Nipah Virus Encephalitis: Serial MR Study of an Emerging Disease1

¹ From the Departments of Neuroradiology (C.C.T.L., Y.Y.S., F.H.) and Neurology (K.E.L., W.L.L.), National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore; Department of Medicine, National University Hospital, Singapore (P.A.T.); Department of Infectious Disease, Tan Tock Seng Hospital, Singapore (C.C.L.); Department of Neurology, Singapore General Hospital (A.P.A.); and Department of Radiology, Changi General Hospital, Singapore (B.K.M.L.). From the 2000 RSNA scientific assembly. Received February 21, 2001; revision requested April 9; revision received May 16; accepted June 20. Supported in part by National Medical Research Council grant NMRC/NRN99/005. 

	ABSTRACT

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PURPOSE: To report the serial magnetic resonance (MR) imaging findings of the Nipah virus.

MATERIALS AND METHODS: Twelve patients underwent serial MR imaging. Eight patients were examined at the outbreak; 11, at 1 month; and seven, at 6 months. Contrast material–enhanced MR images, diffusion-weighted images, and single-voxel proton MR spectroscopic images were reviewed. Clinical and neurologic assessment, as well as analysis of the size, location, and appearance of brain lesions on MR images, were performed.

RESULTS: During the outbreak, all eight patients had multiple small foci of high signal intensity within the white matter on T2-weighted images. In six patients, cortical and brain stem lesions were also detected, and five patients had diffusion-weighted MR imaging–depicted hyperintensities. One month after the outbreak, five patients had widespread tiny foci of high signal intensity on T1-weighted images, particularly in the cerebral cortex. Diffusion-weighted images showed decreased prominence or disappearance of lesions over time. There was no evidence of progression or relapse of the lesions at 6-month follow-up. MR spectroscopy depicted reduction in N-acetylaspartate–to-creatine ratio and elevation of choline-to-creatine ratios.

CONCLUSION: The Nipah virus has findings unlike other viral encephalitides: small lesions that are primarily within the white matter, with transient punctate cortical hyperintensities on T1-weighted images.

　

Index terms: Brain, MR, 13.121411, 13.121412, 13.121413, 13.121415, 13.141416, 13.12143, 13.12144, 13.12145 • Encephalitis, 13.253

	INTRODUCTION

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An epidemic of fatal infectious encephalitis occurred among pig farmers in Malaysia in 1998–1999 (1). In Singapore, where live pigs are imported from Malaysia, the 1999 outbreak affected workers at a pig slaughterhouse (2–7). Although initially it was suspected to be Japanese encephalitis, the cause was later found to be a previously unknown member of the Paramyxoviridae family, named the Nipah virus (8–10). The emergence of a severe pig-borne (11,12) encephalitis with a high mortality rate (10,13) has caused a great deal of interest (14–19) (Tambyah PA, personal communication, 1999), and information is still being collected on this disease.

The Nipah virus is taxonomically related to the Hendra virus (9,20,21), another newly isolated paramyxovirus responsible for the disease in humans and horses in Australia (22–25). There has been a case report of delayed fatal reactivation after the Hendra virus outbreak (23). More recently, neurologic relapse and late-onset encephalitis have also been reported (10,26) in Malaysian patients with the Nipah virus. The purpose of this study was to report the serial magnetic resonance (MR) imaging findings of the Nipah virus.

	MATERIALS AND METHODS

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Twelve patients (11 men, one woman; age range, 24–65 years; mean age, 44.5 years) were examined. Ten pig slaughterhouse workers in Singapore and two Malaysian pig farmers (one man and one woman) were included on the basis of epidemiologic and clinical diagnoses. Serologic confirmation was obtained with an enzyme-linked immunosorbent assay by using a protocol developed by the Centers for Disease Control in Atlanta, Ga (2).

All MR studies were performed with 1.5-T MR clinical imagers during the initial outbreak (1–12 days of hospital stay), at 1 month (19–39 days), and at 6 months (179–197 days). The pulse sequences were as follows: transverse T1 weighted (repetition time msec/echo time msec, 400–600/12–14) and fast spin-echo T2 weighted (3,500–5,400/83–105 ), transverse and/or coronal fluid-attenuated inversion recovery, or FLAIR (9,000/110, inversion time of 2,500 msec), and gradient echo (740–980/25–40, 20° flip angle). Contrast material–enhanced sequences with 0.1 mmol of intravenously administered gadolinium-based contrast material (Magnevist, Schering, Berlin, Germany; or Omniscan, Nycomed, Oslo, Norway) per kilogram of body weight were performed in three planes. All images in all sequences were 5-mm thick with a spacing of 2 or 3 mm. For studies performed during the acute outbreak and at 1 month, a variety of pulse sequences were performed at different hospitals and included at least transverse T1- and T2-weighted sequences. At 6 months, imaging protocols were standardized and performed at one center. Institutional review board approval and informed consent were obtained for our study.

