What is the approach to diagnosis, treatment, and management of pediatric and neonatal encephalitis?

Pediatric and Neonatal Encephalitis: Comprehensive Management Approach

Prompt recognition and treatment of pediatric and neonatal encephalitis is essential for improving outcomes, with early administration of acyclovir for suspected HSV encephalitis being critical to reduce mortality and morbidity. 1

Etiology

• Infectious causes:

  • Viral: HSV (most common identified cause), enteroviruses, VZV, influenza, measles
  • Bacterial: Tuberculosis, Listeria, Brucella
  • Parasitic: Toxoplasmosis, malaria

• Non-infectious causes:

  • Autoimmune: Anti-NMDA receptor encephalitis (second most common identified cause)
  • Para-infectious: ADEM (Acute Disseminated Encephalomyelitis)
  • Acute Necrotizing Encephalopathy (ANEC): Associated with viral infections, particularly influenza 2

Epidemiology

• Neonatal HSV encephalitis presents at mean age of 24 ± 20 days 3
• HSV-1 encephalitis and anti-NMDA receptor encephalitis are the most frequently identified etiologies in children 4
• Mortality rate for ANEC is high, with fewer than 10% of patients recovering completely 2
• Significant neurological sequelae occur in survivors, with developmental delay being common 3

Pathophysiology

• Infectious encephalitis: Direct invasion of brain parenchyma by pathogens
• Para-infectious encephalitis: Immune-mediated response following infection
• ANEC: Cytokine-mediated brain edema triggered by abnormal immune response to viral infections 2
• Autoimmune encephalitis: Aberrant immune response against neuronal antigens

Clinical Presentation

History and Physical Examination

• Key clinical features that should raise suspicion:

  • Current or recent febrile illness
  • Altered behavior, personality, cognition or consciousness
  • New onset seizures (present in 67% of neonatal HSV cases) 3
  • New focal neurological signs 1

• Neonatal HSV encephalitis typically presents with:

  • Seizures
  • Lethargy
  • Temperature changes
  • Apnea 3

• Specific clinical features suggesting particular etiologies:

  • Lower cranial nerve involvement: Enteroviruses (especially EV-71)
  • Myoclonus: Flaviviruses
  • Respiratory drive disturbance: Alphaviruses
  • Rash: Measles, VZV, rickettsial infections 1

Evaluation

Initial Workup

1. Neuroimaging: MRI is preferred over CT (recommendation level B) 1, 5

   • For ANEC: Bilateral thalamic involvement is diagnostic 2

2. Lumbar Puncture: (unless contraindicated by significant brain shift/swelling) 1

   • CSF analysis for:
     • Cell count (monocytosis/lymphocytosis in HSV)
     • Protein (elevated in HSV)
     • Glucose (depressed in HSV)
     • PCR for viral pathogens (recommendation level A) 1, 3, 5
     • Serology (recommendation level B) 5

3. EEG: 100% sensitivity in neonatal HSV encephalitis 3

4. Additional investigations based on clinical suspicion:

   • For returning travelers: Malaria testing (thick and thin blood films) 1
   • For suspected autoimmune encephalitis: Antibody testing (anti-NMDA receptor, voltage-gated potassium channel complex) 1

Differential Diagnosis

• Metabolic encephalopathy
• Toxic encephalopathy
• Septic encephalopathy
• Vascular disorders
• Neoplastic/paraneoplastic syndromes
• Reye's Syndrome (protracted vomiting, encephalopathy, elevated ammonia) 2

Treatment and Management

Empiric Therapy

• Start empiric therapy immediately while awaiting diagnostic results:
  • Acyclovir (60 mg/kg/day divided q8h IV for neonates; 30 mg/kg/day divided q8h IV for children) for suspected HSV encephalitis (recommendation level A) 1, 5
  • Empirical antibiotics if bacterial etiology cannot be excluded 2

Specific Therapy Based on Etiology

1. HSV Encephalitis:

   • Acyclovir (recommendation level A) 1, 5

2. VZV Encephalitis:

   • Acyclovir may be effective (class IV evidence) 5

3. Enterovirus Encephalitis:

   • No specific treatment recommended
   • Consider pleconaril (if available) or IVIG in severe cases (recommendation level C) 1

4. ANEC:

   • High-dose IV methylprednisolone (1g daily for 3-5 days)
   • IVIG (2g/kg over 5 days)
   • Initiate within 24 hours of symptom onset 2
   • For refractory cases: Consider plasma exchange 2

5. Autoimmune Encephalitis:

   • Early immunomodulatory treatment (within 7 days) associated with better functional outcomes 4

Supportive Care

• Airway management and ventilatory support for patients with falling level of consciousness (recommendation level A) 1
• Management of raised intracranial pressure 1
• Seizure control with appropriate anticonvulsants 2
• Hemodynamic support following pediatric shock protocols 2
• Consider ECMO for refractory shock or respiratory failure 2

Prognosis

• HSV encephalitis: Improved outcomes with early acyclovir therapy 3
• ANEC: Generally poor prognosis with high mortality rate 2
• Autoimmune encephalitis: Better outcomes with early immunomodulatory treatment 4
• Overall: Developmental delay and upper motor neuron findings are common sequelae 3

Complications

• Developmental delay
• Motor deficits
• Cognitive impairment
• Behavioral problems
• Seizure disorders (though less common with early treatment) 3

Rehabilitation and Follow-up

• Discharge planning:

  • Definite or suspected diagnosis should be established
  • Outpatient follow-up and rehabilitation plans formulated (recommendation level A) 1

• Comprehensive rehabilitation approach:

  • Neuropsychology
  • Child and adolescent mental health teams
  • Speech and language therapy
  • Neuro-physiotherapy
  • Occupational therapy 1

• Follow-up imaging:

  • MRI at 4-6 weeks to evaluate lesion evolution 2

• Medication tapering:

  • For ANEC: Steroids should be tapered over at least 4-6 weeks 2

Pearls and Pitfalls

Pearls

• Early administration of acyclovir in suspected HSV encephalitis is critical
• EEG and CSF analysis have 100% sensitivity in neonatal HSV encephalitis 3
• MRI is superior to CT for diagnosis of encephalitis 1, 5
• Early immunomodulatory treatment improves outcomes in autoimmune encephalitis 4

Pitfalls

• Delaying acyclovir administration while awaiting diagnostic confirmation
• Failing to consider non-infectious causes of encephalitis
• Inadequate follow-up and rehabilitation planning
• TNF antagonist therapy is contraindicated in patients with demyelinating diseases 2
• Failure to recognize returning travelers at risk for malaria and other tropical infections 1
• Discharging patients without adequate information about their condition and follow-up plans 1