Case 4 -
West Nile Rhombenencephalitis (confirmed by PCR testing of blood and brain)
Gregory N. Fuller
Anderson Cancer Center
Click on each slide thumbnail image for an enlarged view
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)
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
- Newman W, Southam CM. Virus treatment in advanced cancer: a pathological study of fifty-seven
cases. Cancer 7:106-118, 1954.
- Southam CM, Moore E. Induced virus infections in man by the Egypt isolates of West Nile virus. Am J
Trop Med Hyg 3:19-50, 1954.
- Nash D, Mostashari F, Fine A, Miller J, et al. The outbreak of West Nile Virus infection in the New
York City area in 1999. N Engl J Med 2001;344:1807-14.
- West Nile Virus Activity-----United States, October 24-30, 2002. MMWR Morb Mortal Wkly Rep
- Public Health Dispatch: Investigations of west Nile Virus infections in recipients of blood
transfusions. MMWR Morb Mortal Wkly Rep 2002;51:973-4.
- West Nile Virus Infection in organ donor and transplant recipients—Georgia and Florida, 2002. MMWR
Morb Mortal Wkly Rep 2002;51:790
- Investigations of West Nile virus infections in recipients of organ transplantation and blood
transfusion—Michigan, 2002. MMWR Morb Mortal Wkly Rep 2002;51:879.
- Olejnik E. Infectious adenitis transmitted by Culex molestus. Bull of
the Research Council of Israel 1952;2:210-1
- Goldblum N, Sterk VM, Paderski B. The clinical features of the disease and the isolation of West Nile
virus from the blood of nine human cases. Am J Hygiene 1954;59:89-103.
- Campbell LG, Marfin AA, Lanciotti RS and Gubler DJ. West Nile Virus. Lancet Inf Dis 2002;2:519-29.
- Mostashari F, Bunning ML, Kitsutani PT, Singer DA, et al. Epidemic West Nile Encephalitis, New York
1999: results of a household-based seroepidemiological survey. Lancet 2001;358:261-4.
- 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.
- 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.