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Encephalitis after inhalation of measles virus A pathogenetic study in hamsters.

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Encephahtis afier Inhalation of Measles Virus:
A Pathogenetic Study in Hamsters
Irma M. Parhad, MD,” Kenneth P. Johnson, MD,t Jerry S. Wolinsky, MD,$ and Peggy Swoveland, MSt
A neuroadapted strain of measles virus (HNT) was administered by inhalation to newborn hamsters. Primary
replication of virus in the lung was followed by the transient appearance of virus in spleen within 7 to 9 days of
inoculation. A terminal encephalitis occurred between 6 and 60 days in 31% of infected hamsters, and virus was
recovered by explant culture of these brains. Virus could not be cultured directly from brain or tissue homogenates.
At least 7% of hamsters that had survived the infection for two months had antibody to measles virus. The histopathological change in morbid animals was limited to the central nervous system (CNS) and consisted of small
foci of necrosis, perivascular mononuclear cell infiltrates, intracytoplasmic and intranuclear inclusions, and vacuolated pyknotic neurons. Immunofluorescent studies disclosed measles antigen in the lungs and brain. This hamster
model of measles encephalitis following a “natural” route of inoculation appears to represent a faithful reproduction of certain CNS complications of natural measles infection in humans, i.e., measles encephalitis and subacute
sclerosing panencephalitis.
Parhad IM, Johnson KP, Wolinsky JS, Swoveland P: Encephalitis after inhalation of measles virus: a
pathogenetic study in hamsters. Ann Neurol 9:21-27, 1981
Central nervous system (CNS) complications of
encephalitis and subacute sclerosing panencephalitis (SSPE)-are uncommon y e t
serious clinical occurrences of a common respiratory infection [ 2 7 , 321. The pathway and conditions
of measles virus spread to the CNS remain unclear
[ 3 2 ] . In humans, there is evidence that measles is
naturally acquired through the respiratory tract and
may disseminate to various organs by a leukocyteassociated viremia [ 1 7 , 27, 371.
Animal models for measles encephalitis and SSPE
are abundant [ 3 , 4, 8, 9 , 11, 2 2 , 2 5 , 28, 45, 46, 48,
5 11. However, a systematic study delineating the
pathway of viral dissemination from a peripheral site
to the CNS is lacking. We therefore introduced a
neuroadapted strain of measles virus, HNT, by inhalation into newborn hamsters and studied the temporal sequence of viral dissemination to the CNS,
especially at early time points before the development of clinical disease.
Materials and Methods
HNT is a hamster-neuroadapted strain of
Philadelphia-26, which was originally isolated from the
blood of a patient with acute measles [481. It had been
passed more than 100 times in hamster brains and multiple
times in a continuous green monkey kidney cell line
From the Department of Neurology, University of California,
San Francisco, School of Medicine, San Francisco, CA, and the
?Veterans Administration Hospital, 4150 Clement St, San Fran-
cisco, CA 94121.
Received Mar 3 1, 1980, and in revised form May 5. Accepted for
publication May 12, 1980.
(Vero). Before the strain was used for these studies, 6
newborn hamster brain-to-brain passages were made. Stock
virus consisted of a clarified 10% homogenate of infected
brain in phosphate-buffered saline (PBS) and had a 50%
tissue culture infectious dose (TCID,,) of 104.45
per milliliter in Vero cells.
For control studies, HNT virus was inactivated by exposure to ultraviolet irradiation for 60 minutes. Before being
used, the material was tested for infectivity by inoculation
into Vero cells and observation for cytopathic effect (CPE).
No CPE was seen after ultraviolet irradiation of virus.
Pregnant golden Syrian hamsters (California
Department of Health Services, Fairfield, CA) were obtained at approximately 1 3 to 15 days’ gestation. Threeday-old hamsters were lightly anesthetized with ether. A
drop of 10% wlv suspension of virus was applied to the
nostrils and mouth. The hamsters were held in a supine
position for 2 to 3 minutes and were watched as they inhaled the inoculum. For every litter so treated, one animal
inhaled India ink to check where the suspension was after 3
to 5 minutes. In all cases, India ink was seen in the bronchoalveolar tree. India ink was never seen in the region of
the cribriform plate or intracranially. Control animals were
treated similarly with inactivated HNT virus.
