Day: July 28, 2025

What Causes Encephalitis?

Patient Presentation
A 2-month-old male came to clinic for followup after discharge from the neonatal intensive care unit. He was a former 38 week gestation male who had been delivered vaginally to a mother with little prenatal care. His hospital stay had been complicated by initial respiratory distress, poor feeding and then a seizure at 7 hours of life. He was treated for presumed sepsis and/or meningitis with antibiotics and acyclovir and transferred to a regional children’s hospital. He developed a vesicular rash within the first day. Both his cerebrospinal fluid (CSF) and rash were positive for herpes simplex. His brain magnetic resonance imaging (MRI) showed hypointensity on T1 weighted images and hyperintensity of T2 weighted images in the white matter of left temporal-occipital region. His electroencephalogram (EEG) was consistent with this imaging showing unilateral sharp waves in the left temporal area. His ophthalmological examination was normal as was his conjunctival swab. His repeat lumbar puncture at 22 days of life was normal. He was treated for a total of 28 days of acyclovir. His hearing test was normal. He was eating well but somewhat slowly by bottle without emesis since discharge home.

The pertinent physical exam showed a healthy appearing male whose weight was 4.73 (25%), length = 69 cm (50%), head circumference = 37.2 cm ( 10%) and he had normal vital signs. He would look at the examiner but would drift away. He had increased tone throughout with exaggerated neonatal reflexes. He could pick up his head when prone and turn from one side to the other.

The diagnosis of an infant with neonatal herpes simplex virus encephalitis was confirmed. The family already had appointments for infectious disease, developmental disabilities, ophthalmology, audiology and physical therapy. He received his well care and vaccinations, with followup in 2 months time.

Discussion
Encephalitis is inflammation of the brain parenchyma which causes neurologic dysfunction. Evidence of neurological dysfunction for more than 24 hours and inflammation are needed to be consistent with encephalitis. Encephalopathy is used when there is neurological dysfunction for more than 24 hours and no evidence of inflammation. Meningoencephalitis is used when there is encephalitis along with evidence of involvement of the meninges such as meningeal signs of leptomeningeal enhancement on radiological imaging.

The usual evaluation for encephalitis begins with MRI of the brain/spinal cord, lumbar puncture with opening pressure and EEG. CSF is often tested for viral panels, parasitic diseases and evidence for general or specific autoimmune disease. Blood testing includes complete blood count, liver function tests, erythrocyte sedimentation rate, C-reactive protein, blood culture and viral polymerase chain reaction panels. Surface cultures for viruses are often done. Other testing could include eye exam, toxicology, and even brain biopsy and metagenetic testing. Treatment is directed against specific infectious causes if identified or highly suspected. Autoimmune encephalitis testing may take time and therefore treatment may be begun with steroids, IVIG or other treatment before testing is complete.

Two of the most common entities are herpes simplex encephalitis (HSE) and N-methyl-d-aspartate receptor (NMDAR)

HSE occurs in all ages. The incidence is about 20-40 per 100,000, and up to 70% of patients will die without treatment. Severe morbidity is seen in up to 20%. Encephalitis commonly has an acute onset with a fulminant course, leading to coma and death in untreated patients. HSE usually involves the temporal lobe and CSF findings include pleocytosis with a predominance of lymphocytes. Prodrome is fever, headache, malaise and then often fulminant neurological symptoms occur including mental status changes, seizures, and coma. Other symptoms such as amnesia, ataxia, psychiatric problems and behavioral problems are among the potential many problems. Neonates will present with irritability, feeding problems, lethargy, seizures, or tremors. Treatment is acyclovir for a minimum 21 days in neonates.

