What is Encephalitis?
Encephalitis is inflammation of the brain parenchyma characterized by altered mental status lasting ≥24 hours, typically accompanied by fever, seizures, focal neurologic findings, or abnormal CSF/neuroimaging, and can result from direct viral infection, post-infectious immune processes, or autoimmune mechanisms. 1
Core Definition and Pathophysiology
Encephalitis represents brain inflammation that fundamentally differs from encephalopathy, which involves brain dysfunction without direct inflammatory processes in the brain parenchyma. 1 The inflammation can arise through three distinct mechanisms:
- Direct infection of brain tissue by pathogens (viruses, bacteria, fungi, or parasites) 1
- Post-infectious immune-mediated processes such as acute disseminated encephalomyelitis (ADEM) following viral infections or vaccinations 1
- Autoimmune mechanisms such as anti-NMDA receptor encephalitis, which now accounts for 41% of encephalitis cases in patients under 30 years old 2
Clinical Diagnostic Criteria
The International Encephalitis Consortium established standardized criteria requiring one major criterion plus multiple minor criteria: 1
Major Criterion (Required):
- Altered mental status (decreased consciousness, lethargy, or personality change) lasting ≥24 hours with no alternative cause identified 1
Minor Criteria (≥2 for possible encephalitis; ≥3 for probable/confirmed):
- Documented fever ≥38°C within 72 hours of presentation 1
- Generalized or partial seizures not attributable to preexisting disorder 1
- New focal neurologic findings 1
- CSF white blood cell count ≥5/mm³ 1
- Brain parenchymal abnormalities on neuroimaging suggestive of acute encephalitis 1
- EEG abnormalities consistent with encephalitis 1
Critical Diagnostic Pitfalls
Normal CSF and neuroimaging do NOT exclude encephalitis—the disease can occur without significant CSF pleocytosis or demonstrable imaging abnormalities. 1, 3 This is a common trap that delays diagnosis and treatment.
The clinical presentation overlaps significantly with meningitis, making differentiation challenging at initial presentation, though mental status changes typically appear earlier in encephalitis. 1 Most cases present with fever, headache, altered consciousness, and may include behavioral changes, cognitive dysfunction, focal neurologic signs, or seizures. 1, 4
Etiologic Spectrum
Viral infections cause 69% of confirmed cases, with herpes simplex virus (HSV-1 and HSV-2) being the most common identifiable cause in industrialized nations (annual incidence 1 in 250,000-500,000). 3, 2 Other important viral causes include varicella-zoster virus, enteroviruses, West Nile virus, and cytomegalovirus. 3, 2
Bacterial causes (20% of confirmed cases) include Mycobacterium tuberculosis, Treponema pallidum, Bartonella henselae, and Listeria monocytogenes. 3, 2
Autoimmune causes are increasingly recognized, with anti-NMDA receptor encephalitis now surpassing the combined incidence of HSV, West Nile virus, and varicella-zoster virus encephalitis in patients under 30. 2 Notably, 24.5% of patients develop detectable anti-NMDA antibodies within 3 months following HSV encephalitis, representing a post-infectious autoimmune phenomenon. 2
Despite extensive testing, more than 50% of presumed encephalitis cases remain unexplained, which significantly impacts targeted treatment strategies. 1, 2
Epidemiology and Risk Factors
The global incidence varies by geography, ranging from 0.7 to 13.8 per 100,000 in Western countries across all ages. 2 HSV encephalitis shows a bimodal age distribution with peaks in young children and elderly populations. 2 The disease burden is highest in low- and middle-income countries. 2
Clinical Significance and Outcomes
Early recognition and treatment are critical for mortality and morbidity reduction. Aciclovir treatment has dramatically improved outcomes for HSV encephalitis, but delays beyond 48 hours after hospital admission are associated with significantly worse prognosis. 2 Many survivors experience long-term neuropsychiatric disorders, neurocognitive impairment, and physical deficits requiring multidisciplinary management. 5, 4
The distinction between infectious encephalitis and post-infectious/autoimmune encephalitis is therapeutically crucial, as management approaches differ fundamentally—antimicrobials for infectious causes versus immunomodulatory therapy for autoimmune etiologies. 1