VIRAL ENCEPHALITIS.doc

VIRAL ENCEPHALITIS

Background: Acute viral encephalitis (enkephalos + -itis, meaning brain inflammation) is often an unusual manifestation of common viral infections and most commonly affects children and young adults. Most viral infections of the CNS either involve the meninges, leading to aseptic meningitis, or cause mild meningoencephalitis rather than encephalitis.

In general, viral encephalitides can be divided into 4 separate categories based on the cause and pathogenesis of the following complications: acute viral encephalitis; postinfectious encephalomyelitis; slow viral infections of the CNS; and chronic degenerative diseases of the CNS, which are presumed to be of viral origin. This article focuses on acute viral encephalitis. For a more detailed description of each viral family, refer to the Infectious Diseases section of eMedicine and the articles Herpes Simplex Encephalitis and West Nile Encephalitis.

Pathophysiology: The initial event in the replicative cycle of a virus is its interaction with receptors present on the surface of a cell. Knowledge of this interaction is important in understanding viral spread, tropism, and pathogenesis. The following cellular receptors have been described for these viruses (see Table 1 for more information):

·         Measles virus - CD46

·         Poliovirus - CD155

·         Herpes simplex virus (HSV) - Heparan sulfate; Hve A, B, and C; tumor necrosis factor receptor superfamily 14 (TNFSF14); HVEM; Prr1 and Prr2; and nectin-1 and nectin-2

·         Rabies virus - AChR, NCAM, and NGFR

·         Human immunodeficiency virus-1 (HIV-1) - CD4, CCR5/3, and CXCR4

·         JC virus - N-linked glycoprotein and alpha 2-6 sialic acid

Despite viral tropism, the pattern of distribution of lesions in the brain is rarely sufficiently specific to enable identification of the infecting virus.

Table 1. Physiological Role of Known Viral Receptors

*Abbreviations: PV – Poliovirus; TNF – Tumor necrosis factor; AChR – Acetylcholine receptor; NCAM – Neural cell adhesion molecule; NGFR – Nerve growth factor receptor; CCR – Chemokine receptor

The pathophysiology of viral encephalitis varies according to the viral family. Viruses enter the CNS through 2 distinct routes: hematogenous dissemination or neuronal retrograde dissemination. Hematogenous spread is the most common path. Humans are usually incidental terminal hosts of many viral encephalitides. Arbovirus encephalitides are zoonoses, with the virus surviving in infection cycles involving biting arthropods and various vertebrates, especially birds and rodents. The virus can be transmitted by an insect bite and then undergoes local replication in the skin.

Transient viremia leads to seeding of the reticuloendothelial system and muscles. After continuous replication, secondary viremia leads to seeding of other sites, including the CNS. In fatal cases, little histopathologic change is noted outside the nervous system. St. Louis encephalitis is an exception, as renal involvement is occasionally present.

On gross examination, variable degrees of meningitis, cerebral edema, congestion, and hemorrhage are observed in the brain. Microscopic examination confirms a leptomeningitis with round-cell infiltration, small hemorrhages with perivascular cuffing, and nodules of leukocytes or microglial cells. Demyelination may follow the destruction of oligodendroglias, and involvement of ependymal cells may lead to hydranencephaly. Neuronal damage is seen as chromatolysis and neuronophagia. Areas of necrosis may be extensive, especially in eastern equine encephalitis and Japanese B encephalitis. Recent experimental evidence has shown that arboviruses can induce apoptotic cell death in neurons in the brains of their hosts. Patients who survive the initial illness associated with viral encephalitis feature varying degrees of repair, which may include calcification.

Another form of CNS spread is through retrograde neural dissemination. Rabies usually spreads to the CNS through retrograde peripheral nerve dissemination. Rabies virus tends to exhibit tropism for the temporal lobes, affecting the Ammon horns. One of the possible routes of CNS spread for HSV is through the olfactory tracts. Herpesvirus encephalitis in infants is usually part of a widespread infection that produces focal necrotic lesions with typical intranuclear inclusions in many organs. In adults and in some children, lesions are confined to the brain. Necrotic foci may be macroscopically evident as softening. Inclusion bodies are found readily in the margins of areas of necrosis; focal perivascular infiltration and neuronal damage are evident. Herpesviruses have tropism for the temporal cortex and pons, but the lesions may be widespread.

