What is the etiology of neonatal and pediatric encephalitis?

Etiology of Neonatal and Pediatric Encephalitis

The most common causes of encephalitis in children are viral pathogens, with herpes simplex virus (HSV) being the most frequently identified cause in industrialized nations, followed by West Nile virus, enteroviruses, and other herpesviruses. 1, 2

Viral Causes

Herpes Viruses

• Herpes Simplex Virus (HSV)

  • Most common identified viral cause in industrialized nations 1
  • Annual incidence of 1 in 250,000 to 500,000 1
  • Bimodal age distribution with peaks in childhood and elderly 1
  • HSV-1 accounts for ~90% of cases; HSV-2 for ~10% 1
  • HSV-2 occurs primarily in neonates and immunocompromised patients 2
  • Presents with seizures, lethargy, and temperature changes in neonates 3

• Varicella Zoster Virus (VZV)

  • Common cause, especially in immunocompromised patients 2
  • Often presents as multifocal leukoencephalopathy in immunocompromised patients 1

• Cytomegalovirus (CMV)

  • Occurs almost exclusively in immunocompromised patients 2

Other Viral Causes

• Enteroviruses

  • Common cause of encephalitis in children 2
  • Enterovirus 71 has been identified as a significant cause with high mortality (50% in some studies) 4
  • Can be associated with a brainstem syndrome 2
  • Large outbreaks reported with enterovirus 71 2

• Arboviruses

  • West Nile virus - among most common causes in the US 2
  • Japanese encephalitis virus (geographically variable) 4

• Other Viruses

  • Measles virus (can cause three distinct encephalitic syndromes) 2
    1. Acute encephalitis during primary infection
    2. Subacute encephalopathy in immunocompromised patients
    3. Subacute sclerosing panencephalitis (SSPE) years after infection
  • Mumps virus 4
  • Influenza viruses (H1N1 may cause more neurological manifestations) 2
  • Rotavirus (can cause encephalopathy with convulsions and cerebellar signs) 2

Non-Viral Infectious Causes

Bacterial

• Mycoplasma pneumoniae

  • Commonly identified in some studies, but pathogenic role unclear 2
  • Generally diagnosed by serologic methods 2
  • Rarely detected within CNS 2

• Other Bacteria

  • Listeria monocytogenes (brainstem encephalitis) 2
  • Mycobacterium tuberculosis (subacute/chronic presentation) 2
  • Borrelia burgdorferi (Lyme neuroborreliosis) 2

Parasitic and Fungal

• Parasites account for approximately 3% of confirmed/probable cases 2
• Fungi account for approximately 1% of confirmed/probable cases 2
• Toxoplasma gondii (especially in immunocompromised) 2

Non-Infectious Causes

Immune-Mediated

• Acute Disseminated Encephalomyelitis (ADEM)

  • Post-infectious or post-vaccination 2
  • Often temporally related to prior infection outside CNS 2

• Antibody-Associated Encephalitis

  • Voltage-gated potassium channel complex antibodies 2
  • N-methyl-D-aspartate (NMDA) receptor antibodies 2
  • May be paraneoplastic (e.g., limbic encephalitis with ovarian teratomas) 2
  • Initially reported in adults but increasingly recognized in children 2

Metabolic Encephalopathies

• Can mimic infectious encephalitis 2
• Characterized by symmetrical neurological findings, myoclonus, signs of liver failure 2

Epidemiology and Diagnostic Challenges

• In many cases (32%-75%), the etiology remains unknown despite extensive evaluation 2
• In the California Encephalitis Project, a confirmed or probable agent was identified in only 16% of cases 2
• Of confirmed/probable cases: 69% viral, 20% bacterial, 7% prion, 3% parasitic, 1% fungal 2
• Approximately 10% of patients initially thought to have infectious encephalitis ultimately receive a non-infectious diagnosis 2

Clinical Presentation Patterns

• Brainstem Involvement

  • Lower cranial nerve involvement suggests enteroviruses (especially EV-71) 2
  • Respiratory drive disturbance may indicate certain viral etiologies 2
  • Autonomic dysfunction can be seen in rabies 2

• Neonatal Presentation

  • Seizures (common in 6/9 neonates with HSV) 3
  • Lethargy (6/9 neonates) 3
  • Temperature changes (5/9 neonates) 3
  • Apnea (3/9 neonates) 3

Diagnostic Approach

The diagnostic approach should be guided by epidemiologic clues, including:

• Season of the year
• Geographic location
• Prevalence of disease in the community
• Travel history
• Recreational activities
• Occupational exposures
• Insect or animal contacts
• Vaccination history
• Immune status of the patient 2

Early diagnosis and treatment are critical, as delays beyond 48 hours after hospital admission are associated with worse outcomes 1.

Key Considerations for Clinicians

• A high index of suspicion is required for neonatal HSV encephalitis 3
• The constellation of febrile illness with altered behavior, personality, cognition, consciousness, new seizures, or focal neurological signs should raise suspicion of encephalitis 2
• CSF testing and EEG have shown 100% sensitivity in laboratory-confirmed HSV cases 3
• Consider both infectious and non-infectious causes in the differential diagnosis 2

Early recognition and appropriate treatment are essential to improve outcomes in pediatric encephalitis, particularly for treatable causes such as HSV.