Paediatric Status Epilepticus

Quick Answer

One-liner: Paediatric status epilepticus (PSE) is a neurological emergency defined as a seizure lasting ≥5 minutes or recurrent seizures without full recovery, requiring immediate benzodiazepine administration, followed by second-line agents (levetiracetam or phenytoin per ConSEPT/EcLiPSE trials), and escalation to anaesthesia with continuous EEG monitoring for refractory cases.

Paediatric SE affects 17-23 per 100,000 children annually with highest incidence in infants <1 year [1]. Febrile seizures are the most common cause (25-30%) in young children, followed by CNS infections, epilepsy-related causes, and metabolic derangements [2]. The pathophysiology involves GABA-A receptor internalization and NMDA receptor upregulation, explaining progressive benzodiazepine resistance [3]. ICU priorities include immediate stabilization (ABC, glucose check), time-based antiepileptic escalation, identification and treatment of underlying cause, and continuous EEG monitoring for refractory cases. Aboriginal and Torres Strait Islander children face barriers to emergency care access, particularly in remote communities [4]. Mortality is 3-5% overall but increases to 20-30% in super-refractory SE [5]. Neurological morbidity is primarily related to aetiology and seizure duration - emphasizing the critical importance of early, aggressive treatment.

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CICM Exam Focus

What Examiners Expect

Second Part Written (SAQ):

Common SAQ stems:

• "A 2-year-old febrile child is brought to the emergency department with ongoing generalised tonic-clonic seizures. Seizure duration is now 10 minutes despite prehospital diazepam 5mg PR. Outline your time-based management approach (12 marks) and list your differential diagnoses (4 marks)."
• "A 4-year-old known epileptic on valproate presents with refractory status epilepticus unresponsive to benzodiazepines and levetiracetam. Outline your approach to anaesthetic management of refractory SE (10 marks), including EEG targets (5 marks)."
• "Discuss the pathophysiology of benzodiazepine resistance in prolonged status epilepticus and the implications for management (15 marks)."

Expected depth:

• Operational definition (≥5 minutes vs traditional 30 minutes)
• Time-based management algorithm with specific drug doses
• ConSEPT and EcLiPSE trial evidence for second-line agents
• GABA receptor internalization and NMDA receptor trafficking
• Continuous EEG monitoring indications and targets
• Age-specific aetiologies (febrile, CNS infection, metabolic)
• Complications (rhabdomyolysis, aspiration, hyperthermia, neuronal injury)

Second Part Hot Case:

Typical presentations:

• 18-month-old intubated and sedated post-refractory SE, now on midazolam infusion
• 5-year-old with fever and ongoing subtle seizures despite multiple agents
• 3-year-old known epileptic with possible non-convulsive SE post-apparent seizure cessation

Examiners assess:

• Systematic A-E examination appropriate for age
• Recognition of subtle/ongoing seizure activity
• Assessment of fontanelle, pupils, signs of raised ICP
• Review of sedation and antiepileptic drug levels
• Integration of EEG findings with clinical assessment
• Communication with family about prognosis
• Recognition of complications (aspiration, hyperthermia)

Second Part Viva:

Expected discussion areas:

• Pathophysiology: GABA/glutamate imbalance, receptor trafficking, excitotoxicity
• Age-related epilepsy syndromes and their ICU relevance
• Benzodiazepine pharmacology and resistance mechanisms
• Evidence for phenytoin vs levetiracetam (ConSEPT, EcLiPSE)
• Anaesthetic agent selection and PRIS risk
• Continuous EEG interpretation (Salzburg criteria)
• Family communication and prognosis discussion

Examiner expectations:

• Confident paediatric dosing knowledge (mg/kg calculations)
• Understanding of developmental seizure susceptibility
• Safe escalation pathway to anaesthesia
• Knowledge of super-refractory SE management options
• Indigenous health awareness for access and cultural considerations

Common Mistakes

• Not checking blood glucose in all seizing children (ALWAYS CHECK)
• Using adult doses without weight-based calculation
• Failing to recognise ongoing non-convulsive SE
• Forgetting lumbar puncture in febrile child (meningitis rule-out)
• Not anticoagulating with prolonged propofol/thiopentone infusions
• Overlooking propofol infusion syndrome risk in paediatric patients
• Not involving paediatric neurology early

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Key Points

Key Points: The 10 things you MUST know for CICM exams:

1. Operational Definition: Seizure ≥5 minutes OR ≥2 seizures without full recovery of consciousness - treatment must begin at 5 minutes (ILAE 2015 t₁ time point) [6]

2. Pathophysiology: Prolonged seizures → GABA-A receptor internalization (reduced benzodiazepine efficacy) + NMDA receptor upregulation (increased excitotoxicity) [3]

3. Most Common Causes by Age:

   • 6 months - 5 years: Febrile seizures (25-30%)
   • All ages: CNS infection (10-20%), epilepsy/AED non-compliance (20-25%), metabolic (hypoglycaemia, hyponatraemia, hypocalcaemia) [2]

4. First-Line Treatment: Benzodiazepines

   • Midazolam IM/buccal: 0.2 mg/kg (max 10 mg) if no IV access
   • Lorazepam IV: 0.1 mg/kg (max 4 mg)
   • Diazepam PR: 0.5 mg/kg (max 20 mg) - slower but available in remote settings [7]

5. Second-Line Agents (ConSEPT/EcLiPSE evidence):

   • Levetiracetam: 40-60 mg/kg IV over 10 minutes (max 3000 mg)
   • Phenytoin: 20 mg/kg IV over 20 minutes (max 1500 mg)
   • Both equally effective (~50-55% seizure cessation); levetiracetam preferred for safer profile [8][9]

6. Refractory SE Definition: Failure of benzodiazepine + one second-line agent → requires intubation and anaesthesia

7. Anaesthetic Options:

   • Midazolam infusion: 0.1-0.4 mg/kg/hr (safe, tachyphylaxis occurs)
   • Propofol: CAUTION in children <16 years - PRIS risk (limit <4 mg/kg/hr, <48 hours)
   • Thiopentone: 3-5 mg/kg bolus, 3-5 mg/kg/hr infusion (severe hypotension)
   • Ketamine: 1-2 mg/kg bolus, 1-5 mg/kg/hr (NMDA antagonist, useful in late SE) [10]

8. EEG Monitoring: Mandatory for refractory SE - target seizure suppression; burst suppression (1:5 ratio) for super-refractory SE [11]

9. Prognosis: Mortality 3-5% overall; neurological morbidity related to:

   • Aetiology (acute symptomatic > febrile > idiopathic)
   • Duration (>60 minutes = higher morbidity)
   • Age (<1 year = higher vulnerability) [5]

10. ALWAYS CHECK BSL: Hypoglycaemia is reversible cause - Dextrose 10% 2.5 mL/kg (= 250 mg/kg glucose) IV [12]

Memory Aids

Mnemonic SEIZE: Time-Based SE Management

• S: Stabilise (ABC, oxygen, glucose check) - 0-5 minutes
• E: Emergency benzodiazepine (first dose) - 5 minutes
• I: If still seizing, second benzodiazepine - 10 minutes
• Z: Zero tolerance for delay, second-line agent - 10-20 minutes
• E: Escalate to anaesthesia if refractory - >40 minutes

Mnemonic FITS: Causes of Paediatric SE

• F: Febrile (most common in young children)
• I: Infection (meningitis, encephalitis)
• T: Toxins/Trauma/Tumour
• S: Sugar low (hypoglycaemia), Sodium low (hyponatraemia), Seizure disorder (epilepsy breakthrough)

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Definition & Epidemiology

Definition

Paediatric status epilepticus is defined using the ILAE 2015 operational definition, which identifies two critical time points [6]:

• t₁ (Threshold for treatment initiation): 5 minutes for generalised tonic-clonic seizures

  • At this point, seizures are unlikely to stop spontaneously
  • Emergency treatment must begin

• t₂ (Threshold for long-term consequences): 30 minutes for generalised tonic-clonic seizures

  • Risk of irreversible neuronal injury begins
  • Justifies more aggressive treatment

Practical Definition: A seizure lasting ≥5 minutes OR ≥2 seizures without full recovery of consciousness between episodes.

Classification by Response to Treatment:

Classification by Semiology:

Epidemiology

International Data:

• Incidence: 17-23 per 100,000 children per year [1]
• Age distribution: Bimodal - highest in infants <1 year (51-156 per 100,000) and decreasing with age [13]
• Median age: 2-3 years
• Proportion progressing to RSE: 23-43% [14]
• Proportion progressing to SRSE: 10-15% of RSE cases [15]

Australian/NZ Data (ANZPIC Registry, State Registries):

• SE accounts for 0.5-1% of paediatric ICU admissions in Australia [16]
• Higher rates in remote and regional areas (delayed access to definitive care)
• RFDS retrieval data shows median transport time >4 hours from remote communities
• Aboriginal and Torres Strait Islander children face significant access barriers

Mortality:

• Overall SE mortality: 3-5% [5]
• Refractory SE mortality: 10-15%
• Super-refractory SE mortality: 20-30%
• Mortality by aetiology:
  • "Febrile SE: <1%"
  • "Acute symptomatic (stroke, infection, trauma): 15-20%"
  • "Anoxic brain injury: 30-50%"

Risk Factors for SE:

• Age: <1 year (highest risk)
• History of epilepsy: 20-25% of children with epilepsy experience SE [17]
• Febrile illness: In susceptible children 6 months - 5 years
• CNS abnormality: Prior brain injury, developmental delay
• Acute illness: Infection, metabolic derangement

High-Risk Populations:

• Aboriginal and Torres Strait Islander children: 2-3× higher rates of febrile seizures, delayed access to tertiary care, higher rates of CNS infections [4]
• Māori children: Similar health disparities in New Zealand
• Remote/rural populations: Delayed access to emergency care, prolonged seizure duration before treatment
• Children with epilepsy: Especially those on polytherapy or with drug-resistant epilepsy

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Applied Basic Sciences

This section bridges First Part basic sciences with Second Part clinical practice

Anatomy

Relevant Neuroanatomy for Paediatric SE:

Hippocampus and Temporal Lobe:

• Highly susceptible to seizure-induced injury
• CA1 and CA3 pyramidal neurons particularly vulnerable
• Hippocampal sclerosis can result from prolonged SE → mesial temporal lobe epilepsy
• Developing brain more susceptible but also more plastic for recovery

Cerebral Cortex:

• Primary motor cortex involvement → focal motor SE (Jacksonian march)
• Generalised seizures involve bilateral cortical synchronization
• Ictal activity spreads via cortical connections and thalamic relay

Thalamus:

• Critical relay for cortical synchronization
• Pulvinar nucleus involvement seen on MRI (pulvinar sign)
• Thalamocortical circuits maintain seizure activity

Brainstem:

• Respiratory centres (medulla) → apnoea during seizures
• Reticular activating system → impaired consciousness
• Autonomic centres → cardiovascular instability

Age-Specific Anatomical Considerations:

• Fontanelle: Open anterior fontanelle in infants (<18 months) allows assessment of ICP
• Skull sutures: Unfused sutures accommodate some cerebral oedema
• Myelination: Incomplete myelination affects seizure propagation patterns

Physiology

Normal Neuronal Physiology:

Excitatory-Inhibitory Balance:

• Glutamate (excitatory): Primary excitatory neurotransmitter, acts on AMPA and NMDA receptors
• GABA (inhibitory): Primary inhibitory neurotransmitter, acts on GABA-A receptors
• Normal brain function requires precise balance between excitation and inhibition

Ion Channel Function:

• Voltage-gated Na⁺ channels → action potential initiation
• Voltage-gated K⁺ channels → repolarization
• Voltage-gated Ca²⁺ channels → neurotransmitter release, intracellular signalling
• GABA-A receptor-mediated Cl⁻ channels → hyperpolarization (inhibition)

Developmental Differences in Paediatric Brain:

• Higher neuronal excitability in immature brain
• GABA may be excitatory in neonates (Cl⁻ gradient reversed due to immature KCC2 transporter)
• Increased seizure susceptibility but also increased neuroplasticity
• Lower seizure threshold compared to adult brain

Pathophysiology

Mechanisms of Seizure Initiation and Propagation:

Phase 1: Seizure Initiation (0-5 minutes):

1. Paroxysmal depolarizing shift (PDS): Abnormal burst firing in epileptogenic focus
2. Synchronization: Spread to adjacent neurons via gap junctions and synaptic connections
3. Failure of surround inhibition: GABAergic interneurons fail to contain spread
4. Generalization: Thalamocortical recruitment → bilateral cortical involvement

Phase 2: Self-Sustaining Activity (5-30 minutes):

1. Glutamate accumulation: Excess synaptic glutamate → sustained excitation
2. GABA depletion: Exhaustion of presynaptic GABA stores
3. Metabolic compensation: Increased cerebral blood flow maintains oxygen/glucose delivery
4. Catecholamine surge: Hypertension, tachycardia, hyperglycaemia

Phase 3: Receptor Trafficking and Resistance (20-30+ minutes):

GABA-A Receptor Internalization (Critical for CICM exams) [3][18]:

• Prolonged neuronal firing → excess calcium influx
• Clathrin-mediated endocytosis removes GABA-A receptors from synaptic membrane
• Surface GABA-A receptors reduce by 50% within 30 minutes of continuous seizure activity
• Clinical consequence: Progressive benzodiazepine resistance
• Mechanism: Calcium activates phosphatases → dephosphorylation of receptor β subunits → internalization signal

NMDA Receptor Upregulation:

• Simultaneously, NMDA receptors traffic TO the synaptic membrane
• NMDA receptor surface expression increases 3-fold during prolonged SE [19]
• Clinical implication: NMDA antagonists (ketamine) become more effective in late/refractory SE
• Explains rationale for early ketamine use in refractory cases

Phase 4: Metabolic Decompensation (>30-60 minutes):

Neuronal Injury Mechanisms [20]:

1. Excitotoxicity:

   • Excess glutamate → NMDA receptor overactivation
   • Massive Ca²⁺ influx → mitochondrial dysfunction
   • ATP depletion → Na⁺/K⁺ ATPase failure → cytotoxic oedema

2. Oxidative Stress:

   • Mitochondrial Ca²⁺ overload → ROS production
   • Lipid peroxidation → membrane damage
   • DNA damage → apoptosis activation

3. Inflammation:

   • Microglial activation within hours
   • IL-1β, TNF-α, IL-6 release
   • Blood-brain barrier breakdown (24-72 hours)

4. Selective Neuronal Vulnerability:

   • Hippocampal CA1 and CA3 neurons most vulnerable
   • Cerebellar Purkinje cells
   • Cortical layers III and V

Pharmacology

Key ICU Drugs for Paediatric SE:

1. Benzodiazepines (First-Line)

Mechanism: Positive allosteric modulators of GABA-A receptors

• Bind to α/γ subunit interface
• Increase frequency of Cl⁻ channel opening (not duration - that's barbiturates)
• Require endogenous GABA for effect (explains reduced efficacy with GABA depletion)

RAMPART Trial Evidence (PMID: 22150065) [7]:

• IM midazolam 10 mg vs IV lorazepam 4 mg in prehospital SE
• Seizure cessation: IM midazolam 73.4% vs IV lorazepam 63.4%
• Time to drug administration faster with IM (no IV access required)
• Conclusion: IM midazolam at least as effective, preferred in prehospital setting

2. Levetiracetam (Second-Line)

Mechanism:

• Binds synaptic vesicle protein SV2A
• Modulates synaptic vesicle release
• Reduces glutamate release
• Exact anticonvulsant mechanism not fully understood

ICU Dosing: 40-60 mg/kg IV over 10-15 minutes (max 3000 mg)

Advantages:

• No cardiac monitoring required
• No drug-drug interactions
• Renally excreted (dose adjust in renal impairment)
• No hypotension
• Safe in hepatic impairment

Disadvantages:

• Behavioural side effects (irritability, aggression) in some children
• Limited evidence in very young infants

3. Phenytoin/Fosphenytoin (Second-Line)

Mechanism:

• Voltage-gated Na⁺ channel blocker
• Stabilizes inactive state of Na⁺ channels
• Prevents repetitive firing

ICU Dosing:

• Phenytoin: 20 mg/kg IV at max 1 mg/kg/min (max 50 mg/min)
• Fosphenytoin: 20 mg PE/kg IV at 2-3 mg PE/kg/min (max 150 mg PE/min)

Critical Monitoring:

• Continuous ECG: Risk of bradycardia, AV block
• Blood pressure: Hypotension common (propylene glycol in phenytoin)
• Infusion rate critical - reduce if hypotension or arrhythmia

Contraindications: 2nd/3rd degree AV block, sinus bradycardia

4. Phenobarbital (Alternative Second-Line/Third-Line)

Mechanism:

• GABA-A receptor agonist (at barbiturate binding site)
• Increases duration of Cl⁻ channel opening
• At high doses, direct GABA-mimetic (does not require endogenous GABA)

