What is the differential diagnosis for a 1-year-old patient with rapidly progressing meningoencephalitis, already treated with empiric antibiotics and acyclovir (antiviral medication)?

Differential Diagnosis for Rapidly Progressing Meningoencephalitis in a 1-Year-Old Already on Empiric Therapy

In a 1-year-old with rapidly progressing meningoencephalitis despite empiric antibiotics and acyclovir, you must urgently consider resistant bacterial pathogens, non-HSV viral etiologies (particularly enterovirus and HHV-6), autoimmune/post-infectious encephalitis, and less common infectious causes including tuberculosis and fungal infections. 1

Primary Infectious Considerations

Viral Etiologies Beyond HSV/VZV

• Enterovirus is the most frequently identified viral cause in pediatric meningoencephalitis, accounting for 65.2% of viral cases in one series, and may not respond to acyclovir 2
• Human Herpesvirus-6 (HHV-6) is increasingly recognized in young children with meningoencephalitis and requires specific testing beyond standard HSV PCR 3
• Other herpesviruses including CMV and EBV should be considered, particularly if the child has any immunocompromising conditions 1

Resistant or Inadequately Covered Bacterial Pathogens

• Partially treated bacterial meningitis from common organisms (Streptococcus pneumoniae, Neisseria meningitidis, Group B Streptococcus) may show atypical progression if antibiotic penetration is inadequate or resistance exists 1, 4
• Mycobacterium tuberculosis presents with subacute to rapidly progressive meningoencephalitis and requires specific consideration, especially with travel history or TB exposure 5
• Listeria monocytogenes should be considered if empiric coverage did not include ampicillin, as this pathogen requires specific antibiotic coverage 1

Autoimmune and Post-Infectious Encephalitis

Anti-NMDAR Encephalitis

• Post-HSV autoimmune encephalitis develops in 24.5% of children with HSV encephalitis by 3 months, presenting as clinical deterioration or failure to improve despite appropriate acyclovir therapy 1
• Anti-NMDAR encephalitis is now the single most common cause of encephalitis in patients under 30 years, exceeding all viral causes combined in this age group 1
• This should be strongly considered if the child shows slow response to acyclovir or develops recrudescent symptoms after initial improvement 1

Other Autoimmune Etiologies

• Acute disseminated encephalomyelitis (ADEM) and other para-infectious immune-mediated processes must be considered, particularly if there are symmetrical neurological findings 1

Non-Infectious Mimics

Metabolic and Toxic Causes

• Inborn errors of metabolism should be considered if there is history of similar episodes, symmetrical neurological findings, myoclonus, or signs of liver failure 1
• Look for acidosis or alkalosis on laboratory testing as clues to metabolic etiology 1

Other Considerations

• Vascular events including stroke or cerebral venous thrombosis can mimic infectious meningoencephalitis 1
• Neoplastic or paraneoplastic processes are less likely in a 1-year-old but should be considered if imaging shows mass lesions 1

Critical Diagnostic Steps at This Juncture

Immediate CSF Re-evaluation

• Repeat lumbar puncture is essential if not contraindicated, even if acyclovir has been started, as HSV PCR remains positive for 7-10 days after treatment initiation 1
• Send CSF for: expanded viral PCR panel (including enterovirus, HHV-6, CMV, EBV), bacterial culture, TB culture and PCR, fungal studies, and consider next-generation sequencing if available 1
• CSF pleocytosis with elevated protein and low glucose suggests bacterial or TB etiology, while normal or mildly abnormal CSF does not exclude viral encephalitis 5, 4

Advanced Neuroimaging

• MRI with contrast is superior to CT and should be obtained urgently if not already done, as CT may be normal even in severe CNS infections 1
• MRI patterns may suggest specific etiologies: temporal lobe involvement suggests HSV, while white matter changes may indicate ADEM or metabolic disease 1
• Consider stereotactic brain biopsy if no diagnosis is made after the first week and focal abnormalities are present on imaging, as this can change management 1

Autoimmune Testing

• Send serum and CSF for anti-NMDAR antibodies and other autoimmune encephalitis panels, particularly if there is clinical deterioration despite appropriate antimicrobial therapy 1
• Consider empiric immunomodulation with steroids if autoimmune etiology is suspected, though this remains investigational 1

HIV Testing

• HIV testing should be performed on all children with encephalitis regardless of apparent risk factors, as undiagnosed HIV predisposes to multiple CNS pathogens including CMV, TB, and Cryptococcus 1

Common Pitfalls to Avoid

• Do not assume acyclovir failure means non-viral etiology: Consider HHV-6, enterovirus, or post-viral autoimmune encephalitis 1, 3
• Do not rely on absence of fever or classic meningeal signs: Fever is present in only 6-39% of neonatal bacterial meningitis cases, and neck stiffness has only 51% sensitivity in children 1, 4
• Do not stop diagnostic workup prematurely: Empirical antimicrobial use can create false reassurance and delay identification of alternative treatable etiologies 1
• Do not delay brain biopsy indefinitely: If no diagnosis after one week with focal imaging abnormalities, biopsy should be strongly considered as it is now relatively safe with modern stereotactic techniques 1