—  SPECIALTY CONFERENCE  —

Neuropathology

Case 4 - West Nile Rhombenencephalitis (confirmed by PCR testing of blood and brain)

Gregory N. Fuller
Anderson Cancer Center
Houston, Texas


Click on each slide thumbnail image for an enlarged view
Clinical History:
In the late summer of 2002, a 71-year-old man with a history of myelodysplasia five months out from a matched unrelated donor stem cell transplant developed progressively increasing weakness and was noted to have a fever of 38.3 ° C. The patient had been receiving regular blood product transfusions for anemia and thrombocytopenia. He was admitted to an outside hospital for presumed infection and was started on multiple antibiotics. Following several family-witnessed seizure-like episodes the patient was started on phenytoin and transferred to MDACC. Upon admission, an EEG showed marked diffuse generalized slowing that was non-reactive to exogenous stimulation, consistent with severe encephalopathy. An MRI showed multiple bright signal intensities on T2-weighted and FLAIR sequences throughout the brain stem, including the medulla, pons and midbrain. Lumbar puncture showed normal glucose with elevated protein (147 mg per deciliter). A Gram stain for bacteria, India ink preparation for cryptococcus and bacterial cultures were negative. Serum samples were sent to the CDC for viral pathogen PCR testing. The patient developed progressive liver failure, attributed to graft-versus-host disease, and became increasingly obtunded. He died one week after admission and an autopsy was performed.

Diagnosis - West Nile Rhombenencephalitis (confirmed by PCR testing of blood and brain)


Case 4 - Figure 1 - West Nile Encephalitis. Although non-specific, the most distinctive morphologic feature of West Nile encephalitis is the microglial nodule. At the low scanning magnification shown here (40x), a microglial nodule is recognized as a localized area of hypercellularity in an otherwise evenly distributed neuropil, inviting closer inspection. (H&E)
Case 4 - Figure 2 - West Nile Encephalitis. At higher magnification (100x), microglial nodules consist of a heterogeneous mixture of cellular elements, including microglia, reactive astrocytes and lymphocytes. Microglial nodules can be seen in both the gray matter and the white matter in West Nile encephalitis. (H&E)


Case 4 - Figure 3 - West Nile Encephalitis. Some microglial nodules incorporate degenerating neurons and, occasionally, frank neuronophagia. (H&E, 100x)
Case 4 - Figure 4 - West Nile Encephalitis. Perivascular lymphocytic infiltrates are also commonly seen in West Nile encephalitis. (H&E, 100x)

Discussion
West Nile Virus (WNV) is a single stranded RNA virus of the family Flaviviridae(which also includes the yellow fever, dengue fever, Japanese encephalitis and St. Louis encephalitis viruses). The virus has long been endemic in many countries in Africa, Asia and Europe (the name stems from an outbreak in Egypt from which the index strain, Egypt 101, was isolated), and summertime epidemics, as are now being seen in the United States, were first recognized in Israel in 1950. Transmission to humans occurs primarily through mosquito vectors, although iatrogenic cases transmitted via transfusion and transplantation are increasingly recognized. The earliest iatrogenic cases were deliberate inoculations of the virus (Egypt 101) into cancer patients performed as a therapeutic trial.1,2  The viral transmission cycle principally involves a migratory bird reservoir, with humans and other mammals, such as horses, serving only as incidental hosts.

WNV initially appeared in the United States in 1999 with an epidemic of meningoencephalitis in New York.3  With each ensuing annual active mosquito season (late summer), WNV has spread progressively westward from the east coast. This pattern of spread is directly attributable to the migration routes of the avian hosts. The number of human cases of WNV infection in the United States reported in 2002 (as of October) to the Centers for Disease Control and Prevention (CDC) was 3,419, with 180 deaths.4  At least thirty-three cases of possible blood transfusion-related WNV infection are under investigation by the CDC.3  The CDC has also confirmed transmission of WNV through organ transplantation (6,7).

The incubation period for WNV ranges from 3 to 14 days.8,9  The clinical features are varied, with most infections being completely asymptomatic. In the 1999 New York City epidemic, it is estimated that 20% of persons infected with the WNV developed fever.3  Clinically symptomatic WNV usually presents with sudden onset of fever, headache, and myalgia, and gastrointestinal symptoms (nausea, vomiting, stomach pain) are a common accompaniment. In typical cases, the acute phase of the disease lasts for less than a week with rapid full recovery. A generalized rosealor or maculopapular rash of the chest, back and upper extremities, together with generalized lympadenopathy, is seen in up to 50% of patients .10  Severe neurologic disease in WNV infection is uncommon with only approximately 1 in 150 resulting in meningitis or encephalitis.11  Neurologic disease varies from headache to coma and a flaccid paralysis closely resembling poliomyelitis occurs in approximately 10% of cases with neurologic symptoms .3  The risk factor most clearly associated with encephalitis and death is age. In the New York study, an age of 75 years or older was associated with significantly higher incidence of encephalitis and death .3  Therapy for WNV infection is essentially supportive. Antiviral agents such as ribavirin and interferon alpha are effective in decreasing viral replication in vitro but data regarding their clinical efficacy is lacking.

The primary histologic hallmarks of West Nile infection of the central nervous system are non-specific: microglial nodules and perivascular lymphocytic infiltrates. The leptomeninges and nerve roots can also show lymphocytic infiltrates. Similar features to those observed in West Nile encephalitis can be seen in a number of other pathologic conditions, such as other viral infections, hypoxia, and paraneoplastic encephalitis. In autopsy series of patients dying from West Nile infection, the brain stem, in particular the medulla, often shows the most prominent microglial activation 12 and rhombenencephalitis is a common neuroimaging presentation. Definitive diagnosis can be made by PCR testing of blood, CSF or, at autopsy, brain. Historically, autopsy studies were critical in the initial identification of West Nile virus as the causative agent in the New York City outbreak of 1999.13 

References

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  4. West Nile Virus Activity-----United States, October 24-30, 2002. MMWR Morb Mortal Wkly Rep 2002;51:974-5.
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  7. Investigations of West Nile virus infections in recipients of organ transplantation and blood transfusion—Michigan, 2002. MMWR Morb Mortal Wkly Rep 2002;51:879.
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  12. Sampson BA, Ambrosi C, Charlot A, Reiber K, Veress JF, Armbrustmacher V. The pathology of human West Nile infection. Hum Pathol 31:527-531, 2000.
  13. Shieh WJ et al. The role of pathology in an investigation of an outbreak of West Nile encephalitis in New York, 1999. Emerg Infect Dis 6:370-372, 2000.