CELL CULTURES. Hamster tissues were processed as homogenates and primary cultures and by co-cultivation with
Vero cells in the earlier part of the experiment. Virus could
Present address: Departments of *Pathology and *$Neurology,
The Johns Hopkins University School of Medicine, Ba!timore,
MD 21205.
Address reprint requests to Irma M. Parhad, MD, Neuropathology Division, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
0364-5134/81/010021-07$01.25 @ 1980 by the American Neurological Association 2 1
not be cultured from the homogenates. The results obtained by primary culture and cocultivation were identical.
Later experiments used only primary culture. For primary
culture of hamster brain, lung, spleen, kidney, and liver,
tissues were finely minced and trypsinized with 0.25% calcium and magnesium-free trypsin (Gibco, Grand Island,
NY) in PBS for 10 to 15 minutes at room temperature.
Dissociated cells were centrifuged at 400 g, washed two
times with calcium- and magnesium-free PBS, suspended
in Lebowitt medium (L-15) (Microbiological Associates,
Bethesda, MD), supplemented with 20'9% fetal calf serum
(FCS), gluramine 10 mM/dl (Gibco, Grand Island, NY),
100 unitdm1 penicillin, and 5 0 kg/ml of streptomycin,
seeded into plastic flasks (Corning Glassworks, Corning,
NY) and incubated as closed stationary cultures at 37°C.
Once a monolayer formed, the FCS concentration in the
media of these primary cultures was gradually dropped to
5%. Confluent primary cultures were observed for CPE for
at least 21 days. Before being discarded, the cultures that
lacked CPE were washed and hemadsorbed with an 0.2%
suspension of monkey red blood cells (RBC) for 9 0 minutes at 37"C, followed b17 a PBS wash; they were then surveyed for hemadsorbing cells. T h e supernatant of explant
cultures that had CPE was passed onto Vero monolayer
cultures maintained in L-15 with 5% FCS to check for the
presence of free virus.
Heparinized whole blood was cultured in two ways. It
was directly applied on a monolayer of Vero cells for 30
minutes to 1 hour, after which the monolayer was washed
with calcium- and magnesium-free PBS and maintained in
L-15 medium with log, FCS. Heparinized blood was also
diluted up to 5 ml with L-15 and overlaid on a 6 ml gradient
of Ficoll-Paque (Pharmacia Fine Chemicals, Piscataway,
NJ), centrifuged (400 g ) for 45 minutes at room temperature and the mononuclear cells removed from the interphase. Mononuclear cells washed once in L-15 were cultured as explants on Vero cell monolayers maintained with
L-15 medium containing 10% FCS. Cultures were incubated at 37°C and watched for at least 2 1 days; negative
cultures were screened for hemadsorption of monkey
RBC before being discarded.
Hemagglutination inhibition (HAI) test was done by the microtiter method [261
using antigen made by standard methods from Vero cells
infected with the Edmonston strain of measles virus [261.
Tissues from brain, lung,
spleen, and kidney were rapidly frozen in tubes immersed
in a slurry of dry ice and alcohol and were stored at -70°C.
Cryostat-cut 5 p thick sections were air dried, fixed for 10
minutes in cold acetone, and stained by an indirect immunofluorescent method [29]. Optimal specific fluorescence was obtained by using a 1: 20 dilution of serum from
a patient with SSPE (HA1 titer, 1 : 5 12), followed by a
fluorescein-conjugated goat antihuman gamma globulin
(Gibco, Grand Island, NY) diluted 1 : 10. Controls consisted of tissue from mock-infected animals processed in
identical manner and infected material reacted with the
fluorescein conjugate alone. Nonspecific staining was not
seen in any of the control sections.
22 Annals of Neurology Vol 9 No 1 January 1981
PREPARATION FOR HISTOLOGY. Portions of collected
brain, lung, kidney, and spleen were fixed in Bouin's solution (750 ml of picric acid, 250 ml of 40% formalin, and 5 0
ml of glacial acetic acid). Two or more areas from each
brain and one area from lung, kidney, and spleen from each
animal were embedded in paraffin, sectioned, and stained
with hematoxylin and eosin.
