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Human Hendra virus infection causes acute and

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Neuropathology and Applied Neurobiology (2009), 35, 296–305 doi: 10.1111/j.1365-2990.2008.00991.x

Human Hendra virus infection causes acute and

relapsing encephalitis
K. T. Wong*, T. Robertson†, B. B. Ong‡, J. W. Chong*, K. C. Yaiw*, L. F. Wang§, A. J. Ansford‡ and
A. Tannenberg‡
*Department of Pathology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia, †Royal Brisbane &
Women’s Hospital, ‡Queensland Health Pathology & Scientific Services, Brisbane, Queensland, and §CSIRO Livestock
Industries, Australian Animal Health Laboratory and Australian Biosecurity Cooperative Research Center, Geelong,
Victoria, Australia

K. T. Wong, T. Robertson, B. B. Ong, J. W. Chong, K. C. Yaiw, L. F. Wang, A. J. Ansford and A. Tannenberg (2009)
Neuropathology and Applied Neurobiology 35, 296–305
Human Hendra virus infection causes acute and relapsing encephalitis

Aim: To study the pathology of two cases of human
Hendra virus infection, one with no clinical encephalitis
and one with relapsing encephalitis. Methods: Autopsy
tissues were investigated by light microscopy, immunohis-
tochemistry and in situ hybridization. Results: In the
patient with acute pulmonary syndrome but not clinical
acute encephalitis, vasculitis was found in the brain, lung,
heart and kidney. Occasionally, viral antigens were dem-
onstrated in vascular walls but multinucleated endothelial
syncytia were absent. In the lung, there was severe inflam-
mation, necrosis and viral antigens in type II pneumocytes
and macrophages. The rare kidney glomerulus showed
inflammation and viral antigens in capillary walls and
podocytes. Discrete necrotic/vacuolar plaques in the brain
parenchyma were associated with antigens and viral
RNA. Brain inflammation was mild although CD68+
microglia/macrophages were significantly increased.
Cytoplasmic viral inclusions and antigens and viral RNA
in neurones and ependyma suggested viral replication. In
the case of relapsing encephalitis, there was severe wide-
spread meningoencephalitis characterized by neuronal
loss, macrophages and other inflammatory cells, reactive
blood vessels and perivascular cuffing. Antigens and
viral RNA were mainly found in neurones. Vasculitis was
absent in all the tissues examined. Conclusions: The case
of acute Hendra virus infection demonstrated evidence
of systemic infection and acute encephalitis. The case of
relapsing Hendra virus encephalitis showed no signs of
extraneural infection but in the brain, extensive inflam-
mation and infected neurones were observed. Hendra
virus can cause acute and relapsing encephalitis and the
findings suggest that the pathology and pathogenesis are
similar to Nipah virus infection.

Keywords: encephalitis, Hendra virus, Henipavirus, human, infection, pathogenesis, pathology

Because it shares a high degree of similarity in genome

Introduction
Hendra virus (HeV), an emerging paramyxovirus from the
family Paramyxoviridae was first discovered in Australia in
1994 following an outbreak in horses and humans [1].
Correspondence: Kum Thong Wong, Department of Pathology,
Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur,
Malaysia. Tel: +603 7967 5762; Fax: +603 7955 6845; E-mail:
wongkt@um.edu.my
296
organization and sequence and other biological character-
istics to another recently discovered virus, the Nipah virus
(NiV), both viruses have been placed in the newly created
genus Henipavirus [2,3]. There is good evidence that the
natural hosts of HeV and NiV are pteropid fruit bats [4–6],
whose range includes northern Australia, southeast
Asia, the Indian subcontinent and eastern Africa. Hence,
it was not surprising that after the first NiV outbreaks in
© 2009 Blackwell Publishing Ltd
 Table 1. Clinicopathological findings in four cases of human Hendra virus infection

Positive IHC† and/or ISH staining in Final

Probable autopsy tissues pathological‡
Case incubation or clinical
# Clinical presentation* period Light microscopy of autopsy tissues CNS tissues Non-CNS tissues diagnosis

