Basics
Description
Encephalitis is inflammation of the brain parenchyma, which results in alterations in mental status, motor or sensory symptoms, speech problems, or seizures. This inflammation may be due to direct brain invasion by an infectious pathogen or immune-mediated from an inflammatory processes due to acute or chronic illnesses.
Epidemiology
- Exact incidence is unknown, but infants and children are predominantly affected.
- Encephalitis due to enterovirus or arbovirus has a peak incidence between summer and early autumn. Many cases of viral encephalitis occur in epidemics.
General Prevention
- Routine immunization for measles, mumps, rubella, and influenza and, if travelling to endemic area (e.g., Southeast Asia), consideration of immunization for Japanese encephalitis
- Careful hand washing, avoid tick and mosquito exposure (DEET [N,N-diethyl-meta-toluamide] repellant, mosquito netting, appropriate dress), and insect control (drainage of stagnant water, insecticides)
Pathophysiology
- Transmission of infectious pathogens can be by the blood-borne route, by retrograde spread through peripheral nerves (such as HSV or rabies), or rarely by direct inoculation of the brain.
- Encephalitis may also result indirectly, by immune-mediated injury due to parainfectious (i.e., acute disseminated encephalomyelitis or mycoplasma) or inflammatory/paraneoplastic causes (i.e., anti-NMDA receptor encephalitis). Such immune-mediated mechanisms involve cytokine effects and cytotoxic antibodies on neurons.
Etiology
- In most cases, the underlying cause remains unknown. Of those with known etiology, the majority are due to viral agents, followed by bacterial, autoimmune, parasitic, and fungal causes.
- The most common viral causes include HSV 1 and 2, enteroviruses, arboviruses (West Nile virus [WNV]), and other herpesviruses (CMV, EBV, HHV-6, VZV). HSV-1 typically presents with focal seizures, often of temporal lobe origin and encephalopathy. HSV-2 is the predominant cause of neonatal HSV infection. Enteroviruses and arboviruses typically cause disease in the summer and fall. WNV presents as an acute flaccid paralysis, extrapyramidal symptoms, and cranial nerve palsies. Other viruses may be considered given specific historical features (rabies with animal bite or bat exposure or with prominent hydrophobia) or history of travel (Japanese encephalitis virus).
- Bacterial causes include Listeria, Francisella tularensis, Bartonella, Mycobacterium, Rickettsia, Mycoplasma, Borrelia, and Chlamydia.
- Fungal and parasitic causes include Cryptococcus, Blastomyces, Histoplasma, Paracoccidioides, Naegleria, Toxoplasma, Plasmodium, and Toxocara.
- Parainfectious etiologies include acute disseminated encephalomyelitis (ADEM), acute hemorrhagic leukoencephalitis, postinfectious cerebellitis, and Mycoplasma encephalopathy. ADEM typically presents with encephalopathy and focal neurologic symptoms, with an MRI showing multifocal white matter lesions.
- Other inflammatory or paraneoplastic etiologies include anti-NMDA receptor encephalitis, voltage-gated potassium channel complex antibody, aquaporin-4 autoimmunity, SREAT (steroid-responsive encephalopathy associated with thyroid disease), systemic lupus erythematosus, and other vasculitis. Anti-NMDA receptor encephalitis typically presents subacutely with encephalopathy, sleep disturbance, seizures, perioral dyskinesias, and autonomic disturbances.
Diagnosis
History
- Symptoms include fever, headache, photophobia, altered mental status, irritability, gait disturbance, and seizures.
- Ask for focal neurologic symptoms. A recent viral illness, recent travel, animal exposures, tick or mosquito bites, immunizations, and immune status may provide clues to etiology.
- A history of maternal herpes infection or prolonged rupture of membranes should be queried in neonates.
Physical Exam
- Hypertension, bradycardia, or apnea may suggest impending herniation due to brain swelling.
- Altered mental status is the hallmark of encephalitis and ranges from mild confusion to stupor and coma. Distinguishing infectious from postinfectious encephalitis usually cannot be done reliably on clinical grounds.
- Specific neurologic findings suggestive of a specific etiology include focal seizures and focal neurologic findings (HSV); hydrophobia, pharyngeal spasms, and mood disturbance (rabies); facial nerve palsy (Lyme disease); flaccid paralysis or polio-like syndrome (WNV); and ataxia (VZV).
- Nonneurologic findings suggesting a specific etiology include respiratory symptoms (Mycoplasma), adenopathy and splenomegaly (EBV), petechial skin rash (Rickettsia), morbilliform rash (measles), erythematous maculopapular rash (enterovirus), and parotitis (mumps).
Diagnostic Tests & Interpretation
Lab
- Routine labs such as electrolytes, glucose, renal and liver function, and CBC are usually nonspecific.
