Necrotizing Meningoencephalitis of Maltese Dogs
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Vet Pathol 32:230-235 (1995)
Necrotizing Meningoencephalitis of Maltese Dogs
I. H. STALK,B. CHADWICK,B. DAYRELL-HART,
B. A. SUMMERS,
AND T. J. VANWINKLE
Laboratory of Pathology (IHS, TVW) and Department of Clinical Studies (BD), School of Veterinary Medicine,
University of Pennsylvania, Philadelphia, PA; Department of Pathology,
School of Veterinary Studies, Murdoch University, Perth, WA, Australia (BC); and
Department of Pathology, New York State College of Veterinary Medicine,
Cornell University, Ithaca, NY (BAS)
Abstract. The clinical and pathologic features of five young Maltese dogs with a necrotizing meningoen-
cephalitis were studied and compared with published reports of the necrotizing meningoencephalitis of Pug
dogs. The ages of the Maltese dogs ranged from 9 months to 4 years. Four dogs were male, and one was female.
The dogs had a history of seizures with or without other neurologic signs for 3 days to 20 weeks prior to death.
Cerebrospinal fluid examination in three dogs revealed a pleocytosis and elevated levels of protein. At necropsy,
the cerebrum was asymmetrically swollen in four dogs, with a loss of distinction between the gray and white
matter and mild to moderate asymmetrical dilation of the lateral ventricles. Histologically, there was extensive
necrosis and nonsuppurative inflammation of the cerebral gray and white matter, overlying meninges, and
adjacent thalamus and hippocampus. The 4-year-old dog had the longest duration of clinical signs and had little
inflammation but extensive atrophy of affected areas, with astrocytosis. The clinical course and pathologic
changes in these Maltese dogs are indistinguishable from those in reported cases of necrotizing meningoen-
cephalitis of Pug dogs, indicating that this lesion is probably not unique to Pug dogs.
Key words: Dogs; encephalitis; Maltese dogs; meningoencephalitis.
Meningoencephalitis with necrosis of the neuropa- more seizures and was returned to the veterinarian for further
renchyma occurs in dogs secondary to a variety of examination. At that time, an initial cerebrospinal fluid (CSF')
infectious agents, including protozoa, viruses, and fun- evaluation revealed a high white blood cell (WBC) count (85
gi; however, in many dogs the cause of the meningo- WBC/mm3) and protein content (33 mddl). The differential
cell count was 50 neutrophils, 25 lymphocytes, and 10 mono-
encephalitis is unknown. We report here on five Mal-
cytes. Despite continued treatment with phenobarbital, dexa-
tese dogs that had a necrotizing meningoencephalitis methasone, and amoxicillin, the clinical signs progressed and
of unknown etiology that resembles the necrotizing the dog was referred to the VHUP. On physical examination,
meningoencephalitis of Pug dogs. the dog had ataxia, hind-limb paresis (which was worse on
the left), postural deficits in both hind limbs and the left
Materials and Methods forelimb, and a left menace deficit with normal pupillary
Three Maltese dogs (Nos. 1-3) were clinically evaluated at light response. A second CSF evaluation was within normal
the Veterinary Hospital of the University of Pennsylvania limits. Computed tomography (CT) scans revealed a radio-
(VHUP). One dog (No. 4) was evaluated by a private prac- lucent, non-contrast-enhancing area in the left cerebrum and
titioner and one dog (No. 5 ) was seen at the Murdoch Uni- dilation of the ventricular system. Magnetic resonance im-
versity Veterinary Hospital (MUVH) in Western Australia. aging (MRI) revealed high-signal regions in the right parietal
The signalment and clinical findings of these five animals are and left frontal areas as well as asymmetrically dilated lateral
summarized in Table 1. ventricles. The radiographic interpretation was that an ische-
Dog No. 1 was a 4-year-old male that was presented to mic or inflammatory condition existed. Despite therapy, sei-
the referring veterinarian because of seizures. The dog had zure activity continued with increasing frequency and the
been vaccinated 6 months previously with a distempedhep- dog was euthanatized 5 months after the initial seizure.
