/m² weekly x 4 weeks (anti-CD20, B-cell depletion)
   • Evidence: Retrospective studies show 50-70% response in autoimmune SE (NMDA receptor, LGI1)³²

5. Ketogenic diet:

   • Indication: SRSE in children or adults refractory to all agents
   • Mechanism: Shift metabolism to ketone bodies, anticonvulsant effect
   • Protocol: Enteral high-fat, low-carbohydrate diet (4:1 ratio fat:carb+protein)
   • Evidence: Case series show 50-60% seizure reduction in paediatric SRSE
   • Monitoring: Blood ketones (target 3-5 mmol/L), glucose, pH

6. Electroconvulsive therapy (ECT):

   • Indication: Case reports only, last-resort therapy
   • Evidence: Very limited, case series only

7. Neurosurgical intervention:

   • Focal resection: If focal SE with identifiable lesion (tumour, dysplasia)
   • Hemispherectomy: Paediatric cases with hemispheric lesions
   • Vagal nerve stimulation (VNS): Limited evidence

Non-Convulsive Status Epilepticus (NCSE) Management

NCSE requires a different approach than CSE, as the urgency and aggressiveness of treatment depend on the clinical context³³³⁴.

Risk Stratification

Treatment Protocol for NCSE

High-risk NCSE (comatose, post-CSE):

1. Benzodiazepines: Lorazepam 4 mg IV or midazolam 10 mg IM
2. Second-line AED: Levetiracetam 60 mg/kg or phenytoin 20 mg/kg
3. If refractory: Consider general anaesthesia (same as CSE)

Low-risk NCSE (awake, absence SE):

1. Benzodiazepines: Lorazepam 2-4 mg IV (may terminate absence SE)
2. Second-line AED: Levetiracetam 40-60 mg/kg or valproate 30-40 mg/kg
3. Avoid general anaesthesia unless truly refractory

Monitoring and Weaning

• Continuous EEG monitoring: Mandatory to confirm seizure cessation
• Clinical improvement: Must correlate with EEG improvement (Salzburg criteria)
• Weaning anaesthesia: Gradual reduction over 12-24 hours, monitor for recurrence

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Complications

Neurological Complications

Systemic Complications

Iatrogenic Complications

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Prognosis

Mortality

• Overall mortality: 10-20%²³
• Age-dependent:
  • "Children: 3-5%"
  • "Adults (20-60 years): 10-15%"
  • "Elderly (greater than 60 years): 20-38%"
• By SE type:
  • "Convulsive SE: 15-22%"
  • "Non-convulsive SE: 18-25% (similar to CSE)"
  • "Refractory SE: 30-40%"
  • "Super-refractory SE: 40-50%"

Predictors of Poor Outcome

Long-Term Neurological Outcomes

• Cognitive impairment: 30-50% of survivors (memory, executive function)³⁵
• Epilepsy: 10-20% develop chronic epilepsy after SE (status epilepticus-induced epilepsy)
• Hippocampal sclerosis: 20-40% (MRI findings, mesial temporal lobe epilepsy)
• Return to baseline: 40-60% of patients return to pre-SE neurological status

Factors Associated with Good Outcome

• Early treatment (below 30 minutes)
• Young age (below 60 years)
• Idiopathic/cryptogenic aetiology (vs acute symptomatic)
• Non-refractory SE (responds to first- or second-line agents)
• Absence of hypoxia or severe metabolic derangement

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Special Populations

Pregnancy

Eclampsia is a common cause of SE in pregnancy (seizures in pre-eclampsia).

