Viral Encephalitis

Encephalitis is defined as the inflammation of the brain parenchyma. The inflammatory changes can lead to headache, stiffness in neck, sensitivity to light, confusion, seizures and focal neurologic deficits. Viral encephalitis is the most common type of encephalitis and often coexists with viral meningitis.

Introduction

  • Encephalitis is defined as the inflammation of the brain parenchyma.
  • The inflammatory changes can lead to headache, stiffness in neck, sensitivity to light, confusion, seizures and focal neurologic deficits.
  • Viral encephalitis is the most common type of encephalitis and often coexists with viral meningitis.
  • Viral encephalitis tends to be more common in younger people compared to elderly individuals.
  • Many cases of viral encephalitis go undetected (about 30%–40% of cases) because of the lack of tests and mild symptoms. In addition, studies show that many patients develop high levels of antibodies to viruses but show no symptoms.

Epidemiology

  • The incidence of viral encephalitis is 3.5 to 7.5 per 100,000 people, with the highest incidence in the young and elderly.
  • The epidemiology of certain viral causes of encephalitis has changed through time. For example,
    • Vaccination has led to a decrease in the incidence of encephalitis due to mumps and measles.
    • On the other hand, EBV and CMV encephalitis are seen more frequently now because they occur in immunocompromised individuals, such as
      • AIDS
      • Organ Transplant recipients
      • Chemotherapy patients
  • Other important epidemiologic factors like,
    • Time of the year: Arboviruses (i.e., eastern equine, western equine, St. Louis, Venezuelan equine, Zika, and West Nile) cause disease during the summer months when mosquitoes are active.
    • Geography: St. Louis encephalitis is primarily seen in the Midwest and South.
    • Animal or Insect exposure: Tick-borne encephalitis occurs mainly in the North-Central and the Northeastern United States.

Etiology

  • Infectious encephalitis can be viral, bacterial, fungal, protozoal, or helminthic in etiology.
  • Viruses are the most prevalent identified cause, accounting for about 70% of confirmed cases of encephalitis.
  • Some common causative viral encephalitides are shown in Table 1.
  • In the United States, the most common causes of viral encephalitis are:
      1. Herpes simplex virus (HSV-1 and HSV-2)
      1. West Nile virus (Arboviruses)
      1. Enteroviruses (Coxsackievirus)
  • The Powassan virus is carried by ticks and causes encephalitis in the Midwestern United States

Table 1: Etiologic Agents of Viral Encephalitis

Table 1: Etiologic Agents of Viral Encephalitis
Group
Family
Virus
Herpesviridae
Herpes Simplex Virus (HSV) Varicella- Zoster Virus (VZV) Epstein-Barr Virus (EBV) Cytomegalovirus (CMV) Human Herpes Virus-6 (HHV-6)
Polyomaviridae
JCV BKV
Adenoviridae
Adenovirus
Picornaviridae
Enteroviruses Poliovirus
Retroviridae
Human Immunodeficiency Virus-1/2 (HIV-1/2)
Rabdhoviridae
Rabies
Paramyxoviridae
Mumps Measles
Togaviridae
Eastern Equine Encephalitis (EEE) Western Equine Encephalitis (WEE) Venezuelan Equine Encephalitis (VEE)
Flaviviridae
St Louis Encephalitis (SLE) West Nile Virus (WNV) Japanese Encephalitis (JE) Powassan Virus (POW) Murray Valley Encephalitis (MVE) Far Eastern Subtype (FE-TBEV) Siberian Subtype (S-TBEV) Western Subtype (W-TBEV)
Bunyaviridae
California Virus La Crosse Virus (LAC) Toscana Virus (TOSV)
Group
Family
Virus
DNA Viruses
Herpesviridae
Herpes Simplex Virus (HSV) Varicella- Zoster Virus (VZV) Epstein-Barr Virus (EBV) Cytomegalovirus (CMV) Human Herpes Virus-6 (HHV-6)
Polyomaviridae
JCV BKV
Adenoviridae
Adenovirus
RNA Viruses
Picornaviridae
Enteroviruses Poliovirus
Retroviridae
Human Immunodeficiency Virus-1/2 (HIV-1/2)
Rabdhoviridae
Rabies
Paramyxoviridae
Mumps Measles
Arbovirus Group
Togaviridae
Eastern Equine Encephalitis (EEE) Western Equine Encephalitis (WEE) Venezuelan Equine Encephalitis (VEE)
Flaviviridae
St Louis Encephalitis (SLE) West Nile Virus (WNV) Japanese Encephalitis (JE) Powassan Virus (POW) Murray Valley Encephalitis (MVE) Far Eastern Subtype (FE-TBEV) Siberian Subtype (S-TBEV) Western Subtype (W-TBEV)
Bunyaviridae
California Virus La Crosse Virus (LAC) Toscana Virus (TOSV)