atitis/leptospirosis/parvovirus/parainfluenza combination Dog No. 2 was a 16-month-old male who had been vac-
vaccine. At presentation, the dog circled to the right and cinated for distemper and rabies during the first year of life.
wandered aimlessly. The dog was hospitalized and treated The dog was presented to the referring veterinarian with a
with diazepam, phenobarbital, and dexamethasone. Com- 2-3-week history ofprogressive vision loss and a recent onset
plete blood count (CBC), serum chemistry panel, and uri- of seizure activity. Serum chemistry and UA evaluation pro-
nalysis (UA) results were within normal limits. The dog im- duced no significant findings, and the dog was treated with
proved slightly and was discharged after 2 days. There was prednisone. The dog improved only slightly and was referred
gradual improvement over 2 months, but then the dog had to the VHUP. At presentation, the dog circled to the left,
230
Downloaded from vet.sagepub.com by guest on October 26, 2015Vet Pathol 3 2 3 , 1995 Meningoencephalitis of Maltese Dogs 23 1
had right postural deficits, and lacked a menace response Table 1. Signalment and clinical findings for five Maltese
bilaterally but had normal pupillary light responses. An in- dogs with necrotizing meningoencephalitis.
creased number of white blood cells were seen in the CSF
(50 WBC/mm3), but a differential cell count was not done. csl-
~ ~~
Duration of
A CT scan revealed asymmetrical dilation of the lateral ven- No.
Dog Age Sex Clinical signs WBC/ Protein
tricles and dilation of the third and fourth ventricles and mm3 (mg/dl)
aqueduct. There was a contrast-enhancing area in the left 1 4 years M 20 weeks 85 33
parietal lobe, which was suggestive of necrosis or edema. It 161
MRI findings were similar, with ventricular system dilation 2 1 year M 6 weeks 50 QNS
and a high-signal area in periventricular white matter of the 59$ 126$
left parietal region. Differential diagnoses included neoplasia, 3 2 years M 3 days NE NE
inflammation, and hemorrhage. A clinical diagnosis of gran- 4 9 months F 4 days NE NE
ulomatous meningoencephalitis was made. The dog was 5 13 months M 4 weeks 247 111
treated with prednisolone and chloramphenicol, but clinical * Cerebrospinal fluid. Normal values: 0-5 WBC/mm3; 0-25 mg
signs progressed. A second CSF evaluation 3 weeks after the protein/dl. QNS = quantity not sufficientto test. NE = not evaluated.
first revealed elevated white blood cells (59 WBC/mm3) and t Second sample, 15 days later.
protein (126 mg/dl). A differential cell count was not done. 11 Second sample, 21 days later.
The dog was euthanatized 4 weeks after presentation to the
VHUP. necropsied by the pathology sections of the institution at
Dog. No. 3 was a 2-year-old male that had never been which they were clinically evaluated. Tissue samples of major
vaccinated. After its first seizure, the dog was presented to organs were fixed in 10% neutral buffered formalin with the
the VHUP for evaluation. CBC, serum chemistry, and UA exception of brains, which were fixed in 50% formalin. The
results were unremarkable. The dog was normal for the next spinal cord was also removed from dog Nos. 1 and 5. The
36 hours but then had a second seizure. The dog was treated private practitioner performed the necropsy on dog No. 4,
with Valium and phenobarbital but continually paddled and fixed the brain and liver in 10% neutral buffered formalin,
was later euthanatized. and submitted these tissues to the Laboratory of Pathology
Dog No. 4 was a 9-month-old female that had been vac- at the University of Pennsylvania for histologic evaluation.
cinated for coronavirus and distemper virus 3 weeks prior
For all five dogs, representative sections of central nervous
to presentation to a local veterinarian because of a seizure
system and other organs were processed routinely for his-
episode. The dog had bradycardia and tachypnea and was
topathology and stained with hematoxylin and eosin (HE).
slightly dull, but the neurologic examination was otherwise In dog No. 2, only the brain was examined histologically.
