Adult female alpaca (Vicugna
pacos).The animal had a five-week
duration of illness that consisted of
progressive severe weight loss, and a
subacute onset of unilateral blindness on the
left, with right head tilt and circling to the
right. There were palpably soft areas of the
skull that were originally diagnosed as skull
fractures. Radiographs were not taken.
Treatments included antibiotics, steroids,
non-steroidal anti-inflammatory drugs, and
supportive therapy. In the absence of
response to treatment, a brain tumor was
suspected and the owner elected euthanasia.
The referring veterinarian
removed the head and disposed of the
remainder of the carcass. The calvarium was
deformed with pronounced nodular doming
and multifocal marked thinning and translucency
over the caudodorsal aspect of the
left and, to a lesser extent, the right cerebral
hemispheres. The calvarium and intact brain
were fixed in formalin and submitted to the
CAHFS- San Bernardino laboratory for
histologic examination. On removal of the calvarium, a large, firm
mass with several, irregular, soft areas were
identified in the right cerebral hemisphere. The caudal half of the right hemisphere was
moderately enlarged, misshapen and firm,
with focal nodularity of the meningeal
surface of the caudolateral aspect of the
hemisphere. