The findings and conclusions in this work are those of the author and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
Overview Of Viral Encephalitis
Infections of the central nervous system (CNS) are usually associated with tremendous clinical significance. Because of the unique anatomic structure and physiologic functions of the CNS, even mild neurologic damage caused by infectious processes can produce serious consequences with a potentially fatal outcome. Based on the involved anatomic structures, CNS infections are generally classified as meningitis, encephalitis, or myelitis; although bacterial infections usually cause meningitis, viral infections often involve multiple structures and produce meningoencephalitis, encephalomyelitis, or meningoencephalomyelitis. A common semantic practice is to apply the term encephalitis to describe these viral infections collectively. A great number of viruses have tropism for the neural tissues and account for serious acute encephalitis Viral encephalitis can be further divided into three categories based on pathogenesis:
(1) diseases resulting from human-to-human transmission or decreased immunity (encephalitis caused by herpesviruses, enterovirus;
(2) zoonotic diseases acquired by direct contact with an animal (encephalitis caused by rabies virus, Nipah virus, etc.); and
(3) diseases acquired from an insect arthropod vector (encephalitis caused by West Nile virus, eastern equine encephalitis virus, etc.).
This chapter focuses on diseases in category 3, whereas diseases in categories 1 and 2 are discussed in other chapters covering the specific etiologic agents. Viral encephalitis can occur sporadically or in epidemics, either in particular geographic areas or with a worldwide distribution. Viruses can infect individuals of all ages from neonates to the elderly, but some viruses favor particular age groups. There are many possible entry pathways of viral agents into the CNS, such as hematogenous spread, respiratory inhalation, the oral route, or cutaneous inoculation. Most viruses reach the nervous system via the bloodstream during a temporary phase of viremia after replication in infected distant organs. Some viruses, such as rabies virus and herpes zoster virus, may reach the CNS along peripheral nerves through retrograde axonal transport. The manifestations of viral encephalitis are remarkably diverse, ranging from asymptomatic or mild illness to fatal infection. The signs and symptoms of the different categories of encephalitis are usually similar and cannot be clinically differentiated.
Common manifestations include fever, headache, nuchal rigidity, mental status changes, sensory or motor deficits, and seizures. Clinical diagnosis of viral encephalitis is often challenging because of the anatomic and physiologic obstacles of the brain and spinal cord, including their unique immunologic surveillance system and the blood-brain barrier. Although clinical manifestations, patient history, and physical examination can suggest a possible diagnosis of viral encephalitis, they are often unreliable for determining the actual pathologic process given that other noninfectious diseases can present with similar clinical manifestations. Electroencephalography (EEG), magnetic resonance imaging (MRI), and computerized axial tomography (CAT) scans may provide anatomic and dimensional information of the lesions to suggest the areas of CNS involvement, but their sensitivity and specificity vary widely among different encephalitides, as well as severity and stages of the illness.
Routine laboratory studies, including complete blood counts, biochemical assays, and cerebrospinal fluid (CSF) examination, show mostly nonspecific findings. Furthermore, these laboratory test results may not represent the actual disease process because of the lack of clinicopathologic correlation. In contrast, if neural tissue samples are available, pathologic examination with pertinent testing including immunohistochemistry and polymerase chain reaction (PCR) can provide a more accurate diagnosis, as well as insight for understanding the pathogenesis of viral infections.
The histopathologic features in viral encephalitis correlate with the properties of the infecting virus, the host immune responses, and the topographic areas of involvement. Once the virus reaches the brain parenchyma, a widely disseminated infection of neurons and glial cells may ensue. This will provoke an acute immune response with inflammatory cell infiltration into the perivascular space parenchyma and leptomeninges. The degree of inflammation varies; typically lymphocytes predominate with more T cells and fewer B cells. Some viral infections may be associated with more abundant polymorphonuclear cells, especially during the acute phase.
Vascular involvement with inflammatory cells can be seen in some viral infections, such as the Nipah virus or human herpes viruses. The infected neurons are surrounded by clusters of inflammatory cells, activated microglial cells, and macrophages with phagocytic activities. The diseased neurons gradually disintegrate. Eventually, residual microglial nodules replace the destroyed neurons. Neuronal necrosis and lysis of glial cells result in cerebral edema and loss of neurologic functions. Gray matter is usually more involved than white matter in most acute viral infections.
Focal areas of parenchymal hemorrhage are commonly seen in viral encephalitis. Although immune responses will eventually terminate the infection, the damage is often irreversible and the patient may be left with permanent neurologic sequelae or progress to death. Most acute viral CNS infection results in nonspecific histopathologic findings as described earlier, such as perivascular cuffing, parenchymal and meningeal inflammation, neuronal necrosis, neuronophagia, microglial nodule, and reactive gliosis. However, aggregates of viral particles may form inclusion bodies in the nucleus or cytoplasm of infected neurons and glial cells in some viral infections. These intranuclear or intracytoplasmic inclusion bodies are helpful for etiologic diagnosis ( For instance, the presence of Negri bodies in the hippocampus and cerebellum are pathognomonic of rabies virus infection whereas Cowdry type A inclusions with hemorrhagic necrosis in the temporal lobe are commonly associated with human herpes simplex virus infections. Unfortunately, these helpful morphologic features are not observed in other more common viral encephalitides, such as those caused by enteroviruses and arboviruses. Therefore, more specific tests are required for a definitive etiologic diagnosis.
Book: PATHOLOGY OF INFECTIOUS DISEASES
by Gary W. Procop, MD, MS