Diffusion-weighted MR imaging was performed by using single-shot spin-echo echo-planar sequences (8,000–10,000/105–173). Diffusion-sensitizing gradients were applied in three orthogonal planes with a b factor of 750 and 1,000 sec/mm². The isotropic diffusion-weighted MR images were reviewed. Apparent diffusion coefficients (ADCs) were calculated by means of a logarithmic subtraction by using semiautomated software (Functool; GE Medical Systems, Milwaukee, Wis). Some diffusion-weighted MR studies were not analyzed due to software incompatibility. The largest lesion that was visible on diffusion-weighted MR images was selected, and the region of interest was compared with an equivalent contralateral normal-appearing region of interest (21–32 mm², placed by C.C.T.L.). The results of ADC calculations were displayed as both an ADC and a percentage of contralateral normal brain.

Proton MR spectroscopy was performed by using a single-voxel with point-resolved spectroscopic, or PRESS, sequence with automated water and fat suppression (PROBE/SV; GE Medical Systems). Data were acquired (500–2,000/144) with eight signals. Semiautomated software was used to calculate N-acetylaspartate (at 2.02 ppm)-to-creatine (at 3.0 ppm) ratio (NAA/Cr) and choline (at 3.2 ppm)-to-Cr ratios (Cho/Cr). The largest lesion on T2-weighted images was selected. The maximum voxel dimensions were 2 x 2 x 2 cm to decrease partial volume averaging by normal tissue.

A total of 26 studies in 12 patients were reviewed. Eight patients were examined during the outbreak; 11, at 1 month; and seven, at 6 months. Twenty-five studies—seven at the outbreak, 11 at 1 month, and seven at 6 months—included contrast-enhanced sequences. Twenty-two studies—six during the outbreak, nine at 1 month, and seven at 6 months—included diffusion-weighted MR images. Sixteen studies—two during the outbreak, seven at 1 month, and seven at 6 months—included MR spectroscopic examinations. All serial studies performed in each patient were analyzed at the same reading by four experienced neuroradiologists and radiologists (C.C.T.L., B.K.M.L., Y.Y.S., F.H.) with consensus. The number, location, and appearance of each lesion on each pulse sequence were evaluated. The clinical and neurologic findings at outbreak, 1 month, and 6 months were assessed by the attending physicians (K.E.L., W.L.L., P.A.T., C.C.L., A.P.A.).

	RESULTS

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The clinical and radiologic features are summarized in the Table.

fig.ommitted  Summary of Clinical and Serial MR Findings of Nipah Virus Encephalitis

 
Acute Outbreak
During the outbreak, eight patients underwent MR imaging. All eight studies showed multiple small lesions smaller than 1 cm in the cerebral white matter (Fig 1), including the corpus callosum and internal and external capsules. In six patients, lesions were also detected in the cortex, pons, and cerebellar peduncle. All lesions were hyperintense on T2-weighted or FLAIR images, and some (28 lesions in four patients) were enhanced after contrast material administration.

fig.ommitted  Figure 1a. Patient 2. (a) Transverse T2-weighted image (4,000/84 ) obtained during acute infection shows multiple white matter foci of high signal intensity (arrowheads show some) within the cerebral white matter. (b) Transverse diffusion-weighted image (10,000/95; b factor, 1,000 sec/mm2) shows only the largest lesion (arrowhead) to be hyperintense. Calculated ADC is 0.442 x 10-3 mm2/sec. (c) Transverse T1-weighted MR image (540/14) obtained at 1 month shows multiple punctate hyperintensities (arrowheads show some) in the cerebral cortex. These lesions completely disappeared 6 months after the outbreak (not shown).

