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1
Department of Radiology, University of Malaya Medical Center, Jalan
Universiti, 59100 Kuala Lumpur, Malaysia.
2
Department of Medicine, University of Malaya Medical Center, Jalan Universiti,
59100 Kuala Lumpur, Malaysia.
3
Department of Pathology, University of Malaya Medical Center, Jalan
Universiti, 59100 Kuala Lumpur, Malaysia.
Received October 20, 1999;
accepted after revision January 4, 2000.
Address correspondence to S.A. Sarji.
Abstract
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MATERIALS AND METHODS. MR imaging of the brain was performed in 31 patients with Nipah encephalitis divided into three groups. The first group (14 patients) underwent MR imaging during the acute phase of the illness and the second group (10 patients) during the later phase of the acute illness. The third group consisted of six patients who underwent MR imaging because they experienced neurologic relapse and one patient who had late-onset encephalitis. Spin-echo T1- and T2-weighted sequences and T2-weighted fluid attenuated inversion recovery (FLAIR) sequences were performed. Contrast-enhanced MR imaging was performed in four patients.
RESULTS. The FLAIR sequences revealed abnormalities in all patients studied. MR imaging findings in both the acute and later phases of encephalitis were similar; the main feature of both phases was the presence of discrete high-signal-intensity lesions, measuring 2-7 mm, disseminated throughout the brain, mainly in the subcortical and deep white matter of the cerebral hemispheres. Neither mass effect nor cerebral edema was seen. There was no correlation with the focal neurologic signs, depth of coma, and outcome of the patients. The lesions were attributed to widespread microinfarctions from underlying vasculitis of cerebral small vessels. Features found on MR imaging in relapsed and late-onset encephalitis differed from the features in acute encephalitis in that confluent cortical involvement was the prominent finding in the former, as opposed to discrete focal lesions in the subcortical and deep white matter in the latter.
CONCLUSION. MR imaging is a sensitive and specific diagnostic tool for evaluating Nipah encephalitis.
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The patients with Nipah encephalitis who were admitted to our medical center were pig farmers and those who had close contact with pigs. The probable mode of transmission to humans was thought to be close contact with tissue fluids from infected pigs [2]. The Nipah virus causes a febrile encephalitic illness and severe cases were characterized by reduced conscious level, seizures, focal neurologic signs, and brainstem dysfunction. The virus has a high mortality rate in the acute phase, during which patients may undergo rapid neurologic deterioration, coma, and death. Neurologic relapse may also occur. During the initial stages of the outbreak, a number of patients with acute encephalitis who were seen at our center underwent brain CT, but these examinations did not reveal any abnormalities. Hence, MR imaging was performed in these patients at various phases of the illness to study the patterns of cerebral involvement in Nipah encephalitis, which could help with its diagnosis and perhaps explain the pathogenesis of brain involvement. In this article, we describe the spectrum of brain changes on MR imaging in patients with Nipah encephalitis.
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The 31 patients included in this study comprised 23 men, one boy, and seven women. The age range was 15-68 years, with a mean age of 37.5 years. A total of 32 MR imaging examinations was performed in 31 patients. One patient underwent MR imaging in both the acute and later phases of encephalitis. For the purpose of this study, these patients were divided into three groups. MR imaging of the first group (14 patients) was performed in the acute phase (mean duration from onset of acute symptoms to MR imaging, approximately 7 days). The second group consisted of 10 patients who underwent MR imaging in the later phase of encephalitis (mean duration from onset of symptoms to MR imaging, approximately 54 days). In the third group, MR imaging was performed in six patients who had neurologic relapse and in one patient who developed late-onset encephalitis. In this one patient, serology was positive and an earlier MR imaging study had normal findings, but symptoms of encephalitis manifested 10 weeks later. The patient subsequently died and an autopsy was performed.
Severity of coma was assessed by the Glasgow Coma Scale (GCS) and divided into patients with a GCS score of 10 or less and those with a GCS score of more than 10 at the time of MR imaging. MR imaging was performed using a 1.5-T superconducting system, (Vision; Siemens, Erlangen, Germany). The MR imaging sequences were spin-echo T1- (TR/TE, 650/14; one excitation) and T2- (3800/90; two excitations) weighted as well as T2-weighted fluid attenuated inversion recovery (FLAIR) (9000/110; one excitation) sequences. Inversion time was 2500 msec. Images were obtained in the axial plane and coronal plane with a 10-mm slice thickness. T1- weighted contrast-enhanced examination with gadopentetate dimeglumine (0.1 mmol/kg) was performed in four patients. The MR images were evaluated independently by two radiologists.
The extent of brain involvement on MR images was graded as extensive if there were 10 or more focal lesions, lesions that were confluent, or both and as not extensive if there were fewer than 10 focal lesions. The outcome of the patients was graded as those who recovered with no neurologic deficits, those who recovered with residual neurologic deficits, and those who died.
The patients' blood and CSF were tested against Hendra viral antigen using the IgM capture enzyme-linked immunoabsorbent assay (ELISA) method [2]. CSF was also examined for WBC and protein levels. Statistical analysis was carried out using the chi-square test when appropriate.
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MR Imaging Findings in Acute and Later Phases of Encephalitis
MR imaging revealed abnormalities in the brains of all 23 patients in the
acute and later phases of encephalitis. Lesions were shown with better clarity
and extent on the FLAIR images. All 23 patients had MR imaging findings of
small discrete lesions measuring 2-7 mm disseminated in the subcortical and
deep white matter of the cerebral hemispheres (Figs.
1 and
2). The number of discrete
lesions ranged from as few as two to innumerable. Extensive brain involvement
on MR imaging (defined as the presence of more than 10 focal lesions, lesions
that were confluent, or both) occurred in 70% of patients. Most lesions were
round, but some appeared as strips (Fig.
3). Lesions in the cerebral cortex were present in 44% of the
patients (Fig. 4). Evidence of
blood products in the lesions was present on MR imaging in one patient in the
later phase of encephalitis (Fig.
5A,5B).
There was no predilection for a particular site in the brain except for the
temporal lobe, which was involved in 30% of the patients
(Fig. 6). Lesions in the pons
were observed in 22% of the patients. Lesions in the cerebral peduncle were
present in three patients (10%). One patient had a focal lesion in the
cerebellum. There was a lack of edema around the lesions, no mass effect, and
an absence of generalized cerebral edema in all patients. Hyperintense signal
intensity in the subarachnoid spaces on FLAIR images was not present in any of
the patients, and contrast-enhanced MR imaging performed in four patients with
acute encephalitis showed neither enhancement of lesions nor significant
enhancement of the meninges.
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No correlation appears to exist between focal neurologic signs and findings on MR imaging. Of the 23 patients, five patients had nystagmus, cerebellar signs, or both, and MR imaging revealed posterior fossa lesions in three of these patients. However, MR imaging also revealed posterior fossa lesions in five of the 18 patients who had no evidence of nystagmus or cerebellar signs. Segmental myoclonus involving the diaphragm (five patients), anterior part of the neck (one patient), and the limbs (two patients) was observed in five patients and expressive dysphasia in one patient. No corresponding cerebral lesions were found in patients with segmental myoclonus. However, the MR imaging examination did not include the spinal cord. Small focal lesions in the subcortical and deep white matter of the cerebral hemispheres, cerebral peduncles, and cerebellum were present on MR imaging in the patient with expressive dysphasia, and these findings did not correspond with this focal sign.
Of the 23 patients, 16 (70%) tested positive for antibodies against Hendra viral antigen in the blood. Abnormal CSF findings were found in 15 patients (65%), and 10 patients (43%) tested positive for antibodies against the viral antigen in their CSF. Eleven patients had a GCS score of 10 or less, and 12 patients had a GCS score of more than 10 at the time of MR imaging. No correlation was observed between the extent of brain involvement on MR imaging and the severity of coma (p < 0.05). Eleven patients recovered without neurologic deficits, seven patients recovered with some neurologic deficits, and five patients died. The extent of brain involvement on MR imaging and the outcome of the patients did not correlate (p < 0.05).