ICU Dosing: 15-20 mg/kg IV at max 1 mg/kg/min (max 100 mg/min)

Role in Paediatrics:

• First-line for neonatal seizures
• Alternative second-line if levetiracetam/phenytoin contraindicated
• High rate of respiratory depression (50% require intubation)

5. Midazolam Infusion (Third-Line - Anaesthesia)

ICU Dosing:

• Loading: 0.2 mg/kg IV over 2 minutes
• Infusion: 0.05-0.4 mg/kg/hr, titrate to EEG

Advantages: Rapid onset, short half-life, familiar to ICU staff

Disadvantages:

• Tachyphylaxis within 24-48 hours
• May require escalating doses
• Hypotension (30-50% need vasopressors)

6. Propofol (Third-Line - CAUTION in Children)

ICU Dosing:

• Loading: 1-2 mg/kg IV
• Infusion: 1-4 mg/kg/hr

CRITICAL WARNING - Propofol Infusion Syndrome (PRIS) [21]:

• Higher risk in children (mitochondrial immaturity)
• Risk factors: Dose >4 mg/kg/hr, duration >48 hours, young age, critical illness
• Features: Metabolic acidosis, rhabdomyolysis, cardiac failure, renal failure
• TGA/PBS: Propofol NOT recommended for sedation in children <16 years for >24 hours
• If used: Limit to <4 mg/kg/hr, <48 hours, monitor CK, lactate, triglycerides daily

7. Ketamine (Third-Line - Increasingly Used)

Mechanism:

• Non-competitive NMDA receptor antagonist
• Blocks glutamate-mediated excitotoxicity
• Particularly effective in late SE when NMDA receptors upregulated [10]

ICU Dosing:

• Loading: 1-2 mg/kg IV
• Infusion: 1-5 mg/kg/hr

Advantages:

• Haemodynamically stable (sympathomimetic)
• NMDA antagonism targets late SE pathophysiology
• Neuroprotective (blocks excitotoxicity)
• No respiratory depression at standard doses

Evidence: Systematic reviews suggest 64-90% response rate in RSE [22]

8. Thiopentone (Third-Line - Super-Refractory SE)

Mechanism: Barbiturate - GABA-A agonist + direct Cl⁻ channel opening

ICU Dosing:

• Loading: 3-5 mg/kg IV over 5-10 minutes
• Infusion: 1-5 mg/kg/hr (titrate to EEG burst suppression)

Indications: Super-refractory SE, when other agents fail

Disadvantages:

• Severe hypotension (90% require vasopressors)
• Myocardial depression
• Very long half-life (18-24 hours) → prolonged recovery
• Immunosuppression

Pathology

Histopathology of SE-Induced Brain Injury:

Acute Changes (0-24 hours):

• Neuronal eosinophilia (red neurons)
• Nuclear pyknosis
• Cytoplasmic vacuolization
• Particularly in hippocampal CA1, CA3 regions

Subacute Changes (24-72 hours):

• Microglial activation
• Astrocyte swelling
• Early BBB breakdown
• Perivascular inflammation

Chronic Changes (weeks to months):

• Hippocampal sclerosis (gliosis replacing neurons)
• Mossy fibre sprouting (aberrant axonal connections)
• Acquired channelopathies → epileptogenesis
• Mesial temporal lobe epilepsy development

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Clinical Presentation

ICU Admission Scenarios

Typical Presentations:

Scenario 1: Febrile Status Epilepticus (Most Common)

• Age: 18-month-old
• History: Upper respiratory infection for 2 days, fever 39.5°C, generalized tonic-clonic seizure started at home, prehospital diazepam PR given, still seizing on arrival (total duration 15 minutes)
• Examination: Actively seizing, cyanotic, tachycardic, hot, responsive to neither voice nor pain
• Severity: Established SE, requires second-line agent

Scenario 2: CNS Infection with SE

• Age: 3-year-old
• History: 3 days of fever, vomiting, irritability, then focal seizures progressing to generalised, neck stiffness
• Examination: Photophobia, bulging fontanelle (if <18 months), petechial rash (meningococcal), Brudzinski's sign positive
• Severity: High priority for LP, empiric antibiotics + aciclovir

Scenario 3: Known Epileptic with Breakthrough SE

• Age: 7-year-old with focal epilepsy on levetiracetam
• History: Missed 2 doses of medication due to gastroenteritis, developed generalised seizures
• Examination: Post-ictal drowsiness, focal weakness (Todd's paresis)
• Severity: May respond to AED top-up, but beware underlying infection

Scenario 4: Toxin Ingestion

• Age: 2-year-old
• History: Found with grandmother's medication bottles (tricyclic antidepressants), developed seizures
• Examination: Mydriasis, dry mouth, tachycardia, urinary retention
• Severity: High mortality risk, need specific antidote considerations

Symptoms & Signs

History:

• Seizure description: Generalised or focal, motor features, duration
• Preceding symptoms: Fever, headache, vomiting, behavioural change
• Past medical history: Known epilepsy, developmental delay, previous seizures
• Medications: Current AEDs, recent changes, compliance
• Family history: Epilepsy, febrile seizures
• Access to medications/toxins: Accidental ingestion risk

Examination:

General:

• Active seizure: Tonic-clonic movements, cyanosis, salivation
• Post-ictal: Drowsy, confused, posturing, Todd's paresis
• Vital signs: Tachycardia, hypertension (early), hypotension (late), hyperthermia

A - Airway:

• During seizure: Assess patency, suction secretions, lateral positioning
• Do NOT insert oral airway during active seizure (dental trauma)
• Stridor may indicate aspiration

B - Breathing:

• Respiratory rate: Often irregular during seizure
• SpO₂: May be <90% due to impaired ventilation
• Apnoea: Common during tonic phase
• Auscultation: Aspiration (right lower lobe crackles)

C - Circulation:

• Heart rate: Tachycardia (early), bradycardia (late/severe)
• Blood pressure: Hypertension (early), hypotension (late)
• Perfusion: CRT may be prolonged in decompensation
• Peripheral cyanosis common during seizure

D - Disability/Neurology:

• GCS: Assess between seizures (post-ictal depression normal)
• Pupils: Dilated during seizure, slow reactive post-ictally
• Fontanelle (infants): Bulging → raised ICP (meningitis, hydrocephalus)
• Focal signs: Todd's paresis, eye deviation → structural lesion
• Meningism: Neck stiffness, Kernig's, Brudzinski's signs

E - Exposure/Everything Else:

• Temperature: Hyperthermia (fever as cause, or consequence of prolonged seizure)
• Skin: Rash (meningococcal petechiae), neurocutaneous stigmata (tuberous sclerosis)
• Trauma signs: Head injury, NAI concerns

Severity Scoring

Status Epilepticus Severity Score (STESS) [23]:

• Prognostic tool for mortality in SE
• Components: Age, history of seizures, seizure type, level of consciousness
• Paediatric applicability: Developed in adults, limited validation in children

General PICU Scores:

• PIM3 (Paediatric Index of Mortality 3): Calculated on admission
• PELOD-2 (Paediatric Logistic Organ Dysfunction 2): Organ dysfunction assessment

Differential Diagnosis

Key Differentials:

1. Febrile convulsion (simple): <15 min, generalised, single event - not SE but may progress

2. Psychogenic non-epileptic seizures (PNES): Eyes closed, pelvic thrusting, prolonged duration without physiological correlate, normal EEG - rare in young children

3. Rigors: Rhythmic shaking with fever, child responsive, stops with gentle restraint

4. Syncope with convulsive movements: Brief (<1 min), preceded by pallor/presyncope, rapid recovery

5. Movement disorders: Dystonia, chorea - not associated with LOC

6. Breath-holding spells: Triggered by crying, brief cyanosis/pallor, rapid recovery

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Aetiology by Age

Aetiology Framework

Age-Specific Causes (Critical for CICM Exams):

Detailed Aetiology

1. Febrile Seizures (Most Common in 6 months - 5 years) [24]:

Definition: Seizure associated with fever (≥38°C) in child 6 months - 5 years, without CNS infection or other defined cause

Types:

• Simple febrile seizure: <15 min, generalised, single episode
• Complex febrile seizure: >15 min, focal features, or recurrent within 24 hours
• Febrile status epilepticus: >30 minutes (or >5 min by operational definition)

Epidemiology: 2-5% of children experience febrile seizures, 5% of these progress to SE

Risk factors for prolonged febrile seizures: Lower temperature at seizure onset, younger age, developmental delay