Management:

1. Magnesium sulphate (first-line for eclampsia):
   • Loading dose: 4-6 g IV over 15 minutes
   • Maintenance: 1-2 g/hr infusion
   • Monitor Mg²⁺ levels (therapeutic 2-4 mmol/L), reflexes, UO
2. Benzodiazepines: Lorazepam 4 mg IV if seizures continue
3. Levetiracetam: Preferred AED (lower teratogenicity than phenytoin/valproate)
4. AVOID valproate (teratogenic, neural tube defects)
5. Urgent obstetric review: Delivery of foetus may be required

Neonatal/Paediatric SE

Common causes:

• Acute symptomatic: Hypoxic-ischaemic encephalopathy, meningitis, inborn errors of metabolism
• Genetic: Dravet syndrome, SCN1A mutations

Management differences:

• Pyridoxine-dependent seizures: Trial of pyridoxine 100 mg IV if refractory neonatal seizures
• Weight-based dosing: Lorazepam 0.1 mg/kg, levetiracetam 60 mg/kg, phenytoin 20 mg/kg
• Ketogenic diet: More evidence in paediatric SRSE (50-60% seizure reduction)

Alcohol Withdrawal Seizures

Management:

1. Benzodiazepines: Lorazepam 4 mg IV or diazepam 10-20 mg IV (may require higher doses)
2. Thiamine 100 mg IV (prevent Wernicke's encephalopathy)
3. Phenobarbital: Consider as second-line (effective for alcohol withdrawal)
4. Avoid phenytoin (less effective for alcohol withdrawal seizures)
5. Long-term: Alcohol withdrawal protocol, addiction services

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Intensive Care Management

Airway and Ventilation

Intubation indications:

• Refractory SE requiring general anaesthesia
• Respiratory failure (SpO₂ below 90%, PaCO₂ greater than 60 mmHg)
• GCS ≤8 (loss of airway reflexes)
• Aspiration risk (vomiting, secretions)

Ventilation strategy:

• Target PaCO₂ 35-45 mmHg (avoid hypoventilation → hypercapnia → cerebral vasodilation → ↑ ICP)
• Target SpO₂ 94-98% (avoid hyperoxia)
• PEEP 5-8 cmH₂O (avoid excessive PEEP → ↑ intrathoracic pressure → ↓ cerebral venous return → ↑ ICP)
• Lung-protective ventilation: Tidal volume 6-8 mL/kg ideal body weight

Haemodynamic Management

Blood pressure targets:

• Early SE (0-30 min): Hypertension common (SBP 180-220 mmHg). Do NOT treat (cerebral autoregulation intact, brain requires high BP to maintain perfusion).
• Late SE (greater than 30 min): Hypotension common (SBP below 90 mmHg). Treat aggressively:
  • "IV fluids: 0.9% NaCl 20 mL/kg bolus"
  • "Noradrenaline (first-line vasopressor): Start 0.05-0.1 mcg/kg/min, titrate to MAP ≥65 mmHg"
  • "Vasopressin (adjunct): 0.04 units/min (useful if high-dose noradrenaline required)"

Monitoring:

• Arterial line: Continuous BP monitoring (mandatory in RSE)
• Central venous catheter: Vasopressor/anaesthetic infusions, CVP monitoring
• Echocardiography: If myocardial dysfunction suspected (thiopentone, PRIS)

Temperature Management

Hyperthermia (greater than 39.5°C):

• Common in SE (30-50% of cases), associated with poor outcome
• Active cooling:
  • Ice packs to groin, axillae, neck
  • Cooling blanket (target 37-38°C)
  • Cold IV fluids (4°C 0.9% NaCl)
  • Paracetamol 1 g IV q6h
• Dantrolene: Consider if severe hyperthermia (greater than 41°C) refractory to cooling (1 mg/kg IV, repeat to max 10 mg/kg)

Avoid induced hypothermia (no evidence of benefit in SE, may worsen coagulopathy)

Glucose Management

Tight glycaemic control:

• Target BSL 6-10 mmol/L (avoid hypoglycaemia and hyperglycaemia)
• BSL monitoring: q1-2h (capillary or arterial)
• Insulin infusion if BSL greater than 10 mmol/L (hyperglycaemia worsens neuronal injury)
• Dextrose 50% 50 mL IV if BSL below 4.0 mmol/L (hypoglycaemia may precipitate seizures)