normal. Over the next few days, the dog had episodes of Sections of brain from dog Nos. 1,2, and 3 were also stained
weakness, recumbency, dullness, drooling, and focal facial with Lux01 fast blue-Holmes. One section of brain from dog
seizures that alternated with periods when the dog was bright, Nos. 1, 2, 3, and 5 was stained for glial fibrillary acid protein
alert, and ambulatory. One period of opisthotonos was noted (GFAP) in an immunocytochemical procedure using poly-
on the fourth day. The dog was treated with diazepam, phe- clonal antibody (1 : 3,000 dilution) (Dako Corp., Carpinteria,
nobarbital, dexamethasone, and chloramphenicol and de- CA) and streptavidin-biotin. Sections of brain from all five
spite clinical improvement was found dead 4 days after pre- dogs were stained for canine distemper virus antigen using
sentation. a monoclonal antibody to the nucleocapsid protein of canine
Dog No. 5 was a 13-month-old male. This dog had re- distemper virus,5 diluted 1 : 1,000, in a streptavidin-biotin
ceived two distemper/hepatitis/parvovirus vaccinations pri- procedure.
or to 4 months of age and a follow-up parvovirus vaccination
at 4 months of age. The dog was presented to the MUVH Results
with an acute onset of seizure activity. Seizures, which were
not related to external stimuli, recurred over a 3-week period, Significant gross and histologic lesions were limited
with an interictal phase of 4-5 days. The dog was generally to the central nervous system.
normal during the interictal period, although one neurologic
Gross lesions
examination revealed slight hind-limb ataxia, mild bilateral
hind-limb proprioceptive deficit and a behavioral change In dog No. 1, the left cerebral hemisphere was pale
described as increasing nervousness or mild hysteria, partic- gray and swollen. T h e right hemisphere was firm,
ularly when handled. CSF analysis revealed marked leuko- slightly shrunken, and white dorsally with congested
cytosis (247 WBC/mm3) with elevated protein (1 11 mg/dl). meninges laterally and ventrally. On cut surface, there
The differential cell count was 217 lymphocytes, 27 mono- was a loss of distinction between gray and white matter
cytes, and 3 neutrophils. CBC, serum chemistry, and UA i n the rostra1 and middle left cerebrum. T h e right lat-
were unremarkable except for elevated alkaline phosphatase
eral ventricle was moderately dilated, and the right
(540 U/liter; normal = 20-1 84 U/liter). A clinical diagnosis
of granulomatous meningoencephalitis was made, and ther- cerebrum was thinner than the left because of severe
apy with prednisolone was begun. The dog responded poorly atrophy of the white matter.
and was euthanatized 1 week later. No gross lesions were noted i n dog No. 2.
All five dogs were necropsied. Dog Nos. 1,2, 3, and 5 were In dog No. 3, the lateral ventricles were mildly di-
Downloaded from vet.sagepub.com by guest on October 26, 2015232 Stalk, Chadwick, Dayrell-Hart, Summers, and Van Winkle Vet Pathol 3 2 3 . 1995
Fig. 1. Brain, cross section at level of septal nuclei; dog
No. 4.The right side of the brain is swollen. There is a soft
area with a loss of distinction between gray and white matter
in the right cerebrum extending from the coronal sulcus (ar-
row) ventrally to the lateral aspect of the septal nucleus (ar-
rowhead) and medially to the internal capsule. Bar = 0.5 cm.
lated, and the cerebellum and brain stem were com-
pressed. On cut surface, portions of the cerebrum were
soft and gray, and there was loss of distinction between
gray and white matter. Changes were most severe in
the ventral cerebrum.
Fig. 2. Right dorsal cerebrum, base of endomarginal sul-
In dog No. 4, the right piriform and right frontal
cus (*); dog No. 1. There is marked atrophy of the cerebral
lobes were 'Oft and tan with defined sulci' On gray (G) and white (W) matter with marked astrocytosis. HE.
cut surface, there was a soft area in the right ventral Bar = ~ m .
cerebrum with loss of distinction between gray and
white matter, whereas in the right dorsolateral cere-
brum the white matter was slightly widened and poorly mesencephalon. The sclerotic areas were poorly de-
demarcated from adjacent gray matter (Fig. 1). marcated from adjacent tissue by a zone of astrocytic
In dog No. 5 , the lateral ventricles were moderately gliosis, which extended into the right thalamus and left
dilated. Most of the cerebral gyri were flattened. On medial corona radiata. Astrocytic gliosis was also pres-
cut surface, there were multifocal to confluent areas of ent in the corpus callosum and hippocampus bilaterally
discoloration with loss of distinction between gray and and in the caudal ventral cerebrum. Endothelial cell
white matter. These changes were most severe in the hypertrophy was present in the right ventral cerebrum.
occipital and ventral cerebrum. The meninges overlying the sclerotic areas were nor-
mal, but adjacent meninges had mild infiltrates of lym-
Histologic lesions phocytes and macrophages. Small numbers of peri-
In dog No. 1, the left lateral ventricle was mildly vascular lymphocytes and plasma cells were also seen
dilated and the right was moderately dilated. The entire within the spinal cord. GFAP staining of a section of
right cerebral cortex from the frontal lobe through the left rostra1 cerebrum demonstrated large numbers of
occipital lobe, excluding the piriform cortex, was astrocytic fibers in the submeningeal cortex. A few lep-
markedly thinner than the left, with replacement of tomeningeal vessels of the spinal cord had mild peri-
normal parenchyma by numerous astrocytes (Fig. 2). vascular infiltrates of lymphocytes.
Several cavitations up to 1 mm in diameter were pres- In dog No. 2, the dorsal and lateral frontal lobe, the
ent at the junction between gray and white matter. adjacent internal capsule, the right side of the thala-
Perivascular cuffs of lymphocytes were present in these mus, and the right and left hippocampus were affected.
sclerotic areas, in the adjacent parenchyma, in the non- There were extensive areas of necrosis in both white
sclerotic cerebral cortex bilaterally, and in the right and gray matter with infiltrates of macrophages and
Downloaded from vet.sagepub.com by guest on October 26, 2015Vet Pathol 32:3, 1995 Meningoencephalitis of Maltese Dogs 233
Fig. 3. Cerebrum, endomarginal gyrus; dog No. 2. There Fig. 4. Cerebrum, ectosylvian gyrus; dog No. 3. There
is a marked focal infiltration of lymphocytes in the meninges are extensive infiltrates of lymphocytes and macrophages and
and multifocal infiltration around vessels in the parenchyma. scattered neutrophils in the meninges, perivascularly, and in
HE. Bar = 750 pm. the neuropil of the cortex. HE. Bar = 40 pm.
lymphocytes and with perivascular cuffs of lympho- most severe in the right ventral lateral cerebral cortex,
cytes (Fig. 3). Scattered neutrophils were also present. including the piriform cortex, and extended from the
Within affected areas, vessels had plump endothelial frontal lobe caudally through the temporal lobe. Scat-
cells. Astrocytosis was present both within and pe- tered lymphocyte foci were in the contralateral cerebral
ripheral to the lesions. The leptomeninges had mild cortex. In addition, in dog No. 4 at the periphery of
infiltrates of lymphocytes, macrophages, and plasma necrotic areas there were ischemic neurons character-
cells. Staining with Luxol fast blue-Holmes demon- ized by cytoplasmic hypereosinophilia and nuclear
strated decreased myelin in affected white matter. pyknosis.
GFAP stain demonstrated increased numbers of as- Lesions in dog No. 5 were similar to those of dog
trocytes with prominent fibers in white matter pre- Nos. 3 and 4. They were predominantly in the cere-
dominantly adjacent to the necrotic areas. Severely brum and most severe in the gray matter. Rare peri-
sclerotic areas alternated with areas of active inflam- vascular cuffs of lymphocytes were noted in the mes-
mation and necrosis in some sections of the cerebral encephalon and spinal cord. Small numbers of
cortex. lymphocytes and macrophages were present in the lep-
Lesions in dog No. 3 were limited to the neocortex tomeninges of the mesencephalon and cerebellum.