2. CNS Infection (10-20%) [25]:

Bacterial Meningitis:

• Organisms: Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae (declining with vaccination)
• Features: Fever, headache, vomiting, meningism, petechial rash (meningococcal)
• Management: LP if safe, empiric ceftriaxone + dexamethasone

Viral Encephalitis:

• Organisms: HSV (most important - treatable), enterovirus, arboviruses
• Features: Altered behaviour, personality change, focal seizures, fever
• HSV encephalitis: Temporal lobe predilection, high mortality if untreated
• Management: Empiric IV aciclovir pending HSV PCR

3. Electrolyte Disturbances:

Hypoglycaemia (BSL <3.0 mmol/L) [12]:

• Most important reversible cause - ALWAYS CHECK
• Higher risk: Infants, diabetics, sepsis, malnutrition
• Treatment: Dextrose 10% 2.5 mL/kg IV (= 250 mg/kg glucose)

Hyponatraemia (Na <125 mmol/L):

• Causes: SIADH, water intoxication, adrenal insufficiency
• Treatment: Hypertonic saline 3% (2-3 mL/kg) for seizures

Hypocalcaemia (Ca <2.0 mmol/L or iCa <1.0 mmol/L):

• Causes: Vitamin D deficiency, hypoparathyroidism, DiGeorge syndrome
• Treatment: Calcium gluconate 10% 0.5 mL/kg IV (max 20 mL)

4. Trauma:

• Traumatic brain injury with intracranial haemorrhage
• Non-accidental injury (consider in infants with unexplained seizures)
• Subdural haematoma (especially in <2 years)

5. Toxins/Ingestions:

• Tricyclic antidepressants: Wide QRS, anticholinergic features
• Isoniazid: Pyridoxine-responsive seizures
• Organophosphates: Cholinergic crisis
• Camphor, local anaesthetics, theophylline

6. Epilepsy (Breakthrough Seizures) [17]:

• AED non-compliance (most common)
• Subtherapeutic drug levels (growth, drug interactions)
• Intercurrent illness lowering seizure threshold
• Sleep deprivation

7. Genetic Epilepsy Syndromes:

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Clinical Assessment

ABC Assessment

Primary Survey:

A - Airway:

• Position child safely (recovery position if ongoing seizure)
• Suction secretions
• Consider jaw thrust if obstructed
• Intubation indications:
  • Refractory SE requiring anaesthesia
  • Persistent hypoxia (SpO₂ <90%) despite oxygen
  • Aspiration or airway compromise
  • GCS ≤8 post-ictally

B - Breathing:

• High-flow oxygen (15 L/min non-rebreather) to all seizing children
• Target SpO₂ >94%
• Assess for aspiration (right lower lobe crackles)
• Prepare for bag-mask ventilation if apnoeic

C - Circulation:

• IV/IO access (essential for AED administration)
• Cardiac monitoring (arrhythmias, especially with phenytoin)
• Fluid resuscitation if hypotensive (20 mL/kg 0.9% NaCl)

D - Disability:

• BLOOD GLUCOSE - MUST CHECK IMMEDIATELY
• If BSL <3.0 mmol/L: Dextrose 10% 2.5 mL/kg IV
• Pupils (size, reactivity)
• Posturing (decorticate, decerebrate)
• Temperature (treat hyperthermia)

E - Exposure:

• Full examination for trauma, rash, needle marks
• Temperature measurement
• Signs of NAI (bruising patterns, burns)

Glucose Check

CRITICAL - Always Check Blood Glucose:

Why:

• Hypoglycaemia is immediately reversible cause
• Prolonged hypoglycaemia causes permanent neuronal damage
• Common in infants, sepsis, malnourished children

Treatment:

• Dextrose 10%: 2.5 mL/kg IV (= 250 mg/kg glucose)
• Avoid dextrose 50% in children (hyperosmolar, risk of extravasation injury)
• Recheck glucose in 15-30 minutes

Glucose Requirements in SE:

• Seizures increase cerebral glucose consumption
• May require maintenance dextrose infusion (D10% at maintenance rate)

Temperature Assessment

Hyperthermia in SE:

• Common consequence of prolonged seizure activity
• Temperature >40°C associated with worse outcome
• Management:
  • Remove excess clothing
  • Tepid sponging
  • Paracetamol 15 mg/kg IV
  • Active cooling if >40°C (ice packs, cooling blanket)
  • Avoid shivering (increases metabolic demand)

Fever as Cause:

• Febrile seizures most common cause in young children
• Antipyretics reduce recurrence but don't stop ongoing seizure
• Must still exclude meningitis/encephalitis

Signs of Raised ICP

Recognition (Important for decision to LP):

Infants (open fontanelle):

• Bulging fontanelle - key sign
• Separation of sutures
• "Setting sun" eyes (downward gaze)
• Increased head circumference

Older Children:

• Headache, vomiting (especially morning)
• Papilloedema (may take hours to develop)
• Cushing's reflex (bradycardia, hypertension, irregular breathing)
• Altered consciousness
• Focal neurological signs

Management if Signs of Raised ICP:

• DO NOT PERFORM LP without imaging
• Urgent CT brain
• Head-up positioning (30°)
• Consider osmotherapy (mannitol, hypertonic saline)
• Neurosurgical consultation

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Investigations

Laboratory Investigations

Bedside Tests (Immediate):

• Blood glucose (BSL): MANDATORY in all seizing children

  • "Normal: 3.5-7.8 mmol/L"
  • Treat if <3.0 mmol/L

• Capillary blood gas:

  • pH: Typically acidotic (7.1-7.3) in prolonged SE
  • "PaCO₂: May be elevated (hypoventilation) or low (post-ictal hyperventilation)"
  • "Lactate: Elevated (5-15 mmol/L common) - reflects muscle activity + hypoxia"
  • "HCO₃: Low (metabolic acidosis)"

• Core temperature: Rectal or tympanic

Blood Tests (First 15-30 minutes):

Specific Tests Based on Clinical Suspicion:

• HSV PCR (CSF): If encephalitis suspected
• Metabolic screen: Amino acids, organic acids (infants with unexplained SE)
• Autoimmune panel: NMDA receptor, LGI1, GABA-B antibodies (refractory SE)
• Genetic testing: SCN1A for Dravet syndrome if recurrent febrile SE

Neuroimaging

CT Brain (Non-Contrast):

Indications:

• Focal seizures or focal neurological signs
• Signs of raised ICP
• Head trauma
• Prolonged post-ictal altered consciousness
• Before LP if concern about mass lesion

Findings:

• Intracranial haemorrhage
• Space-occupying lesion
• Cerebral oedema
• Hydrocephalus
• May be normal in early SE (changes develop over hours)

MRI Brain:

Indications:

• Unexplained SE (cryptogenic)
• Focal SE
• Suspected encephalitis
• Persistent altered consciousness despite seizure control

Findings in SE [26]:

Lumbar Puncture

Indications:

• Febrile seizure with meningism
• Prolonged post-ictal altered consciousness
• Immunocompromised child
• Infant <6 months with fever + seizure (meningitis signs unreliable)
• Suspicion of CNS infection or autoimmune encephalitis

Contraindications:

• Signs of raised ICP (bulging fontanelle, papilloedema, focal signs)
• Cardiorespiratory instability
• Coagulopathy
• Skin infection at LP site

Timing:

• Do NOT delay empiric antibiotics for LP if bacterial meningitis suspected
• LP can be performed after stabilization and CT if needed

CSF Analysis:

Additional CSF Studies:

• HSV PCR: Gold standard for HSV encephalitis
• Enterovirus PCR: Common viral cause
• Autoimmune panel: NMDA, LGI1, GABA-B antibodies

Electroencephalography (EEG)

Indications for Continuous EEG (cEEG) Monitoring [11]:

1. All refractory SE - mandatory to guide anaesthetic titration
2. Non-convulsive SE suspected - comatose child post-CSE
3. Unexplained coma - without clear cause
4. Titrating anaesthetic agents - target seizure suppression or burst suppression
5. Weaning anaesthesia - detect seizure recurrence

Duration of Monitoring:

• Minimum 24 hours for comatose patients
• Continuous until 24-48 hours post-anaesthetic withdrawal
• 95% of seizures detected within 48 hours of monitoring [27]

EEG Patterns:

• may need treatment | | Burst suppression | Alternating bursts and flat periods | Target for anaesthetic therapy | | Electrocerebral silence | No activity | Severe injury or drug-induced |

Salzburg Criteria for NCSE [28]:

