We report the first case of West Nile virus (WNV) encephalitis in which the only MRI abnormality during the initial phase of the infection was restriction in water mobility observed on diffusion-weighted imaging (DWI). The potential impact of hyperacute DWI in WNV encephalitis is discussed.
Case report.
A 58-year-old woman, 2 years after liver transplantation and taking 1.5 g mycophenolate mofetil and 200 mg cyclosporine daily, was admitted with fever and myoclonic jerks. Admission CSF revealed 58 cells (18 neutrophils and 17 lymphocytes), glucose 80 mg/100 mL, and protein 60 mg/100 mL. Serum virology shell vial assay for cytomegalovirus, varicella zoster, and herpes simplex, and viral tube culture were negative. Serum hemagglutinin inhibition for WNV antibodies (immunoglobulin [Ig] G and IgM) was negative on admission and days 7, 12, and 19 (titers <1:10 at the Ontario Ministry of Health Laboratory), becoming positive on day 36 with titers ≥1:2,560. Serum plaque reduction neutralization was also positive at 1:160 (Zoonotic Diseases and Special Pathogens Section, National Microbiologic Laboratory, Winnipeg, Canada). Noncontrast CT on day 4 was normal. MR examinations at 1.5 T on days 5 and 13 included T1- (pregadolinium and postgadolinium) and T2-weighted sequences, fluid-attenuated inversion recovery (FLAIR), and DWI sequence (repetition time [TR] 10,000/echo time [TE] 95, b = 1000 s/mm). Apparent diffusion coefficient (ADC) maps were calculated from the DWIs using DPTools (http://www.neuronet-software.org). Circular regions of interest (ROIs) containing 49 pixels were centered on abnormal areas in the pons and thalami. The first MRI (figure) showed questionable nonenhancing hyperintensity in the central pons, extending into the midbrain on FLAIR and DWI. There were decreased ADC values in the FLAIR and DWI hyperintense areas in the pons (0.299 ± 0.082 × 10−3 mm2/s), and normal ADC values (0.764 ± 0.048 × 10−3 mm2/s) in the thalami. New nonenhancing lesions appeared on MRI on day 13 in both thalami accompanied by extensive increased T2 signal throughout the midbrain, pons, medulla, and cerebellar hemispheres (see figure). The pons now showed increased ADC values (0.661 ± 0.074 × 10−3 mm2/s) along with the thalami (1.297 ± 0.066 × 10−3 mm2/s) (see supplementary figures on the Neurology Web site; go to www.neurology.org). Mycophenolate mofetil and cyclosporine were discontinued. The patient failed to respond to acyclovir, ribavirin, and supportive treatment and died 2 months after admission. Postmortem pathology of the brain showed meningoencephalitis with intense mononuclear inflammatory cell infiltration, reactive gliosis, tissue edema, and swollen axons in the thalami and the pons (see figure). The brainstem showed inflammation with areas of necrosis. Parenchymal and perivascular foamy macrophages were present in the deep nuclei of the thalamus and cerebellum. There was near global loss of cerebellar Purkinje cells.
Figure. Initial MRI on day 5 of hospital admission: (A) fluid-attenuated inversion recovery (FLAIR) image; (B) T2-weighted image; (C) diffusion-weighted image (DWI); and (D) apparent diffusion coefficient (ADC) map. The FLAIR and T2-weighted images were normal except for questionable increased signal in the pons. There was no enhancement on postgadolinium T1-weighted images. However, there was increased signal in the center of the pons and in the vermis on DWI. The ADC map confirms marked restriction of water diffusion especially in the central pons (low diffusion values are blue in the color scale; high values are green to red). Second MRI was performed 8 days after the first MRI. (E) Axial FLAIR image showed evolving hyperintensities in the pons and the upper part of the vermis (also seen in both thalami on higher slices). There was slight leptomeningeal enhancement on postgadolinium T1-weighted images. Histologic section through the pons using trichrome stain is shown (F). Note the inflammatory cells (dark blue nuclei) surrounding the vessels and infiltrating the brain parenchyma. Black arrow indicates a swollen axon.
Discussion.
DWI provides information on the mobility of water molecules in tissues and has become widely accepted and used for detecting acute ischemic brain injury. Highly mobile extracellular water is thought to shift into the intracellular compartment, generating “cytotoxic edema” during acute arterial stroke.1 Movement of water is more restricted in the intracellular environment, resulting in hyperintensity on DWI with low ADC values. Decreased ADC values reflect intracellular edema, and increased ADC values correspond to an increase in the extracellular space (“vasogenic edema”). Water diffusion in biologic tissue is highly dependent on the ratio of extracellular to intracellular space and is greater in the extracellular space compared with that in the intracellular space.2 DWI findings in patients with other forms of viral encephalitis, such as herpes simplex, rotaviruses, and Japanese encephalitis (which on MRI has a similar appearance and involves similar brain structures as WNV encephalitis), have highlighted the restriction in water diffusion suggesting cytotoxic edema.3–5⇓⇓ Later phases showed higher ADC values indicating conversion from cytotoxic to vasogenic edema. Alternatively, restricted diffusion may be the result of brain infiltration by inflammatory cells, leading to an increase in cellularity of tissue. The concept is similar to that proposed for low ADC values in patients with highly cellular brain tumors such as lymphoma.6 Acute demyelination can also produce a restriction in water movement7 and could explain our observations because the pons is rich in myelinated fiber tracks. Unfortunately, these features are nonspecific in terms of distinguishing viral vs ischemic or demyelinating injury.
Conclusion.
DWI with low ADC values may be an early indication of WNV encephalitis, appearing at a time when conventional MRI is virtually normal. DWI in additional patients with acute WNV is needed to confirm this. It is not known if these early MRI findings are specific to WNV infection or if they are common to other viral encephalitides as well.
Footnotes
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Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the December 23 issue to find the title link for this article.
- Received April 18, 2003.
- Accepted August 21, 2003.
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