Encephalitis¶
Chapter 142 | Part 5: Infectious Diseases · Part 5 – Infectious Diseases: Bacterial · Chapter 142
Key Clinical Points¶
- HSV encephalitis is the most common cause of sporadic acute encephalitis in immunocompetent adults.
- MRI findings in HSV encephalitis typically show asymmetric hyperintensity in the frontotemporal, cingulate, or insular regions.
- CSF HSV PCR sensitivity is ~96% and specificity ~99% in the first week of illness; may be negative in the first 72 hours.
- Acyclovir is the treatment of choice for HSV encephalitis (10 mg/kg IV q8h for adults, 15–20 mg/kg IV q8h for children).
- WNV is the most common cause of epidemic encephalitis in the US since 2002.
- Naegleria fowleri causes primary amebic meningoencephalitis with near 100% mortality.
- Rabies presents with hydrophobia, aerophobia, and autonomic hyperactivity; PEP must be administered before symptoms develop.
- Autoimmune encephalitis mimics viral encephalitis and is associated with specific antibodies (NMDA receptor, LGI-1).
- Supportive care includes ICP monitoring, seizure management, and fever suppression.
- Brain biopsy is reserved for cases with progressive deterioration despite acyclovir and negative CSF PCR.
1. DEFINITION & OVERVIEW¶
• Definition (Harrison's 22e): Encephalitis is defined as an inflammation of the brain caused either by infection, usually with a virus, or from a primary autoimmune process. • Clinical Context: ◦ Often presents as meningoencephalitis (involvement of meninges) or encephalomyelitis (involvement of spinal cord/nerve roots). ◦ Presentation: Acute febrile illness with altered consciousness (confusion, lethargy, coma), behavioral abnormalities, focal neurological signs, seizures, or psychiatric symptoms. ◦ Hypothalamic-pituitary axis involvement → can cause temperature dysregulation, diabetes insipidus, or SIADH.
2. EPIDEMIOLOGY¶
• Incidence: Estimated 20,000 annual cases in the US (actual numbers likely higher). ◦ Most cases remain of unknown cause despite comprehensive testing. • Arboviruses: ◦ Historically caused epidemics (EEE, WNV, St. Louis encephalitis). ◦ WNV responsible for >90% of arbovirus neuroinvasive disease since 2002. ◦ 28,684 confirmed WNV cases (1999–2022) resulting in 2,641 deaths. ◦ 1,599 reported cases in 2023 (encephalitis, meningitis, AFM). • Trends: ◦ Peak transmission: August–September. ◦ Powassan virus: Increasing in NE US and Midwest since 2006. ◦ Emerging pathogens: Nipah virus (SE Asia), Toscana virus (Europe), Zika virus, chikungunya virus.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
• Non-Viral Etiology: ◦ Naegleria fowleri (primary amebic meningoencephalitis): Associated with warm, iron-rich water; near 100% mortality. ◦ Acanthamoeba/Balamuthia: Granulomatous amebic encephalitis (subacute/chronic). ◦ Baylisascaris procyonis (raccoon pinworm): Exposure to raccoon feces; causes eosinophilia in children.
3.1 Viral Etiology¶
• Herpesviruses: HSV-1, HSV-2, VZV, EBV. ◦ HSV pathogenesis: Direct neuronal injury with preferential involvement of temporal lobes. • Arthropod-borne (Arboviruses): ◦ Flaviviruses: WNV, Japanese encephalitis virus. ◦ Alphaviruses: EEE virus, chikungunya virus. ◦ Bunyaviruses: La Crosse virus, Jamestown Canyon virus. • Other Viral: ◦ Enteroviruses (EV-A71, EV-D68). ◦ Parechovirus 3 (HPeV3) in infants <3 months. • Table 142-1 Summary: ◦ Common: Herpesviruses, Cytomegalovirus, HSV-1, HSV-2, Human herpesvirus 6, VZV, EBV, Arboviruses, WNV, St. Louis encephalitis virus, Zika, Enteroviruses. ◦ Less Common: Rabies, EEE, Powassan, Cytomegalovirus, Colorado tick fever, Mumps, Jamestown Canyon.
4. CLINICAL FEATURES¶
• General Presentation: Acute febrile illness with altered consciousness (confusion, lethargy, coma). • Neurological Manifestations: ◦ Focal or generalized seizures. ◦ Psychiatric symptoms: Hallucinations, agitation, personality changes, psychosis. ◦ Focal neurological signs: Any focal disturbance possible. • Hypothalamic-Pituitary Involvement: Temperature dysregulation, diabetes insipidus, SIADH. • Flavivirus (WNV) Specifics: ◦ Deep gray matter involvement (basal ganglia, thalamus). ◦ Movement disorders: Tremor, myoclonus. ◦ Acute Flaccid Paralysis (AFP): Poliomyelitis-like with spinal cord FLAIR/T2 signal changes.
