John Davis, PhD, MD
DESCRIPTION 
Encephalitis is defined as an inflammatory process of the brain parenchyma, and is usually associated with clinical or laboratory evidence of neurologic dysfunction. It is important to distinguish acute (usually infectious) encephalitis from post-infectious processes [such as acute demyelinating encephalomyelitis (ADEM)] and two other entities—meningitis and encephalopathy—which are different pathogenic processes with separate etiologies and prognoses.
EPIDEMIOLOGY
Incidence/Prevalence
In the USA, the overall incidence of encephalitis (acute) has been estimated at 7.3/100,000. It accounts for 19,000 hospitalizations annually in the USA. Globally, most estimates of encephalitis incidence range from 6.24 to 7.4/100,000, though a recent study has found extremes of estimates from 0.07 to12.6/100,000.
RISK FACTORS
Risk factors for encephalitis depend on the etiology (see Etiology, below). For infectious etiologies, epidemiologic exposure and concurrent immunosuppressive conditions are the two greatest risk factors.
Genetics
Genetic predisposition to acquisition of infectious encephalitis is rare, though mutations that affect prognosis have been described, as have some genetic factors associated with non-infectious encephalitis (e.g., hereditary Creutzfeldt–Jacob disease).
GENERAL PREVENTION
Some infectious encephalitides may be preventable by minimizing epidemiologic exposures (e.g., mosquito or tick prevention/avoidance; avoiding areas of high endemicity, etc.). Some causes of encephalitis are vaccine preventable (e.g., Japanese encephalitis).
PATHOPHYSIOLOGY
Infectious agents may spread to the brain parenchyma by four main routes: Hematogenous seeding, direct inoculation (usually traumatic), direct extension (e.g., from sinus disease), or from peripheral nerves [e.g., rabies, herpes simplex virus (HSV)]. Infectious agents cause damage/destruction of brain tissue. Regardless of the etiology, the inflammatory response can also cause damage to surrounding brain parenchyma, which leads to examine the findings consistent with the damaged area(s).
ETIOLOGY
- Etiologies of encephalitis may be infectious or non-infectious. Non-infectious causes include autoimmune, paraneoplastic, and collagen vascular diseases. However, in most case series, the majority of encephalitides are of unknown etiology. Of those encephalitides with identified etiologies, the majority are infectious. Infectious etiologies may be classified by agent (e.g., prion, virus, bacterium, fungus, parasite), or by epidemiology (e.g., time of year, geographic location, vector).
- Viral: Of infectious etiologies, viral are most common, and include all herpesviruses [mostly HSV-1, HSV-2, and varicella-zoster virus (VZV)], enteroviruses (especially poliovirus), most arboviruses (WEE, EEE, WNV, St. Louis encephalitis virus, California encephalitis virus/La Crosse encephalitis virus, Powassan virus, Japanese encephalitis virus, yellow fever virus, tick-borne encephalitis virus), and a few notable others, including HIV, JC virus, EBV, measles, mumps, influenza, adenovirus, and rabies.
- Bacterial: Common bacterial etiologies of isolated encephalitis include Borrelia burgdorferi (agent of Lyme disease), Treponema pallidum (agent of syphilis), Mycobacterium tuberculosis, Mycoplasma, Rickettsiae, Coxiella, and Anaplasma.
- Fungal: Common fungal causes of isolated encephalitis include: Coccidioides, Histoplasma, Cryptococcus and Aspergillus.
- Parasitic: Common parasitic causes of encephalitis include: Several of the free-living amebae (Naegleria, Balamuthia, Acanthameba and Sappinia), Toxoplasma gondii, agents of microsporidiosis (e.g., Encephalitozoon cuniculi), Plasmodium spp. (agents of malaria), Trypanosoma spp. (agents of African trypanosomiasis in particular), and the common agents of eosinophilic meningitis and encephalitis (Baylisascaris, Angiostrongylus, and Gnathostoma).
- Other comments: Prions are also etiologic agents of encephalitis (vCJD, Kuru). New agents of encephalitis are continually being reported (e.g., lymphocytic choriomeningitis virus, Sappinia diploidea), as are newly appreciated encephalitic manifestations of well-known pathogens (e.g., hepatitis A, rotavirus).
COMMONLY ASSOCIATED CONDITIONS
Encephalitis can often be associated with meningitis, or can follow as a consequence of treated/resolved meningitis (ADEM). Encephalitis may be seen in conjunction with, or be confused for, focal suppurative infections (e.g., brain abscess, subdural/epidural empyema, etc.).
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HISTORY
Patients with acute encephalitis usually present with fever, headache, and altered mental status. Fever and headache in particular help to differentiate between encephalitis and encephalopathy. Epidemiologic aspects of the history are essential in narrowing the broad differential of acute encephalitis.
PHYSICAL EXAM
As above, fever may be present, along with depressed or fluctuating mental status, or focal neurologic deficits. Seizures are not uncommon. Some infectious etiologies of encephalitis present with a rash, either concurrent with the encephalitis, or offset by a characteristic time.
DIAGNOSTIC TESTS AND INTERPRETATION
Lab
Initial Lab Tests
Initial evaluation of encephalitis should include peripheral blood CBC with differential, complete blood chemistries with liver function tests.
Imaging
Initial Approach
Magnetic resonance imaging (MRI) is the most helpful modality, as it can help distinguish between isolated white- or gray-matter processes, focal suppurative infection and other processes. If MRI is not possible, brain CT with contrast may be helpful.