Causes of Viral encephalitis

  • Herpes simplex virus (HSV-1, HSV-2)
  • Other herpes viruses: Varicella-zoster virus (VZV), Cytomegalovirus (CMV), Epstein-Barr virus (EBV), Human herpesvirus 6 (HHV6)
  • Adenoviruses
  • Influenza A
  • Enteroviruses, poliovirus
  • Measles, mumps and rubella viruses
  • Rabies
  • Arboviruses—for example, Japanese B encephalitis, St Louis encephalitis virus, West Nile encephalitis virus, Eastern, Western, and Venezuelan equine encephalitis virus, tick-borne encephalitis viruses
  • Bunyaviruses—for example, La Crosse strain of California virus
  • Reoviruses—for example, Colorado tick fever virus
  • Arenaviruses—for example, lymphocytic choriomeningitis virus
  • SARS-CoV-2 virus
Derived from: Ferrari, S., Toniolo, A., Monaco, S., Luciani, F., Cainelli, F., Baj, A., Temesgen, Z., & Vento, S. (2009). Viral encephalitis: Etiology, clinical features, diagnosis and management. Open Infectious Diseases Journal, 3(1), 1-12. https://doi.org/10.2174/1874279300903010001

Pathophysiology

  • Viruses invade the host at a site outside the CNS and replicate. Most then reach the spinal cord and brain hematogenously.
  • HSV, rabies, and herpes zoster virus travel to the CNS from nerve endings in a retrograde manner.

Clinical Manifestations

History

  • The most important elements that need to be asked in history include immune status, exposure to insects or animals, travel history, vaccination history, geography, and time of year.
  • Some clinical findings(systemic and neurological) and their causing viruses are shown in Table 3 and Table 4.

Sign and Symptoms

  • Fever
  • Headache
  • Seizures
  • Neck stiffness
  • Altered mental status
  • Papilledema
  • Sensitivity to light
  • Sensitivity to sound
  • Vomiting
  • Aches in muscles or joints
  • In severe cases, encephalitis symptoms may include:
    • Weakness or partial paralysis in the arms and legs
    • Double vision
    • Impairment of speech or hearing
    • Coma
  • Neuropsychiatric features such as
    • Behavioral changes, hallucinations, and/or cognitive decline are often seen.

Table 2: Neurological Finding of Viral Encephalitis - Neurological

Neurological Finding of Viral Encephalitis
Clinical presentation
Possible infectious agent
VZV (in children), EPV, Mumps virus, St. Louis encephalitis virus
HIV, Human transmissible spongiform encephalopathies, sCJD and variant Creutzfeldt-Jakob disease (vCJD), Measles virus (Subacute sclerosing panencephalitis (SSPE))
Japanese encephalitis virus, St. Louis encephalitis virus, West Nile virus, Nipah virus
Japanese encephalitis virus, West Nile virus, Tick-borne encephalitis virus, Enterovirus (enterovirus-71, coxsackieviruses), Poliovirus
HSV, West Nile virus, Enterovirus 71

Table 3: Systemic manifestation of Viruses causing Encephalitis

Systemic manifestation of Viruses causing Encephalitis
Clinical presentation
Possible infectious agent
HIV, EBV, CMV, Measles virus, Rubella virus, West Nile virus,
VZV, B virus, Human herpesvirus 6, West Nile virus, Rubella virus, certain Enteroviruses,
Venezuela equine encephalitis virus, Nipah virus, Hendra virus, Influenza virus, Adenovirus,
CMV, West Nile virus, St Louis encephalitis virus (early)
Derived from: Ekmekci, H., Ege, F., & Ozturk, S. (2013). Cerebrospinal Fluid Abnormalities in Viral Encephalitis. Encephalitis. https://doi.org/10.5772/54590

Investigation

Lumbar puncture (LP)/CSF Analysis

  • Lumbar puncture (LP) is an essential initial diagnostic study for evaluating patients with viral encephalitis.
  • CSF evaluation should also include polymerase chain reaction (PCR) testing for HSV-1, HSV-2, and enteroviruses.
  • CSF analysis between viruses, bacteria and fungus is shown in Table 4.