5. DIFFERENTIAL DIAGNOSIS¶
• Infectious Mimics: Mycobacteria, fungi, Listeria, Bartonella, neurosyphilis. • Autoimmune Encephalitis: ◦ NMDA receptor antibodies. ◦ LGI-1/CASPR2 antibodies. ◦ Hashimoto's encephalopathy (thyroglobulin/tyroperoxidase). • Other: Prion diseases, Amebic infections (Naegleria, Acanthamoeba, Balamuthia).
6. INVESTIGATIONS & DIAGNOSIS¶
• Neuroimaging & EEG: ◦ MRI/FLAIR: Most sensitive for HSV (80% show temporal lobe involvement; >90% with FLAIR and diffusion-weighted sequences). Absence of temporal lobe lesions reduces likelihood of HSV. ◦ EEG: Temporal lobe periodic sharp-and-slow complexes (HSV); generalized slowing (WNV). • CSF Analysis: ◦ Lymphocytic pleocytosis (>5 cells/μL in 95% of cases). ◦ Normal glucose, mildly elevated protein. • Specific Pathogen Testing: ◦ HSV PCR: Sensitivity ~96%, specificity ~99% in first week. May be negative in first 72h; repeat if suspicion remains high. ◦ WNV: Best test is CSF IgM (70–80% positive by end of week 1). Serum WNV IgM indicates infection but not necessarily neuroinvasive disease. ◦ VZV: CSF IgM may be present even with negative PCR. Both tests should be performed for suspected VZV CNS disease. ◦ EBV: Specificity of EBV CSF PCR is unknown; detection of EBV CSF IgM or intrathecal synthesis strongly supports diagnosis. ◦ mNGS: Allows unbiased detection of all agents (except prions); can be confirmed by independent pathogen-specific techniques; risk of false positives due to high sensitivity. • Diagnostic Algorithm: 1. Clinical suspicion based on symptoms/signs. 2. Neuroimaging (MRI/CT) and EEG. 3. CSF analysis with PCR for HSV, CMV, EBV, enteroviruses. 4. Repeat PCR if initial negative but clinical suspicion high. 5. Brain biopsy reserved for progressive cases with negative CSF PCR.
6.1 Diagnostic Test Utility¶
• MRI/FLAIR: Most sensitive for HSV; 80% show temporal lobe involvement (increases to >90% with FLAIR/diffusion-weighted). ◦ Note: Absence of temporal lobe lesions should prompt consideration of other diagnoses. • EEG: Temporal lobe periodic discharges in HSV, generalized slowing in WNV. • CSF PCR: Gold standard for HSV, CMV, EBV, enteroviruses. ◦ EV-A71 detection via RT-PCR has lower sensitivity (~30%). • WNV Testing: CSF IgM is the best test; Serum IgM indicates infection but not specific neuroinvasive disease. • mNGS: Unbiased detection of all agents (except prions); can be confirmed by independent pathogen-specific techniques.
7. MANAGEMENT & TREATMENT¶
- HSV Encephalitis Treatment: ◦ Acyclovir: 10 mg/kg IV q8h (adults); 15–20 mg/kg IV q8h (children).
- WNV Management: Supportive care only.
- Rabies Management: ◦ Postexposure prophylaxis (PEP): Rabies immunoglobulin and vaccine. ◦ Note: Treatment after symptoms develop has ~100% mortality.
- Autoimmune Encephalitis: Immunotherapy (corticosteroids, IVIG, plasmapheresis).
- Amebic Infections: ◦ Naegleria: No effective treatment approved. ◦ Acanthamoeba/Balamuthia: Miltefosine.
- Baylisascaris procyonis: Albendazole 15 mg/kg PO q12h.
8. PROGNOSIS & COMPLICATIONS¶
• HSV Encephalitis: Mortality ~10–20% without treatment; ~7–10% with treatment. • WNV: Mortality 5–15%; long-term neurological deficits common. • Rabies: Near-universal fatality after symptoms develop. • Autoimmune Encephalitis: Prognosis varies by antibody type (NMDA receptor has better outcomes than LGI-1). • Amebic Infections: ~100% mortality for Naegleria; variable for Acanthamoeba/Balamuthia.
9. SPECIAL CONSIDERATIONS¶
• Immunocompromised Hosts: ◦ CMV: Ventricular enlargement with subependymal enhancement on T1 postcontrast. ◦ EBV/VZV: Cerebellar T2/FLAIR abnormalities common in children. • Renal Impairment (Acyclovir Dosing): ◦ CrCl >50 mL/min: Standard dose. ◦ CrCl 30–50 mL/min: 5 mg/kg IV q12h. ◦ CrCl <30 mL/min: 5 mg/kg IV q24h.