• EDs >2.5 Hz, OR
• EDs ≤2.5 Hz PLUS one of:
  • EEG improvement after benzodiazepine
  • Clinical improvement after benzodiazepine
  • Subtle ictal phenomena
  • Spatiotemporal evolution

---

ICU Management

Time-Based Protocol

Overview - Critical Time Points:

Time (min)  0 ─────5─────10────15────20────30────40────60────
            │      │      │     │     │     │     │     │
            ▼      ▼      ▼     ▼     ▼     ▼     ▼     ▼
          ABC   BZD#1  BZD#2        2nd line      3rd line/
          O₂              ───────────▶           Anaesthesia
          Glucose         Levetiracetam
          Access          OR Phenytoin

        STABILISATION  │  BENZODIAZEPINES  │  2nd LINE  │  REFRACTORY SE

Phase 1: Stabilisation (0-5 Minutes)

Immediate Actions:

Airway:

• Position child safely (recovery position if ongoing seizure)
• Suction secretions
• Jaw thrust if obstruction
• Do NOT insert bite block during active seizure
• Apply high-flow oxygen 15 L/min via non-rebreather

Breathing:

• Assess respiratory effort, SpO₂
• Bag-mask ventilation if apnoeic
• Target SpO₂ >94%

Circulation:

• Obtain IV/IO access immediately
• If no IV: Proceed with IM midazolam (do not delay)
• Cardiac monitoring

Disability:

• CHECK BLOOD GLUCOSE (bedside glucometer)
• If BSL <3.0 mmol/L: Dextrose 10% 2.5 mL/kg IV
• Measure temperature

Exposure:

• Remove excess clothing
• Look for signs of trauma, rash, ingestion

Phase 2: First-Line - Benzodiazepines (5-10 Minutes)

First Benzodiazepine Dose (at 5 minutes or on arrival if already >5 min):

If Seizures Continue at 10 Minutes - Second Benzodiazepine Dose:

• Repeat the same benzodiazepine at same dose
• Maximum total benzodiazepine: 2 doses
• Do not give more than 2 benzodiazepine doses before moving to second-line agent

Monitoring After Benzodiazepines:

• Respiratory rate, SpO₂ (respiratory depression risk)
• Blood pressure
• Prepare bag-mask ventilation

Phase 3: Second-Line Agents (10-20 Minutes)

If Seizures Continue Despite Two Benzodiazepine Doses:

ConSEPT and EcLiPSE Trial Evidence [8][9]:

Conclusion: Levetiracetam and phenytoin are equally effective. Choose based on:

• Levetiracetam preferred: No cardiac monitoring needed, safer profile
• Phenytoin preferred: Already on levetiracetam, cardiac disease (paradoxically), availability

Levetiracetam Protocol:

• Dose: 40-60 mg/kg IV (max 3000 mg)
• Infusion: Over 10-15 minutes
• Monitoring: No cardiac monitoring required
• Advantages: No drug interactions, renally excreted, well-tolerated

Phenytoin/Fosphenytoin Protocol:

• Dose: 20 mg/kg (max 1500 mg) or 20 mg PE/kg for fosphenytoin
• Infusion rate: Phenytoin max 1 mg/kg/min (max 50 mg/min)
• CRITICAL: Continuous ECG monitoring during infusion
• Stop if: Bradycardia, hypotension, arrhythmia
• Fosphenytoin advantage: Faster infusion (3 mg PE/kg/min), less local irritation

Alternative: Phenobarbital:

• Dose: 15-20 mg/kg IV (max 1000 mg)
• Infusion rate: Max 1 mg/kg/min (max 100 mg/min)
• Indication: If levetiracetam AND phenytoin contraindicated/unavailable
• Monitoring: High risk of respiratory depression, prepare for intubation

Phase 4: Third-Line - Refractory SE (20-40 Minutes)

Definition: Seizures continuing after benzodiazepines + one second-line agent

Decision to Intubate and Anaesthetize:

Indications:

• Continued seizure activity despite 2nd line agent
• Respiratory failure (SpO₂ <90% despite oxygen)
• Aspiration or airway compromise
• Super-refractory SE (>24 hours)

Pre-Intubation Checklist:

• Experienced paediatric intubator
• Weight-based drug doses prepared
• Vasopressor infusion available (anaesthetics cause hypotension)
• Continuous EEG monitoring arranged
• Arterial line for BP monitoring

RSI in Status Epilepticus:

Anaesthetic Infusion Options:

1. Midazolam Infusion (First Choice in Most PICUs):

• Loading: 0.2 mg/kg IV bolus
• Infusion: Start 0.05 mg/kg/hr, titrate to EEG
• Range: 0.05-0.4 mg/kg/hr
• Advantages: Safe, familiar, short half-life
• Disadvantages: Tachyphylaxis after 24-48 hours

2. Propofol Infusion (CAUTION in Children):

• Loading: 1-2 mg/kg
• Infusion: 1-4 mg/kg/hr (DO NOT EXCEED 4 mg/kg/hr)
• Duration limit: <48 hours preferred
• CRITICAL: Monitor for PRIS (CK, lactate, triglycerides daily)
• If PRIS suspected: STOP immediately, supportive care

3. Ketamine Infusion (Increasingly Used):

• Loading: 1-2 mg/kg
• Infusion: 1-5 mg/kg/hr
• Rationale: NMDA antagonist effective in late SE (NMDA receptor upregulation)
• Advantages: Haemodynamically stable, neuroprotective
• Disadvantages: Increased secretions, emergence phenomena

EEG Targets for Anaesthetic Titration:

Duration of Anaesthesia:

• Maintain EEG target for 24-48 hours before weaning
• Wean slowly over 12-24 hours
• If seizures recur on weaning → re-bolus and increase infusion

Phase 5: Super-Refractory SE (>40 Minutes / >24 Hours)

Definition: SE continuing >24 hours despite anaesthetic therapy OR recurring on anaesthetic weaning

Incidence: 10-15% of RSE cases

Mortality: 20-30%

Additional Therapeutic Options:

1. Thiopentone (if not already using):

• Loading: 3-5 mg/kg IV
• Infusion: 1-5 mg/kg/hr, titrate to burst suppression
• Monitoring: Severe hypotension (80-90% need vasopressors), myocardial depression
• Duration: Can be used for days/weeks in SRSE

2. Ketamine Addition:

• Add ketamine infusion 1-5 mg/kg/hr to existing anaesthesia
• NMDA antagonism provides mechanistically different approach
• May allow dose reduction of GABA agonists

3. Immunotherapy (if Autoimmune Aetiology Suspected):

Indications:

• Cryptogenic SE (no cause found)
• CSF pleocytosis
• MRI limbic encephalitis pattern
• FIRES (Febrile Infection-Related Epilepsy Syndrome)

First-Line Immunotherapy:

• Methylprednisolone: 30 mg/kg/day (max 1g) × 3-5 days
• IVIg: 0.4 g/kg/day × 5 days (total 2 g/kg)

Second-Line Immunotherapy:

• Plasma exchange (PLEX): 5-7 exchanges
• Rituximab: 375 mg/m² weekly × 4 weeks (anti-CD20)

4. Ketogenic Diet [29]:

• High-fat, low-carbohydrate diet induces ketosis
• Anticonvulsant mechanism: ketone bodies, metabolic effects
• Protocol: Initiate via NGT, 4:1 fat:carbohydrate ratio
• Target: Blood ketones 3-5 mmol/L
• Evidence: Case series show 50-90% response in paediatric SRSE

5. Other Options (Limited Evidence):

• Inhaled anaesthetics (isoflurane): Requires specialized equipment
• Therapeutic hypothermia: 32-34°C, case reports only
• Magnesium sulphate: 50-100 mg/kg bolus
• Pyridoxine: 100 mg IV trial (neonates - pyridoxine-dependent seizures)

---

Monitoring & Complications

ICU-Specific Monitoring

Continuous Monitoring:

• Continuous EEG: Mandatory for RSE/SRSE, interpret with Salzburg criteria
• SpO₂, HR, BP: Continuous
• Temperature: Continuous (treat hyperthermia aggressively)
• Neurological observations: GCS/RASS q1-2h, pupils q4h

Intermittent Monitoring:

• Blood glucose: Initially q1h, then q2-4h when stable
• ABG/VBG: q4-6h in acute phase
• Electrolytes: q6-12h
• CK: Daily (rhabdomyolysis monitoring)
• AED levels: If on phenytoin, phenobarbital

Drug-Specific Monitoring:

Complications

Neurological Complications:

