6. Encephalitis

Quick Recap

Neurology System, Protocol 6/12. Nests closely with Meningitis (Protocol 5) — many patients present with overlapping meningoencephalitis.

1. Definition

Encephalitis = infection/inflammation of the brain PARENCHYMA (vs meningitis = meninges). Cerebral dysfunction is the key differentiating trait, manifesting as altered mental status, motor/sensory deficits, personality changes, movement disorders, aphasia, or psychiatric symptoms (hallucinations, delusions, paranoia). Many patients show both parenchymal AND meningeal inflammation and are more accurately termed "meningoencephalitis."

2. Herpes Simplex Virus (HSV) Encephalitis — The Must-Not-Miss Diagnosis

HSV is notable both for its high morbidity/mortality AND its responsiveness to timely antiviral therapy — this combination makes early empiric treatment essential rather than optional pending confirmation.

Presentation: fever + altered mental status; focal findings (hemiparesis, aphasia, ataxia, focal seizures) common.

CSF: usually hemorrhagic with moderate lymphocytic pleocytosis and elevated protein.

EEG: focal slowing or epileptiform activity, TYPICALLY OVER THE TEMPORAL LOBES — a useful localizing clue.

Imaging: hemorrhagic lesions on CT/MRI may appear in the subacute/chronic phase or if treatment is delayed — do not wait for characteristic imaging findings to treat, as their absence early does not exclude HSV.

Management: start acyclovir IV empirically and continue until HSV PCR is CONFIRMED NEGATIVE — do not wait for PCR results before starting. Untreated mortality approaches 70%. Once started, acyclovir should be given IV for the ENTIRE treatment duration (no oral step-down).

Rule of thumb from the Meningitis protocol: add acyclovir empirically for ANY patient >50 years old presenting with encephalitis symptoms, given the stakes of missing a treatable cause.

3. Varicella-Zoster Virus (VZV) Encephalitis

Second most common sporadic viral encephalitis worldwide (behind HSV). Typically presents with a painful dermatomal rash PRIOR to neurologic involvement — but the rash can notably be ABSENT, so its absence should not lower suspicion in the right clinical context (older or immunocompromised patients, usually via reactivation). Presentation: focal deficits, altered consciousness, cranial neuropathies, seizures, aphasia, weakness. VZV can also cause a vasculopathy of large and small cerebral arteries leading to ischemic stroke or intracerebral hemorrhage — a distinct mechanism from direct parenchymal infection, worth considering in VZV-associated stroke-like presentations. Treatment: prompt IV acyclovir, same principle as HSV.

4. Arthropod-Borne (Vector-Borne) Encephalitis

Spread via mosquito or tick: St. Louis encephalitis, California encephalitis, Japanese B encephalitis, Eastern/Western equine encephalitis, West Nile virus (the most common viral encephalitis in the US). West Nile presents with systemic symptoms (fever, myalgias, rash) in most, but a small subset develop serious neurologic sequelae: flaccid quadriparesis, encephalopathy, movement disorders, death. CSF shows IgM titers against West Nile virus. Treatment is generally SUPPORTIVE ONLY — unlike HSV/VZV, there is no proven specific antiviral therapy, an important distinction driving different urgency/expectation-setting with families.

5. Autoimmune Encephalitis (Cross-reference)

Anti-NMDA-receptor and other autoimmune/paraneoplastic encephalitides present with a similar altered-mental-status/psychiatric/seizure picture but require an entirely different treatment pathway (immunotherapy: steroids, IVIG, plasmapheresis, tumor screening for paraneoplastic triggers) rather than antivirals. Should be actively considered when infectious workup (including HSV PCR) is negative and the clinical course doesn't fit a typical infectious pattern, particularly with prominent psychiatric symptoms, movement disorder, or seizures refractory to standard therapy (see Status Epilepticus protocol's SRSE section, which specifically flags autoimmune/paraneoplastic encephalitis as a cause responding well to immunotherapy).

6. HIV/Immunocompromised-Host Encephalitis Considerations

CNS Toxoplasmosis: risk rises sharply as CD4+ falls below 100 cells/mm3. Presents with fever, headache, altered mental status, focal deficits, seizures. Ring-enhancing lesions on contrast CT/MRI — note this appearance is NOT specific to toxoplasmosis; differential for ring-enhancing lesions also includes bacterial brain abscess, cryptococcoma, CNS fungal infection (aspergillosis), and syphilitic gummas.

Cryptococcal meningoencephalitis: below CD4+ 50 cells/mm3 — severe headache, photophobia, possible coma, markedly elevated ICP is characteristic. Serial lumbar punctures (even with normal opening pressure) have been shown to DECREASE MORTALITY in cryptococcal meningitis — this is a genuinely distinct, evidence-supported management step beyond just antifungal therapy, worth not missing.

Other must-consider causes with rapid deterioration + imaging abnormalities in immunocompromised hosts: herpesvirus encephalitides (HSV, CMV, VZV), primary CNS lymphoma (EBV-associated), progressive multifocal leukoencephalopathy (JC polyomavirus).

Immune Reconstitution Inflammatory Syndrome (IRIS): life-threatening complication of ART, typically within days-weeks of initiation — can be indistinguishable from an acute opportunistic infection. Most commonly involves M. tuberculosis, MAC, P. jirovecii, dimorphic fungi, CMV, at new or previously known infection sites. Empiric corticosteroids are NOT broadly recommended for IRIS despite theoretical rationale, though may be considered in specific scenarios (e.g., P. jirovecii-associated IRIS) — the general principle is corticosteroid use here remains controversial/case-specific, not a default response.

HIV 4th-generation testing should be sent in every patient with altered mental status of unclear cause — a positive result dramatically changes the differential and workup.