Nutrition

Enteral nutrition:

• Start within 24-48 hours if haemodynamically stable
• Route: Nasogastric tube (oral gastric if intubated)
• Caution with thiopentone: Causes ileus, delayed gastric emptying (may require TPN)

AED interactions:

• Phenytoin: Interacts with enteral feeds (hold feeds 1 hour before/after dose, or use fosphenytoin)

Monitoring

Essential monitoring in RSE:

• Continuous EEG (cEEG): Mandatory for anaesthetic titration, NCSE detection
• Arterial line: Continuous BP monitoring
• ECG telemetry: Cardiac arrhythmias, QTc prolongation
• Core temperature: Hyperthermia monitoring
• Urine output: Target 0.5-1.0 mL/kg/hr (rhabdomyolysis, AKI risk)

Daily investigations:

• UEC: AKI, electrolyte disturbances
• LFTs: Hepatotoxicity (valproate, phenytoin)
• FBC: Thrombocytopenia (valproate)
• CK: Rhabdomyolysis (target below 5,000 U/L)
• Lactate: Lactic acidosis, PRIS
• AED levels: Phenytoin, valproate, carbamazepine (if used)
• Triglycerides (if on propofol greater than 48 hrs): PRIS monitoring

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CICM Exam Practice

SAQ 1: Initial Management of Generalised Tonic-Clonic Status Epilepticus

Question: A 45-year-old man is brought to the emergency department by ambulance with a continuous generalised tonic-clonic seizure that has lasted 10 minutes. Outline your initial assessment and management.

Model Answer:

Definition: Status epilepticus is a seizure lasting ≥5 minutes or ≥2 seizures without full recovery of consciousness (ILAE 2015). This patient has convulsive SE requiring immediate treatment to prevent neuronal injury (t₂ = 30 minutes).

Initial Stabilisation (ABCDE):

Airway:

• Position in recovery position (left lateral) to reduce aspiration risk
• Suction oropharynx if secretions/vomitus present
• Do NOT insert oral airway or bite block during active seizure (risk of dental trauma)
• Prepare for intubation if respiratory failure or refractory SE

Breathing:

• High-flow oxygen 15 L/min via non-rebreather mask (target SpO₂ greater than 94%)
• Monitor SpO₂, RR, ETCO₂
• VBG/ABG: Assess hypoxia, hypercapnia, lactic acidosis

Circulation:

• Two large-bore IV cannulae (14-16G)
• ECG monitoring, continuous BP monitoring
• IV fluid resuscitation: 0.9% NaCl 20 mL/kg bolus if hypotensive (SBP below 90 mmHg)

Disability:

• Blood glucose (BSL): ALWAYS check in all seizure patients
  • "If BSL below 3.0 mmol/L: Dextrose 50% 50 mL IV + Thiamine 100 mg IV"
• GCS score, pupil size/reactivity, focal neurological signs

Exposure:

• Core temperature (hyperthermia greater than 40°C indicates severe SE)
• Active cooling if T greater than 39.5°C (ice packs, paracetamol 1 g IV)
• Examine for trauma (tongue biting, posterior shoulder dislocation)

Pharmacological Management:

First-line (5-20 minutes): Benzodiazepines

• Lorazepam 0.1 mg/kg IV (4 mg adult) over 2 minutes
• Repeat after 5 minutes if seizures continue (max 2 doses)
• If no IV access: Midazolam 10 mg IM (deltoid or vastus lateralis)

Second-line (20-40 minutes): Non-sedating AED (if seizures continue)

• Levetiracetam 60 mg/kg IV (max 4,500 mg) over 10 minutes (preferred)
• Alternatives: Phenytoin 20 mg/kg IV (50 mg/min, requires ECG monitoring), Valproate 40 mg/kg IV