1. Cerebral Oedema:

• Incidence: 30-50% in prolonged SE
• Mechanism: Cytotoxic (early) + vasogenic (late)
• Presentation: Decreasing GCS, pupil changes, Cushing's reflex
• Management: Head elevation, osmotherapy, neurosurgical referral

2. Hypoxic-Ischaemic Brain Injury:

• Incidence: 10-20% in prolonged SE
• Mechanism: Mismatch between metabolic demand and oxygen delivery
• MRI findings: Watershed territory injury, DWI restriction
• Prevention: Early seizure termination, maintain oxygenation

3. Hippocampal Sclerosis:

• Long-term consequence of prolonged SE
• Leads to mesial temporal lobe epilepsy
• MRI: Hippocampal volume loss, T2 hyperintensity

4. Non-Convulsive SE Post-CSE:

• Incidence: 14-20% after apparent clinical seizure cessation
• Diagnosis: Continuous EEG mandatory to detect
• Management: Continue AED therapy, EEG-guided

Systemic Complications:

1. Aspiration Pneumonia:

• Incidence: 30-50%
• Prevention: Lateral positioning, early intubation if needed
• Management: Suctioning, antibiotics if confirmed aspiration

2. Rhabdomyolysis:

• Incidence: 20-30% in prolonged convulsive SE
• Mechanism: Sustained muscle contraction
• Monitoring: CK, urine myoglobin, renal function
• Treatment: Aggressive fluid resuscitation, maintain UO >1-2 mL/kg/hr

3. Hyperthermia:

• Incidence: 30-50%
• Core temperature can exceed 40°C
• Management: Active cooling, paracetamol, treat underlying cause
• Significance: Associated with worse neurological outcome

4. Lactic Acidosis:

• Expected in prolonged seizures
• Usually resolves with seizure cessation
• Treat severe acidosis (pH <7.1) supportively, ensure oxygenation

5. Hypoglycaemia:

• Common in late SE (glycogen depletion)
• Monitor glucose frequently
• Treat promptly with dextrose

Iatrogenic Complications:

1. Propofol Infusion Syndrome (PRIS) [21]:

• Features: Metabolic acidosis, rhabdomyolysis, cardiac failure, renal failure, lipemia
• Risk factors: Dose >4 mg/kg/hr, duration >48 hours, young age
• Prevention: Limit dose and duration, daily monitoring
• Treatment: STOP propofol immediately, supportive care

2. Respiratory Depression from Benzodiazepines:

• Incidence: 10-20%
• Management: Bag-mask ventilation, intubation if persistent

3. Phenytoin-Induced Arrhythmias:

• Bradycardia, AV block, asystole (rare)
• Prevention: Slow infusion rate, continuous ECG
• Treatment: Stop infusion, atropine for bradycardia

---

Prognosis

Mortality

Short-Term Outcomes:

• Overall SE mortality: 3-5% [5]
• Febrile SE mortality: <1%
• Refractory SE mortality: 10-15%
• Super-refractory SE mortality: 20-30%
• PICU mortality: 2-5%

Aetiology-Specific Mortality:

• Febrile seizures: <1%
• CNS infection: 5-15%
• Epilepsy breakthrough: 3-5%
• Acute symptomatic (stroke, trauma): 15-25%
• Hypoxic-ischaemic: 30-50%

Morbidity

Neurological Morbidity [30]:

Types of Neurological Morbidity:

• Cognitive impairment (memory, attention, processing speed)
• Behavioural changes
• Motor deficits (hemiparesis, ataxia)
• Development of chronic epilepsy

Prognostic Factors

Good Prognostic Factors:

• Febrile or idiopathic aetiology
• Short seizure duration (<30 minutes)
• Rapid response to first-line treatment
• Older age (>1 year)
• No pre-existing neurological abnormality

Poor Prognostic Factors [31]:

• Acute symptomatic aetiology (CNS infection, stroke, trauma)
• Age <1 year
• Prolonged seizure duration (>60 minutes)
• Refractory or super-refractory SE
• Non-convulsive SE
• Pre-existing neurological abnormality
• Low initial GCS

Long-Term Follow-Up

Required Follow-Up:

• Paediatric neurology review at 1-3 months
• Developmental assessment (especially in young children)
• EEG if not already done or if abnormal
• MRI brain if not done acutely
• AED optimization
• Seizure action plan for family/school

---

Australian/NZ Context

ANZICS Recommendations

ANZICS Paediatric Study Group:

• Standardized approaches to paediatric SE management across ANZ
• Quality improvement initiatives for seizure management
• PICU benchmarking data through ANZPIC Registry

Key ANZ Practice Points:

• Levetiracetam increasingly preferred as second-line (ConSEPT/EcLiPSE influence)
• Phenytoin remains available and used
• Thiopentone more commonly available than pentobarbital
• Ketamine usage increasing based on emerging evidence

Indigenous Health Considerations

Aboriginal and Torres Strait Islander Children [4]:

Health Disparities:

• 2-3× higher rates of febrile seizures
• Higher rates of CNS infections (meningitis, encephalitis)
• Delayed access to tertiary care (especially in remote communities)
• Higher rates of developmental disability and epilepsy

Access Barriers:

• Geographic isolation (>60% live in remote/very remote areas)
• Limited emergency services in remote communities
• RFDS/NETS retrieval times often >4-6 hours
• Language barriers, interpreter needs
• Historical distrust of healthcare system

Culturally Safe Care:

• Involve Aboriginal Health Workers (AHWs) and Aboriginal Liaison Officers (ALOs)
• Family/community involvement in decision-making
• Respect for cultural protocols (sorry business, kinship systems)
• Plain language communication
• Written seizure action plans in accessible formats
• Community education programs for febrile seizure management

Māori Children (New Zealand):

• Similar health disparities to Aboriginal Australians
• 2× higher rates of epilepsy-related hospitalizations
• Whānau (extended family) involvement critical
• Māori Health Workers involvement
• Respect for tikanga (customs) and manaakitanga (hospitality)

Retrieval Medicine

Remote/Rural SE Management:

Prehospital Care:

• Community-based seizure first aid education
• IM midazolam training for remote health workers
• Telehealth consultation with PICU/neurology
• Early activation of retrieval services

Retrieval Considerations:

• RFDS/NETS/CareFlight coordination
• Limited resources during transport (single nurse/doctor)
• Weight-based drug preparation before transport
• Continuous EEG not available in most retrieval services
• Ensure adequate sedation/paralysis for transport

Aeromedical Considerations:

• Altitude effects on cerebral oedema
• Pressure changes in aircraft cabin
• Motion may exacerbate seizures (if not controlled)
• Limited access to patient in fixed-wing aircraft

---

SAQ Practice

SAQ 1: Febrile Status Epilepticus Management

Time Allocation: 10 minutes
Total Marks: 20

Stem: A 22-month-old previously well boy is brought to the emergency department by ambulance. He developed a fever (39.5°C) earlier today and then had a generalised tonic-clonic seizure at home that has been ongoing for 15 minutes. Prehospital, he received diazepam 5 mg PR at 8 minutes but continues to seize.

Observations on arrival:

• HR: 160 bpm
• BP: 95/60 mmHg
• RR: 32/min
• SpO₂: 90% on 10L O₂
• Temperature: 39.8°C
• GCS: Unable to assess (actively seizing)

Question 1.1 (8 marks)

Outline your immediate management of this child in the first 10 minutes.

Question 1.2 (6 marks)

The seizure stops after your second-line agent. List 6 differential diagnoses for febrile status epilepticus in this age group, and identify which investigations you would prioritise.

Question 1.3 (6 marks)

Discuss the pathophysiology of benzodiazepine resistance in prolonged status epilepticus and the implications for management.