Diagnostic Procedures/Other
Lumbar puncture is essential in classifying a process as meningitic, encephalitic, or post-infectious. In addition, CSF can be subjected to numerous tests that allow for confirmation of etiologies of encephalitis. The standard evaluation of CSF should include cell count with differential, total protein, and glucose concentration, Gram stain and general bacterial culture, and other stains and cultures as appropriate (e.g., fungal stain and culture, AFB smear and mycobacterial culture). In addition, CSF may be sent for specific confirmation of particular pathogens such as T. pallidum (VDRL); Cryptococcus and Aspergillus (antigen tests); and the human herpesviruses, JC virus, HIV, WNV, enterovirus, adenovirus, B. burgdorferi, M. tuberculosis, T. gondii and Aspergillus spp. (PCR testing available in many places). Where PCR testing is not available, paired (acute and convalescent) serologies or antibody titers in the CSF may be helpful in making the diagnosis. In cases where a diagnosis is required, brain biopsy is the gold standard diagnostic test, though this is done very rarely.
Pathological Findings
The most common specimen analyzed is the CSF. The characteristic finding of encephalitis is a pleocytosis in the CSF. For viral etiologies, this is usually lymphocytic in nature, though early in viral processes it may be neutrophil predominant. HSV has been reported to have a characteristic hemorrhagic component (RBCs seen in the CSF), though this may be present in any encephalitis with a necrotizing component. A marked neutrophilic pleocytosis, particularly in the setting of hypoglycorrhachia (low CSF glucose) is indicative of a bacterial process, as is the case with bacterial meningitis. Hypoglycorrhachia with a lymphocytic pleocytosis is often indicative of a fungal process.
DIFFERENTIAL DIAGNOSIS
Differential considerations along with encephalitis include meningitis (both infectious and non-infectious), encephalopathy (global dysfunction without associated inflammatory process), and focal suppurative infections (e.g., brain abscess, empyema, etc.).
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MEDICATION
First Line
- Empiric treatment of possible infectious encephalitis (in the setting of possible meningitis): vancomycin 1 g IV q12h, ceftriaxone 2 g IV q12h, ampicillin 2 g IV q6h, acyclovir 10 mg/kg IV q8h.
- HSV or VZV encephalitis: acyclovir 10 mg/kg IV q8h.
- Cytomegalovirus encephalitis: Ganciclovir 5 mg/kg IV q12h.
- B. burgdorferi (Lyme disease): ceftriaxone 2 g IV q24h (preferred) or penicillin 5 MU IV q6h (preferred) or doxycycline 100 mg PO TID (alternative).
- M. tuberculosis (empiric treatment in the absence of susceptibility data): isoniazid 300 mg PO q24h, rifampin 600 mg PO q24h, pyrazinamide 25 mg/kg PO q24h (max 2 g daily), ethambutol 15 mg/kg PO q24h (max 1.6 g daily).
- Leptospira spp.: Penicillin 1.5 MU IV q6h (severe disease) or ceftriaxone 1 g IV q24h (severe disease) or doxycycline 100 mg PO q12h (mild disease).
- T. gondii: Pyrimethamine (200 mg PO loading dose x1, then 75 mg PO daily) given with either sulfadiazine 1.5 g PO q6h (preferred) or clindamycin 600 mg PO q6h (alternative).
- Rickettsia rickettsii (agent of Rocky mountain spotted fever): Doxycycline 100 mg PO q12h.
- Allergies to first line agents should trigger consultation with an infectious diseases expert.
ADDITIONAL TREATMENT
General Measures
Hospitalization and close clinical monitoring are warranted, as patients with encephalitis can be clinically tenuous, and can become critically ill quickly.
Issues for Referral
Infectious diseases consultation is appropriate for assistance in evaluation of possible infectious etiologies and further optimization of evaluation and diagnostic tests.
Additional Therapies
- Anti-epileptics (for seizure management)
- Measures for management of elevated intracranial pressure (ICP) (e.g., controlled hyperventilation, osmotic diuresis, sedation/neuromuscular blockade).
COMPLEMENTARY AND ALTERNATIVE THERAPIES
None have been studied in randomized, controlled trials in the setting of acute encephalitis.
SURGERY/OTHER PROCEDURES
Neurosurgical intervention may be required if brain biopsy is desired. Occasionally, elevated ICP may complicate encephalitis, and neurosurgical placement of an external ventricular drain, or other decompressive strategy such as craniotomy, may be required. As most infectious encephalitides are diffuse processes, there is usually little role for surgical debridement.
IN-PATIENT CONSIDERATIONS
Initial Stabilization
- Supportive care is dictated by the clinical status of the patient. Some may require only close clinical monitoring on a medical floor. Others may be obtunded and require intubation for airway protection. As mentioned above (see Surgery/Other Procedures), some may develop increased ICP and may require intensive care level monitoring and treatment. Some may require pressor support for dysautonomia that can accompany severe encephalitis. Still others may develop seizures and require intensive care monitoring and control of their seizure activity with anti-epileptic medication.
Admission Criteria
The inclusion of encephalitis on the differential diagnosis is sufficient to warrant admission to the hospital.
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FOLLOW-UP RECOMMENDATIONS
Some causes of encephalitis are reportable to authorities, depending upon local statutes (e.g., arboviruses, HIV, rabies, syphilis, etc.).
PROGNOSIS
The mortality rate associated with encephalitis in the USA has been reported at 5.1/100,000. The rate is higher in men, African-Americans, and those of extremes of age (<1 year or >65 years). The rate is much higher for the immunocompromised, and patients with HIV have over a thousand-fold increase in rate of death due to encephalitis compared to their non-HIV infected counterparts. By etiology, the highest cause of death was encephalitis of unknown etiology (approximately 86% of all encephalitis deaths), whereas the highest cause of known etiology was due to HSV (approximately 10%).
COMPLICATIONS
- Seizure
- Elevated ICP (and its sequelae)
- Permanent neurologic deficit
- Death
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