Fellow’s quick read · Infectious Diseases
Encephalitis
IDSA 2008 · Tunkel AR, Glaser CA, Bloch KC, et al. · reviewed 2026-09-08
Personal study digest for a new ID fellow. Recommendations are from the IDSA 2008 encephalitis guideline (CID 2008;47:303–27; DOI). The “What’s changed since 2008” section is reviewer synthesis of newer evidence, each claim cited. Not a substitute for the full guideline.
In one line
Start acyclovir on every patient with suspected encephalitis—HSV PCR on every CSF—and add doxycycline if tick exposure or summer season raises suspicion for rickettsial disease. The biggest gap in this 2008 guideline is the entire field of autoimmune encephalitis, which now accounts for as many cases as infectious causes.
When to suspect encephalitis
- Altered mental status + fever + focal neurologic signs or seizures. The triad is the classic trigger, but encephalitis can present as isolated behavioral change, personality shift, or new psychiatric symptoms—especially autoimmune forms.
- Distinguish from meningitis (meningeal signs without parenchymal dysfunction) and ADEM (multifocal white-matter demyelination, often post-infectious or post-vaccination) (B-III).
- Use epidemiologic clues: season (arboviruses peak late summer/early fall), geography (West Nile, Eastern equine), animal/tick exposure, travel, immune status, recent vaccination (A-III).
Workup the fellow drives
- MRI brain in all patients—the most sensitive neuroimaging study (A-I). Temporal-lobe signal → HSV until proven otherwise. CT only if MRI unavailable (B-III).
- LP and CSF analysis essential unless contraindicated (A-III): cell count, protein, glucose, Gram stain, culture, HSV PCR on every specimen (A-III). If HSV PCR negative but syndrome compatible (temporal lesions, hemorrhagic CSF), repeat HSV PCR at 3–7 days (B-III).
- Arboviral serologies: CSF IgM for West Nile, St. Louis encephalitis, Eastern equine encephalitis (depending on season/geography) (A-III).
- Additional CSF PCR in immunocompromised: CMV, HHV-6, JC virus, West Nile (A-III).
- EEG in all patients—not for etiology but to detect subclinical seizures (A-III).
- Blood/stool/NP cultures and respiratory viral testing as epidemiology dictates (B-III).
- Brain biopsy reserved for deteriorating patients with unknown etiology despite acyclovir (B-III).
Empiric & definitive therapy
Empiric (start immediately)
| Scenario | Drug / dose / route | Strength |
|---|---|---|
| All suspected encephalitis | Acyclovir 10 mg/kg IV q8h | A-III |
| Tick exposure / rickettsial clues | Add doxycycline 100 mg IV/PO q12h | A-III |
| Bacterial meningitis not excluded | Add empiric meningitis coverage (vancomycin + ceftriaxone ± ampicillin) | A-III |
Pathogen-specific therapy
| Pathogen | Regimen | Strength |
|---|---|---|
| HSV-1/2 | Acyclovir 10 mg/kg IV q8h × 14–21 d | A-I |
| VZV | Acyclovir 10–15 mg/kg IV q8h | B-III |
| CMV (immunocompromised) | Ganciclovir 5 mg/kg IV q12h + foscarnet 60 mg/kg IV q8h | B-III |
| Listeria | Ampicillin 2 g IV q4h + gentamicin; alt: TMP-SMX | A-III |
| TB meningoencephalitis | RIPE × 9–12 mo + adjunctive dexamethasone | B-I |
| Rickettsia / Ehrlichia / Anaplasma | Doxycycline 100 mg IV/PO q12h | A-II to A-III |
| Lyme (B. burgdorferi) | Ceftriaxone 2 g IV daily; alt: cefotaxime, penicillin G | B-II |
| Cryptococcus | AmB deoxycholate + flucytosine (induction); alt: lipid AmB + flucytosine | A-I / A-II |
| Toxoplasma | Pyrimethamine + sulfadiazine; alt: TMP-SMX | A-I |
| ADEM | Corticosteroids; plasma exchange if no response; IVIG third-line | B-III |
Duration & stopping
- HSV encephalitis: 14–21 days of IV acyclovir. Repeat CSF HSV PCR near end of therapy—if still positive, extend treatment (B-III).