Table 4: CSF Analysis

CSF Analysis
Characteristics
Bacterial meningitis
Viral encephalitis
Fungal meningitis
Tuberculous meningitis
Pressure
Normal-mildly increased
Normal-mildly increased
Increased
Glucose
Normal (low levels may be seen in some cases such as HSV encephalitis)
Low
Low
Cell count
Lymphocytic predominance (maybe neutrophilic early on)
Mononuclear
PNL/mononuclear
Protein
High
High
High
Lactic acid
normal to moderately increased
?
?
Derived from: Ekmekci, H., Ege, F., & Ozturk, S. (2013). Cerebrospinal Fluid Abnormalities in Viral Encephalitis. Encephalitis. https://doi.org/10.5772/54590

Imaging and Other Studies

  • CT
    • Computed tomography (CT) helps in detecting any space-occupying lesions that may contribute to increased intracranial pressure.
    • In HSV encephalitis, CT can demonstrate low-density areas with mass effect in the temporal lobe, which can progress to hemorrhagic lesions. These lesions usually appear 3-5 days after the infection.
    • Typically normal in WNV.
  • MRI
    • Herpes simplex encephalitis (HSE)
      • Magnetic Resonance Imaging (MRI) is also the most sensitive imaging modality for showing findings consistent with HSV encephalitis, such as temporal and frontal lobe involvement.
      • Hyperintensity on T2 (Figure-1) in one or both temporal lobes, which may extend into the insular cortex.
      • Gadolinium enhancement around the periphery of the infection
    • Arbovirus encephalitis (West Nile Virus
      • One-third have enhancement of meninges or periventricular areas
      • Lesions are seen in the cortex, basal ganglia, cerebellum, brainstem, and spinal cord.
  • EEG
    • EEG may show abnormalities in patients with seizures
    • Herpes simplex encephalitis (HSE)
      • Relatively sensitive noninvasive procedure, but specificity is poor
        • Sensitivity – 84%
        • Specificity – 32.5%
      • Characteristic EEG – spike and slow-wave activity and PLEDS (periodic lateralized epileptiform discharges), which arise from the temporal lobe.
    • Japanese encephalitis (JE) is often associated with 3 EEG patterns that include
      • 1) diffuse delta activity with spikes
      • 2) diffuse continuous delta activity and
      • 3) alpha comma activity.
  • Blood tests or urine and stool tests to identify organisms or antibodies responsible for an infection. For instance, IgM antibodies in serum (or CSF) to WNV may aid in diagnosis of WNV encephalitis in the appropriate clinical setting.
  • A sputum culture tests the material that is coughed up from the lungs to see if certain infections are present.
  • Brain biopsy and PCR may also help establish the etiology in some cases.
  • About 10% of patients will have normal CSF studies
  • FilmArray Meningitis/Encephalitis (ME) Panel (Biofire diagnostics) is a rapid multiplex diagnostic tool that requires only a small amount of CSF and can provide immediate detection (about 1 hr) of any of the 14 pathogens, including enterovirus, CMV, HSV 1 & 2, HHV-6, human parechovirus, and VZV. The test automatically conducts extraction of nucleic acids, reverse transcription, nucleic acid amplification, and subsequent detection resulting in a very high sensitivity and specificity. Of note, the panel does not detect EBV due to concerns of false-positives. (PMID 27335149)

Differential diagnosis

  • Infectious
    • Bacterial, fungal, protozoal, or helminthic encephalitis
    • Tuberculosis
    • Brain abscess
    • Neurosyphilis
  • Noninfectious
    • Malignancy
    • Autoimmune
    • Paraneoplastic diseases (e.g., anti-NMDA receptor encephalitis)
    • Drug-induced delirium
    • Toxic exposure (e.g. Carbon monoxide poisoning)