- Selected serologic testing depending on the suspected agent (e.g., WNV and Mycoplasma) can provide confirmatory diagnosis of underlying etiology.
- Toxicology screen should be done to rule out overdose or toxin exposure as the cause for altered mental status.
- Lumbar puncture is performed urgently, once the patient is stabilized and signs and symptoms of intracranial pressure are excluded (broad-spectrum treatment should commence if these conditions are not met).
- In addition to measuring opening pressure (frequently elevated), other studies should include CSF cell count and differential (lymphocytic predominance suggests a viral process, whereas neutrophilic predominance suggests bacterial or early viral processes), red blood cells (in the absence of a traumatic tap, red blood cells are suggestive of necrotizing encephalitis associated with HSV), protein (often elevated), glucose (usually normal), Gram stain and bacterial culture (20% of patients with suspected encephalitis are diagnosed with bacterial meningitis), and HSV polymerase chain reaction (PCR). Initial studies may be normal, which does not rule out the diagnosis of encephalitis if clinical suspicion is high.
- Other PCR-based tests on CSF including enterovirus, Borrelia burgdorferi, and WNV may be considered depending on the situation.
- In immunocompromised hosts, CSF should be sent for fungal stains and culture (and serum for cryptococcal serum antigen).
- In those patients suspected of paraneoplastic etiology, an extended panel of autoimmune antibodies should be investigated in the serum and CSF.
Imaging
Imaging is performed urgently to rule out surgically remediable conditions (e.g., abscess or hematoma). MRI (or if not available, CT) of the brain with and without contrast medium is preferred. Neuroimaging can be normal or demonstrate focal or diffuse parenchymal enhancement (HSV-2 has a preference for the medial temporal lobe).
Diagnostic Procedures/Other
- An EEG usually shows diffuse generalized slowing. Findings of periodic lateralized discharges are suggestive but not diagnostic of HSV.
- Brain biopsy: rarely performed
Differential Diagnosis
Several conditions can resemble encephalitis including metabolic (acute electrolyte disturbance, inborn errors of metabolism), toxic (ingestions), structural (acute obstructive hydrocephalus or shunt obstruction), vascular (cerebral vasculitis, ischemic or hemorrhagic stroke, septic embolization, sinus thrombosis), endocrine (hypothyroid crisis, pituitary infarction), infectious (bacterial meningitis, brain abscess, subdural empyema, viral meningitis), or epileptic disorders (status epilepticus).
Treatment
Medication
Initial treatment should target bacterial and viral agents until culture results are confirmed or negative.
- Bacterial meningitis: vancomycin (15-20 mg/kg IV q6-8h, monitor levels) plus either cefotaxime (225-300 mg/kg/24 h IV q6-8h) or ceftriaxone (100 mg/kg/24 h IV divided q12-24h; use for ≥1 month old). Treat until cultures are negative at 48 hours.
- HSV encephalitis: acyclovir (>28 days-<12 years: 20 mg/kg/dose IV q8h; ≥12 years: 10 mg/kg/dose IV q8h). Acyclovir is continued for a minimum of 21 days if HSV is confirmed. PCR may be falsely negative in 5-10% of cases-contact an infectious diseases consultant if there is a high clinical suspicion. Monitor renal function while on acyclovir.
- Rickettsial infection (characteristic rash with exposure to ticks in an endemic region) or ehrlichiosis (headache, rash, leukopenia, thrombocytopenia, typical blood smear, transaminase elevation, with exposure to ticks in an endemic region): Consider empiric doxycycline.
- There is no evidence from controlled clinical trials that corticosteroids, IVIG, and therapeutic hypothermia are useful in cases of infectious encephalitis.
- Mycoplasma encephalopathy: erythromycin (benefit sustained from this medication is controversial given probable parainfectious mechanism)
- ADEM: high-dose IV corticosteroids 20-30 mg/kg/day — 3 days followed by prednisolone taper. In refractory cases, either IVIG or plasmapheresis can be considered.
- Anti-NMDA receptor encephalitis: high-dose IV corticosteroids, IVIG, or plasmapheresis. Rituximab has been used in combination with 1st-line agents.
- Immunotherapy is also recommended for other inflammatory or paraneoplastic causes of encephalitis.
Inpatient Considerations
Initial Stabilization
- Careful attention to cardiorespiratory status is essential as is ruling out potential cerebral herniation. Children with severe encephalitis require intensive care with careful cardiorespiratory monitoring. Isolation precautions are based on type of suspected organism.
- Seizures: IV benzodiazepines (lorazepam, midazolam, or diazepam) are used acutely. Status epilepticus should be aggressively managed with a loading dose of fosphenytoin or levetiracetam. Barbiturate coma or midazolam infusion may be needed in refractory cases. In children with reduced level of consciousness, or those treated for refractory status epilepticus, EEG monitoring should be considered.
