Epidemiology and Risk Factors. Herpes simplex virus (HSV) infections of the central nervous system are of several types: (1) an acute encephalitis, (2) a benign recurrent lymphocytic meningitis, (3) an acute facial nerve paralysis, (4) recurrent ascending myelitis, and (5) a neuritis localized to a single sensory nerve. Neonatal HSV infections occur at a rate of approximately 1 in 3500 to 5000 deliveries per year in North America. Three forms of infection of the newborn are recognized: infection localized to the skin, eye, and mouth (SEM); encephalitis; and disseminated disease with involvement of the CNS. Neonatal HSV infections are usually caused by HSV type 2 (HSV^.y
In children aged 6 months or older and in adults, HSV type 1 (HSV-1) is the most common cause of sporadic fatal encephalitis. Herpes simplex encephalitis is estimated to occur in 1 in 250,000 to 500,000 persons per year. WJ HSV- 2 is increasingly recognized as the etiological agent of benign recurrent lymphocytic meningitis, and HSV-1 as the etiological agent of acute facial nerve paralysis, Bell's palsy.
Pathogenesis and Pathophysiology. The human herpesviruses are neurotropic viruses that are able to establish active and latent infections in the CNS and can cause tissue damage through viral replication in nervous tissue and reactivation from the latent state. [w] The pathogenesis of neonatal HSV disease is different from that of HSV disease in older infants, children, and adults. Neonatal HSV infection is acquired most commonly when the fetus comes in contact with infected maternal genital secretions. The type of maternal infection, whether primary or recurrent, has a significant influence on the risk of infection to the fetus. Maternal primary infection at the time of delivery is associated with a fetal risk of infection of approximately 35 percent. Maternal recurrent infection at the time of delivery is associated with a significantly lower risk to the fetus of approximately 3 percent. 
There are two forms of HSV encephalitis during the neonatal period. In babies with encephalitis alone, the illness begins, on average, within 2 weeks of birth. Infection of the CNS by HSV in these neonates is thought to occur by intraneuronal routes. The majority of these babies do not develop skin lesions, and brain disease is often localized to one or both temporal lobes, but it can progress to involve other areas of the brain. In contrast, in newborns with encephalitis resulting from disseminated disease, symptoms of brain involvement begin at the age of 7 to 9 days or earlier. The CNS becomes infected through bloodborne spread of the virus, and neuroimaging procedures reveal multiple areas of hemorrhagic necrosis throughout the cerebral cortex.  ,
In children and adults, HSV-1 encephalitis occurs as either an acute infection or as reactivation of latent infection in the trigeminal ganglion. Infection most commonly involves the temporal cortex, the orbital-frontal cortex, and the limbic structures. In most cases the initial infection begins in the oral cavity, and the virus spreads transneuronally along a division of the trigeminal nerve to the trigeminal ganglion. ^ In experimental animal models of HSV-1 encephalitis, intranasal inoculation leads to viral entry via the olfactory nerve with subsequent infection of the olfactory bulb. Infection then develops in the temporal cortex analogous to human disease; however, the olfactory bulb is rarely affected in humans, and therefore the olfactory nerve is less likely to be the site of viral entry in humans. The extent and severity of CNS disease is related to the neurovirulence of the virus, the degree of viral inoculum, the immunocompetence of the individual, and possibly genetic determinants of susceptibility to HSV infection. 
The human herpesviruses have the ability to establish lifelong latent infection in the peripheral sensory ganglia (PSG), in the trigeminal ganglion, and in the motor neurons of the hypoglossal nucleus. During acute infection, cells that are infected with HSV-1 ultimately die. The pathogenesis of virus that establishes latency is fundamentally different. Following peripheral inoculation, HSV-1 DNA viral particles are carried by retrograde axonal flow to the PSG. Since HSV is a lytic virus and replication within a cell results in cell death, latency cannot be established in cells in which the virus has completed a full replication cycle. During attachment of HSV-1 to the axonal membrane of the peripheral nerve, the virus loses its envelope, and the contents of the tegument as well as the capsid are transported to the neuronal nucleus. Vmw65, an HSV-1 transactivating protein that is a component of the viral tegument, has a role in this process. The amount of Vmw65 that is carried with the virus to the cell nucleus eventually determines the fate of the infection. If sufficient amounts reach the neuronal cell body, a replication cycle ensues, and the cell dies; if, however, the amount of Vmw65 is insufficient, no replication cycle begins, and latent infection is established. [w] No infectious viral particles are present during latent infection. During latent HSV-1 infection the linear DNA is present as a circular molecule that is not integrated into the host cell DNA.  External stimuli triggering reactivation of HSV include injury to tissues innervated by the neurons harboring latent infection, and the systemic conditions of exposure to sun, fever, malignancy, and immunosuppression. Even after numerous repeated bouts of reactivation, most patients do not have permanent sensory loss or any other neurological deficit in the affected dermatome, presumably because reactivation is not associated with significant destruction of latently infected neurons. [w] [108 W  The nature of the latent state of the HSV virus in the trigeminal ganglion is not as well understood as HSV infection in the peripheral nervous system. CNS disease as
a result of HSV-1 infection, herpes encephalitis, in immunocompetent individuals is a very rare single event, whereas HSV infection in the peripheral nervous system may recur many times during an individual's lifetime. It is estimated that in approximately a third of patients, HSV-1 encephalitis occurs during the primary viral infection, and that in the other 70 percent, HSV-1 encephalitis is due to reactivation of latent infection in the trigeminal ganglion. [w] The pathogenesis of herpes simplex virus infection as a cause of benign recurrent lymphocytic meningitis is postulated to be due to HSV-2 primary infection or to reactivation in a sacral dorsal root ganglion that seeds the CSF subarachnoid space and produces meningitis.  The pathogenesis of herpes simplex viral infection in acute facial nerve paralysis is presumed to be reactivation of latent infection in the geniculate ganglion. W
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