Encephalitis

Definition, Etiology, PathogenesisTop

Encephalitis is an inflammatory process involving the nervous tissue in the brain and frequently also the meninges (meningoencephalitis) and the subarachnoid space. It is caused by the presence of microorganisms in the brain parenchyma (among others, this may be due to the progression of meningitis).

1. Etiologic agents: Encephalitis is usually caused by viruses, including herpes simplex virus (HSV) and varicella-zoster virus (VZV); flaviviruses such as West Nile (WNV), St Louis, and Powassan viruses; and rarely by measles, mumps, or rubella viruses, cytomegalovirus (CMV), enteroviruses (type 71), rabies virus, HIV, Epstein-Barr virus (EBV), influenza viruses, human herpesvirus 6 (HHV–6), or fungi (Candida spp, Cryptococcus neoformans, Aspergillus spp).

2. Reservoir and transmission: These vary with etiologic agents. The reservoir is predominantly humans; the only exception is rabies virus, in which case the reservoir is wild animals (foxes, squirrels, bats), dogs, and less frequently cats. In flaviviruses, such as WNV, birds may be the reservoirs and infections are spread via mosquito or tick vectors. Depending on the pathogen, transmission occurs through airborne droplets, direct contact with sick individuals or human secretions, or vectors; in rabies, transmission is through a bite of an infected animal or direct contact of injured skin or mucosa with animal saliva.

3. Epidemiology: The incidence of viral encephalitis in some countries is between 1 to 2 cases per 100,000 persons per year. In the case of certain viruses (VZV, enteroviruses, tick-borne encephalitis virus [TBEV] [in endemic areas outside North America]) occurrence is seasonal. Risk factors: Enclosed areas, public beaches and swimming pools, hypogammaglobulinemia, impaired cell-mediated immunity, contact with stray or wild animals (rabies), living in regions endemic for TBEV, contact with sick individuals. Risk factors for fungal central nervous system (CNS) infections: see Meningitis.

Clinical Features and Natural HistoryTop

In many patients neurologic features are preceded by prodromal manifestations (influenza-like symptoms: diarrhea, fever, lymphadenopathy), manifestations of an underlying condition (eg, measles, mumps, varicella), or both. A particularly severe and highly dynamic course of the disease is associated with herpes simplex encephalomyelitis (herpetic skin and mucosal lesions are usually absent). The dominant clinical features include altered mental status, fever of various grades, and focal neurologic deficits: alterations of mental status that may be qualitative (psychotic and personality disorders) and quantitative (various degrees of impairment, which may progress to coma); headache, nausea and vomiting, bradycardia (clinical features of cerebral edema and increased intracranial pressure [see Stroke]); focal and generalized seizures; spastic paresis or paralysis and other features of involvement of the pyramidal neurons (motor neuron disease); paresis or paralysis of the cranial nerves (most frequently III, VI, IV, and VII); flaccid paralysis (indicating brainstem injury); cerebellar signs (predominantly in the course of cerebellitis associated with varicella); memory impairment, including severe amnestic disorders; motor or mixed aphasia; autonomic hyperactivity—excessive sweating, alternating bradycardia and tachycardia, hypothermia or hyperthermia, and hypersalivation (sialorrhea; eg, in the course of rabies).

DiagnosisTop

Diagnostic Tests

1. Magnetic resonance imaging (MRI) (preferred) or computed tomography (CT) of the head is mandatory in every patient suspected of encephalitis. Abnormalities may be observed even in early stages of the disease (particularly on MRI); their location and features may be suggestive of etiology or exclude other causes. Patients with acute encephalitis may have features of cerebral edema.

2. Analysis of cerebrospinal fluid (CSF) (see Laboratory Tests): Elevated opening pressure with a slight predominance of mononuclear cells, increased protein levels, or both. In patients with meningoencephalitis, CSF abnormalities depend on etiology. Increased intracranial pressure (eg, in cerebral edema) is a contraindication to lumbar puncture; if features of cerebral edema or focal deficits are present, the patient’s eligibility for lumbar puncture should be determined on the basis of MRI or CT.

3. Microbiologic studies: As in meningitis. The basis for establishing the etiology of viral CNS infections is detection of viral genetic material in CSF by polymerase chain reaction (PCR) or reverse transcriptase–polymerase chain reaction (RT-PCR); if clinical features suggest herpes simplex encephalitis and PCR results are negative, consider repeat PCR testing after 3 to 7 days.

