Acute phase

It is unusual to see macroscopic lesions. In severe cases, vascular congestion, petechial hemorrhages, and focal necrosis may be evident in the spinal gray matter or brain stem.

Acute phase

The extent of histologic involvement almost always exceeds that predicted by the clinical manifestations. The distribution of lesions is variable. The spinal gray matter is usually involved, particularly the anterior horn cells. The disease also shows a predilection for the motor nuclei in the pons and medulla, the reticular formation, and deep cerebellar nuclei (Fig. 12.2). Apart from the precentral gyrus, the cerebral cortex is usually spared.

There is intense inflammation in the leptomeninges and affected gray matter (Fig. 12.3). Neutrophils are found initially, but lymphocytes soon predominate. Lymphocytic cuffing of blood vessels is a conspicuous feature.

The histologic hallmark of the viral infection of neurons is neuronophagia (aggregation of microglia and macrophages around dead neurons, Fig. 12.4). Clusters of microglia (microglial nodules) mark the sites of destroyed neurons for several weeks after their resorption.

There is often congestion of small blood vessels in the areas of inflammation. This may be associated with perivascular hemorrhage and, occasionally, focal necrosis. Enterovirus 71 infection has been associated with widespread inflammation in the spinal gray matter, brain stem, hypothalamus, subthalamic and dentate nuclei, and necrotizing lesions in the dorsomedial pons and medulla.

Chronic phase

In patients coming to necropsy several years after the acute illness, there is wasting of the affected muscles, and thinning and gray discoloration of the corresponding anterior spinal nerve roots.

Examination of the affected regions shows an obvious loss of motor neurons (Fig. 12.5) and atrophy and fibrosis of anterior nerve roots. There may be scanty residual inflammation. These changes apart, the parenchyma of the affected spinal cord or brain stem is usually remarkably well preserved.

Acute phase

Most cases show obvious congestion and hemorrhagic necrosis involving the temporal lobes (Fig. 12.9) and, to a greater or lesser extent, the insulae, cingulate gyri, and posterior orbital frontal cortex (Fig. 12.9). The lesions are often somewhat asymmetric. Occasionally, in very early disease, the brain may appear macroscopically normal. In contrast, in patients dying some weeks after the onset of disease the liquefactive necrosis in these regions will have progressed to cavitation and atrophy.

Acute phase

The earliest lesions contain relatively scanty parenchymal inflammation, although there are moderate numbers of lymphocytes and macrophages in the overlying leptomeninges (Fig. 12.10). The lesions extend from the pial surface through the cerebral cortex and into the white matter. The affected neurons, glia, and endothelial cells tend to have slightly hypereosinophilic cytoplasm. Many of the nuclei are pyknotic or disintegrating; others contain homogeneous eosinophilic inclusions (Fig. 12.10), some surrounded by an irregular rim of condensed marginated chromatin. Clumps of eosinophilic inclusion material may also be visible in the cytoplasm. Inclusions are usually best seen in cells towards the edge of lesions.

Most lesions are usually at a more advanced stage, containing sheets of necrotic cells, foci of hemorrhage, and an intense perivascular and interstitial infiltrate of lymphocytes and macrophages (Fig. 12.11). There may be neuronophagia and, later, microglial nodules. Nuclear inclusions are sparse at this stage.

Herpesvirus nucleocapsid particles are approximately 100 nm in diameter and may be seen within the nuclei of infected cells by electron microscopy (Fig. 12.12). Viral antigen is readily demonstrable by immunohistochemistry (Fig. 12.13) for up to approximately 3 weeks after the onset of encephalitis, and viral DNA can be detected in frozen or paraffin sections by in situ hybridization (Fig. 12.14) or polymerase chain reaction (PCR) amplification with suitable primers.

Chronic phase

In long-term survivors of untreated or unsuccessfully treated herpes encephalitis, affected parts of the brain are shrunken and cavitated and show yellow-brown discoloration (Fig. 12.15).

The normal gray and white matter is replaced by cavitated glial scar tissue (Fig. 12.15). Occasional clusters of lymphocytes are still seen in the meninges and brain parenchyma (Fig. 12.15).

Although virus is no longer demonstrable by culture, electron microscopy, or immunohistochemistry, in most cases viral DNA is readily detectable, even in paraffin-embedded material, by PCR. It should be noted, however, that on using highly sensitive nested PCR techniques, very small amounts of herpesvirus DNA have been detected in apparently normal brain tissue.