The MR imaging findings in the acute phase did not differ from those in the later phase of the illness. MR imaging was performed in the acute phase and in the later phase of the illness in one patient. The findings in the acute phase were multiple small focal lesions in the subcortical and deep white matter throughout the cerebral hemispheres, small focal lesions in the pons, and confluent involvement of the right temporal lobe. A repeated MR imaging study 7 weeks later showed slight improvement in the temporal lobe, but lesions in the rest of the brain remained the same. No new lesions were noted.
MR Imaging Findings in Relapse Cases
Six patients who recovered from Nipah encephalitis underwent MR imaging
because of recurrence of neurologic dysfunction. Unfortunately, they had no
previous MR imaging during the initial acute episode. One patient developed an
isolated left third nerve palsy, and MR imaging revealed a focal lesion in the
region of the oculomotor nucleus in the left midbrain. The other five patients
had neurologic relapse, which included recurrent headache or seizures and
cognitive dysfunction. MR imaging showed patchy areas of confluent cortical
involvement, mainly in the cerebral hemispheres (Figs.
7A,7B
and
8A,8B).
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One patient was found to be seropositive early in the outbreak but was asymptomatic with no abnormal findings on MR imaging at that time. However, she presented 10 weeks later with frontal headache and seizures. MR imaging revealed confluent cortical involvement of the right frontal lobe (Fig. 9A,9B). She deteriorated rapidly 36 hr after the second MR imaging study and died. A brain-only autopsy showed necrosis and acute inflammation of the cortex and adjacent white matter, mainly in the right frontal lobe. There was evidence of neuronal death, neuronophagia, parenchymal inflammation, and perivascular cuffing, typically encountered in a primary viral encephalitis. Neither vasculitis nor microinfarction was evident.
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The findings on MR imaging in Nipah encephalitis were predominantly small focal lesions in the subcortical and deep white matter and, to a lesser extent, in the gray matter. There was a paucity of mass effect and cerebral edema, even in cases in which innumerable lesions were scattered throughout the brain. On reviewing the literature, these features differed from the MR imaging descriptions of other sporadic endemic viral encephalitides. Because of the association of those affected with pigs, the outbreak of encephalitis in Malaysia was initially thought to be caused by Japanese encephalitis. The MR imaging features of Japanese encephalitis are described as high-signal-intensity areas on T2-weighted and low-signal-intensity areas on T1-weighted images, involving the white matter, brainstem, basal ganglia, and, classically, the thalami bilaterally [8, 9]. Hemorrhage into the thalami occurs with Japanese encephalitis, and MR imaging reveals the signal intensities of the blood products on corresponding T1- and T2-weighted images [10]. The MR imaging findings in all our patients were clearly not similar to Japanese encephalitis. In Eastern equine encephalitis, focal lesions in the basal ganglia and thalami are described as the characteristic features on MR imaging [11]. Again, these were not the MR imaging findings in our patients. Our MR imaging findings also differed from those of herpes simplex encephalitis, for which the classic description is early edematous changes with confluent high-signal areas on T2-weighted MR images in the temporal lobe and limbic system, which later frequently hemorrhages [4]. Thus, we believe the MR imaging features in Nipah encephalitis are unique.