Third-line (40-60 minutes): General anaesthesia (if refractory SE)

• Intubation and ventilation
• Midazolam infusion: Load 0.2 mg/kg, infusion 0.05-2.0 mg/kg/hr
• Continuous EEG monitoring (titrate to seizure suppression or burst suppression 1:5)

Investigations:

• Bedside: BSL, ECG, VBG/ABG, core temperature
• Blood: FBC, UEC, LFTs, Ca²⁺/Mg²⁺/PO₄³⁻, CK, lactate, AED levels, toxicology screen, blood cultures (if febrile)
• Neuroimaging: CT brain (non-contrast) within 1 hour if patient stable
• LP: If fever + altered mental status (meningitis, encephalitis)
• Continuous EEG: If NCSE suspected, comatose post-SE, or RSE

Complications to Monitor:

• Rhabdomyolysis (CK greater than 5,000 U/L), hyperthermia (greater than 40°C), lactic acidosis, aspiration pneumonia, cerebral oedema, cardiac arrhythmias

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SAQ 2: Refractory Status Epilepticus Management

Question: A 32-year-old woman with known epilepsy has been treated for convulsive status epilepticus with IV lorazepam and IV levetiracetam 60 mg/kg, but continues to have generalised tonic-clonic seizures 45 minutes after presentation. Describe your management of refractory status epilepticus.

Model Answer:

Definition: Refractory status epilepticus (RSE) is SE that fails to respond to benzodiazepines + one second-line AED (≥2 agents total). This patient has RSE and requires intubation and general anaesthesia.

Immediate Management:

Pre-Intubation Preparation:

• Large-bore IV access (14-16G x 2)
• Arterial line for continuous BP monitoring
• Central venous catheter for anaesthetic infusions and vasopressors
• Prepare vasopressors: Noradrenaline infusion ready (anaesthetic agents cause hypotension)
• Continuous EEG monitoring: Mandatory for titration to burst suppression or seizure suppression

Intubation:

• RSI (Rapid Sequence Intubation):
  • Preoxygenation (high-flow O₂)
  • "Induction: Avoid propofol/thiopentone (already planned as maintenance anaesthesia). Use midazolam 0.2 mg/kg or ketamine 2 mg/kg (haemodynamically stable)."
  • "Paralysis: Rocuronium 1.2 mg/kg or suxamethonium 1.5 mg/kg"
  • Intubate with cuffed ETT (size 7.0-8.0)
  • "Confirm placement: ETCO₂, chest auscultation, CXR"

Ventilation Strategy:

• Mode: Volume-controlled or pressure-controlled
• Tidal volume: 6-8 mL/kg ideal body weight (lung-protective ventilation)
• PEEP: 5-8 cmH₂O
• FiO₂: Target SpO₂ 94-98%
• Targets: PaCO₂ 35-45 mmHg, PaO₂ greater than 80 mmHg

Anaesthetic Agent Selection:

First-line anaesthetic: Midazolam infusion (preferred in most ICUs)

Dosing:

1. Loading dose: 0.2 mg/kg IV over 2 minutes (repeat every 5 min until seizures stop, max 2 mg/kg total)
2. Initial infusion: 0.05-0.1 mg/kg/hr
3. Titration: Increase by 0.05-0.1 mg/kg/hr every 15-30 min until EEG target reached
4. Maintenance: 0.05-2.0 mg/kg/hr (may require escalation due to tachyphylaxis)

EEG Target:

• Seizure suppression: Complete cessation of electrographic seizures (preferred initial target)
• Burst suppression: 1:5 ratio (1 second burst : 5 seconds suppression) if seizures recur on weaning

Monitoring:

• Continuous EEG: Titrate to target, detect seizure recurrence
• Arterial BP: Target MAP ≥65 mmHg
• Vasopressor support: Noradrenaline 0.05-0.1 mcg/kg/min if SBP below 90 mmHg
• Core temperature: Active cooling if T greater than 39.5°C
• BSL: q1-2h, target 6-10 mmol/L
• UO: Target 0.5-1.0 mL/kg/hr