1 49-year-old man, presented with influenza-like 6 days Blood vessels: Brain Lung Acute Hendra
illness, followed by respiratory and renal failure Vasculitis/endotheliitis in brain, lung, (neurones, ependyma, (type II pneumocytes, infection with
and cardiac irritability. Died after about 12 days heart and kidney blood vessels) blood vessels) encephalitis§
of admission Brain: Kidney
Small necrotic/vacuolar plaques in the (glomeruli, capillaries,
cerebrum and cerebellum, in addition to tubules)
mild meningitis and mild parenchymal
inflammation
Lung:
Severe parenchymal inflammation and
necrosis. Incidental fungal infection in the
lungs was also noted
Other organs:
Generally mild or focal inflammation in
the parenchyma of other organs

2 35-year-old man who first presented with 12 days Brain: Brain All tissues negative Relapsing
headache, drowsiness and meningitis but after 13 (13 months) Mainly confluent geographic areas of (neurones mainly; Hendra
months was readmitted with fever, seizures, neuronal loss, gliosis and parenchymal possibly also glial and encephalitis
neurological deficits and coma. Died after 25 days and perivascular inflammation were inflammatory cells)
of admission observed mainly in the cerebral cortex

© 2009 Blackwell Publishing Ltd, Neuropathology and Applied Neurobiology, 35, 296–305
Other non-CNS organs:
No vasculitis, necrosis or significant
inflammation in the lung, heart, kidney,
liver and spleen

3 40-year-old man presented with influenza-like 5 days NA¶ NA NA Acute Hendra

illness, myalgia, headache and vertigo of 5-day infection
duration. Recovered apparently well after 6 weeks
4 Adult female (age unknown) presented with dry 7 days NA NA NA Acute Hendra
cough and sore throat, cervical infection
lymphadenopathy, fever, body aches and
tiredness. Recovered and apparently well

*Information (age, sex, clinical presentation, incubation period) compiled from references [12–14].
†IHC, immunohistochemistry; ISH, in situ hybridization; CNS, central nervous system. ISH was not performed on non-CNS tissues of Case #1 due to insufficient tissues.
Human Hendra virus infection

‡Pathological diagnosis available for Cases # 1 and 2 only.

§Acute encephalitis based on our pathological evidence only; clinical encephalitis was not reported.
¶NA = tissues not available for study.
297
298 K. T. Wong et al.

Malaysia and Singapore [7–9], sporadic NiV outbreaks
continued to be seen in these regions, notably in Bang-
ladesh and India [10,11]. Although so far HeV infection
has only been reported from Australia, like NiV, there is
every possibility that future outbreaks may occur in other
countries as well, given the wide range of fruit bats.
HeV-infected horses acted as intermediate hosts for
human infections [1,6]. Of the four human cases that
have been reported to date (Table 1), two were fatal and all
had close contact with infected horses before developing
the disease [12–14]. Previous publications on human
HeV infection have concentrated mainly on epidemiologi-
cal, virological and clinical aspects with no detailed data
on pathological features [1,3,12,14]. Moreover, the target
cells of HeV in natural human infections have not been
fully investigated.
Studies of acute human NiV infection have demonst-
rated that blood vessels and a broad range of parenchymal
cells were susceptible to infection [15]. The most severely
involved tissues were in the central nervous system (CNS),
but the lung, kidney, lymphoid and other organs were also
susceptible. Two distinct clinicopathological forms of
encephalitis were recognized, viz. acute and relapsed/late-
onset NiV encephalitis [15,16]. Acute NiV encephalitis
appears as part of the acute infection that occurs 1–2
weeks after viral exposure [17]. Pathologically, it is charac-
terized by necrotic plaques believed to be associated with
vasculitis-induced thrombosis and neuronal infection.
This dual pathogenetic mechanism of tissue damage con-
sisting of microinfarction and direct neuronal infection
appears to be unique among viral encephalitides [15].
On the other hand, relapsed/late-onset NiV encephalitis
usually presents several weeks after the acute infection
has subsided, with new episodes of neurological manifes-
tations. Relapsed encephalitis occurs in survivors who
initially present with acute encephalitis and late-
onset encephalitis is found in those with acute, mild,
nonencephalitic infection earlier. Relapsed/late-onset
encephalitis generally have similar clinicopathological
characteristics that are distinguishable from acute NiV
encephalitis [16,18]. Pathological findings suggested a
true recurrence of infection rather than postinfectious
encephalomyelitis as viral antigens/RNA in neurones
could be demonstrated. However, vasculitis and multi-
nucleated endothelial cells or syncytia were not demon-
strated [15,16].
Of the two HeV human fatalities included in this study
(Table 1), Case # 1 presented clinically as an acute HeV
infection characterized by a predominant pulmonary syn-
drome with no apparent clinical encephalitis [12,14].
However, studies of acute HeV infection in horses, guinea
pigs and other animals [1,19,20] suggest that there is some
similarity to acute NiV infection in that vasculitis and
encephalitis can occur [15]. Hence, we hypothesize that
there may be histological evidence of CNS involvement in
Case # 1. In the case of relapsing HeV encephalitis (Table 1,
Case # 2), it was previously reported that in addition to
parenchymal inflammation and viral antigens, occasional
multinucleated endothelial cells were observed in blood
vessels in the brain and other organs [14]. Our objective is
to undertake a more detailed study of the neuropathology
of human HeV infection by studying the histopathological
features, in particular CNS pathology and by investigating
viral localization with immunohistochemistry (IHC) and
in situ hybridization (ISH) in infected tissues.
Materials and methods
Formalin-fixed, paraffin-embedded autopsy tissues of
various major organs were sectioned at 5–7 microns and
routinely stained with haematoxylin and eosin. These
organs/tissues included brain, lung, heart, kidney, liver
and spleen (Table 1: Cases # 1 and 2); pancreas, thyroid,
adrenal, lymph node and intestine (Case # 1 only) and
spinal cord (Case # 2 only). IHC to detect HeV antigens was
performed on further sections. A standard immunoperoxi-
dase protocol was followed [21], using a primary mouse
anti-Hendra polyclonal antibody (1:1000 dilution; gift

Figure 1. Acute Hendra virus infection: vasculitis and endotheliitis involving blood vessels in the meninges (A, arrows), brain parenchyma
(D, arrows; E), lung (B, arrow) and heart (C, arrow), with intramural or subendothelial inflammatory cells. Viral antigens demonstrated in
endothelial cells lining a meningeal capillary (F, arrow; inset). Inflammation in the lung (G) characterized by intra-alveolar inflammation,
necrosis, macrophages and the rare multinucleated giant cell (inset, arrow). Proliferating type II pneumocytes and alveolar macrophages
were positive for viral antigens (H). Kidney glomerulus with surrounding inflammation and thrombotic plug (I, arrow) and viral antigens
in capillary walls, podocytes and other cells (J). A–E, G, I: haematoxylin & eosin stain. F, H, J: immunohistochemistry/DAB/Mayer’s
haematoxylin. Magnification: A–F, H–J, G (inset): ¥40 obj; G: ¥10 obj. Bar: A–F, I, J = 50 microns; G = 100 microns; G (inset), H = 25
microns.

© 2009 Blackwell Publishing Ltd, Neuropathology and Applied Neurobiology, 35, 296–305
 Human Hendra virus infection 299

A B C

D F G

H I J

© 2009 Blackwell Publishing Ltd, Neuropathology and Applied Neurobiology, 35, 296–305
300 K. T. Wong et al.