---

Model Answer

Question 1.1 (8 marks)

Systematic A-E Approach and Time-Based Escalation:

A - Airway (1 mark):

• Position in recovery/lateral position to protect airway
• Suction secretions, jaw thrust if needed
• Do NOT insert oral airway during active seizure

B - Breathing (1 mark):

• High-flow oxygen 15L via non-rebreather (SpO₂ 90% concerning)
• Prepare bag-mask ventilation
• Consider intubation if persistent hypoxia

C - Circulation (1 mark):

• Establish IV/IO access urgently
• Attach cardiac monitoring
• Prepare fluid bolus (20 mL/kg 0.9% NaCl) if hypotensive

D - Disability (2 marks):

• CHECK BLOOD GLUCOSE immediately (mandatory in all seizing children)
• If BSL <3.0 mmol/L: Dextrose 10% 2.5 mL/kg IV
• Prepare antiepileptic medications

E - Exposure (1 mark):

• Reduce temperature: remove clothing, tepid sponging, paracetamol 15 mg/kg IV
• Look for rash (meningococcal), signs of trauma

Antiepileptic Escalation (2 marks):

• Second benzodiazepine NOW (already received one dose at 8 min):
  • Lorazepam 0.1 mg/kg (2.2 mg for 22 kg child) IV, OR
  • Midazolam 0.2 mg/kg IM if no IV
• If seizure continues at 20 minutes:
  • Levetiracetam 40 mg/kg IV over 10 minutes (880 mg), OR
  • Phenytoin 20 mg/kg IV over 20 minutes (requires ECG monitoring)

---

Question 1.2 (6 marks)

Differential Diagnoses (3 marks - 0.5 marks each):

1. Simple febrile seizure prolonged (febrile status epilepticus)
2. Bacterial meningitis (Streptococcus pneumoniae, N. meningitidis)
3. Viral encephalitis (HSV, enterovirus)
4. Electrolyte disturbance (hyponatraemia from viral illness/vomiting)
5. First presentation of epilepsy (triggered by fever)
6. Dravet syndrome (SCN1A mutation - prolonged febrile SE in first year)

Priority Investigations (3 marks):

• Blood glucose (immediate - reversible cause)
• FBC, UEC, blood cultures (infection workup, electrolytes)
• Lumbar puncture (if safe) - CSF cell count, protein, glucose, Gram stain, culture, HSV PCR
  • Defer if signs of raised ICP, do CT first if concerns
• Start empiric antibiotics (ceftriaxone 50 mg/kg) AND aciclovir (20 mg/kg) if LP delayed
• CT brain only if focal signs, raised ICP concerns, or before LP

---

Question 1.3 (6 marks)

Pathophysiology of Benzodiazepine Resistance (4 marks):

GABA-A Receptor Internalization:

• Prolonged seizure activity causes excessive neuronal firing
• Sustained calcium influx activates phosphatases
• Dephosphorylation of GABA-A receptor β subunits
• Clathrin-mediated endocytosis removes GABA-A receptors from synaptic membrane to cytoplasm
• Surface GABA-A receptors reduce by 50% within 30 minutes of continuous seizure

NMDA Receptor Upregulation:

• Simultaneously, NMDA receptors traffic TO the synaptic membrane
• Surface NMDA receptor expression increases 3-fold during prolonged SE
• Leads to increased excitotoxicity and sustained seizure activity

Clinical Implications for Management (2 marks):

1. Early aggressive treatment is critical - benzodiazepines most effective in first 20-30 minutes before receptor internalization occurs

2. Do not delay second-line agents - escalate promptly at 20 minutes regardless of benzodiazepine response

3. NMDA antagonists (ketamine) become more effective in late/refractory SE when NMDA receptors are upregulated - consider earlier use in refractory cases

4. Higher doses of benzodiazepines are NOT the answer - reduced receptors mean diminishing returns; move to different drug classes

---

SAQ 2: Refractory Status Epilepticus

Time Allocation: 10 minutes
Total Marks: 20

Stem: A 5-year-old girl with known epilepsy (Dravet syndrome on valproate and clobazam) is admitted to PICU with refractory status epilepticus. She has received:

• Buccal midazolam 10 mg at home
• IV lorazepam 4 mg in ED
• IV levetiracetam 2000 mg (60 mg/kg)
• IV phenytoin 700 mg (20 mg/kg)

She continues to have generalised tonic-clonic seizures despite these medications. Total seizure duration is now 45 minutes.

Current Status:

• Intubated and ventilated for airway protection
• HR: 145 bpm, BP: 85/50 mmHg
• SpO₂: 98% on FiO₂ 0.4
• Temperature: 39.2°C
• Midazolam infusion commenced at 0.2 mg/kg/hr

Question 2.1 (8 marks)

Outline your management of this child's refractory status epilepticus, including anaesthetic agent options and EEG monitoring targets.

Question 2.2 (6 marks)

Describe the options for super-refractory status epilepticus if seizures continue beyond 24 hours despite anaesthesia.

Question 2.3 (6 marks)

Discuss the specific considerations for status epilepticus in a child with Dravet syndrome.

---

Model Answer

Question 2.1 (8 marks)

Confirm Refractory SE and Optimise Current Management (2 marks):

• This is refractory SE (failure of benzodiazepine + ≥2 second-line agents)
• Ensure adequate midazolam dosing - titrate infusion upward
• Continuous EEG monitoring is mandatory - attach now if not already

Anaesthetic Agent Escalation (3 marks):

Option 1: Increase midazolam infusion:

• Bolus: Additional 0.1-0.2 mg/kg
• Infusion: Increase to 0.3-0.5 mg/kg/hr, may need up to 1-2 mg/kg/hr
• Disadvantage: Tachyphylaxis develops within 24-48 hours

Option 2: Add ketamine (recommended):

• Loading: 1-2 mg/kg IV
• Infusion: 1-5 mg/kg/hr
• Rationale: NMDA antagonist effective in prolonged SE (NMDA receptors upregulated)
• Haemodynamically favourable (BP low)

Option 3: Thiopentone (if above fail):

• Loading: 3-5 mg/kg IV
• Infusion: 1-5 mg/kg/hr
• Caution: Severe hypotension expected, prepare vasopressors (noradrenaline)

Avoid prolonged propofol in this 5-year-old (PRIS risk)

EEG Monitoring Targets (2 marks):

• Initial target: Electrographic seizure suppression
• If seizures recur on weaning: Escalate to burst suppression (1:5 ratio = 1 sec burst : 5 sec suppression)
• Maintain EEG target for 24-48 hours before attempting wean
• Wean slowly over 12-24 hours, monitoring for seizure recurrence

Supportive Measures (1 mark):

• Arterial line for BP monitoring
• Vasopressor support (noradrenaline) for hypotension (MAP target appropriate for age)
• Treat hyperthermia actively
• Optimize electrolytes (Na, Ca, Mg, glucose)

---

Question 2.2 (6 marks)

Super-Refractory SE Options (6 marks - 1 mark each):

1. Thiopentone infusion (if not already used):

   • 1-5 mg/kg/hr, titrate to burst suppression
   • Most effective barbiturate for SRSE
   • Significant hypotension, immunosuppression

2. Ketamine addition/optimization:

   • Increase to 5-10 mg/kg/hr
   • Can combine with midazolam infusion
   • Mechanistically different (NMDA antagonism)

3. Immunotherapy (consider autoimmune/inflammatory component):

   • Methylprednisolone 30 mg/kg × 3-5 days
   • IVIg 0.4 g/kg × 5 days
   • Rationale: FIRES (Febrile Infection-Related Epilepsy Syndrome) can present similarly

4. Ketogenic diet:

   • High-fat, low-carbohydrate via NGT
   • 4:1 fat:carbohydrate ratio
   • Target blood ketones 3-5 mmol/L
   • 50-90% response in paediatric SRSE

5. Inhaled anaesthetics (isoflurane):

   • 0.8-2.0% via specialized anaesthetic ventilator
   • Requires scavenging system
   • Limited availability in most PICUs

6. Therapeutic hypothermia (limited evidence):

   • 32-34°C
   • Case reports only, not standard practice

---

Question 2.3 (6 marks)

Dravet Syndrome Considerations (6 marks):

Background (1 mark):

• Caused by SCN1A mutation (sodium channel dysfunction)
• Characterized by prolonged febrile and afebrile seizures from first year of life
• Highly pharmacoresistant epilepsy

Medications to AVOID (2 marks):

• Sodium channel blockers worsen Dravet syndrome:
  • Phenytoin/fosphenytoin - may exacerbate seizures
  • Carbamazepine, oxcarbazepine, lamotrigine - all contraindicated
• This patient appropriately received levetiracetam (safe) but phenytoin use was suboptimal

Preferred Antiepileptics (2 marks):

• Valproate (already on) - first-line
• Clobazam (already on) - effective adjunct
• Stiripentol - specifically approved for Dravet (TGA registered)
• Fenfluramine - newer agent with evidence in Dravet
• Cannabidiol - FDA/TGA approved for Dravet syndrome

Acute SE Management Modifications (1 mark):

• Benzodiazepines remain first-line and are safe
• Levetiracetam preferred over phenytoin for second-line
• Phenobarbital is acceptable alternative
• Ketamine may be particularly useful (NMDA mechanism)
• Aggressive cooling important (fever is strong trigger)

---

Viva Scenarios

Viva 1: Benzodiazepine-Resistant Seizures

Stem: "A 3-year-old boy is brought to your PICU from the emergency department. He presented with generalised tonic-clonic seizures that have continued for 25 minutes despite receiving IV lorazepam 4mg and midazolam 5mg IM. He has no past medical history and has been unwell with viral symptoms for 2 days. His temperature is 39°C."