Alternative Anaesthetic Agents (if midazolam fails or contraindicated):

Propofol:

• Loading: 1-2 mg/kg, infusion 2-10 mg/kg/hr
• Limit to 48-72 hours (PRIS risk if greater than 4 mg/kg/hr greater than 48 hrs)
• Monitor: Daily triglycerides, CK, lactate

Thiopentone (most effective for super-refractory SE):

• Loading: 3-5 mg/kg, infusion 3-7 mg/kg/hr
• EEG target: Burst suppression 1:5 ratio
• Adverse effects: Severe hypotension (80-90% require vasopressors), ileus

Ketamine (if GABA agonists fail):

• Loading: 1-2 mg/kg, infusion 1-5 mg/kg/hr
• Advantages: NMDA antagonist, haemodynamically stable
• Evidence: 64% seizure control in RSE (Gaspard et al., PMID: 23731110)

Weaning Protocol:

1. Maintain EEG target for 24-48 hours seizure-free
2. Reduce infusion rate by 20-25% every 4-6 hours
3. Monitor continuous EEG for seizure recurrence
4. If seizures recur: Re-bolus, increase infusion rate, consider alternative agent

Investigations:

• Daily: UEC, LFTs, FBC, CK, lactate, AED levels
• MRI brain (once stabilised): DWI/FLAIR (hippocampal swelling, cortical hyperintensity, pulvinar sign)
• LP (if not already done): HSV PCR, autoimmune panel (NMDA receptor antibodies)

Complications:

• Propofol infusion syndrome (PRIS): Monitor CK/lactate daily, STOP propofol if metabolic acidosis
• Hypotension: Vasopressor support (noradrenaline, vasopressin)
• Tachyphylaxis: Midazolam tolerance after 24-48 hrs (may require dose escalation or agent switch)

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Viva 1: Non-Convulsive Status Epilepticus (NCSE)

Scenario: You are the ICU consultant. A 62-year-old man was admitted 3 days ago with subarachnoid haemorrhage (SAH) from a ruptured MCA aneurysm, which was clipped. He is intubated and sedated. The nursing staff report that despite stopping sedation 24 hours ago, he remains comatose (GCS 6) with intermittent subtle facial twitching. The neurosurgical team asks you to review.

Examiner Questions and Model Answers:

Q1: What is your differential diagnosis for persistent coma in this patient?

A1: The differential for persistent coma post-SAH includes:

1. Non-convulsive status epilepticus (NCSE) – High-risk population (SAH, 10-20% prevalence), subtle facial twitching is a clue.
2. Delayed cerebral ischaemia (DCI) – Vasospasm typically occurs days 4-14 post-SAH.
3. Hydrocephalus – Acute or communicating hydrocephalus post-SAH.
4. Residual sedation – Propofol/midazolam accumulation (less likely 24 hrs post-cessation).
5. Re-bleed or new haemorrhage – Aneurysm re-rupture (rare post-clipping).
6. Metabolic encephalopathy – Hyponatraemia (SIADH), hypoglycaemia, hepatic/renal failure.

NCSE is high on the differential given the subtle facial twitching and SAH as a risk factor.

Q2: What investigation would you prioritise, and why?

A2: Continuous EEG (cEEG) monitoring is the priority investigation.

Rationale:

• NCSE cannot be diagnosed clinically; EEG is mandatory for diagnosis.
• SAH is a high-risk population for NCSE (10-20% prevalence).
• Subtle motor signs (facial twitching) suggest ictal activity.
• Salzburg Criteria require EEG confirmation (epileptiform discharges greater than 2.5 Hz, or below 2.5 Hz + clinical/EEG improvement with benzodiazepine trial).