A B

C D

E F G H

© 2009 Blackwell Publishing Ltd, Neuropathology and Applied Neurobiology, 35, 296–305
 Human Hendra virus infection 301

Figure 2. Acute Hendra virus infection in the central nervous system. (A) Subtle vacuolar plaque (thin arrows) in the cerebellar molecular
layer consisting of fine neuropil vacuolation with adjacent eosinophilic Purkinje cells (thick arrow). (B) Necrotic/vacuolar plaque in the
dentate nucleus, showing neuronal loss, coarse neuropil vacuolation and mild inflammation. Some surviving/degenerate neurones were still
present (arrows). Fine granular viral antigens in the neuropil (C) within a vacuolar plaque in the cerebellar molecular layer. (D) Viral
antigens in the cytoplasm (thin arrows) and processes (thick arrow) of neurones found within or adjacent to a necrotic/vacuolar plaque in
the dentate nucleus. Eosinophilic viral inclusions (E) and viral antigens (F, thick arrow) and viral RNA (G) in the cytoplasm of neurones in
the hippocampus pyramidal layer. Viral protein was also detected in the nucleus (F, thin arrow). (H) Plaque-like cluster of neurones and
adjacent ependymal cells (arrow) in the periaqueductal grey matter of the midbrain staining positive for viral antigens. A, B, E:
haematoxylin & eosin stain; C, D, F, H: immunohistochemistry/DAB/Mayer’s haematoxylin; G: in situ hybridization/NBT/BCIP/Mayer’s
haematoxylin. Magnification: A, B, H: ¥10 obj; C–G: ¥40 obj. Bar: A–D = 50 microns; E–G = 25 microns, H = 100 microns.

from Dr SR Zaki, CDC, Atlanta, USA), with slight modifica-
tions in that our assay utilized the ENVISION detection
method (DakoCytomation, Copenhagen, Denmark). The
slides were counter-stained with haematoxylin, dehy-
drated through serial ethanols and xylene and cover-
slipped before microscopic examination. IHC to CD68 to
detect microglia/macrophages were performed as previ-
ously described [22].
The DNA probes were prepared from a plasmid contain-
ing the whole N gene of HeV, using a standard polymerase
chain reaction (PCR) that incorporated digoxigenin-11-
dUTP to produce a digoxigenin-labelled DNA probe of
271 bp, as previously described [22]. The forward and
reverse primers for the PCR were, respectively, 5′-gca-atg-
gct-gac-aga-gat-ga-3′ (N gene nucleotide position:
745–764, Genbank accession number: AF017149) and
5′-gct-cga-ggc-cct-att-tct-ct-3′ (nucleotide position:
1035–1016). The PCR conditions were 95°C for 3 min;
followed by 35 cycles of 94°C for 30 s, 56°C for 1 min,
72°C for 30 s; and 72°C for 10 min, final extension. The
ISH protocol used was as described previously [23] and
performed on all tissues except for the non-CNS tissues of
Case # 1 (Table 1), as these tissues were insufficient for
this purpose.
For IHC and ISH assays, HeV-infected hamster tissues
(courtesy of Dr Fabian Wild, France) served as positive
controls. Negative control tissues included normal CNS
tissues and CNS tissues known to be infected by Enterovi-
rus 71 [22] and measles virus [24]. For both assays, dupli-
cate procedures that omitted the primary antibody and
probe, respectively, were performed as additional negative
controls.
Results
Acute HeV infection (Table 1, Case # 1)
The light microscopic features are summarized in the
Table 1. Vasculitis and endotheliitis were observed in
© 2009 Blackwell Publishing Ltd, Neuropathology and Applied Neurobiology, 35, 296–305
blood vessels in the brain, lung, kidney and heart
(Figure 1A–E). In contrast to perivascular cuffing, vascu-
litis was characterized by karyorrhexis and intramural or
subendothelial inflammatory cells. However, no convinc-
ing endothelial syncytia or multinucleated giant cells were
found. Occasional thrombotic plugs were detected in the
pulmonary blood vessel and rarely in glomerular capillar-
ies (Figure 1I). Viral antigens were observed in some
vascular endothelium and possibly smooth muscle cells,
in the brain (Figure 1F), lung and kidney (Figure 1J).
Choroid plexus showed no evidence of vasculitis or virus.
In the lung, there was severe parenchymal inflamma-
tion, necrosis, intra-alveolar macrophages/inflammatory
cells, prominent type II pneumocyte proliferation and
occasional alveolar membranes (Figure 1G). The kidney
showed the rare focal glomerulitis (Figure 1I) and focal
inflammation around necrotic tubules. There was evi-
dence of emperipolesis and the occasional bizarre multi-
nucleated giant cell in the lymph nodes. Viral antigens
were demonstrated in alveolar type II pneumocytes, intra-
alveolar macrophages and the occasional glomeruli and
tubules (Figure 1H,J).
In the brain parenchyma, there were both subtle and
more obvious discrete necrotic or vacuolar plaques, in the
cerebellum (Figure 2A,B), the gray and white matter of
the cerebral cortex (Figure 3A), corpus callosum, hippoc-
ampus, thalamus, external capsule and globus pallidus.
The most obvious necrotic plaques were found in the
white matter consisting of eosinophilic axonal spheroid-
like material (Figure 3A). The vacuolar plaques comprised
neuropil vacuolation, mild parenchymal infiltration by
mononuclear inflammatory cells and mild perivascular
cuffing. In addition, neuronal loss may be evident in
neuronal areas (Figure 2B). In the cerebellar molecular
layer, vacuolar plaques consisted of small fine vacuoles
(Figure 2A). Occasional neuronal bodies at the peri-
phery of a plaque may show cytoplasmic eosinophilia
(Figure 2A). Eosinophilic cytoplasmic viral inclusions
were detected in neurones in the hippocampus (pyramidal
302 K. T. Wong et al.

A E

C D F

G H I J

© 2009 Blackwell Publishing Ltd, Neuropathology and Applied Neurobiology, 35, 296–305
 Human Hendra virus infection 303

Figure 3. Acute and relapsing Hendra encephalitis. Acute Hendra encephalitis (A–D): necrotic/vacuolar plaque in cerebral white matter
consisting of eosinophilic, axonal spheroid-like material (A, inset). Increased number of CD68+ microglia/macrophages in necrotic/vacuolar
plaques in the cerebellar dentate nucleus (B) and cerebellar molecular layer (C) and around neurones, neuronophagia (D). Severe
meningoencephalitis in relapsing Hendra encephalitis (E–J): large confluent areas of inflammation in the cerebral cortex (E, arrows)
consisting of perivascular cuffing, reactive blood vessels (F), parenchymal inflammation, necrosis and neuronal loss. Inflammatory cells
comprised mainly of macrophages, lymphocytes and some plasma cells (G). Focal areas of viral antigens were found either within or at the
edge of inflammatory lesions (H, arrows), mainly in neurones and possibly glial and inflammatory cells (I). Viral RNA was demonstrated
mainly in neurone-like cells (J, arrows). A, E–G: haematoxylin & eosin; B–D, H, I: immunohistochemistry/DAB/Mayer’s haematoxylin; J: in
situ hybridization/NBT/BCIP/Mayer’s haematoxylin. Magnification: A, D, G, I, J: ¥40 obj; B, C, F: ¥10 obj; E, H: ¥4 obj. Bar: A, D = 50
microns; A (inset), B, C, E, F, H = 100 microns, G, I, J = 25 microns.

layer) (Figure 2E) and thalamus and ependymal cells.
There were no nuclear inclusions detected. Overall, by
light microscopy, parenchymal and meningeal inflamma-
tion and perivascular cuffing were mild and prominent
microglial nodules were not observed. However, CD68
IHC showed an increased number of microglial cells/
macrophages in and around necrotic/vacuolar plaques
(Figure 3B,C) and surrounding some neurones, neu-
ronophagia (Figure 3D).
Viral antigens and/or RNA were detected in the neu-
ropil and in single or plaque-like groups of neurones
(both soma and processes) in the cerebellum (dentate
nucleus, molecular and granular layers), cerebral cortex,
midbrain (periaqueductal gray area, substantia nigra),
hippocampus (pyramidal layer, dentate gyrus, entorhinal
cortex), thalamus and ependymal and subependymal
cells (Figure 2C,D,F–H). Positive neurones were often,
but not always, found in or near necrotic/vacuolar
plaques (Figure 2C,D). Conversely, not all plaque-like
neuronal virus antigen positivity was associated with
necrosis or prominent vacuolation (Figure 2H). Necrotic
plaques in the white matter were not associated with
viral antigens/RNA.
Relapsing HeV infection (Table 1, Case # 2)
Only the CNS tissues and mainly the cerebral cortex
showed evidence of inflammation although very focal
areas in the pons, cerebellum and spinal cord were also
inflamed. Inflammatory lesions were usually extensive
and consisted of intense infiltration of macrophages, lym-
phocytes and some plasma cells, with prominent perivas-
cular cuffing (Figure 3E–G). There was severe neuronal
loss, glial proliferation and an increased number of
reactive blood vessels (Figure 3F). More discrete, plaque-
like, but otherwise similar inflammatory lesions, were
occasionally observed. There was no evidence of vasculi-
tis, endothelial syncytia or thrombosis and viral inclusions
were not prominent.
© 2009 Blackwell Publishing Ltd, Neuropathology and Applied Neurobiology, 35, 296–305
Within inflamed areas, focal viral antigens/RNA were
demonstrated mainly in surviving neurones (Figure 3H–J)
and possibly in some glial/inflammatory cells as well.
Overall, inflammation was much more extensive than
viral antigens/RNA. Severe meningitis was found over
many areas of the cerebral cortex (Figure 3E). All the
non-CNS organs were uninflamed and in particular, no
vasculitis, multinucleated endothelial syncytia or viral
antigens/RNA were detected.
Discussion
Pathological findings in the two cases confirmed that HeV
was neuronotropic and could cause CNS infection giving
rise to acute and relapsing encephalitis, respectively. In the
patient with acute HeV infection without apparent clinical
encephalitis (Case # 1), mild vasculitis, meningitis, paren-
chymal inflammation, necrotic/vacuolar plaques and
neuronal infection were found in the CNS, features that
have not been previously reported in acute infection.
It was postulated that the characteristic and well-defined
necrotic plaque described in acute NiV encephalitis is the
result of a combination of neuronal infection and micro-
infarction following vasculitis-induced thrombosis [15].
This was because in the vicinity of necrotic plaques, vas-
culitis, thrombus-occluded vessels and/or infected neu-
rones were often observed together [15]. In our case
of acute HeV encephalitis, the necrotic/vacuolar plaques
may be equivalent to the necrotic plaque in acute NiV
encephalitis. There was evidence that the necrotic/
vacuolar plaques were associated with neuronal infection
by HeV. Vasculitis and viral antigens could be demonstrated
in cerebral vessels, although admittedly, these abnormal
vessels are not necessarily found near the plaques.
Thrombus-occluded blood vessels were also absent.
Vasculitis was also noted in the lung, heart and kidney
and vascular thrombi were identified in the lung and glom-
eruli. Hence, we think it is possible that vasculitis-induced
thrombosis and microinfarction could have occurred in the
304 K. T. Wong et al.
CNS at some stage of the acute infection. Multinucleated
endothelial syncytia, a unique feature of endothelial infec-
tion, is observed in acute NiV infection but this was not
observed in this HeV case. The reasons for this disparity
could include the rarity of multinucleated endothelial syn-
cytia (only found in 27% of acute NiV encephalitis) [15], a
relatively mild CNS involvement, disintegration of throm-
botic plugs over time or inadequate sampling. Within or
near the discrete white matter necrotic plaques, there was
