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Perspective |
1 Department of Radiology, Wayne State University, Detroit, MI.
2 Department of Radiology, Harper University Hospital, 3390 John R, Detroit, MI
48201.
3 Department of Pathology, Wayne State University, Detroit, MI.
Received March 24, 2004; accepted after revision July 20, 2004.
Address correspondence to I. T. Zak
(izak{at}dmc.org).
OBJECTIVE. Our objective is to present a brief review of the clinical aspects of West Nile virus infection with emphasis on the spectrum of MRI findings.
CONCLUSION. West Nile virus infection has become endemic in the United States and radiologists should become aware of the diverse imaging appearances in the central nervous system.
West Nile Virus has emerged in recent years as a serious threat to human and animal health. The most serious manifestation of West Nile virus infection in humans is fatal encephalitis. West Nile virus encephalitis is on the list of designated nationally notifiable arboviral encephalitides. The timely identification of persons with acute West Nile virus or other arboviral infections may have significant public health implications and will likely augment the public health response and reduce the risk of additional human infections.
Epidemiology
West Nile virus was first isolated from a febrile adult woman in the West Nile District of Uganda in 1937 [1]. The ecology was characterized in Egypt in the 1950s. The virus became recognized as a cause of severe human meningoencephalitis in elderly patients during an outbreak in Israel in 1957. Equine disease was first noted in Egypt and France in the early 1960s. The first appearance of West Nile virus in North America was in 1999 during an outbreak in New York [2, 3]. During 1999, West Nile virus was detected in four U.S. states and resulted in 62 cases of severe encephalitis and seven deaths.
After the 1999 outbreak of West Nile virus encephalitis in New York, investigators found that West Nile virus survived in overwintering mosquitoes and the disease became endemic in northeastern New York. Female mosquitoes, which are the predominant host that hatch in late summer, can hibernate during winter and, if infected with the virus, can transmit it to their larvae the following season. Thus, the virus survived and continued to be a major endemic health problem [4].
During 2002, human infections with West Nile virus have been reported from 40 U.S. states. In 2002, the Centers for Disease Control and Prevention (CDC) reported 4,156 human cases of West Nile virus, including 284 deaths. In 2003, the CDC reported 9,862 human cases of West Nile virus, including 264 deaths.
Life Cycle and Transmission
West Nile virus is maintained in nature when an arthropod vector transmits the virus between vertebrate hosts. The primary vector for West Nile virus in the United States is the Culex pipiens mosquito that commonly breeds in urban areas and prefers to feed on birds. The main route of human infection with West Nile virus is through the bite of an infected mosquito. Mosquitoes become infected when they feed on infected birds, which may circulate the virus in their blood for a few days. The virus eventually enters the mosquito's salivary glands. Subsequently, the virus may be injected into humans and animals [5]. The virus has been detected in many wild bird species, including the American crow. Humans and other domestic animals are considered "deadend" hosts because they do not contribute to the transmission cycle (Fig. 1).
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During the 2002 West Nile virus epidemic, other methods of transmission represented a small proportion of the cases identified, including transmission through transplanted organs and through blood transfusions [6, 7]. There was one reported case of transplacental West Nile virus transmission and one suspected case of transmission through breast feeding [8, 9]. Two cases of West Nile virus infection were reported in laboratory workers [10].
Clinical Manifestations
The incubation period for the West Nile virus is thought to range from 3 to 14 days. Most West Nile virus infections are mild and often clinically unapparent [11]. It is estimated that 20% of the people who become infected will develop mild symptoms, including fever, headache, and generalized aches that last 3 to 6 days [5, 12].
It is estimated that one in 150 of patients infected with the West Nile virus will develop meningoencephalitis. Patients at higher risk of severe infections and death include the immunocompromised, elderly, and very young, with symptoms including severe headache, high fever, neck stiffness, stupor, disorientation, coma, tremors, convulsions, muscle weakness, and abnormal movements [5, 12–15]. Vitritis and chorioretinitis have been reported in patients with West Nile virus infection [16]. Some patients with West Nile virus infection present with acute flaccid paralysis similar to poliomyelitis [5, 17–19]. A minority of patients with severe disease developed a maculopapular or morbilliform rash involving the neck, trunk, arms, or legs. According to the CDC 2002 data, the mortality rate in clinically apparent cases is estimated at 7%, with most of the deaths related to complications of meningoencephalitis. Most of the patients who survive the disease will have complete recovery; however, some patients with meningoencephalitis and more commonly those with acute flaccid paralysis will require long-term rehabilitation [12].
Clinical Diagnosis
The diagnosis of West Nile virus infection is based on a high index of clinical suspicion and specific laboratory tests. West Nile virus, or other arboviral diseases such as St. Louis encephalitis, should be strongly considered in persons who develop unexplained encephalitis or meningitis in summer or early fall. Total leukocyte counts in peripheral blood are generally reported to be normal or slightly elevated with lymphocytopenia. Hyponatremia is sometimes present, particularly among patients with encephalitis.
Examination of the cerebrospinal fluid (CSF) may show pleocytosis, usually with a predominance of lymphocytes. Protein is universally elevated. Glucose is typically normal [5, 12, 15]. West Nile virus testing for patients with meningoencephalitis can be obtained through local or state health departments. The most efficient diagnostic method is detection of IgM antibody to West Nile virus in CSF) collected within 8 days of onset using the IgM antibody capture enzyme-linked immunosorbent assay (MAC-ELISA). Detection of IgM antibody in the CSF is more specific for central nervous system infection because IgM antibody does not cross the blood–brain barrier [5]. The finding that West Nile virus IgM antibody may persist in blood for up to 500 days makes testing of a single blood sample problematic [20]. Thus, acute and convalescent blood samples are necessary for confirmation.
Imaging of West Nile Virus Infection
CT has been reported as normal in most cases of West Nile virus meningoencephalitis. MRI is reported as abnormal in more than one third of cases. The imaging findings are generally nonspecific. Findings in the brain can mimic demyelinating processes including multiple sclerosis, postinfectious acute disseminated encephalomyelitis, the nonspecific white matter lesions of chronic white matter ischemia of microvascular disease, herpes, and other viral encephalitis. Findings in the spinal cord and cauda equina can mimic transverse myelitis, acute disseminated encephalomyelitis, viral myelitis, Guillian-Barre syndrome, and leptomeningeal metastatic disease.
MRI may show thickening and enhancement of the leptomeninges [21]. Patchy foci of abnormal T2 signal on spin-echo and FLAIR sequences indistinguishable from other forms of acute or chronic demyelinating processes are common findings [18, 19, 22] (Fig. 2). These lesions typically have no associated mass effect or abnormal enhancement (Fig. 3). Follow-up MRI shows complete resolution of these T2 signal abnormalities. Some patients develop symmetric T2 signal abnormalities in the brainstem, basal ganglia, and thalami (Fig. 4). On one occasion, a patient presented with seizure activity and MRI showed findings similar to herpes encephalitis; however, the T2 signal abnormalities in the medial temporal lobes typically did not cause significant mass effect and no abnormal enhancement was seen (Fig. 5). In our experience, hemorrhage has not been encountered and to our knowledge has not been reported in West Nile virus meningoencephalitis. Involvement of the spinal cord and nerve roots is seen in patients with West Nile virus infection presenting with acute flaccid paralysis [22]. MRI shows discrete foci of T2 signal abnormality in the spinal cord and these findings mimicked the features of transverse myelitis in one patient (Fig. 6). Thickening and abnormal enhancement of the cauda equina are also seen (Figs. 7A and 7B).
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It appears that the temporal changes of West Nile virus infection may be altered in immunocompromised patients. A case of progressive West Nile virus encephalitis in a patient with leukemia was described (Buttman JA, 2002 Radiological Society of North America meeting). We encountered progressive West Nile virus infection in one patient with AIDS. This patient was previously stable on anti-HIV medications and presented to the emergency department with changes in mental status. Initial hematologic and laboratory investigations were normal. CSF analysis was reported negative for known HIV pathogens, but serology for West Nile virus was confirmed as positive. MRI study of the brain showed symmetric T2 signal abnormalities in the thalami and cerebral peduncles (Fig. 8A). Four weeks later, a repeat brain MRI examination showed complete resolution of the T2 signal abnormalities in the thalami and midbrain with interval development of new symmetric T2 signal abnormalities in the dentate nuclei (Fig. 8B). A few days later, the patient died of probable progressive West Nile virus meningoencephalitis complicating existing HIV infection. An altered appearance and behavior of West Nile virus infection in HIV patients is not unique. A similar phenomenon has been described in immunocompromised patients with herpes encephalitis.
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Diffusion-weighted imaging has been as reported useful in the imaging of West Nile virus encephalitis. Only two of our patients had a diffusion MRI sequence included as part of the initial study. In one patient, foci of restricted diffusion corresponded to the existing T2 signal abnormalities and thus was considered T2 shine-through. In another patient, a diffusion signal abnormality was reported out of proportion to the existing T2 signal abnormality (Figs. 9A and 9B). It is likely that diffusion-weighted imaging may help in the early detection of encephalitis and before the development of T2 signal abnormality on conventional MRI [23].
Pathology
A report of four autopsies performed on patients who died of West Nile virus encephalitis has been published by the Chief Medical Examiner of New York City. The fatalities occurred during the 1999 epidemic. Autopsy disclosed encephalitis in two instances and meningoencephalitis in the other two. The inflammation was mostly mononuclear and formed microglial nodules and perivascular clusters in the white and gray matter. The brainstem, particularly the medulla, was involved most extensively. In two cases, the cranial nerve roots had endoneural mononuclear inflammation [24].
Treatment
Treatment is supportive, often involving hospitalization, IV fluids, respiratory support, and prevention of secondary infections for patients with severe disease. Ribavirin in high doses and interferon alfa-2b were found to have some activity against West Nile virus in vitro [25], but no controlled studies have been completed on the use of these or other medications, including steroids, antiseizure medications, or osmotic agents in the management of West Nile virus encephalitis.
Disease control relies heavily on public education and organized, sustained mosquito vector control.
People who survive West Nile virus infection are assumed to develop a lifelong immunity. There is no scientific evidence of recurrent or chronic West Nile virus infection. A vaccine of limited value has been developed for horses. No vaccine has yet been developed for human use [26].
References
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