Clinical Studies
Eighty-five 3-day-old hamsters inhaled HNT strain of
virus. Twenty control 3-day-old hamsters inhaled inactivated HNT virus. Twenty-seven of the animals
treated with live virus were randomly killed up to day
9 postinoculation (PI). In the remaining group of 58
infected animals and in the 20 control animals, there
was a cannibalization rate of approximately 20% up
to day 6 PI. In the group treated with live virus, there
was an additional 31% (18 hamsters) mortality between days 6 and 60 PI. The sick animals fed poorly
and developed a terminal neurological syndrome
characterized by seizures and a slow, ataxic gait. No
additional deaths occurred in the control group observed to day 60 PI (Fig 1).
Virological a n d Serological Studies
Immediately after inhalation of virus and daily for the
next 9 days, 3 animals were randomly killed. Portions
of lung, spleen, kidney, and brain were individually
pooled for primary culture and blood pooled for explant culture on Vero cell monolayers. Virus was recovered from the lung at all times. Virus was recovered from the spleen on days 7 to 9 PI and from
F i g I . Percentage mortality in 3-day-old hamsters after inha) and in control 3lation of H N T strain of virus (day-old hamsters after inhalation of inactivated H N T strain
(- - - - -1. Thefirst group consisted of 58 animals, the control
group of 20 animals. Both groups were watched for 60 days
postinhalation (DPI).
F i g 2. Presence (+) or absence (-) of HNT strain of virus as
noted by the presence or absence of cytopathic eHect in primary
cultures of brain, spleen, and lung. Three-day-old hamsters inhaled HNT virus and 3 animals were randomly killed daily
(except on day 8) up to 10 days postinhalation (DPI).From
days 10 t o 22 postinhalation, sick animals were selected and
individually processed f o r viral studies. Virus could be recovered
from the lung at all times: virus appeared transiently in the
spleen and was seen in the brain aft.. 9 days. No virus could
be cultured from the blood at any time.
F i g 3 . Indirect immunojluorescence technique showingjluorescence of measles-specific antigen within the cytoplasm of infected cells (arrow) of the lung tissue. The hamster inhaled the
virus at 3 days of age and was killed 21 days later. ( ~ 4 9 8
before 10% reduction.)
the brain on day 9 (Fig 2). Because primary cultures
were used, no assessment of the amount of virus present was possible. Between days 10 and 22 PI, a total
of 9 sick animals were identified and individually
studied in a similar manner. All of these animals had
virus recoverable from lung and brain by primary
culture but virus was not found in any other organ
culture (Fig 2). In addition, the cell-free supernatant
from the primary cultures with CPE, when passed
onto Vero monolayer cultures, then produced CPE
in the latter.
At 2 months, there remained 27 animals ( 4 6 % )
that had received live virus; none showed clinical
evidence of encephalitis. These animals were divided
into five groups. Portions of brain and lung tissue
from each group were pooled for primary culture,
tissue from each animal was individually processed
for histological study, and pooled sera of each group
was used for antibody determination by HAI. Virus
was not recovered from either brain or lung. However, two groups had significant measles antibody titers (1:8 and 1 : 64); measles antibody titers in the
other three groups were less than 1: 2.
Pathological Findings
Clinically ill animals sacrificed between days 6 and 22
PI were studied by routine histological and immunofluorescent techniques. No histological abnormalities were found in the lung; however, by indirect
immunofluorescence, measles-specific antigen was
seen within infected cells (Fig 3 ) . Viral specific antigens were first seen at day 6 PI and were noted
throughout the course of the clinical disease.
The neuropathological findings could be divided
into acute and subacute forms. In the few animals
that developed clinical signs of encephalitis before
Parhad et al: Measles Encephalitis 23
F i g 4. Measles syncytia (arrow), i.e., eosinophilic homogeneous
masses surrounded by many nuclei, in the cerebellar cortex of a
hamster that inhuled the virus at 3 da.ys of age and was
sacri’ic-ed 9 dais later. The empty space in the ceater is an artgact where necrotic tissue has fallen out. (H&E; X430 before
10% reduction.)