- Empiric acyclovir: discontinue once HSV PCR is negative, MRI lacks temporal-lobe signal, and an alternative diagnosis is established.
- TB meningoencephalitis: 9–12 months total; dexamethasone taper over weeks.
- Cryptococcal: induction ≥2 weeks → consolidation with fluconazole ≥8 weeks → maintenance until immune reconstitution.
Key decisions a fellow owns
- Don’t wait for the PCR to start acyclovir. HSV is the most treatable and most devastating if missed.
- Repeat HSV PCR at 3–7 days if the first is negative but the clinical picture fits (temporal lesions, hemorrhagic CSF). False negatives occur early.
- Think autoimmune. If infectious workup is negative, send autoimmune encephalitis antibodies (anti-NMDA-R, LGI1, CASPR2, GABA-B). This is the biggest diagnostic advance since 2008 (see “What’s changed”).
- Add doxycycline in summer/fall if any tick exposure history or southeastern US geography. Rickettsial encephalitis is rapidly fatal if untreated.
- EEG early. Nonconvulsive status epilepticus mimics encephalopathy and is treatable.
- Involve neurology early for seizure management, prognostication, and consideration of brain biopsy in refractory cases.
What’s changed since 2008
Reviewer synthesis — not the guideline. Each claim cited.
- Autoimmune encephalitis is now a co-equal diagnostic category. The 2008 guideline mentions “noninfectious” causes only in passing. Graus et al. 2016 published consensus criteria (possible / probable / definite autoimmune encephalitis) that transformed the field. Anti-NMDA receptor, LGI1, CASPR2, GABA-B, and AMPA-R antibodies—all discovered after 2008—now explain a large share of previously “unknown etiology” cases. Any fellow evaluating encephalitis must send an autoimmune antibody panel alongside the infectious workup. Graus et al., Lancet Neurol 2016;15:391–404 (DOI; PMID 26906964)
- Anti-NMDA-R encephalitis treatment defined. Titulaer et al. reported the largest treatment cohort (n=577): first-line immunotherapy (steroids, IVIG, or PLEX) → 53% improve within 4 weeks. Non-responders who received second-line therapy (rituximab or cyclophosphamide) had significantly better outcomes (OR 2.69, p=0.012). 81% achieved good outcomes (mRS 0–2) at 24 months. Early treatment and avoiding ICU admission predicted recovery. Titulaer et al., Lancet Neurol 2013;12:157–65 (DOI; PMID 23290630)
- International Encephalitis Consortium (IEC) case definitions. Venkatesan et al. 2013 published the first consensus case definition and diagnostic algorithm for encephalitis, standardizing the approach the 2008 guideline left implicit. Venkatesan et al., CID 2013;57:1114–28 (DOI; PMID 23861361)
- BioFire FilmArray ME Panel (FDA cleared 2015). Multiplex PCR testing CSF for 14 pathogens (6 bacteria, 7 viruses, Crypto) in ~1 hour—a diagnostic technology the 2008 guideline could not have anticipated. High sensitivity for HSV, enterovirus, and Crypto; variable PPV for some bacterial targets (interpret in clinical context). Now standard of care in most US EDs. Myint et al., Microbiol Spectr 2024;13:e0001424 (DOI; PMID 39714177)
- Metagenomic next-generation sequencing (mNGS) for CSF. Unbiased pathogen detection from CSF is emerging for culture-negative encephalitis, especially in immunocompromised patients or when standard panels return negative. Not yet standard of care but increasingly available at referral centers. Graff et al., J Pediatric Infect Dis Soc 2021;10(Suppl 4):S78–S87 (DOI; PMID 34951470)