4. Serologic studies (not useful in immunocompromised patients): Specific IgM levels in CSF (HSV, VZV, EBV, WNV, TBEV where endemic), alternatively specific IgG levels in CSF and serum (CSF levels 20-fold higher than serum levels confirm a CNS infection). Results are usually negative during the first 1 or 2 weeks of encephalitis.

5. Electroencephalography (EEG) is always indicated. The EEG patterns are relatively specific in herpes simplex encephalitis, showing a temporal slowing pattern, and are often detectable earlier than neuroimaging abnormalities.

Differential Diagnosis

Meningitis, intracranial mass (abscess, subdural empyema, intracranial hematoma, primary or metastatic brain tumor, cysticercosis or echinococcosis of the brain), stroke or subarachnoid hemorrhage, cerebral vasculitis (isolated or in the course of systemic diseases), metabolic disturbances (hypoglycemia or hyperglycemia, hyponatremia, hypocalcemia), poisoning (medications, illicit drugs), hepatic or uremic encephalopathy, epilepsy, status epilepticus, psychosis, postinfectious encephalitis (an autoimmune process associated with a viral disease [eg, measles or rubella] or extremely rarely caused by certain vaccines [eg, against rabies or measles], leading to multifocal demyelination, usually mild or moderately severe [low mortality]; CSF negative for viruses; necessary differentiation from multiple sclerosis; MRI essential for diagnosis).

TreatmentTop

Infection Treatment

1. IV acyclovir (INN aciclovir) 10 mg/kg every 8 hours should be initiated promptly on an empiric basis in all patients with encephalitis (particularly if severe), without waiting for virologic confirmation of the diagnosis (in herpes simplex encephalitis the effectiveness of treatment is correlated with its prompt initiation). Continue the treatment for 3 weeks in those with virologically confirmed HSV.

2. In the case of justified suspicion or a confirmed specific etiology, consider the following:

1) CMV: IV ganciclovir (5 mg/kg by infusion every 12 hours for 3 weeks) in combination with IV foscarnet (60 mg/kg every 8 hours or 90 mg/kg every 12 hours).

2) VZV: IV acyclovir 10 to 15 mg/kg by infusion every 8 hours for 10 to 14 days; alternatively you may use ganciclovir.

3) HHV-6 in patients with impaired cell-mediated immunity: Our pattern of practice involves ganciclovir or foscarnet. Cidofovir may also be considered.

4) Fungal infections: see Meningitis.

Supportive Treatment

As in meningitis. Supportive treatment is crucial in encephalitis. Empiric glucocorticoids are not used.

Follow-UpTop

The effectiveness of treatment is confirmed by the resolution of signs and symptoms and improvement in the patient’s general clinical condition. It is not necessary to perform a routine follow-up CSF examination. In case of a lack of improvement or development of complications, repeat CSF analysis and neuroimaging studies (preferably MRI). Postinflammatory CSF abnormalities may persist for considerable time after the resolution of the acute phase of the disease.

ComplicationsTop

In acute encephalitis: status epilepticus, brain herniation (as a result of raised intracranial pressure), syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Late complications include permanent paresis or paralysis, epilepsy, psychotic disorders, memory impairment, dementia, and aphasia.

PrognosisTop

Prognosis is poor. Mortality rates are particularly high in herpes simplex encephalitis (in patients receiving no specific antiviral treatment, mortality rates are 70%-80%; in patients in whom treatment is initiated early, prior to loss of consciousness, the mortality rate is 30%). Encephalitis or cerebellitis in the course of varicella. Fungal CNS infections: see Meningitis.

PreventionTop

1. Vaccination against measles, mumps, rubella, VZV, influenza, poliomyelitis, rabies in high-risk individuals (long-term travelers, veterinary workers, those interacting with wild animals).

2. Passive immunoprophylaxis: In special cases administer varicella-zoster immunoglobulin (VZIG), rabies immunoglobulin (RIG), or antimeasles virus immunoglobulin.

3. Avoidance of any contact with wild animals and stray dogs and cats (prophylaxis of rabies).

4. In endemic areas outside North America nonspecific protection against ticks: see Infection Prevention: Nonspecific Insect and Tick Bite Precautions (prophylaxis of TBEV).