Viral Encephalitis

Etiology

Infectious encephalitis can be viral, bacterial, fungal, protozoal, or helminthic in etiology. The etiology of many cases of encephalitis remains unknown despite extensive workup. Viruses are the most prevalent identified cause, accounting for about 70% of confirmed cases of encephalitis. In the United States, the most common causes of viral encephalitis are herpes simplex virus (HSV), West Nile virus, and the enteroviruses. Some of the other viral etiologic agents include varicella-zoster virus, Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpesvirus type 6 and 7, measles virus, mumps virus, rubella virus, St. Louis virus, eastern equine virus, western equine virus, dengue virus, and rabies virus.[4][5][6]

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, transplant, and chemotherapy patients. Other important epidemiologic factors include the time of the year, geography, and animal or insect exposure. For instance, arboviruses (i.e., eastern equine, western equine, St. Louis, Venezuelan equine, Zika, and West Nile) cause disease during the summer months when mosquitos are active. St. Louis encephalitis is primarily seen in the Midwest and South, whereas tick-borne encephalitis occurs mainly in the North-Central and the Northeastern United States.[7][8][9]

The transmission to the brain is via hematogeneous spread.

In the US, herpes simplex is the most common cause of encephalitis. Individuals who work in the warm humid environments are at risk for arboviruses because of the presence of mosquitoes.

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 are important exceptions to this. They travel to the CNS from nerve endings in a retrograde manner. Once in the brain, the virus and the host’s inflammatory response disrupt neural cell function. On gross examination, there us usually cerebral edema, vascular congestion, and hemorrhage. Infiltration with leukocytes or microglial cells is also a common feature. With EEE and JE, the extent of necrosis can be significant.

Following arbovirus encephalitis, calcification often is seen, especially in children.

Herpes simplex tends to produce focal necrotic lesions with obvious intranuclear inclusions.

Histopathology

Brain histology of individuals with viral encephalitis shows dead neurons with nuclear dissolution and hypereosinophilia within the cytoplasm on light microscopy. Because encephalitis is an inflammatory process, perivascular inflammatory cells such as microglia, macrophages, and lymphocytes are also seen. Virions within neurons can be visualized with electron microscopy, which allows for much greater magnification than light microscopy.

History and Physical

As mentioned above, the cause of many cases of encephalitis remains unknown despite extensive testing. Thus, history and physical exam play a vital role in making the diagnosis of viral encephalitis. Important elements of history include immune status, exposure to insects or animals, travel history, vaccination history, geography, and time of year. The most common sign and symptoms are fever, headache, seizures, and altered mental status. Neuropsychiatric features such as behavioral changes, hallucinations, and/or cognitive decline are often seen. Patients may also have other symptoms or exam findings that are more specific to a given virus. For example, rash and skin vesicles are seen with herpes zoster encephalitis, whereas lymphadenopathy and splenomegaly are usually associated with EBV. HSV encephalitis involves the temporal and frontal lobes, so it is often characterized by psychiatric features, memory deficits, and aphasia. On the other hand, motor symptoms such as choreoathetosis and parkinsonian movements are seen with some arboviruses because they predominately affect the basal ganglia.

Specific features

JE may lead to extrapyramidal symptoms-which mimic Parkinson disease

Enterovirus 71 may cause tremor, myoclonus, ataxia, pulmonary edema, and cranial nerve palsies.

Nipah virus has been shown to produce brainstem and cerebellar signs, hypertension and segmental myoclonus.

Microcephaly is typical of Zika virus infection.

Evaluation

Neuroimaging and lumbar puncture (LP) are essential initial diagnostic studies for evaluating patients with viral encephalitis. Computed tomography (CT) or magnetic resonance imaging (MRI) help exclude increased intracranial pressure and the risk of uncal herniation prior to performing an LP.

CT may show low-density lesions in the temporal lobes when HSV is involved. These lesions usually appear 3-5 day after the infection.

MRI is also the most sensitive imaging modality for showing findings consistent with HSV encephalitis, such as temporal and frontal lobe involvement. Cerebrospinal fluid (CSF) should be analyzed for opening pressure, cell counts, glucose, and protein. CSF evaluation should also include polymerase chain reaction (PCR) testing for HSV-1, HSV-2, and enteroviruses. Additional testing, such as serology for arboviruses and HIV testing, may also be done based on history and clinical presentation. Brain biopsy and body fluid specimen cultures and PCR may also be helpful in establishing the etiology in some cases.[2][10][11]

The CSF will show:

• Normal glucose
• Moderately elevated proteins
• Moderate lymphocytosis

About 10% of patients will have normal CSF studies.

EEG may show abnormalities in patients with seizures. 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.

Treatment / Management

The treatment of viral encephalitis is primarily supportive as there is no specific medical therapy for most central nervous system viral infections. 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 behavioral 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. Although not as effective as it is with HSV, nucleoside analogs are used for other herpesviruses as well. 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 poor prognosis. Although there is limited data on their efficacy in viral encephalitis, steroids and mannitol can be given to relieve increased ICP.[12][13][14](B3)

Seizures may need to be managed with valproic acid or phenytoin. For status epilepticus, one may require benzodiazepines. For behavior alterations, one may need to use antipsychotics for a short time.

Differential Diagnosis

A broad differential diagnosis, both infectious and noninfectious, should be considered for encephalitis. These alternatives include malignancy, autoimmune or paraneoplastic diseases (e.g., anti-NMDA receptor encephalitis), brain abscess, tuberculosis or drug-induced delirium, neurosyphilis, or bacterial, fungal, protozoal, or helminthic encephalitis.

Prognosis

Most patients with viral encephalitis recover without sequelae. Those who remain symptomatic have difficulties in concentration, behavioral 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 behavior following infection with WEE. Following EEE, 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 that may occur in 10-20% of patients over several decades. These seizures often are resistant to medical therapy. Unilateral mesial temporal lobe seizures have good outcomes following neurosurgery.

Complications

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