Other investigations (parallel):

• CT brain (non-contrast): Exclude hydrocephalus, re-bleed, DCI (hypodensity).
• UEC: Hyponatraemia (SIADH common post-SAH).
• BSL: Hypoglycaemia.

Q3: The EEG shows continuous 2.0 Hz generalised spike-wave discharges. How do you interpret this?

A3: This EEG shows epileptiform discharges (EDs) at 2.0 Hz, which is ≤2.5 Hz according to Salzburg Criteria.

Salzburg Criteria Application (patient WITHOUT known epileptic encephalopathy):

• EDs ≤2.5 Hz PLUS one of:
  • EEG improvement after IV benzodiazepine
  • Clinical improvement after IV benzodiazepine
  • Subtle clinical ictal phenomena (facial twitching – present)
  • Spatiotemporal evolution

Diagnosis: "Possible NCSE" based on EDs ≤2.5 Hz + subtle ictal phenomena (facial twitching).

Next step: Diagnostic benzodiazepine trial to confirm NCSE.

Q4: Describe your management plan.

A4:

Immediate Management:

1. Diagnostic Benzodiazepine Trial:

   • Lorazepam 2-4 mg IV over 2 minutes
   • Repeat EEG: Assess for EEG improvement (reduction in spike frequency, amplitude)
   • Clinical assessment: Assess for GCS improvement (eye opening, following commands)
   • If both EEG and clinical improvement occur: Diagnosis of "Certain NCSE" confirmed (Salzburg Criteria).

2. Second-line AED (if NCSE confirmed):

   • Levetiracetam 60 mg/kg IV (max 4,500 mg) over 10 minutes (preferred)
   • Alternatives: Phenytoin 20 mg/kg IV, Valproate 40 mg/kg IV

3. Risk Stratification:

   • This is high-risk NCSE (acute brain injury, SAH, comatose).
   • Treatment urgency: Same as convulsive SE (aim for seizure suppression).

4. If Refractory to Benzodiazepine + AED:

   • Consider general anaesthesia (midazolam infusion, propofol) titrated to EEG seizure suppression.
   • Intubation: Already intubated (favourable).

Monitoring:

• Continuous EEG: Mandatory to assess treatment response, detect seizure recurrence.
• Daily neuro assessment: GCS, pupil reactivity, focal signs.

Investigations (if NCSE confirmed):

• MRI brain (DWI/FLAIR): Assess for SE-induced oedema, DCI.
• Autoimmune panel (if cryptogenic): NMDA receptor antibodies (less likely in SAH context).

Q5: What are the long-term implications of NCSE in this patient?

A5:

• Mortality: NCSE has similar mortality to convulsive SE (18-25%). In SAH patients, NCSE is associated with worse functional outcomes (mRS at 3 months).
• Cognitive impairment: 30-50% of NCSE survivors have memory and executive dysfunction.
• Epilepsy: 10-20% develop chronic epilepsy (status epilepticus-induced epilepsy).
• Hippocampal sclerosis: 20-40% show MRI evidence of hippocampal injury (mesial temporal lobe epilepsy risk).

Follow-up:

• Neurology outpatient review (long-term AED therapy, epilepsy monitoring)
• Neuropsychology assessment (cognitive impairment)
• MRI brain (3 months post-discharge to assess hippocampal sclerosis)

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Viva 2: Super-Refractory Status Epilepticus (SRSE)

Scenario: You are the ICU consultant. A 28-year-old woman with no past medical history presented with new-onset generalised tonic-clonic seizures. She was treated with IV lorazepam, levetiracetam 60 mg/kg, and phenytoin 20 mg/kg, but seizures continued. She was intubated and commenced on midazolam infusion 0.1 mg/kg/hr, titrated to burst suppression on EEG. She has now been on midazolam for 48 hours. Every attempt to wean the infusion results in immediate seizure recurrence on EEG. MRI brain and LP (including HSV PCR) are normal. What is your assessment and management plan?