and were similar to those of dog No. 2, except astro- All five cases were negative for canine distemper
cytic sclerosis was not present. The leptomeninges viral antigen by immunohistochemical methods.
overlying the most severely affected areas had more
severe infiltrations of lymphocytes and macrophages Discussion
(Fig. 4) than were seen in dog No. 2. Lesions in dog The clinical and pathologic findings in these five
No. 4 were similar to those of dog No. 3 and were Maltese dogs are similar to those in reported cases of
Downloaded from vet.sagepub.com by guest on October 26, 2015234 Stalk, Chadwick, Dayrell-Hart, Summers, and Van Winkle Vet Pathol 32:3, 1995
necrotizing meningoencephalitis of Pug d o g ~ land . ~ to vascular bed. No vascular lesions have been reported
those of Pug dogs with necrotizing meningoencepha- in Pug dogs, and none were noted in these Maltese
litis seen at our institutions. The lesions are quite dis- dogs or in Pug dogs we have examined.
tinctive and do not resemble those of any other canine The dog with the longest clinical history (20 weeks,
neurologic disease. dog No. 1) also had the most extensive atrophy and
The definitive diagnosis of this disease is based on astrocytic sclerosis, whereas the dogs with short clinical
histologic findings. The neurologic signs (predomi- courses (3 and 4 days, dog Nos. 3 and 4) did not have
nantly seizure activity) and CSF findings are compat- extensive sclerosis. In dog No. 2, the clinical signs
ible with cerebral disease but are nonspecific. Similar began 6 weeks prior to death, and areas of necrosis and
signs and clinical findings may be present in a variety inflammation alternated with areas of sclerosis.
of inflammatory, necrotizing, and neoplastic condi- The predilection of this disease for the cerebrum is
tions. Several of these dogs had a clinical diagnosis of an important feature, which has also been noted in Pug
granulomatous meningoencephalitis (GME) based on dogs with necrotizing meningoencephalitis. A pre-
the clinical signs and CSF results. There were no lesions dilection for cerebellar and cerebral white matter has
in any other organs that could be correlated with the been noted with focal GME,3 but most inflammatory
necrotizing meningoencephalitis. diseases of the nervous system are not site specific, and
Two dogs (Nos. 1 and 2) were evaluated with MRI many cases of GME involve the brain stem and spinal
and CT scans. The location of the lesions detected cord extensively. Inflammation of the trigeminal gan-
generally correlated with those seen at necropsy. In dog glia was noted in two Pug dogs,' but this site was not
No. 2, the scans had shown dilated third and fourth evaluated in these Maltese dogs.
ventricles, which were considered normal at necropsy. The lesions in these Maltese dogs and in Pug dogs
Results of these ancillary studies were insufficiently previously examined by us and reported by others are
conclusive to permit a definitive diagnosis, but results somewhat suggestive of a viral etiology. Authors of
were compatible with necrotizing meningoencephali- one study proposed that a herpesvirus might be in-
tis. Based on our findings, when MRI or CT scans volved because of some similarities between necrotiz-
suggest a focal inflammatory lesion, necrotizing en- ing meningoencephalitis of Pug dogs and human her-
cephalitis should be considered as a diagnosis. pes simplex type 1 (HSV-1) encephalitis.' In adults
The normal CSF findings (in one of two samples) in with HSV- 1 infection, lesions are localized to the basal
dog No. 1 when the dog was reevaluated later in the frontal-temporal regions and are often unilateral but
course of the disease may have been a reflection of lack do not have extensive deep white matter necrosis.2 In
of active necrosis or meningeal involvement at the time llamas infected with equine herpesvirus- 1, lesions were
of examination or the result of glucocorticoid therapy. most severe in the rostra1 cerebrum, and neuronal
The etiology of this necrotizing meningoencephalitis changes were very mild caudal to the level of the thal-
is unknown. Some reported cases of necrotizing me- amus. These llamas had a vasculitis with edema and
ningoencephalitis in Pug dogs occurred in related an- multifocal hemorrhage and intranuclear inclusion bod-
imals, suggesting that there may be a genetic compo- i e ~Attempts
.~ at virus isolation in Pug dogs with nec-
nent.Ix3 The predilection for purebred animals might rotizing meningoencephalitis have been unsu~cessful.~
also suggest a genetic component. The relationships Our attempt to identify herpesvirus antigen within the
among the dogs in this study is unknown, but the three brains of these dogs was unsuccessful because of dif-
dogs examined at the VHUP were obtained from ficulties in establishing an immunocytochemical pro-
breeders in three different states. cedure for canine herpesvirus in formalin-fixed central
Four of these Maltese dogs were males; however, the nervous system tissues. Canine distemper virus (CDV)
sample size is small and sex predisposition is uncertain. antigen was not identified in the brains of these dogs.