 

fig.ommitted    Figure 1b. Patient 2. (a) Transverse T2-weighted image (4,000/84 ) obtained during acute infection shows multiple white matter foci of high signal intensity (arrowheads show some) within the cerebral white matter. (b) Transverse diffusion-weighted image (10,000/95; b factor, 1,000 sec/mm2) shows only the largest lesion (arrowhead) to be hyperintense. Calculated ADC is 0.442 x 10-3 mm2/sec. (c) Transverse T1-weighted MR image (540/14) obtained at 1 month shows multiple punctate hyperintensities (arrowheads show some) in the cerebral cortex. These lesions completely disappeared 6 months after the outbreak (not shown).

 

fig.ommitted  Figure 1c. Patient 2. (a) Transverse T2-weighted image (4,000/84 ) obtained during acute infection shows multiple white matter foci of high signal intensity (arrowheads show some) within the cerebral white matter. (b) Transverse diffusion-weighted image (10,000/95; b factor, 1,000 sec/mm2) shows only the largest lesion (arrowhead) to be hyperintense. Calculated ADC is 0.442 x 10-3 mm2/sec. (c) Transverse T1-weighted MR image (540/14) obtained at 1 month shows multiple punctate hyperintensities (arrowheads show some) in the cerebral cortex. These lesions completely disappeared 6 months after the outbreak (not shown).

 
Six of eight patients underwent initial diffusion-weighted MR imaging, and five of them had small hyperintense lesions (Fig 1). These represented the larger lesions in the white matter (n = 16) and cortex (n = 1); lesions smaller than 3 mm on T2-weighted images were not visible on diffusion-weighted MR images. ADC analysis in four patients (ADC analysis software was not compatible for one patient) showed restricted ADC (0.442–0.686 x 10^-3 mm²/sec) compared with the contralateral normal tissue (69%–95%).

One Month after Outbreak
One patient died. All 11 surviving patients underwent MR examination: seven underwent serial studies at acute outbreak and at 1 month, and four were examined only at 1 month. In the latter group, small hyperintense lesions were detected on T2-weighted images in the white matter, cortex, and brain stem, some with contrast enhancement.

Among the seven patients who were examined at outbreak and at 1 month, the lesions on T2-weighted images were unchanged in size and distribution. However, in five patients, a multitude (n = 112) of new hyperintense lesions were detected with T1-weighted sequences. These lesions occurred mainly in the cerebral cortex (Fig 1), but a few were found in the white matter (n = 25) (Fig 2), pons and/or cerebellum (n = 5), and putamen and/or thalamus (n = 3). The majority were small 1–2-mm hyperintensities, and only two were laminar, along the cortical gyri (Fig 3). The lesions were not hypointense with spin-echo sequences, but with T2*-weighted gradient-echo sequences performed in three patients, two hypointense lesions were detected in the cerebellar peduncle and putamen in patients 7 and 9, respectively.

fig.ommitted  Figure 2a. Patient 9. (a) Transverse T2-weighted image (4,000/84 ) obtained at 1 month shows multiple bilateral hyperintensities (arrowheads show some) in the cerebral white matter. Many of the lesions seen on transverse T2-weighted images are visible as small areas of high signal intensity on (b) T1-weighted image (540/14).

 

fig.ommitted  Figure 2b. Patient 9. (a) Transverse T2-weighted image (4,000/84 ) obtained at 1 month shows multiple bilateral hyperintensities (arrowheads show some) in the cerebral white matter. Many of the lesions seen on transverse T2-weighted images are visible as small areas of high signal intensity on (b) T1-weighted image (540/14).

 

fig.ommitted  Figure 3a. Patient 6. (a) Transverse T2-weighted fast spin-echo image (5,400-105 ) obtained during acute outbreak shows a cortical lesion (arrow). (b) Transverse T1-weighted image (560/12) obtained 1 month later shows the lesion as a linear cortical hyperintensity (arrow). Scattered hyperintensities (arrowhead shows some) are also visible in the left frontal cortex. These lesions were not visible on T2-weighted images.

 

fig.ommitted  Figure 3b. Patient 6. (a) Transverse T2-weighted fast spin-echo image (5,400-105 ) obtained during acute outbreak shows a cortical lesion (arrow). (b) Transverse T1-weighted image (560/12) obtained 1 month later shows the lesion as a linear cortical hyperintensity (arrow). Scattered hyperintensities (arrowhead shows some) are also visible in the left frontal cortex. These lesions were not visible on T2-weighted images.