Duration: 12 minutes (2 min reading + 10 min discussion)

---

Opening Question: "What are your immediate concerns and priorities?"

Expected Answer (2-3 minutes):

"This child has established status epilepticus that is benzodiazepine-resistant, which is a medical emergency requiring immediate escalation."

Immediate concerns:

1. Ongoing seizure activity causing neuronal injury - need second-line AED now
2. Airway and oxygenation - prolonged seizures impair ventilation
3. Underlying cause - febrile illness concerning for CNS infection (meningitis/encephalitis)
4. Hypoglycaemia - must check and treat immediately

Priorities:

1. ABC stabilisation - high-flow oxygen, IV access
2. Check blood glucose immediately
3. Administer second-line antiepileptic agent (levetiracetam or phenytoin)
4. Investigate for underlying cause - lumbar puncture, blood cultures
5. Empiric antibiotics and aciclovir if CNS infection suspected

---

Follow-up Question 1: "You administer levetiracetam 40mg/kg IV. After 5 minutes, the seizures continue. What is your approach now?"

Expected Answer:

"This is now refractory status epilepticus. I would:"

1. Prepare for intubation and anaesthesia:

   • Call for anaesthetic/senior support
   • Prepare RSI drugs (propofol or thiopentone for induction, rocuronium)
   • Prepare vasopressor (noradrenaline) - hypotension expected

2. Arrange continuous EEG monitoring - essential for titrating anaesthesia

3. Intubate and commence anaesthetic infusion:

   • Midazolam infusion 0.2 mg/kg bolus, then 0.1-0.4 mg/kg/hr OR
   • Consider adding ketamine 1-2 mg/kg bolus, 1-5 mg/kg/hr (NMDA antagonist, haemodynamically stable)

4. Caution with propofol in this age group due to PRIS risk

5. Target: Electrographic seizure suppression on EEG

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Follow-up Question 2: "Explain why benzodiazepines become less effective in prolonged status epilepticus."

Expected Answer:

"This relates to receptor trafficking during prolonged seizure activity:"

GABA-A Receptor Internalization:

• Prolonged neuronal firing causes sustained calcium influx
• Calcium activates phosphatases that dephosphorylate GABA-A receptor β subunits
• This signals clathrin-mediated endocytosis of receptors
• GABA-A receptors are removed from the synaptic membrane and internalized
• Surface receptors reduce by 50% within 30 minutes of continuous seizure

NMDA Receptor Upregulation:

• Simultaneously, NMDA receptors traffic TO the synapse
• NMDA receptor surface expression increases 3-fold
• Increases excitatory glutamate signalling

Clinical Implication:

• Benzodiazepines become progressively ineffective
• Don't delay escalation - the longer the seizure, the harder to terminate
• NMDA antagonists (ketamine) become MORE effective in late SE
• This is the rationale for early ketamine use in refractory cases

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Follow-up Question 3: "The child's lumbar puncture shows CSF WCC 150/mm³ (90% lymphocytes), protein 0.8 g/L, glucose 3.5 mmol/L (serum 6.0). What is your diagnosis and management?"

Expected Answer:

"This CSF picture suggests viral meningoencephalitis."

CSF Interpretation:

• Lymphocytic pleocytosis (150 WCC, 90% lymphocytes)
• Mildly elevated protein
• Normal glucose ratio (>60% of serum)
• Pattern consistent with viral rather than bacterial infection

Most Important Cause to Treat: HSV encephalitis

• Temporal lobe predilection
• Treatable with aciclovir
• High mortality if untreated

Management:

1. IV Aciclovir 20 mg/kg q8h empirically (continue until HSV PCR negative)
2. Send CSF HSV PCR (gold standard)
3. Consider enterovirus PCR, other viral studies
4. MRI brain - look for temporal lobe involvement
5. Continue seizure management and supportive care
6. Repeat LP if clinically indicated

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Viva 2: Investigation Priorities in Paediatric SE

Stem: "A 14-month-old girl presents with her first seizure, which has been ongoing for 12 minutes. There is no fever. She has been increasingly irritable over the past week with decreased oral intake. Her fontanelle appears full."

Duration: 12 minutes (2 min reading + 10 min discussion)

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Opening Question: "What are your immediate concerns?"

Expected Answer:

"This is a non-febrile status epilepticus in an infant with concerning features:"

Immediate Concerns:

1. Raised intracranial pressure - full fontanelle in irritable infant is highly concerning
   • Possible causes: Meningitis, encephalitis, intracranial mass, hydrocephalus, non-accidental injury
2. Ongoing seizure - need to terminate but also investigate cause
3. Hypoglycaemia/metabolic - always check in infants
4. Non-accidental injury - must consider in infant with unexplained neurological symptoms

Management Priorities:

1. ABC stabilisation, terminate seizure with benzodiazepines
2. Check blood glucose immediately
3. Do NOT perform LP until imaging - raised ICP signs present
4. Urgent CT brain
5. Blood tests including FBC, UEC, calcium, liver function, ammonia

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Follow-up Question 1: "Outline your investigation approach, considering the clinical features."

Expected Answer:

Immediate Investigations:

Bedside:

• Blood glucose (hypoglycaemia is reversible)
• VBG (acidosis, lactate)

Blood Tests:

• FBC (infection, malignancy)
• UEC, calcium, magnesium (electrolyte causes)
• LFTs, ammonia (metabolic disease, hepatic encephalopathy)
• Blood cultures (sepsis)
• Coagulation studies (if considering LP later, NAI)

Neuroimaging (Urgent):

• CT brain first - cannot do LP with raised ICP
• Looking for: Mass lesion, hydrocephalus, intracranial haemorrhage (NAI), cerebral oedema

CT Findings Will Guide Further Investigation:

• If hydrocephalus → neurosurgical referral
• If haemorrhage → NAI workup, ophthalmology (retinal haemorrhages), skeletal survey
• If mass → oncology, neurosurgery
• If normal → may proceed to LP once stable

Lumbar Puncture (when safe):

• CSF cell count, protein, glucose
• Gram stain, culture
• Viral PCR panel

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Follow-up Question 2: "CT shows bilateral subdural haematomas of different ages. What is your approach?"

Expected Answer:

"This is highly concerning for non-accidental injury (child abuse)."

Immediate Actions:

1. Medical Stabilisation:

   • Continue seizure management
   • Neurosurgical consultation (may need drainage)
   • Manage raised ICP

2. Child Protection Response:

   • Mandatory notification to child protection services (DOCS/FACS in NSW, DHHS in Victoria)
   • Do NOT discharge child - admit to hospital
   • Detailed documentation of all findings
   • Careful history from carers (keep neutral, document verbatim)

3. Forensic Medical Evaluation:

   • Ophthalmology - dilated fundoscopy for retinal haemorrhages
   • Skeletal survey - healing fractures, rib fractures, metaphyseal corner fractures
   • Detailed photography of any bruising or injuries
   • Social work involvement

4. Multidisciplinary Team:

   • Paediatric intensivist
   • Neurosurgery
   • Child protection team
   • Social worker
   • Police may need to be involved

5. Family Communication:

   • Explain findings factually
   • Do not accuse but explain mandatory reporting obligations
   • Ensure child's safety is paramount

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Follow-up Question 3: "Discuss the Indigenous health considerations if this child were from a remote Aboriginal community."

Expected Answer:

"There are important cultural and access considerations:"

Access Challenges:

• Remote community → significant delay to tertiary care
• RFDS retrieval required - may take 4-6+ hours
• Limited diagnostic capability locally (no CT/MRI)
• May have presented late due to geographic barriers

Cultural Considerations:

• Involve Aboriginal Health Worker (AHW) and Aboriginal Liaison Officer (ALO)
• Extended family/community involvement in decision-making
• Interpreter services if English not first language
• Respect for cultural protocols - sorry business, kinship systems

Child Protection Considerations:

• Aboriginal children over-represented in child protection system
• Important to distinguish NAI from:
  • Traditional practices
  • Delayed presentations due to access
  • Different family structures
• Culturally appropriate assessment essential
• Aboriginal-specific child protection services should be involved

Communication:

• Plain language, visual aids
• Written seizure action plans in accessible formats
• Community education about febrile seizure management
• Follow-up arrangements appropriate for remote setting