- DexEnceph: adjunctive dexamethasone does NOT improve HSV encephalitis outcomes. The first completed phase 3 RCT (n=94, 53 UK hospitals): dexamethasone 10 mg IV QID × 4 days + acyclovir vs acyclovir alone showed no difference in verbal memory at 26 weeks (adjusted difference 1.77, 95% CI −9.57 to 13.12; p=0.76). Safety was acceptable—steroids are unlikely to be harmful, but they do not help. A 2026 meta-analysis pooling DexEnceph + GACHE confirmed no routine benefit. Solomon et al., Lancet Neurol 2026;25:136–46 (DOI; PMID 41579900); Zhang et al., J Neurol 2026;273(10) (DOI; PMID 42704513)
- Acute flaccid myelitis (AFM) and EV-D68. Biennial US outbreaks (2014, 2016, 2018) of paralytic disease in children driven by enterovirus D68—a neurotropic pathogen the 2008 guideline does not mention. Fellows should consider EV-D68 in any child with acute flaccid limb weakness, especially late summer/fall. Kidd et al., Emerg Infect Dis 2020;26(10) (DOI; PMID 32833616)
- Powassan virus: geographic expansion. Tick-borne encephalitis from Powassan (lineage II / deer tick virus) is expanding with Ixodes scapularis range in the northeastern and upper midwestern US. The 2008 guideline mentions Powassan only in the epidemiology tables. No specific treatment; supportive care only.
- Still current: empiric acyclovir for all suspected encephalitis. No trial has challenged the immediate-acyclovir recommendation. It remains the cornerstone.
- Still current: HSV PCR as the primary diagnostic. CSF HSV PCR with repeat at 3–7 days for negatives with compatible syndrome is unchanged practice.
Anki cards minted this run
- Empiric acyclovir for all encephalitis — the non-negotiable first move.
- HSV PCR repeat at 3–7 days — false negatives occur early; temporal-lobe MRI signal warrants repeat.
- Anti-NMDA-R encephalitis: presentation and treatment escalation — the biggest diagnostic gap since 2008; young woman + psychiatric sx + seizures → antibody panel; first-line steroids/IVIG/PLEX, second-line rituximab (Titulaer 2013).
- DexEnceph 2026: adjunctive dexamethasone does NOT improve HSV encephalitis — phase 3, n=94, p=0.76 for verbal memory; safe but not effective (Solomon, Lancet Neurol 2026).
Sources
- 1. Tunkel AR, Glaser CA, Bloch KC, et al. The management of encephalitis: clinical practice guidelines by the IDSA. CID 2008;47:303–27. DOI
- 2. Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15:391–404. DOI PMID 26906964
- 3. Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis. Lancet Neurol 2013;12:157–65. DOI PMID 23290630
- 4. Venkatesan A, Tunkel AR, Bloch KC, et al. Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the IEC. CID 2013;57:1114–28. DOI PMID 23861361
- 5. Solomon T, Hooper C, Easton A, et al. Safety and efficacy of adjunct dexamethasone in adults with HSV encephalitis (DexEnceph). Lancet Neurol 2026;25:136–46. DOI PMID 41579900
- 6. Zhang D, Yang M, Huang Y, et al. Adjunctive corticosteroids in HSV encephalitis: a meta-analysis. J Neurol 2026;273(10). DOI PMID 42704513
- 7. Myint T, Soria J, Gao Y, et al. Comparison of positive BioFire FilmArray ME panels, CSF cultures, clinical presentation. Microbiol Spectr 2024;13:e0001424. DOI PMID 39714177
- 8. Graff K, Dominguez SR, Messacar K. Metagenomic next-generation sequencing for diagnosis of pediatric meningitis and encephalitis: a review. J Pediatric Infect Dis Soc 2021;10(Suppl 4):S78–S87. DOI PMID 34951470
- 9. Kidd S, Lopez AS, Konopka-Anstadt JL, et al. Enterovirus D68–associated acute flaccid myelitis, United States, 2020. Emerg Infect Dis 2020;26(10). DOI PMID 32833616