7. Brain Abscess, Subdural Empyema, Epidural Abscess

Distinct from meningitis/encephalitis — focal, mass-lesion-forming CNS infections.

Sources: direct spread (e.g., infected sinus), hematogenous spread (pneumonia, endocarditis), or penetrating trauma/surgical manipulation.

Presentation: headache LATERALIZING to the abscess side + focal neurologic signs; may show elevated ICP signs (papilledema, vomiting, depressed consciousness).

Diagnosis: contrast neuroimaging — classic ring-enhancing lesion with surrounding edema. Multiple lesions suggest hematogenous spread (e.g., septic emboli from endocarditis) — if endocarditis is the source, obtain cerebral vascular imaging to screen for mycotic aneurysms, a distinct and important downstream complication to actively look for.

Subdural empyema and epidural abscess are NEUROSURGICAL EMERGENCIES — unlike parenchymal brain abscess, which may sometimes be managed with prolonged antibiotics alone in select cases, these two specifically demand urgent surgical involvement.

8. Aseptic Meningitis — The Differential When Infectious Workup Is Negative

Presents similarly to bacterial meningitis (headache, fever, meningismus, photophobia) but patients are usually less toxic-appearing with sensorium less likely to be altered. Most cases are self-limited with favorable outcomes. If microbiologic tests are negative and there's no clinical improvement on antibiotics, actively consider NON-infectious causes:

9. CSF Findings Comparison (Encephalitis vs Meningitis, from Meningitis Protocol Section 5)

Encephalitis CSF is generally milder/less dramatic than bacterial meningitis — a relatively unremarkable CSF profile does NOT exclude encephalitis, especially HSV, which is diagnosed primarily by PCR, EEG, and imaging pattern, not CSF cell counts alone.

10. Investigations Summary

• CSF: cell count/differential, protein, glucose, HSV PCR (mandatory if any suspicion), VZV PCR, West Nile IgM, cryptococcal antigen, multiplex NAAT panel (FilmArray ME panel covers 14 pathogens including bacteria/viruses/Cryptococcus)
• EEG: temporal lobe focal slowing/epileptiform activity supports HSV; also screens for nonconvulsive seizures as a cause of persistent altered mental status
• MRI (preferred over CT for parenchymal detail): temporal lobe changes in HSV; ring-enhancing lesions for abscess/toxoplasmosis/lymphoma differential
• HIV 4th-generation test: in all patients with unexplained altered mental status
• Autoimmune/paraneoplastic panel: if infectious workup negative and clinical picture atypical

11. Organ Support

Seizure management per Status Epilepticus protocol (not prophylactic); ICP management if elevated (esp. cryptococcal meningoencephalitis — serial LPs are a specific evidence-based intervention here); standard ICU supportive care.

12. Consultation Matrix

13. Monitoring Framework

Serial neuro checks, EEG monitoring if seizures/altered mental status disproportionate to apparent severity, repeat imaging if new deficit or failure to improve, serial LP for cryptococcal meningoencephalitis specifically (ICP management), HSV PCR result tracking to guide acyclovir continuation/discontinuation.

14. Complications

Seizures/status epilepticus, cerebral edema/elevated ICP, hemorrhagic transformation (esp. HSV, VZV vasculopathy), abscess/empyema formation, mycotic aneurysm (endocarditis-associated), IRIS (post-ART immunocompromised patients), long-term cognitive/neurologic sequelae. Prevention: prompt empiric acyclovir when HSV/VZV possible, serial LP for cryptococcal ICP management. Rescue: neurosurgical drainage for abscess/empyema, seizure management, ICP-directed therapy.

15. Escalation & De-escalation

Escalate: new focal deficit or failure to improve -> repeat imaging (abscess/hemorrhage/edema), broaden workup (autoimmune panel if infectious negative).

De-escalate: HSV PCR confirmed negative and clinically improving -> discontinue empiric acyclovir; organism/etiology identified -> targeted therapy, appropriate duration.

16. ICU Discharge Criteria

Clinically stable/improving, HSV PCR result-driven acyclovir decision finalized, seizures controlled if present, ICP controlled (esp. cryptococcal), any abscess/empyema addressed surgically if indicated, cognitive/functional assessment for rehabilitation planning.

17. Documentation & Medicolegal Checklist

18. Key Guidelines

IDSA Practice Guidelines for the Management of Encephalitis (Tunkel et al., Clin Infect Dis) — primary reference; verify current edition given evolving autoimmune encephalitis literature.

19. Controversies

Threshold for empiric acyclovir discontinuation after a single negative HSV PCR is debated — some experts recommend a repeat PCR if clinical suspicion remains high and the first test was very early in the illness course, given reported false-negative rates in the first 72 hours. Corticosteroid use in IRIS remains genuinely unresolved outside specific scenarios like PJP-associated IRIS. The line between "infectious encephalitis with negative workup" and "autoimmune encephalitis" can be genuinely difficult to draw clinically, and diagnostic delay in autoimmune cases (given specialized antibody panel turnaround times) remains a practical challenge.

20. References

1. Approach to CNS Infections / Encephalitis chapters. Washington Manual of Critical Care, 4th ed, 2025 (Ch. 37, Ch. 64).
2. HIV/Immunocompromised Host CNS Infections chapter. Washington Manual of Critical Care, 4th ed, 2025 (relevant HIV/opportunistic infection section).
3. Tunkel AR, Glaser CA, Bloch KC, et al. The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2008;47(3):303-327.
4. Chawla R, Todi S, eds. Appendix drug dosing reference (acyclovir, amphotericin, etc). ICU Protocols: A Step-wise Approach, 2nd ed. Springer; 2020.

See also: Meningitis (Neurology System) for the closely overlapping CSF workup and empiric treatment framework.