- Cerebral edema: Cerebral perfusion pressure should be kept at 70 mm Hg or higher for children older than 2 years of age. Conservative measures including fluid restriction, elevation of the head of the bed, and hyperventilation are most commonly used. With impending herniation, mannitol should be considered. Rarely, in malignant cases of cerebral edema, craniectomy can be considered for decompression.
- Investigation for occult tumors should be done with anti-NMDA receptor or other autoantibody-mediated encephalitis. Among girls with anti-NMDA receptor encephalitis, 9% younger than age 14 years and 30% younger than age 18 years were found to have an ovarian teratoma. Tumor resection is required to improve symptoms. Testicular teratoma has been rarely reported
IV Fluids
Closely monitor electrolytes, anticipating possible syndrome of inappropriate antidiuretic hormone or diabetes insipidus.
Ongoing Care
Follow-up Recommendations
- Physical and occupational therapists should be consulted early in the course and will be helpful during the convalescence.
- Neuropsychologic testing is helpful to identify cognitive deficits and direct appropriate services.
- Follow-up with speech pathologists and developmental pediatricians may be indicated.
Prognosis
- Outcome varies greatly and depends on age, etiologic agent, and disease severity at the time of presentation (e.g., patients presenting in coma do worse).
- Outcomes range from complete recovery to focal neurologic deficits, persistent vegetative state, and death.
- Potential complications include aphasia, ataxia, developmental delay, learning disabilities, quadriparesis/hemiparesis, and epilepsy.
Additional Reading
- DuBray K, Anglemyer A, LaBeaud AD, et al. Epidemiology, outcomes and predictors of recovery in childhood encephalitis: a hospital based study. Pediatr Infect Dis J. 2013;32(8):839-844. [View Abstract]
- Gable MS, Sheriff H, Dalmau J, et al. The frequency of autoimmuine N-methyl-D-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the California Encephalitis Project. Clin Infect Dis. 2012;54(7):899-904. [View Abstract]
- Rosenfeld MR, Dalmau J. Anti-NMDA-receptor encephalitis and other synaptic autoimmune disorders. Curr Treat Options Neurol. 2011;13(3):324-332. [View Abstract]
- Sonneville R, Klein IF, Wolff M. Update on investigation and management of postinfectious encephalitis. Curr Opin Neurol. 2010;23(3):300-304. [View Abstract]
- 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. [View Abstract]
Codes
ICD09
- 323.9 Unspecified causes of encephalitis, myelitis, and encephalomyelitis
- 049.8 Other specified non-arthropod-borne viral diseases of central nervous system
- 058.29 Other human herpesvirus encephalitis
- 323.41 Other encephalitis and encephalomyelitis due to other infections classified elsewhere
- 064.00000 Viral encephalitis transmitted by other and unspecified arthropods
- 323.9 Unspecified causes of encephalitis, myelitis, and encephalomyelitis
- 049.9 Unspecified non-arthropod-borne viral diseases of central nervous system
- 063.9 Tick-borne viral encephalitis, unspecified
ICD10
- G04.90 Encephalitis and encephalomyelitis, unspecified
- A85.8 Other specified viral encephalitis
- B00.4 Herpesviral encephalitis
- G05.3 Encephalitis and encephalomyelitis in diseases classd elswhr
- A85.1 Adenoviral encephalitis
- A85.0 Enteroviral encephalitis
- A85.2 Arthropod-borne viral encephalitis, unspecified
SNOMED
- 45170000 Encephalitis (disorder)
- 230162007 Enteroviral encephalitis (disorder)
- 428638009 encephalitis due to Herpesvirus (disorder)
- 230181004 Bacterial encephalitis
- 56529007 Adenoviral encephalitis (disorder)
- 192687008 Arbovirus encephalitis (disorder)
- 95643007 Autoimmune encephalitis (disorder)
FAQ
- Q: Will the child suffer permanent brain injury from encephalitis?
- A: The complications following encephalitis vary greatly from severe mental retardation and cerebral palsy to full recovery. There is a correlation between degree of brain destruction and outcome; however, children frequently recover better than adults with a similar degree of illness.
- A: Outcomes depend on the neurologic status of the patient at presentation and the causative organism. Although many children will make a full recovery, some have persisting neurologic problems including cognitive or motor difficulties, vision or hearing deficits, epilepsy, or personality change. Children with focal deficits or markedly impaired level of consciousness in the acute stage or those with HSV encephalitis are at highest risk of sequelae.
- Q: Is encephalitis highly contagious?
- A: Most cases of encephalitis are not highly contagious, although precautions should be followed with blood or body fluid exposure.