F i g 6. Intrariuclear inclusions (arrows) i n glial cells in the
brainstem of a sick humster that inhaled the virus at 3 days of
age and was killed 21 days later. (H&E; X640.1
Fig 5 . Periuasular lyrnphorytic cuffEng (arrow) seen in the
brainstem region of a sick ataxic hamster that inhaled the
virus at 3 day^ of age and wus killed 22 days Later. ( H 6 E ;
Fig 7 . Vacuolation i n the neuronal cytoplasm (arrow) in the
brainstem region of a sick hamster that inhaled the virus at 3
days of age and was sacrificed22 days later. ( H h E ; X300.)
day 10 PI, lesions consisted of multifocal areas of necrosis containing intracytuplasmic inclusions and
measles syncytia (Fig 4 ) . The lesions were most
commonly seen in the cerebellum and brainstem.
The majority of animals died between days 10 and
22 from a subacute encephalitis characterized by
perivascular lymphocytic infiltration (Fig 5 ) and
scattered foci of eosinophilic intranuclear inclusions
surrounded by pale halos (Fig 6). Neuronal and glial
intracytoplasrnic vacuolation, which was most noticeable in the brainstem, was also seen (Fig 7). Finally,
angular, shrunken hyperchromatic neurons were
present, most prominently among the Purkinje
cells of the cerebellum and motor brainstem nuclei
Annals of Neurology
Vol c)
N o 1 January 1981
munodeficient patients, on the other hand, the
pneumonia can be a more fulminant process, with
measles syncytia noted on pathological examinations
F i g 8. Shrunken, dark Purkinje cells (arrows) and normallooking ones (arrowheads) seen i n the cerebellar cortex ofa sick
hamster that inhaled the virus at 3 days of age and was killed
21 days later. ( H 6 E ; X380 bejore 10% reduction.)
Fig 9. Indirect immunojluorescence technique showing jluorescence of measles-specific antigen within the cytoplasm (arrows)
of the shrunken, dark Purkinje cells seen in Figure 8.
Normal-appearing Purkinje celh did not immunojluo resce.
( X I 5 9 before 10% reduction.)
(Fig 8). These “ischemic” neurons were shown by
immunofluorescence to contain measles-specific antigen (Fig 9).
The 27 clinically well survivors were studied by
histological techniques at day 60 PI. No lesions were
found. No lesions were seen at any time in spleen or
The portal of entry for naturally occurring measles is
the respiratory tract. Virus may be cultured from
respiratory tract secretions and lung during the prodrome [27]. A mild pneumonitis, as evidenced by
chest roentgenogram, occurs in up to 60% of patients with uncomplicated measles [27].Pathological
changes in the lungs of patients dying of measles [42]
and in monkey models [431 are for the most part
nonspecific, consisting of a mild patchy interstitial
pneumonitis or thickening of alveolar walls. In im-
Measles virus can be recovered in humans consistently from the leukocytic fraction of blood, soon
after the appearance of the exanthem [17, 371. Dissemination of virus to many organs may thus occur.
In SSPE, viremia and involvement of organs outside
the CNS has rarely been documented. However,
measles virus has been recovered from lymph nodes
of two patients with SSPE [21] and measles antigen
has been shown to be associated with interstitial
mononuclear cells in lung, spleen, kidney, liver, and
lymph nodes [14, 231.