Treatment

  • The treatment of viral encephalitis is primarily supportive as there is no specific medical therapy for most central nervous system viral infections.
  • Patients with viral encephalitis should be admitted to the hospital for supportive care and IV antiviral therapy. They may require intensive care for frequent neurologic exams and/or respiratory support.
  • A very important exception to this is HSV encephalitis.
    • When started early, acyclovir has been shown to significantly decrease mortality and morbidity and limit the severity of long-term behavioural and cognitive impairment of HSV encephalitis.
    • Therefore, empirically, it is recommended that physicians start all patients with suspected encephalitis on acyclovir.
    • The recommended dose is 10 mg/kg intravenously (IV) every 8 hours for 14 to 21 days.
    • Provide adequate hydration.
    • Renal function should be monitored;
    • if creatinine begins to rise, may need to temporarily discontinue the drug and ensure adequate hydration, although renal dysfunction is almost always reversible.
  • For WNV encephalitis there is no approved treatment
    • Supportive care is very important.
    • A high proportion of patients with spinal cord (motor neuron) involvement will need mechanical ventilation.
  • Acyclovir 10 to 15 mg/kg IV every 8 hours for 10 to 14 days, with possible adjunctive corticosteroids in immunocompetent patients, is recommended for varicella-zoster virus.
  • The recommended treatment for CMV encephalitis is a combination of ganciclovir 5 mg/kg IV every 12 hours and foscarnet 60 mg/kg IV every 8 hours or 90 mg/kg IV every 12 hours for 21 days.
  • Another important component of the management of patients with viral encephalitis is serial intracranial pressure (ICP) monitoring.
    • Elevated ICP is associated with a poor prognosis.
    • Steroids and mannitol can be given to relieve increased ICP.
  • Seizures may need to be managed with antiepileptic medications
    • For status epilepticus, one should follow the standard status epilepticus management protocol.
    • Patients with encephalitis who have seizures that don’t respond well to anti-seizure medications could benefit from a ketogenic diet, which is high in fat and low in carbohydrates.
  • For behavior alterations, one may need to use antipsychotics for a short time. Atypical antipsychotics such as quetiapine or aripiprazole may offer an acceptable side effect profile and titratable dosing when used in oral formulations.
  • A breathing tube, urinary catheter, or feeding tube may be necessary if the person’s encephalitis has caused impaired consciousness.

Follow-up therapy

  • Physical therapy to improve strength, flexibility, balance, motor coordination and mobility
  • Occupational therapy to develop everyday skills and to use adaptive products that help with everyday activities
  • Speech therapy to relearn muscle control and coordination to produce speech
  • Psychotherapy to learn coping strategies and new behavioural skills to improve mood disorders or address personality changes.
  • These interventions should start as soon as medically feasible

Prognosis

  • Most patients with viral encephalitis recover without sequelae.
  • Those who remain symptomatic have difficulties in concentration, behavioural and speech disorders, and/or memory loss.
  • In rare cases, patients may remain in a vegetative state.
  • Some children may develop seizures and changes in behaviour following infection. Children may develop seizures, severe mental retardation and various forms of paralysis.
  • Zike virus infection in pregnancy may be associated with microcephaly.
  • The most common long term complication after viral encephalitis is seizures;
    • These may occur in 10-20% of patients over several decades.
    • These seizures often are resistant to medical therapy.
    • Some children may develop seizures and changes in behavior following infection.
  • Children may have severe mental retardation and various forms of paralysis.
  • In the California encephalitis project, patients with refractory seizures or diffuse cerebral edeam had the highest risk of mortality and neurologic morbidity (PMID 17109290)

Prevention

  • Use proper hygiene and hand-washing to help prevent the spread of viruses and bacteria.
  • Avoid mosquito and tick exposure.
  • Don't share utensils.

Complications

  • Impairment in intelligence
  • Mood and behaviour changes
  • Residual neurological deficits
  • Extrapyramidal symptoms (JE)
  • SIADH and Hyponatremia (St. Louis encephalitis)
  • Encephalopathy
  • Mononeuropathy
  • Flaccid paralysis
  • Epilepsy

Further Reading

  • Ferrari, S., Toniolo, A., Monaco, S., Luciani, F., Cainelli, F., Baj, A., Temesgen, Z., & Vento, S. (2009). Viral encephalitis: Etiology, clinical features, diagnosis and management. Open Infectious Diseases Journal, 3(1), 1-12. https://doi.org/10.2174/1874279300903010001
  • Marc Y. El Khoury, Rene C. Hull, Patrick W. Bryant, Kay L. Escuyer, Kirsten St George, Susan J. Wong, Aarathi Nagaraja, Laura Kramer, Alan P. Dupuis, Treta Purohit ... , Diagnosis of Acute Deer Tick Virus Encephalitis, Clinical Infectious Diseases, Volume 56, Issue 4, 15 February 2013, Pages e40–e47, https://doi.org/10.1093/cid/cis938

Bibliography

  • Ferrari, S., Toniolo, A., Monaco, S., Luciani, F., Cainelli, F., Baj, A., Temesgen, Z., & Vento, S. (2009). Viral encephalitis: Etiology, clinical features, diagnosis and management. Open Infectious Diseases Journal, 3(1), 1-12. https://doi.org/10.2174/1874279300903010001
  • Hakan Ekmekci, Fahrettin Ege and Serefnur Ozturk.Cerebrospinal Fluid Abnormalities in Viral Encephalitis. IntechOpe;n. Published: January 9th 2013. DOI:10.5772/54590 <https://www.intechopen.com/chapters/41749>