 
Nine diffusion-weighted MR studies were performed at 1 month. Only one patient had a single residual lesion with decreased ADC (0.577 x 10^-3 mm²/sec). Three other patients showed faint hyperintensities, but ADC analysis data available in two patients revealed normal or slightly elevated values, compared with the values in the contralateral normal brain.

Six Months after Outbreak
Of the 11 surviving patients, one was lost to follow up, four were well without neurologic sequelae, and six had residual neurologic symptoms. Seven patients who presented for repeat MR examination showed no new lesions on conventional or diffusion-weighted MR images. Most of the lesions were smaller or were not seen, and all but one lesion had resolved at contrast-enhanced imaging.

Of the four patients with T1 lesions detected at 1 month and examined again at 6 months, three showed complete disappearance of the punctate hyperintensities, but in patient 6, eight small lesions were still visible. Gradient-echo sequences performed in all seven patients enabled better visualization of or depicted no change to the two existing hypointense lesions in patients 7 and 9. Three additional hypointensities were detected in the cortex (Fig 4), cerebellar peduncle, and pons.

fig.ommitted  Figure 4a. Patient 7. (a) Transverse T2-weighted fast spin-echo image (4,800/84 ) obtained 1 month after the outbreak shows lesions in the frontal cortex (arrow) and putamen (arrowhead). (b) Transverse T1-weighted image (580/14) at the same position as in a shows a faintly hyperintense ring in the cortical lesion (arrow) but not in the putamen. The lesion was not hypointense on the gradient-echo image. (c) Transverse T2*-weighted gradient-echo image (740/25, 20° flip angle) obtained at 6 months shows that the lesion (arrowhead) has become hypointense.

 

fig.ommitted  Figure 4b. Patient 7. (a) Transverse T2-weighted fast spin-echo image (4,800/84 ) obtained 1 month after the outbreak shows lesions in the frontal cortex (arrow) and putamen (arrowhead). (b) Transverse T1-weighted image (580/14) at the same position as in a shows a faintly hyperintense ring in the cortical lesion (arrow) but not in the putamen. The lesion was not hypointense on the gradient-echo image. (c) Transverse T2*-weighted gradient-echo image (740/25, 20° flip angle) obtained at 6 months shows that the lesion (arrowhead) has become hypointense.

 

fig.ommitted Figure 4c. Patient 7. (a) Transverse T2-weighted fast spin-echo image (4,800/84 ) obtained 1 month after the outbreak shows lesions in the frontal cortex (arrow) and putamen (arrowhead). (b) Transverse T1-weighted image (580/14) at the same position as in a shows a faintly hyperintense ring in the cortical lesion (arrow) but not in the putamen. The lesion was not hypointense on the gradient-echo image. (c) Transverse T2*-weighted gradient-echo image (740/25, 20° flip angle) obtained at 6 months shows that the lesion (arrowhead) has become hypointense.

 
MR Spectroscopy
Sixteen MR spectroscopic studies were performed, two of which were unsuccessful due to insufficient signal from a small voxel size. During the acute outbreak, only two patients underwent imaging with clinical units capable of performing MR spectroscopy. Decreased NAA (NAA/Cr, 1.75–1.85) and elevated Cho peaks (Cho/Cr, 1.15–1.42) were detected. There was no discernible inverted lactate doublet at 1.33 ppm at chemical shift imaging. At 1 month, a similar pattern was found in six patients, the mean values of NAA/Cr and Cho/Cr were 1.57 and 1.33, respectively. The ratios at 6 months were 2.10 and 1.31, respectively.

	DISCUSSION

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The Japanese encephalitis virus was initially thought to be responsible for the encephalitis epidemic among pig workers in Malaysia and Singapore (1). MR imaging performed in patients affected by the Singapore outbreak revealed a pattern of multiple, small, T2-hyperintense, white matter lesions. These findings were not characteristic of Japanese encephalitis, which typically affects the thalami and basal ganglia, sometimes with hemorrhagic transformations (27). This led to a suspicion that some other pathogen was responsible for the outbreak (7). Subsequent isolation of a new Hendra-like paramyxovirus confirmed these suspicions (3,9).