About one-third to one-half of patients with uncomplicated mealses have cerebrospinal fluid (CSF)
pleocytosis [ 12, 331 and transient electroencephalographic abnormalities 1161. Measles virus has been
cultured from brains of patients with measles encephalitis [41, 441 and SSPE [lo, 20, 36, 4 4 , 471. In
addition, measles virus has been recovered from CSF
of patients with measles encephalitis [30, 311 and
measles antigen detected in the mononuclear cells of
CSF in a patient with SSPE [13].Taken together,
these studies suggest that measles virus reaches the
CNS quite often in patients with naturally occurring
Although in humans there is presumptive evidence
for the route of transmission of measles virus to the
CNS [ 2 7 ] ,few animal models have investigated this
subject. Blood from a patient with measles was inoculated by intranasal and subcutaneous routes into
monkeys [40].This study suggested a primary replication of virus in the lung, followed by proliferation
of the virus in the reticuloendothelial system and a
consequent viremia with seeding of virus in various
organs. No virus was found in the brain [40].HNT
inoculated intranasally into hamsters caused a high
percentage of mortality from an encephalitis; however, the route of the transmission of virus to the
CNS was not studied [511. A hamster neuroadapted
strain of measles virus, HBS, inoculated intraperitoneally in newborn hamsters caused encephalitis in
209% of animals. Virus was cultured from lung and
spleen of these animals o n l y after they were
moribund between days 7 and 18 PI [7]. Our systematic search for virus early after peripheral inoculation
suggested a replication in the lung, dissemination
probably via the blood, transient appearance of virus
in the spleen, and a terminal encephalitis in 31% of
infected hamsters. Virus could not be cultured from
the blood by various methods used, which might not
have been sensitive enough to detect cell-associated
virus within a small proportion of circulating teukocytes. N ot all of the surviving hamsters had antibody
Parhad et al: Measles Encephalitis 25
to the virus. This might signify that the virus did not
replicate in all inoculated animals; alternatively, the
immune system of a proportion of the inoculated
newborn hamsters may not have responded with
antibody formation or produced antibody of other
than HA1 specificity.
The lesions seen in brain-i.e., multifocal necrosis, perivascular infiltrates, and intracytoplasmic and
intranuclear inclusions-were
similar to those seen
in patients with measles encephalitis [ 11 or SSPE [ 15,
17, 34, 351 and in animals inoculated with various
strains of measles virus [4,7, 9, 18, 24, 38, 48, 50,
5 I]. The vacuolated neurons seen in our animals have
been described with various viral encephalitides [2,
6, 49, 501 including a subacute measles encephalitis
[50, 511. The pyknotic neurons seen in the brainstem
and Purkinje cells of the cerebellum are consistent
with nonspecific agonal changes; electron microscopic observation failed to show either budding
virions, nucleocapsids, or other evidence of viral
replication within such cells (Parhad and Wolinsky,
unpublished observations, 1779). However, by conventional immunofluorescence, these same neurons
were shown to contain measles antigen, suggesting
that the histopathological changes may have represented a cytopathic effect of defective measles virus
replication within these neural cells. A previous
study on subacute HNT strain measles encephalitis
in weanling mice [ 181 supports this conclusion. These
investigators studied the ultrastructural location of
viral antigen in neurons using immunoperoxidase
methods. Viral antigen was noted within the cytoplasm of cells, but there was no evidence of nucleocapsid o r virion formation. Virus could not be recovered from brain explants of these mice using a
wide variety of rescue techniques [39]. Despite the
apparent defective nature of the viral infection of
hamster neurons in vivo, productive infection could
be readily reestablished in brain explant cultures,
suggesting that an as yet unidentified host factor (or
factors) is important in the induction and maintenance of a block in viral assembly and maturation in
neurons in vivo.
The correlation between the histological alterations and the presence of viral antigen as detected by
indirect immunofluorescence varied according to tissue o r cell type. In the lung, although cells laden with
viral antigen were common, no histological alterations were seen. In the CNS, antigen was invariably
noted in lesions consisting of measles syncytia. However, antigen was also found in individual cells with
only minor histological alterations such as pyknosis
and shrinkage. The variable relationship between the
presence of measles antigen within a cell and the resulting histological alteration might suggest a selective vulnerability of different cells to measles virus.
26 Annals of N e u r o l o g y Vol 9 No 1 January 1981
In this newborn hamster model, encephalitis occurs following a “natural” route of infection and
afflicts a relatively large percentage of animals. It is
therefore a suitable model for further study of the
conditions that affect the development of encephalitis after measles infections.
Supported in part by Grants NS12064, NS14069, and NS07073
from the National Institutes of Health, by the National
Foundation-March of Dimes, and by the Medical Research Service of the Veterans Administration. D r Wolinsky is the recipient
of Research Career Development Award 1 KO4 NS/AI443.
We thank Ms Cheryl Padula and Ms Sue Simmons for their assistance in preparing the manuscript.
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