9.1 Immunocompromised Hosts¶
• CMV Encephalitis: Ventricular enlargement with subependymal enhancement on T1 postcontrast. ◦ Note: Common in immunocompromised patients. • EBV/VZV: Cerebellar involvement common in children.
9.2 Renal Impairment¶
• Acyclovir Dosing Adjustments (based on CrCl): ◦ CrCl >50 mL/min → Standard dose. ◦ CrCl 30–50 mL/min → 5 mg/kg IV q12h. ◦ CrCl <30 mL/min → 5 mg/kg IV q24h.
10. KEY PEARLS & CLINICAL TRAPS¶
• HSV Encephalitis: Look for temporal lobe involvement on MRI/EEG; Acyclovir is the primary treatment. • WNV: Characterized by deep gray matter abnormalities and potential AFM-like presentation. • Autoimmune Mimics: NMDA receptor (seizures, psychiatric) and LGI-1 (facial myokymia). • Naegleria fowleri: High mortality; check history of freshwater exposure. • Rabies: Prevention via PEP is critical before symptom onset.
Reference Tables¶
TABLE 142-1 Viruses Causing Acute Encephalitis in North America COMMON Herpesviruses¶
Harrison's 22e, p.1112
| COMMON | LESS COMMON |
|---|---|
| Herpesviruses Cytomegalovirusa Herpes simplex virus 1b Herpes simplex virus 2 Human herpesvirus 6 Varicella-zoster virus Epstein-Barr virus |
Rabies Eastern equine encephalitis virus Powassan virus Cytomegalovirusa Colorado tick fever virus Mumps Jamestown Canyon virus |
| Arthropod-borne viruses | |
| La Crosse virus | |
| West Nile virusc St. Louis encephalitis virus Zika Enteroviruses |
TABLE 142-2 Use of Diagnostic Tests in Encephalitis The best test for WNV encephalitis is the CSF IgM antibody test.…¶
Harrison's 22e, p.1114
- The best test for WNV encephalitis is the CSF IgM antibody test. The prevalence
of positive CSF IgM tests increases by about 10% per day after illness onset
and reaches 70–80% by the end of the first week. Serum WNV IgM can provide
evidence for recent WNV infection, but in the absence of other findings does not
establish the diagnosis of neuroinvasive disease (meningitis, encephalitis, acute
flaccid paralysis). - Approximately 80% of patients with proven HSV encephalitis have MRI
abnormalities involving the temporal lobes. This percentage likely increases
to >90% when FLAIR and diffusion-weighted MRI sequences are also used.
The absence of temporal lobe lesions on MRI reduces the likelihood of HSV
encephalitis and should prompt consideration of other diagnostic possibilities. - The CSF HSV PCR test may be negative in the first 72 h of symptoms of HSV
encephalitis. A repeat study should be considered in patients with an initial early
negative PCR in whom diagnostic suspicion of HSV encephalitis remains high
and no alternative diagnosis has yet been established. - Detection of intrathecal synthesis (increased CSF/serum HSV antibody ratio
corrected for breakdown of the blood-brain barrier) of HSV-specific antibody
may be useful in diagnosis of HSV encephalitis in patients in whom only late (>1
week after onset) CSF specimens are available and PCR studies are negative.
Serum serology alone is of no value in diagnosis of HSV encephalitis due to the
high seroprevalence rate in the general population. - Negative CSF viral cultures are of no value in excluding the diagnosis of HSV or
EBV encephalitis. - VZV CSF IgM antibodies may be present in patients with a negative VZV CSF
PCR. Both tests should be performed in patients with suspected VZV CNS
disease. - The specificity of EBV CSF PCR for diagnosis of CNS infection is unknown.
Positive tests may occur in patients with a CSF pleocytosis due to other causes.
Detection of EBV CSF IgM or intrathecal synthesis of antibody to VCA supports
the diagnosis of EBV encephalitis. Serologic studies consistent with acute EBV
infection (e.g., IgM VCA, presence of antibodies against EA but not against
EBNA) can help support the diagnosis.
In addition to broad-based PCR assays for bacterial and fungal infections,
metagenomic next-generation sequencing (mNGS) allows for unbiased detection
of nucleic acids from the whole range of infectious agents (except prions), which
can then be confirmed by independent pathogen-specific techniques. Due to
the sensitivity of this technology, there is a risk of false-positive results. As this
technology becomes refined and the turnaround time faster, mNGS is likely to
become a routine test on CSF for the diagnosis of encephalitis.