A sex predilection has not been noted in Pug dogs. However, this result does not exclude the possibility
Four of these dogs were 2 years old or younger. A of a restricted CDV infection that would not be de-
similar age predilection has been noted in Pug dogs.' tected by the methods used.
The vaccination history for these dogs is incomplete Clinically and pathologically, this necrotizing me-
but highly variable. One dog had never been vacci- ningoencephalitis in Maltese dogs closely resembles
nated; others were adequately vaccinated. No corre- necrotizing meningoencephalitis of Pug dogs, and these
lation could be made between vaccination status and two diseases probably are a single entity. We have also
the necrotizing meningoencephalitis. seen similar lesions in a few dogs of other breeds. Re-
The distribution of lesions is not consistent with a cently, we examined a 2-year-old castrated male Shih
vascular etiology. Although lesions were often local- Tzu dog with clinical signs and lesions similar to those
ized, they occasionally were continuous across the mid- of necrotizing meningoencephalitis of Pug dogs. The
line and extended beyond the distribution of a single brain of this dog was negative for CDV using immu-
Downloaded from vet.sagepub.com by guest on October 26, 2015Vet Pathol 32:3, 1995 Meningoencephalitis of Maltese Dogs 235
nohistochemical methods. A nonsuppurative necro- References
tizing encephalitis in Yorkshire terriers has recently Cordy DR, Holliday TA: A necrotizing meningoenceph-
been reported.6 In those dogs, although the distribution alitis of pug dogs. Vet Pathol 26: 19 1-1 94, 1989
O f lesions is different from that Seen in Pug and Maltese 2 Davis RL, Robertson DM: Textbook of Neuropathology,
dogs, the lesions themselves are similar. Evidence of 2nd ed. Williams and Wilfins, Baltimore, MD, 199 1
CDV and canine herpesvirus infection was also not 3 deLahunta A: Veterinary Neuroanatomy and Clinical
identified in the Yorkshire terriers. Instances of com- Neurology, 2nd ed. WB Saunders Co., Philadelphia, PA,
parable lesions in other breeds suggest that the entity 1983
ofnecrotizing meningoencephalitis may be more wide- 4 House JA, G r e g DA, Lubroth J, Dubovi EJ, Torres A:
spread among dogs than previously thought. Experimental equine herpesvirus- 1 infection in llamas
(Lama ,duma). J Vet Diam Invest 3:137-143. 1991
Acknowledgements
5 c,
Orvell SheshberadaranH, Norrby E: Preparation and
characterization of monoclonal antibodies directed against
Clinical diagnostic testing, including computer assisted to- four structural components of canine distemper virus. J
mography and magnetic resonance imaging studies, were Gen Virol 66:443456, 1985
supported by the Charing Cross Research Foundation and 6 Tipold A, Fatzer R, Jaggy A, Zurbriggen A, Vandevelde
Estherena and Donald Schotland. We thank Ms. Juli Burns M: Necrotizing encephalitis in Yorkshire temers. J Small
and Mr. James Hayden for valuable technical assistance. Anim Pract 34:623-628, 1993
Request reprints from Dr. T. J. Van Winkle, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce
Street, Philadelphia, PA 19104 (USA).
Downloaded from vet.sagepub.com by guest on October 26, 2015You can also read