no evidence of infection of glial or other cells whatsoever,
suggesting that microinfarction may be solely involved in
their pathogenesis. If this is correct, focal infarction and
death of oligodendroglial cells surrounding axons may be
responsible for this phenomenon.
As vasculitis was so widespread, we postulate that
viraemia must have occurred, spreading the infection to
multiple organs; hence, acute HeV infection should be
regarded as a systemic infection. Neuronal and other
parenchymal cell infection was probably facilitated by vas-
culitic damage to the blood brain barrier and other vessels.
Like meningeal vessel vasculitis, involvement of the
ependyma could enable virus to enter cerebrospinal fluid
and contribute to further viral spread in the CNS via this
route. It is difficult to determine if clinical encephalitis was
missed as a result of the patient’s severe clinical condition
at admission, or whether clinical encephalitis was not
severe enough to be detected.
Apart from blood vessels, the target cells/tissues in
acute HeV infection seemed to be similar to NiV infection
[15]. Like NiV, HeV was neuronotropic and to a lesser
extent, ependyma were susceptible to infection. Viral
inclusions, and antigens/RNA in neurones and ependyma
in particular, suggest that active viral replication occurs in
these cells. Likewise, type II pneumocytes and alveolar
macrophages may be able to support viral replication.
Overall, like NiV, involvement of glial cells appears to be
rare in HeV infection.
The second fatal case of HeV infection with a relapse of
neurological manifestations 13 months after acute disease
seems to be similar to relapsed NiV encephalitis [16]. The
pathological findings confirmed that the patient had
recurrent infection rather than postinfectious encephalo-
myelitis. At variance to a previous report [14], we found
no evidence of multinucleated endothelial syncytia or vas-
culitis in any of the organs examined, nor any evidence of
viral antigens/RNA in the non-CNS organs. We postulate
that recurrence originated from viral foci that were dis-
seminated to the CNS by viraemia during the acute infec-
© 2009 Blackwell Publishing Ltd, Neuropathology and Applied Neurobiology, 35, 296–305
tion. After 13 months, vasculitis present initially, subsided
and healed, but the virus infection recurred to spread
throughout the CNS. This phenomenon has also been
suggested for relapsed/late-onset NiV encephalitis [16].
Further investigations are needed to determine if the
immune response and other host factors, or viral muta-
tions were responsible for this interesting phenomenon.
In the case of measles, another important human
paramyxovirus, relapsing encephalitis has not been
reported. However, late-onset NiV encephalitis might
arguably be represented by subacute sclerosing panen-
cephalitis and measles inclusion body encephalitis as both
present months to years after the acute infection. As
relapsed NiV encephalitis could occur even after 4 years or
more [25], it is theoretically possible that survivors of
acute HeV infection could still develop encephalitis long
after 13 months. Fortunately, relapsed/late-onset NiV
encephalitis is not uniformly fatal, suggesting that HeV
encephalitis may not be invariably fatal as well [16].
Nonetheless, long-term follow-up of Cases # 3 and 4
(Table 1) is essential and could be invaluable to determine
future disease course. Remarkably, in asymptomatic or
mildly symptomatic NiV-infected patients, despite absence
of neurological manifestations, brain scans may show a
few discrete lesions similar to acute NiV encephalitis [26].
Acknowledgement
This work was partly supported by Malaysian Government
IRPA Grant (06-02-03-0199-PR0060-/04). We are
grateful to Dr Sherif R Zaki, Centers for Disease Control
and Prevention, Atlanta, USA for the generous gift of
anti-Hendra antibodies and to Dr F. Wild, INSERM, Lyon,
France for the infected hamster tissues.
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Received 29 January 2008
Accepted after revision 30 September 2008
Published online Article Accepted on 2 October 2008
Addendum
In July 2008, a further two human cases were reported;
one subsequently succumbed to the infection [ProMED-
mail. Hendra virus, human, equine, Australia (07):
(Queensland). ProMED-mail 2008; 21 Aug: 20080821.
2606. http://www.promedmail.org. Accessed 21 August
2008]. Both cases had contact with infected horses treated
in a veterinary facility in Brisbane, Australia.