Autopsy was not performed in patients from our series who died from acute Nipah encephalitis. However, the main pathologic findings from autopsies of the brains of other patients who died of acute Nipah encephalitis was vasculitis-induced thrombosis, which in turn caused widespread microinfarctions throughout the brain. There was also direct neuronal involvement as evidenced by the presence of occasional viral inclusion bodies [2]. We believe the small focal lesions in the subcortical and deep white matter and cerebral cortex revealed on MR imaging correlate with the microinfarcts found at autopsy of the brains of patients who died of acute Nipah encephalitis. Therefore, MR imaging findings in the acute phase of the infection do support the suggestion that in Nipah encephalitis, the pathogenesis is largely a vasculitic process that involves small vessels, resulting in focal disseminated areas of ischemia and microinfarctions in the CNS. These appear as high-signal-intensity lesions in the white and gray matter of the brain on T2-weighted and FLAIR MR images. Our observation of the lack of mass effect and cerebral edema on MR imaging correlated well with the findings of normal CSF opening pressures on lumbar puncture in most patients. The explanation for this observation may be that the vasculitic process, however extensive, was not severe enough to result in significant cerebral edema, and raised intracranial pressure.
Correlation was poor between focal neurologic signs and MR imaging findings. This may be because MR imaging findings reflected white matter microinfarctions rather than neuronal involvement by the virus in the gray matter of the brain. Alternatively, very small microinfarcts may be undetectable on MR imaging. Correlation was also poor between severity of neurologic status or the depth of coma and MR imaging findings. Coma is likely to be a result of direct involvement of the reticular formation, in which case MR imaging was unable to reveal any abnormalities, as well as widespread microinfarcts and ischemia in the brain. There was, in addition, lack of correlation between patient outcome and MR imaging findings in the brain. Again this is likely because the MR imaging findings largely reflect widespread microinfarcts and ischemia, whereas outcome of the patients is probably mainly related to the extent of direct neuronal involvement.
The widespread distribution of lesions throughout the brain in Nipah encephalitis suggests that infection in the CNS is likely to be via a hematogenous route. Presumably, after initial acquisition of the virus by the host, viremia develops and spreads to the blood vessels of the CNS. Although our cases showed no predilection for a particular site in the brain, involvement of the uncus of the temporal lobe was observed in 30% of patients. This allows us to postulate another possible route of entry of the virus into the brain: direct inhalation of the virus through the nasal airway, along the olfactory bulb and tract into the uncus. This route of entry has also been proposed in herpes simplex encephalitis [12]. Because it is only found in a few patients, the nasal route into the CNS, if it occurs, probably only plays a minor role in Nipah encephalitis.
There appears to be no significant difference in the MR imaging findings in acute and later phase encephalitis as was shown in one patient from our series. In this patient, MR imaging showed no significant change or improvement of lesions and no evidence of new lesions. These findings correlated well with neurologic improvement in the patient. The MR imaging findings in patients with relapse and late-onset encephalitis were markedly different from the findings of early Nipah encephalitis. The distinct confluent involvement of the cortex on MR imaging in these patients suggests a different pathologic mechanism in relapse and late-onset Nipah encephalitis. It is interesting to note the resemblance of these findings with the MR imaging findings reported in a case of late-onset fatal meningoencephalitis caused by the Hendra virus [13]. Because the Nipah virus is also a paramyxovirus related to the Hendra virus, there may be similarities in the pathogenesis of late-onset and relapsed Nipah encephalitis and Hendra encephalitis. The findings in the brain of our patient who died from late-onset disease were typical of primary viral encephalitis rather than disseminated microinfarcts of acute Nipah encephalitis. This appears to correlate well with findings on MR imaging. Further work will be needed to unravel the pathogenesis of early and relapsed or late-onset Nipah encephalitis.
In summary, this new infection has features on cerebral MR imaging that appear distinct from MR imaging descriptions of other primary viral encephalitides. The MR imaging features of late-onset disease and relapsed encephalitis were different from early encephalitis. We conclude that MR imaging is a sensitive and specific diagnostic tool for Nipah encephalitis.
Acknowledgments
We thank all the clinical and nursing staff of University Malaya Medical
Center; Mohd Rani Jusoh from Kuala Lumpur Hospital, and Termizi Thayaparam and
H. T. Chong from Seremban Hospital for referring three of the patients; and
Thomas G. Ksiazek and his team from the Centers for Disease Control and
Prevention, Atlanta, for performing the serologic studies.
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