NMDAR is a very common cause of autoimmune encephalitis. In the pediatric age group the incidence is 0.07-0.085 per 100,000 children. Children usually start with a viral-like prodrome of fever, gastrointestinal symptoms, headache, malaise or upper respiratory infection symptoms. For children they usually present with seizures, movement disorder, focal neurological deficits and are less likely to have psychiatric symptoms for presentation. But “…90% of children will progress to develop at least three symptoms, including psychiatric features, memory disturbance, seizures, dyskinesias, change in level of consciousness, or autonomic dysfunction in the first month of disease onset.” Recovery can be quite slow (3 years +) and 20-25% of children will have relapsing symptoms. First line treatments are steroids, intravenous immunoglobulin, and/or plasma exchange.

Learning Point
About 50% of children will have an identified cause of encephalitis with the general usual evaluation. An additional 30% may have a cause identified with advanced testing.

Causes of encephalitis include:

  • Infectious (affects more commonly gray matter)
    • Viral – these can be transmitted across the blood-brain barrier, through retrograde axononal transport, and by cytotoxicity, inflammation and tissue damage, or vasculitis and ischemia. Combinations of these also occur.
      • Adenovirus
      • Arbovirus
        • Eastern/Western equine encephalitis virus
        • Chikungunya
        • Dengue
        • Japanese encephalitis virus
        • La Cross virus
        • Powassan virus
        • St. Louis virus
        • West Nile virus
      • Cytomegalovirus
      • Enterovirus
      • Epstein- Barr
      • Herpes simplex virus (most common infectious cause in children)
      • Human Parechoviruses
      • Influenza
      • Measles
      • Mumps
      • Rabies
      • Rubella
      • Tick-borne encephalitis
      • Varicella
      • Zika
    • Bacterial
      • Anaplasma
      • Bartonella henselae
      • Borrelia burdorferi
      • Coxiella
      • Ehrlichia
      • Listeria monocytogenes
      • Mycobacerium tuberculosis
      • Mycoplasma pneumoniae
      • Rickettsia
      • Treponema palladium
    • Fungi
    • Parasitic
      • Amoebic
      • Angiostrongulus sp.
      • Bayliascaria procyonis
      • Chagas disease
      • Naegleria fowleria
      • Plasmodium
      • Toxocara
      • Toxoplasma gondii
  • Autoimmune (affects more commonly white matter)
    • Acute disseminated encephalomyelitis (ADEM)
    • N-methyl-d-aspartate receptor (NMDAR) (more common than any single virus cause)
    • Antibody negative autoimmune encephalitis
  • Other
    • Central nervous system vasculitis
    • Hashimoto thyroiditis/encephalopathy
    • Toxins
    • Tumors – ovarian, primary CNS lymphoma

Questions for Further Discussion
1. What do you know about acute disseminated encephalomyelitis (ADEM)?
2. Whyis the opening pressure important when performing a lumbar puncture?
3. What prenatal care should a mother who has known herpes simplex receive?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Encephalitis and Herpes Simplex.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Messacar K, Fischer M, Dominguez SR, Tyler KL, Abzug MJ. Encephalitis in US Children. Infect Dis Clin North Am. 2018;32(1):145-162. doi:10.1016/j.idc.2017.10.007

Hardy D. Autoimmune Encephalitis in Children. Pediatric Neurology. 2022;132:56-66. doi:10.1016/j.pediatrneurol.2022.05.004

Dalmau J, Graus F. Diagnostic criteria for autoimmune encephalitis: utility and pitfalls for antibody-negative disease. The Lancet Neurology. 2023;22(6):529-540. doi:10.1016/S1474-4422(23)00083-2

Ak AK, Bhutta BS, Mendez MD. Herpes Simplex Encephalitis. In: StatPearls. StatPearls Publishing; 2025. Accessed April 8, 2025. http://www.ncbi.nlm.nih.gov/books/NBK557643/

Committee on Infectious Diseases, American Academy of Pediatrics. Red Book: 2024–2027 Report of the Committee on Infectious Diseases (33rd Edition). April 2024. DOI: 10.1542/9781610027373-S3_008_012

Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa