Vet Pathol 3 l : l .
1994 Brief Communications and Case Reports
the nature of the disease in these birds. Presently, the only
preventive measures available to emu farmers are control of
potential arthropod vectors and administration of an inac-
tivated equine vaccine. A specific product has not yet been
approved for birds, and the equine vaccine may not afford
adequate protection in all avian specie^.^.^
References
1 Dein FJ, Carpenter JW, Clark GG, Montali RJ, Crabbs
CL, Tsai TF, Docherty DE: Mortality of captive whoop-
ing cranes caused by eastern equine encephalitis virus. J
Am Vet Med Assoc 189:1006-1010, 1986
2 Eisner RJ, Nusbaum SR: Encephalitis vaccination of
pheasants: a question of efficacy. J Am Vet Med Assoc
183:280-281, 1983
3 Jackson AC, SenGupta SK, Smith JF: Pathogenesis of
Venezuelan equine encephalitis infection in mice and
hamsters. Vet Pathol 28:4 10-4 18, 199 1
4 Ranck FM, Gainer JH, Hanley JE, Nelson SL: Natural
outbreak of eastern and western encephalitis in pen-raised
chukars in Florida. Avian Dis 9:8-20, 1965
Vet Pathol31:111-115 (1994)
Uremic Encephalopathy in a Horse
A. D. WELDON,R. M. LEWIS,AND B. A. SUMMERS
P. R. BOUCHARD,
Key words: Alzheimer type I1 astrocytes; horse; uremia; uremic encephalopathy.
Uremic or renal encephalopathy is an uncommonly re-
ported syndrome of diffuse central nervous system (CNS)
dysfunction that occurs concurrently with, and as a result of,
renal failure. The clinicopathologic syndrome has been de-
scribed in human being^,^.^.^.^.^^.^^ dogs,Ib woodchucks,' rats,6
and a cow.l5 To the authors' knowledge, it has not been
previously reported in the horse. The case reported here
therefore represents the first description of uremic enceph-
alopathy (UE) in the horse and contrasts the histopathologic
lesions from those reported in other species and illustrates a
unique form of reactive astrogliosis in domestic animals.
A 13-year-old grade mare was presented to the Cornell
University College of Veterinary Medicine with a 4-day his-
tory of progressive anorexia, listlessness, and bizarre behav-
ior typified by periodic recumbency, head pressing, and sei-
zure-like activity. Prior to admission, the mare had been
treated daily for an undetermined and presumptive toxicity
with thiamine, atropine, and mineral oil. Upon presentation,
the mare was recumbent and semicomatose. Signs of central
blindness were evident with no menace response and an in-
tact pupillary light response.
On physical examination, she was found to be tachycardic
(heart rate = 120/minute) and normothermic (38 C) with
pink mucous membranes and a capillary refill time of less
than 2 seconds. Rectal examination revealed an impacted
111
5 Riddell C: Nervous system. In: Avian Histopathology,
1st ed., p. 77. American Association of Avian Pathologists,
Inc., Allen Press, Lawrence, Kansas, 1987
6 Shope RE: Eastern viral encephalomyelitis. J Am Vet
Med Assoc 136:339-340, 1960
7 Snoeyenbos GH, Weinack OM, Rosenau BJ: Immuni-
zation of pheasants for eastern encephalitis. Avian Dis 22:
386-390, 1977
8 Tully TN Jr, Shane SM, Poston RP, England JJ, Vice CC,
Cho D-Y, Panigrahy B: Eastern equine encephalitis in a
flock of emus (Dromaius novaehollandiae). Avian Dis 36:
808-812, 1992
9 Williams JE, Young OP, Watts DM, Reed TJ: Wild birds
as eastern and western equine encephalitis sentinels. J Wild1
Dis 7:188-194, 1971
Request reprints from Dr. R. S. Veazey, Department of Vet-
erinary Pathology, School of Veterinary Medicine, Louisiana
State University, Baton Rouge, LA 70803 (USA).
small colon with minimal gas distention. Differential diag-
noses included viral encephalitis, hepatic encephalopathy,
lead poisoning, leukoencephalomalacia, renal failure, pros-
encephalic neoplasia, and colon obstruction.
Among the diagnostic tests performed were a complete
blood count, biochemical profile, and a cerebrospinal fluid
tap. Abnormal results included a mild anemia (packed cell
volume 29%; normal = 3 1-43), a neutrophilic leukocytosis
(white blood cells = 26.1 thousand/& normal = 5.5-12.0;
neutrophils = 24.3 thousand/pl; normal = 2.6-6.5), lym-
phopenia (1.3 thousand/pl; normal = 1.6-6.2), hypoalbu-
minemia (2.1 g/dl; normal = 2.7-3.7), and hyperglobulinem-
ia (4.5 g/dl; normal = 3.44.3). Serum potassium and chloride
concentrations were both low at 2.1 mEq/liter (normal =
2.84.8) and 80 mEq/liter (normal = 97-107), respectively.
The mare also was found to be markedly azotemic with a
blood urea nitrogen (BUN) of 166 mg/dl (normal = 10-27)
and creatinine of 8.2 mg/dl (normal = 1.0-2.0). Cerebrospi-
nal fluid analysis was unremarkable on routine examination.
Due to the clinical findings of severe neurologic dysfunc-
tion and small colon impaction, a poor prognosis was given.
The owners elected to euthanatize the mare.
At necropsy the kidneys were slightly enlarged and pale
tan on both the capsular and cut surfaces. The content of
both the large and small colons was remarkably firm and dry
I12 Brief Communications and Case Reports
Fig. 1. Kidney cortex demonstrating marked diffuse tu-
bular dilation and regeneration with interstitial fibrosis and
nonsuppurative inflammatory infiltrates. In addition, there
is acute tubular necrosis (arrow). Bar = 100 pm.
indicating severe dehydration. There were no gross abnor-
malities of the CNS.
Tissues were fixed in 10% neutral buffered formalin and
processed for routine histologic examination, and 6-pm-thick
sections were stained with hematoxylin and eosin.
Histologically, the kidneys demonstrated severe, subacute,
diffuse tubulo-interstitial nephritis with superimposed acute
tubular necrosis (Fig. 1). There was moderate diffuse tubular
dilatation with expansion of the interstitium by small amounts
of mature connective tissue, moderate edema, and moderate
multifocal predominantly lympho/plasmacytic inflamma-
tory cell aggregates. There were frequent dilated tubules with
amorphous proteinaceous casts and occasional cellular casts
composed of primarily degenerate neutrophils admixed with
sloughed necrotic tubular epithelial cells and occasional
mononuclear inflammatory cells. Most tubules and collecting
ducts had variably flattened and attenuated lining epithelial
cells, and some tubules had plump basophilic epithelial cells
with piling up of cells and rare mitotic figures indicating
regeneration. In addition to the chronic tubulo-interstitial
changes, there were scattered individual and small groups of
acutely necrotic tubules with cytoplasmic hypereosinophilia
and nuclear pyknosis (Fig. 1).
Sections of the CNS from the cerebral cortex, basal nuclei,
Vet Pathol 3 l : l . 1994
Fig. 2. Cerebral cortex gray matter, HE stain. Note the
edematous reactive astrocytes with swollen vesicular nuclei
and a tendency to cluster in small groups usually around
neurons (arrows). Bar = 25 pm. Inset: Higher magnification
of a large astrocytic cluster with marked nuclear vesiculation.
thalamus, midbrain, medulla, cerebellum, and several levels
of the spinal cord were examined histopathologically.
Throughout all regions of the brain but sparing the spinal
cord, there was a marked diffuse reactive astrocytic change.
The astrocytes in both gray and white matter were charac-
terized by marked cellular swelling with indistinct cell bor-
ders, a large amount of clear or sometimes lightly eosinophilic
cytoplasm, and centrally located nuclei. The nuclei were large,
averaging approximately 15 pm in diameter, and were often
irregularly shaped with prominent nuclear indentations and
folds. The chromatin pattern was open-faced with small,
indistinct chromatin bodies. In addition to the individual
cellular changes, within the cortical gray matter and the cer-
ebellar Purkinje cell layer, the astrocytes tended to cluster in
small groups of twc to six cells, often adjacent to neuronal
cell bodies (Fig. 2).
Unstained deparaffinized sections of the cerebral cortex
were immunohistochemically stained for glial fibrillary acid-
ic protein (GFAP) and s-100 antigen using a strepavidin-
biotin procedure (dilutions: GFAP 1 : 3,000, Dako, Santa
Barbara, CA; S-100 1 : 100, Dako). Negative controls were
stained with non-immune serum from the same species as
the primary antibody. Positive control tissue was cerebral
Vet Pathol 3 I : I . I994 Brief Communications and Case Reports 1 I3

Fig. 4. Cerebral cortex white matter glial fibrillary acidic

Fig. 3. Cerebral cortex gray matter glial fibrillary acidic protein immunostain with methyl green counterstain. Note
protein immunostain with Gill's hematoxylin counterstain. the marked positive staining of astrocytic cytoplasmic pro-
Note the complete lack of staining of the reactive astrocytes cesses. Bar = 40 fim.
(arrow). Bar = 25 fim.
animals, the syndrome is less well characterized and is typ-
ically described as a nonspecific CNS disorder with parox-
cortex from an age- and sex-matched normal horse stained ysmal signs of both neuronal depression and excitation in-
with the same procedure. dicating a diffuse neuronal dysfunction.I6
Virtually all reactive gray matter astrocytes were negative The pathologic lesions of UE in human beings are varied,
for GFAP, but the glial limitans and fibrous white matter and no consistent gross or histopathologic abnormalities of
astrocytes retained strongly positive GFAP cytoplasmic fil- the CNS are r e p ~ r t e d . ~In. ~animals ~ - ~ ~ with known or sus-
aments (Figs. 3, 4). Control tissue from the age- and sex- pected renal failure a characteristic white matter spongiform
matched normal horse demonstrated a small amount of change has been described in the brain in two woodchucks
positive fibrillar material at the periphery of most normal with end-stage renal failure, in sheep with experimental
protoplasmic gray matter astrocytes as well as strongly pos- chronic copper toxicity and hemoglobinuric nephrosis, and
itive glial limitans and white matter fibrous astrocytes. In in a Holstein cow with interstitial nephritis.l-ll.15The CNS
contrast, in both the affected and control horse tissues, vir- histopathologic lesions in these cases were all similar and
tually all astrocytes in both the gray and white matter ex- were characterized by spongiform change (polymicrocavi-
hibited positive immunoreactivity for S- 100 antigen with tation) of cerebral, cerebellar, and brainstem white matter.
dense, granular, primarily perinuclear staining (Fig. 5). In addition, swollen astrocytes with large nuclei, prominent
Based upon the laboratory data and gross and histopath- nucleoli, and cytoplasmic distention were noted in the sheep
ologic findings, the final diagnosis was severe, subacute, bi- with copper toxicity.' I These cells correspond to Alzheimer
lateral, chronic, and diffuse tubulo-interstitial nephritis with type I1 astrocytes, which are commonly seen in hepatic en-
superimposed acute tubular necrosis resulting in clinical re- cephalopathy lesions in human beings and some animals.
nal failure and clinical and histopathologic changes of UE. Some of the structures that have been reported as nucleoli
In human beings a specific constellation of clinical signs in Alzheimer type I1 cells may represent chromatin bodies,
has been associated with UE. This includes sensorial cloud- which ultrastructurally are composed of microfilaments and
ing, loss of sustained postural tone (asterixis), tremors, my- g l y ~ o g e nAlzheimer
.~ type I1 cells were not observed in either
oclonus, tetany, motor abnormalities, and c o n v ~ 1 s i o n sIn
. ~ ~ ~the
~ woodchucks or the cow with UE.
I I4 Brief Communications and Case Reports
Fig. 5. Cerebral cortex gray matter S- 100 immunostain
with Gill’s hematoxylin counterstain. Note the diffusely pos-
itive granular cytoplasmic and nuclear staining of astrocytes.
Bar = 25 ym.
The combined lesions of white matter spongy degeneration
and Alzheimer type I1 cells are most commonly associated
with hepatic encephalopathy and have been reported in sev-
eral domestic animal species.? In our experience, lesions of
hepatic encephalopathy in the horse are characterized by a
predominance of Alzheimer type I1 astrocytes with minimal
or no white matter spongy change, and this unique equine
form of reactive astrocytic change was also found in the case
of UE presented here.
The immunohistochemical findings of negative GFAP and
positive S-100 immunoreactivity of the gray matter Alz-
heimer type I1 astrocytes present in this case are also de-
scribed in human beings with Wilson’s disease and resultant
hepatic en~ephalopathy.’.’~ This selective deficit of GFAP
expression is thought to represent an unusual form of pro-
toplasmic reactive change progressing to a degenerative change
and has been referred to as “gliofibrillary dystrophy.”’ This
change can be contrasted with the more typical form of as-
trocytic reaction characterized by hypertrophied cells with
increased GFAP expression and complex cellular branching.
The pathogenesis of the CNS disturbances in uremia is
unknown, but a large number of biochemical abnormalities
are known to occur in uremia. Many uremic toxins, meta-
Vet Pathol 31:l. 1994
bolic disturbances, and amino acid imbalances have been
identified and implicated as causative agents in this syn-
d r ~ m e . ~ . Abnormalities
~~~.~.~~ of -the
~ blood-brain
~ barrier and
transport mechanisms have been identified in experimental
uremia in rats, and the most consistent biochemical abnor-
malities associated with clinical manifestations of UE are
imbalances of concentrations of cerebrospinal fluid amino
acids and their derivatives.2,6 However, there is as yet no
accepted unifying explanation for this clinicopathologic syn-
drome.
Uremic encephalopathy has now been identified as a dis-
tinct clinicopathologic syndrome in a number of domestic
animal species. This represents the first report of UE in a
horse and the lesions are similar to those of equine hepatic
encephalopathy being characterized by a diffuse CNS-reac-
tive astrogliosis or Alzheimer type I1 astrogliosis, without
white matter spongiform change. Though the pathogenesis
of this disorder remains obscure, the combination of clinical
signs, serum and urine laboratory abnormalities, and his-
topathologic findings is distinct and should prove diagnostic
for this syndrome.
Acknowledgement
We thank C. A. Smith for excellent assistance with im-
munocytochemistry.
References
1 Anderson WI, deLahunta A, Hornbuckle WE, King JM,
Tennant BC: Two cases of renal encephalopathy in the
woodchuck (Marmota monax). Lab Anim Sci 40:86-88,
1990
2 Biasioli S, D’Andrea G, Feriani M, Chiaramonte S, Fa-
bris A, Ronco C, LaGreca G: Uremic encephalopathy:
an updating. Clin Nephrol 25:57-63, 1986
3 Greenhouse AH: The neuropathology of renal disease.
In; Pathology of the Nervous System, ed. Minkler J, vol.
1, pp. 1029-1042. McGraw Hill Inc, New York, 1968
4 Hooper PT: Spongy degeneration in the nervous system
ofdomestic animals. Acta Neuropathol31:325-35 1, 1975
5 Horita N, Matsushita M, Ishii T, Oyanagi S, Sakamoto
K: Ultrastructure of Alzheimer type I1 glia in hepato-
cerebral disease. Neuropathol Appl Neurobiol7:97-102,
1981
6 Jeppsson B, Freund HR, Gimmon Z, James JH, von
Meyenfeldt MF, Fisher JE: Blood-brain barrier de-
rangement in uremic encephalopathy. Surgery 92:30-35,
1982
7 Kimura T, Budka H: Glial fibrillary acidic protein and
S- 100 protein in human hepatic encephalopathy: im-
munohistochemical demonstration of two glia-associ-
ated proteins. Acta Neuropathol 70: 17-2 1, 1986
8 Lipman JJ, Lawrence PL, Deboer DK, Shoemaker MO,
Sulser D, Tolchard S, Teschan PE: Role of dialyzable
solutes in the mediation of uremic encephalopathy in the
rat. Kidney Int 37:892-900, 1990
9 Lockwood AH: Neurologic complications of renal dis-
ease. Neurol Clin 7:617-627, 1989
10 Ma KC, Ye ZR, Fang J, Wu JV: Glial fibrillary acidic
Vet Pathol 31:l. 1994 Brief Communications and Case Reports I15

protein immunohistochemical study of Alzheimer 1 &
2 astrogliosis in Wilson’s disease. Acta Neurol Scand 78:
290-296, 1988
1 1 Howell JMcC, Blakemore WF, Gopinath C, Hall GA,
Parker JH: Chronic copper poisoning and changes in
the central nervous system of sheep. Acta Neuropathol
29:9-24, 1974
12 Norenberg MD, Gregorios JB: Uremic encephalopathy.
In: Textbook of Neuropathology, ed. Davis RL, Rob-
ertson DM, pp. 428-429. Williams and Wilkins, Balti-
more, MD, 1985
13 Raskin NH, Fishman RA: Neurologic disorders in renal
failure: Part 1. N Engl J Med 294:143-148, 1976
14 Rotundo A, Nevins TE, Lipton M, Lockman LA, Mauer
SM, Michael AF: Progressive encephalopathy in chil-
dren with chronic renal insufficiency in infancy. Kidney
Int 21:486-491, 1982
15 Summers BA, Smith CA: Renal encephalopathy in a
cow. Cornell Vet 75524-530, 1985
16 Wolf AM: Canine uremic encephalopathy. J Am Anim
HOSPASSOC16~735-738, 1980
Request reprints from Dr. Page Bouchard, Department of
Pathology, College of Veterinary Medicine, Cornell Univer-
sity, Ithaca, NY 14850 (USA).

Vet Pathol 31: 1 15-1 17 (1 994)

Cystic Rete Testis Associated with Cryptorchidism in a Horse

J. SCHUMACHER,
S. D. LENZ,AND W. WALKER

Key words: Cryptorchidism; equine; rete testis; testicular cyst.

Cyst formation in the equine testis occurs rarely. In some

reports, the etiologic diagnosis of the testicular cyst was not
whereas in others, the cysts were associated with
t e r a t o m a ~ . ~This
-~.~report is a description of an equine tes-
ticular cyst unrelated to teratoma.
A 2-year-old unilaterally cryptorchid Clydesdale stallion
was admitted to the Auburn University Large Animal Clinic
for castration. The right testis was in the scrotum, but neither
the left testis nor the left epididymis could be located by
external palpation of the left inguinal canal. Rectal palpation
of the testis and left vaginal ring was not attempted.
The horse was anesthetized and positioned in dorsal re-
cumbency. The left inguinal ring was explored, and the vagi-
nal process was incised to expose the body of the epididymis.
Despite persistent traction on the proper ligament ofthe testis
and enlargement of the vaginal ring to accommodate two
fingers, the testis could not be exteriorized. The vaginal ring
was further enlarged to admit an entire hand. The abdominal
testis was round, with an estimated diameter of 20 cm. Fol-
lowing aspiration of about 1 liter of clear yellow-tinged fluid,
the testis was exteriorized and removed.
The spermatic cord and epididymis appeared grossly nor-
mal. The testis was brown-tan, atrophic (12 x 4 x 1.5 cm),
and flattened lateromedially. A 16- x 16- x 10-cm cyst
protruded from the dorsal surface of the testis. The wall of
the cyst was 2 mm thick and was encompassed by and firmly
adhered to the tunica albuginea. The cyst contained approx-
imately 225 ml of thin, dark yellow, clear fluid, and its lining
was gray to pearlescent and smooth. Multiple sections of the
wall of the cyst, atrophic testis, and epididymis were em-
bedded in paraffin and sectioned. Some sections were stained Fig. 1. Rete testis; horse. The cyst is lined by a single
with hematoxylin and eosin and Masson’s trichrome. layer of cuboidal epithelial cells on a hypocellular substantia
The cyst was lined with a single layer of low cuboidal propria. HE. Bar = 40 pm.