Examiner Questions and Model Answers:

Q1: What is your diagnosis, and what further investigations would you perform?

A1:

Diagnosis: Super-refractory status epilepticus (SRSE).

Definition: SE that continues for greater than 24 hours despite adequate doses of anaesthetic agents, OR recurs on weaning of anaesthesia. This patient has been on midazolam for 48 hours with seizure recurrence on weaning attempts.

Further Investigations:

Autoimmune Encephalitis Workup (most important in young, previously healthy patient with cryptogenic SRSE):

1. CSF studies (repeat LP if initial LP incomplete):

   • Autoimmune antibody panel:
     • NMDA receptor antibodies (most common in young women, ovarian teratoma association)
     • LGI1, GABA_B receptor, AMPA receptor, CASPR2 antibodies
   • CSF cell count: Lymphocytic pleocytosis (10-100 WCC) common in autoimmune encephalitis
   • CSF protein, glucose: Usually normal or mildly elevated protein

2. Serum autoimmune panel: Same antibodies (serum less sensitive than CSF, but may be positive)

3. MRI brain (repeat with contrast):

   • Autoimmune encephalitis patterns: FLAIR hyperintensity in medial temporal lobes, hippocampus, basal ganglia (NMDA receptor encephalitis)
   • SE-induced changes: DWI restriction, FLAIR hyperintensity (cortex, hippocampus)

4. Tumour screen (paraneoplastic association):

   • Pelvic ultrasound or CT abdomen/pelvis: Ovarian teratoma (NMDA receptor encephalitis)
   • CT chest/abdomen/pelvis: Small cell lung cancer, thymoma (other paraneoplastic syndromes)

5. Other investigations:

   • EEG: Extreme delta brush (pathognomonic of NMDA receptor encephalitis, though rare)
   • Metabolic screen: Mitochondrial disorders (lactate, pyruvate), urea cycle disorders (ammonia)

Q2: Describe your immediate management plan for SRSE.

A2:

Immediate Management:

1. Optimise Current Anaesthetic Agent (Midazolam):

• Ensure adequate dosing: Increase midazolam infusion to 2.0 mg/kg/hr if not already at max dose.
• EEG target: Maintain burst suppression 1:5 ratio.
• Monitor for tachyphylaxis: Midazolam tolerance develops after 24-48 hrs (may require escalating doses).

2. Add Ketamine (NMDA antagonist, effective in SRSE):

• Rationale: In prolonged SE, GABA_A receptors internalise (midazolam becomes less effective), while NMDA receptors upregulate. Ketamine is an NMDA antagonist.
• Dosing:
  • "Loading: 1-2 mg/kg IV over 5 minutes"
  • "Infusion: 1-2 mg/kg/hr, titrate up to 5-10 mg/kg/hr"
• Advantages: Haemodynamically stable (sympathomimetic), neuroprotective (blocks glutamate excitotoxicity)
• Evidence: Gaspard et al. (PMID: 23731110): 64% seizure control with ketamine in RSE.

3. Consider Switching to Thiopentone:

• Indication: Most effective anaesthetic agent for SRSE, second-line after midazolam/propofol failure.
• Dosing:
  • "Loading: 3-5 mg/kg IV, repeat 50-100 mg boluses until burst suppression achieved"
  • "Infusion: 3-7 mg/kg/hr"
• EEG target: Burst suppression 1:5 ratio
• Adverse effects: Severe hypotension (80-90% require vasopressors), ileus, immunosuppression
• Monitoring: Vasopressor support (noradrenaline), daily thiopentone levels (therapeutic 30-50 mg/L)

4. Immunotherapy (if autoimmune encephalitis suspected):

First-line immunotherapy:

• Methylprednisolone 1 g IV daily x 3-5 days, OR
• IVIg 0.4 g/kg daily x 5 days

Rationale: Autoimmune encephalitis (especially NMDA receptor) is a common cause of SRSE in young, previously healthy patients. Early immunotherapy improves outcomes.