Frequency:

·         In the US: Epidemiologic studies estimate the incidence of viral encephalitis at 3.5-7.4 per 100,000 persons per year. Overall, viruses are the most common cause of encephalitis. The Centers for Disease Control and Prevention (CDC) estimates an annual incidence of approximately 20,000 new cases of encephalitis in the United States; most are mild in nature. Epidemiological data follow; for additional updated epidemiologic data, see the CDC Division of Vector-Borne Infectious Diseases, Arboviral Encephalitides.

o        The 2 endemic causes of viral encephalitis in the United States are HSV and rabies. HSV encephalitis is the most common form of viral encephalitis and has an incidence of 2 cases per 1 million population per year and accounts for 10% of all cases of encephalitis in the United States.

o        Arboviral encephalitis comprises 150-3000 cases per year, depending on occurrence and intensity of epidemic transmission.

o        West Nile encephalitis had affected 480 individuals, with 24 deaths, as of August 28, 2002.

o        St. Louis encephalitis affected 3000 individuals in 1975.

o        La Crosse encephalitis usually affects 70 individuals per year.

o        Eastern equine encephalitis was confirmed in 153 cases since 1964, and western equine encephalitis was confirmed in 639 cases.

·         Internationally: The annual incidence of viral encephalitis is most likely underestimated, especially in developing countries, because of problems with pathogen detection. Japanese B encephalitis affects at least 50,000 individuals per year.

In a recent study from Finland, the incidence of viral encephalitis in adults was 1.4 cases per 100,000 persons per year. HSV was identified most often as the cause (16%), followed by varicella-zoster (5%), mumps (4%), and influenza A viruses (4%).

Mortality/Morbidity: The mortality rate depends largely on the etiologic agent of the encephalitis. Herpesvirus encephalitis carries a mortality rate of 70% in untreated patients, with severe sequelae among survivors. For details on the incidence of sequelae in survivors, see Complications and Prognosis as well as Tables 2-4.

Sex: Mumps meningoencephalitis affects men more often than women. Men working in areas infested by infected mosquitoes have a higher incidence of arboviral infections.

Age: Children and young adults are usually the most often affected groups. However, severity is usually more pronounced in infants and elderly patients.
 

History:

·         Viral encephalitis is marked by acute onset of a febrile illness.

·         Patients with viral encephalitis generally experience signs and symptoms of leptomeningeal irritation (eg, headache, fever, neck stiffness).

·         Patients with viral encephalitis also develop focal neurological signs; seizures; and alteration of consciousness, starting with lethargy and progressing to confusion, stupor, and coma.

·         Behavioral and speech disturbances are common.

·         Abnormal movements can be seen but are rare.

·         Involvement of the hypothalamic/pituitary axis can lead to hyperthermia or poikilothermia.

·         Specific clues taken from the patient's history depend on the viral etiology. Clinical findings reflect disease progression according to viral tropism for different CNS cell types. Particular clinical manifestations of different encephalitides can be reviewed in Tables 2-4. Some important clinical presentations are as follows:

o        Atypical presentations include a reversible frontal lobe and limbic syndrome without disturbances of consciousness or motor function. These presentations have been described in children with influenza virus infection.

o        HSV-1 encephalitis and HSV-2 encephalitis have subacute forms, presenting with psychiatric syndrome and anterior opercular syndrome, known as benign recurrent meningitis. HSV-1 encephalitis may produce a brainstem encephalitis, and HSV-2 encephalitis may produce a myelitis.

o        West Nile virus infection is usually asymptomatic in areas of endemic disease. In symptomatic individuals, an influenzalike illness occurs after incubation of 3-15 days; CNS involvement occurs in fewer than 15% of cases. Severe neurological infection is more common when the virus is introduced in an area of nonendemic disease. In 1999, during the New York City outbreak, 62 patients developed encephalitis, and 7 died (a case fatality rate of 12%, with all deaths occurring in older patients). Axonal neuropathy, demyelinating polyneuropathy similar to that in Guillain-Barré syndrome, encephalitis with...