Another pathway of infection is along peripheral nerves; centripetal movement of virus is accomplished by the retrograde axoplasmic transport system. HSV, VZV, and rabies virus utilize this peripheral nerve pathway, which explains why the initial symptoms of rabies occur locally, at a segmental level corresponding to the animal bite. It has been shown experimentally that HSV may spread to the central nervous system (CNS) by involving olfactory neurons in the nasal mucosa; the central processes of these cells pass through openings in the cribriform plate and synapse with cells in the olfactory bulb (CNS). Another potential pathway is the trigeminal nerve and gasserian ganglion, however, the role of these pathways in human infection is not certain. Of the different routes of infection, the hematogenous one is by far the most important for the majority of viruses.
Additionally, VZV resides in the sensory ganglia and becomes reactivated later in life, causing shingles decades after the primary infection that produces chicken pox. The JC virus also is latent in tissues, possibly the kidney and bone marrow, only to reemerge under conditions of immunosuppression, to infect the brain.
Mechanisms of Viral Infections
Viruses, once they invade the nervous system, have numerous clinical and pathologic effects. One reason for this diversity is that different cell populations within the CNS vary in their susceptibility to infection with different viruses. To be susceptible to a viral infection, the host cell must have on its cytoplasmic membrane specific receptor sites to which the virus attaches. Thus, some infections are confined to meningeal cells, enteroviruses being the most common, in which case the clinical manifestations are those of aseptic meningitis. Other viruses involve particular classes of neurons of the brain or spinal cord, giving rise to the more serious disorders such as encephalitis and poliomyelitis. The virus or its nucleocapsid must be capable of penetrating the cell, mainly by the process of endocytosis, and of releasing its protective nucleoprotein coating. For viral reproduction to occur, the cell must have the metabolic capacity to transcribe and translate virus-coated proteins, to replicate viral nucleic acid, and, under the direction of the virus’s genome, to assemble virions. Certain viruses depend on cell-surface receptors to ingress into the cell; these relationships have potential therapeutic interest as, for example, the serotonin receptor for entry of the JC virus into oligodendrocytes.
The pathologic effects of viruses on susceptible cells vary greatly. In acute encephalitis, neurons are invaded directly by virus and the cells undergo lysis. There is a corresponding glial and inflammatory reaction. Neuronophagia (phagocytosis of affected neurons and their degenerative products by microglia) is a mark of this phenomenon. In progressive multifocal leukoencephalopathy (PML), there is a selective lysis of oligodendrocytes, resulting in foci of demyelination. In certain congenital infections, for example, measles and rubella, the virus persists in nervous tissue for months or years. In still other circumstances, a viral infection may exist in the nervous system for a long period before exciting an inflammatory reaction (e.g., subacute sclerosing panencephalitis, SSPE); in these cases the disease may be so indolent as to simulate a degenerative disease.
Differentiating cells of the fetal brain have particular vulnerabilities, and viral incorporation may give rise to malformations and to hydrocephalus; an example is mumps virus with ependymal destruction and aqueductal stenosis.
In experimental animals cerebral neoplasms can be induced when certain viral genomes are incorporated into the DNA of the host cell. There is suggestive evidence of such a mechanism relating to EBV in B-cell lymphoma of the brain. The prions have yet other means of affecting cells that do not conform to the traditional concepts of infection and are discussed in a later section of this chapter.