Varicella-zoster virus infections of the Nervous system: Clincal and pathologic correlates

Archives of Pathology & Laboratory Medicine,  Jun 2001  by Kleinschmidt-DeMasters, B K,  Gilden, Donald H

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* Background.-Diseases that present with protean manifestations are the diseases most likely to pose diagnostic challenges for both clinicians and pathologists. Among the most diverse disorders caused by a single known toxic, metabolic, neoplastic, or infectious agent are the central and peripheral nervous system complications of varicellazoster virus (VZV).

Methods.-The pathologic correlates of the neurologic complications of VZV infection, as well as current methods for detecting viral infections, are discussed and presented in pictorial format for the practicing pathologist.

Results.-Varicella-zoster virus causes chickenpox (varicella), usually in childhood; most children manifest only mild neurologic sequelae. After chickenpox resolves, the virus becomes latent in neurons of cranial and spinal ganglia of nearly all individuals. In elderly and immunocompromised individuals, the virus may reactivate to produce shingles (zoster). After zoster resolves, many elderly patients experience postherpetic neuralgia. Uncommonly, VZV can spread to large cerebral arteries to cause a spec

trum of large-vessel vascular damage, ranging from vasculopathy to vasculitis, with stroke. In immunocompromised individuals, especially those with cancer or acquired immunodeficiency syndrome, deeper tissue penetration of the virus may occur (as compared with immunocompetent individuals), with resultant myelitis, small-vessel vasculopathy, ventriculitis, and meningoencephalitis. Detection of the virus in neurons, oligodendrocytes, meningeal cells, ependymal cells, or the blood vessel wall often requires a combination of morphologic, immunohistochemical, in situ hybridization, and polymerase chain reaction (PCR) methods. The PCR analysis of cerebrospinal fluid remains the mainstay for diagnosing the neurologic complications of VZV during life.

Conclusions.-Varicella-zoster virus infects a wide variety of cell types in the central and peripheral nervous system, explaining the diversity of clinical disorders associated with the virus.

(Arch Pathol Lab Med. 2001;125:770-780)

The recognition of patterns of symptoms and signs in patients is essential to the practice of clinical medicine. Pattern recognition also forms the basis for the visually-based specialty of anatomic pathology. Clinicians selectively obtain corroborating laboratory information after formulating a differential diagnosis. Similarly, in the morphologically based disciplines of autopsy and surgical pathology, the pathologist must recognize patterns of disease to narrow the differential diagnosis and to select the tests or additional stains most likely to be informative.

Varicella-zoster virus (VZV), an alpha herpesvirus found exclusively in humans, can cause a wide spectrum of disorders throughout the lifetime of the individual.1-3 Varicella-zoster virus causes an acute febrile exanthamous illness (varicella or chickenpox), usually in childhood. After chickenpox resolves, VZV becomes latent in neurons of cranial and spinal ganglia of nearly all individuals with no corresponding morphologic consequences. In elderly and immunocompromised individuals, VZV may reactivate to produce a dermatomal rash and radicular pain (zoster or shingles). Rarely, VZV reactivates and causes pain without rash (zoster sine herpete). After zoster resolves, many elderly patients experience severe persistent pain (postherpetic neuralgia). Varicella-zoster virus can also spread to the large cerebral arteries, usually in immunocompetent and occasionally in immunocompromised individuals, to produce a spectrum of large-vessel vascular damage, ranging from vasculopathy to vasculitis, with stroke. In immunocompromised patients, particularly those with cancer or the acquired immunodeficiency syndrome (AIDS), VZV spreads not only to arteries, but also to the central nervous system (CNS), with varying tissue penetration of the spinal cord (myelitis) and brain (small-vessel vasculopathy). Depending on infection of oligodendrocytes, ovoid mixed ischemic and demyelinative lesions may be seen at any level of the neuraxis. Rarely, VZV infection in immunocompromised patients produces lesions that predominantly affect the meninges (meningoencephalitis) or ependyma (ventriculitis).

Detection of the presence of the virus often requires a combination of morphologic, immunohistochemical, in situ hybridization, and polymerase chain reaction (PCR) methods.4-7 Given that the virus may be difficult to document in tissues in association with VZV-associated complications, it is not surprising that the recognition of the patterns of disease caused by VZV has been challenging.4 Patients often come to biopsy, or especially autopsy, without clinical suspicion of VZV-induced disease. Pathologists must recognize these varied patterns of disease caused by the virus and pursue the correct definitive tests.

CHICKENPOX (VARICELLA)

Patients in the United States usually become infected with VZV in childhood when they develop acute varicella or chickenpox. Humans are the only reservoir for the virus. In temperate climates, this highly contagious virus has a seasonal prevalence in winter and spring.1 Chickenpox is associated with a widespread vesicular exanthema that occurs without respect to dermatomal distribution (Figure 1) and has been well recognized by parents and pediatricians alike for more than 100 years. An effective vaccine has been developed and, if widespread vaccination programs are implemented and continued in the United States, uncomplicated chickenpox may become a rare infectious disease seldom encountered by a new generation of patients and clinicians. Central nervous system complications are estimated to occur in less than 1% of cases of chickenpox, and even this low number may be an overestimate.2 Many children have only mild neurologic sequelae, with headache, photophobia, and neck stiffness, consistent with mild meningitic symptoms. Cerebellar ataxia is one of the most common neurologic abnormalities, and very rarely, transverse myelitis has been reported.2