Second-line immunotherapy (if no response to first-line):

• Plasma exchange (PLEX): 5-7 exchanges over 10-14 days
• Rituximab: 375 mg/m² weekly x 4 weeks (anti-CD20, B-cell depletion)

Evidence: Retrospective studies show 50-70% response to immunotherapy in autoimmune SE.

5. Other SRSE Therapies (if above fail):

Inhaled anaesthetics (Isoflurane):

• Dosing: 0.8-2.0% via ventilator, titrate to burst suppression
• Evidence: Case series show 60-70% seizure control
• Challenges: Requires ICU ventilator with anaesthetic gas delivery, scavenging system

Ketogenic diet:

• Indication: Paediatric SRSE (limited evidence in adults)
• Protocol: Enteral high-fat, low-carbohydrate diet (4:1 ratio)
• Evidence: 50-60% seizure reduction in paediatric case series

Q3: The autoimmune panel returns positive for NMDA receptor antibodies in CSF. What is your diagnosis and management?

A3:

Diagnosis: NMDA receptor encephalitis (autoimmune encephalitis causing SRSE).

Management:

1. Immunotherapy (first-line):

• Methylprednisolone 1 g IV daily x 5 days, followed by
• IVIg 0.4 g/kg daily x 5 days

2. Tumour Screening and Removal:

• NMDA receptor encephalitis in young women is 50-60% associated with ovarian teratoma.
• Urgent pelvic ultrasound or CT abdomen/pelvis: If teratoma detected, surgical removal (oophorectomy) is curative in 80-90% of cases.
• If no tumour detected: Proceed with second-line immunotherapy.

3. Second-line Immunotherapy (if no response after 2 weeks):

• Rituximab 375 mg/m² weekly x 4 weeks (anti-CD20, B-cell depletion), OR
• Cyclophosphamide 750 mg/m² monthly x 6 months

4. Continue Anaesthetic Agents:

• Maintain midazolam + ketamine (or switch to thiopentone) until clinical and EEG improvement.
• Expected timeline: Immunotherapy response typically seen in 2-4 weeks (slow).

5. Long-term Management:

• Maintenance immunotherapy: Rituximab or azathioprine for 12-24 months to prevent relapse.
• AED therapy: Continue for 6-12 months post-recovery, then taper if seizure-free.

Prognosis:

• With treatment: 70-80% make good recovery (return to baseline neurological function).
• Without treatment: 10-20% mortality, severe neurological disability in survivors.
• Relapse rate: 10-20% (requires long-term immunosuppression).

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References

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Summary

Status epilepticus is a neurological emergency requiring immediate recognition and treatment. The ILAE 2015 definition (seizure ≥5 minutes or ≥2 seizures without recovery) guides clinical decision-making with two critical time points: t₁ = 5 minutes (treatment threshold) and t₂ = 30 minutes (onset of neuronal injury). First-line treatment is benzodiazepines (IV lorazepam or IM midazolam), followed by second-line AEDs (levetiracetam, phenytoin, or valproate—all equally effective per ESETT trial). Refractory SE (failure of 2 agents) requires intubation and general anaesthesia (midazolam, propofol, thiopentone, or ketamine) titrated to EEG seizure suppression or burst suppression. Non-convulsive SE affects 10-20% of ICU patients and is diagnosed using continuous EEG and Salzburg criteria. Super-refractory SE (greater than 24 hours despite anaesthesia) may require ketamine, isoflurane, immunotherapy, or ketogenic diet. Early aggressive treatment (below 30 minutes) is critical to prevent long-term neurological sequelae including hippocampal sclerosis and chronic epilepsy.

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This topic was created for the CICM Second Part Examination. All recommendations are based on current evidence and expert consensus guidelines (Neurocritical Care Society, American Epilepsy Society, ILAE). For the latest updates, refer to primary literature and local institutional protocols.

Footnotes

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