During acute infection, some of the white matter lesions were hyperintense on diffusion-weighted MR images, with restricted diffusion. Diffusion-weighted MR imaging, which is capable of depicting cytotoxic edema within minutes of onset, has been useful in the clinical assessment of acute cerebral infarction (28–30). Although few authors have reported restricted diffusion that results in hyperintense lesions at diffusion-weighted MR imaging in cerebral abscesses (31–34) and viral encephalitis (35–37), there is a paucity of literature about diffusion-weighted MR imaging of intracranial infection. Despite this, diffusion-weighted MR imaging was useful in our study patients during the initial outbreak. On T2-weighted images, small white matter hyperintensities may be due to a variety of causes and may be seen even in patients who are neurologically healthy (38,39). However, in the patients in our study, the conspicuous abnormalities seen on diffusion-weighted MR images and supported by contrast enhancement suggested that viral infection was responsible and that these were not preexisting lesions.

Postmortem studies performed during the outbreak in Malaysia showed endothelial damage and syncytium formation, which led to thrombotic obstruction of small blood vessels in the central nervous system (8,40). Lack of correlation between clinical and radiologic findings, particularly the paucity of cerebellar lesions at MR imaging, has also been observed (5,26). These findings have led to the postulation that microinfarction from vasculitis-induced thrombosis may be responsible for at least some of the MR findings (7,26), particularly in the deep cerebral white matter that is supplied by vulnerable end arteries (41,42). As more studies with diffusion MR imaging are conducted, the nature and importance of cytotoxic edema detected in cerebral infection may become clearer.

Multiple transient T1 hyperintensities, primarily in the cerebral cortex, were seen 1 month after infection. This finding has not, to our knowledge, been seen with viral encephalitis. High-signal-intensity lesions on T1-weighted images may represent fat, methemoglobin, paramagnetic substances, calcium, or macromolecules such as proteins or mucin (43). Methemoglobin from scattered microhemorrhages may cause T1 relaxation, and the development of susceptibility effects on T2*-sensitive gradient-echo sequences would be consistent. However, in the patients in our study, susceptibility was found in only five of the T1 lesions. Even after 6 months, the majority of high-signal-intensity lesions showed no evidence of hemosiderin.

An uncommon cause of T1 hyperintensity is laminar cortical necrosis (44, 45). It is interesting to note the similarity in the time course (45) and the hypoxic ischemic mechanism between laminar cortical necrosis and T1 lesions in the patients in our study. However, white matter and cerebellar and thalamic lesions have not been seen in laminar necrosis, and only two lesions in our study patients showed a linear cortical distribution typical of cortical laminar necrosis; the majority were punctate. Without pathologic correlation, the nature of these transient hyperintense lesions on T1-weighted images remains speculative.

Semiautomated single-voxel proton MR spectroscopy is a technique for analyzing chemical metabolites in the brain. During the acute infection and 1 month after, MR spectroscopy depicted decreased NAA and elevated Cho in our study patients, with lower NAA/Cr and higher Cho/Cr values than those in the published studies in healthy populations (46). These findings are nonspecific and can be caused by a variety of abnormalities (47). There was, however, no discernible lactate detected, which might be expected from anerobic glycolysis in acute cerebral infarction, in our acute studies (48,49). Serial study at 6 months showed recovery of NAA/Cr. Our findings, however, should be interpreted with caution, because the small size of lesions that were examined resulted in partial volume contamination of the voxel by the normal tissue. This factor, together with the small numbers and lack of control spectra, prevented us from drawing firm conclusions.

Six months after the outbreak, all 10 patients continued to recover from their illness with clinical surveillance, some with residual neurologic deficits. There were no instances of acute worsening or clinical relapse of encephalitis. In the seven patients who consented to MR imaging, the lesions were either stable or resolving, with no new lesions developing. In particular, none of the patients in our study showed MR lesions of a cortical confluent pattern, as was reported in the case of relapsed Hendra virus infection (23) or in the delayed changes described in Malaysian studies of Nipah virus encephalitis (26). In the instance of Hendra virus encephalitis, clinical relapse occurred 13 months after initial infection, and we continue to monitor the survivors of the Nipah virus encephalitis.

In conclusion, the pattern of MR findings in brain infection with the Nipah virus is unlike other viral encephalitides, affecting primarily the white matter, with transient cortical T1 hyperintensities at 1 month. The small lesions detected at MR imaging may represent widespread microinfarction from infective vasculitis of the small blood vessels of the brain. Surveillance of survivors of the epidemic at 6 months showed no evidence of clinical or radiologic relapse. Further studies in pathology and radiology are necessary to better understand this lethal emerging infection.

	ACKNOWLEDGMENTS

 
The authors gratefully thank Angela Tan, MBBS, and Haslindah Salim for their assistance.

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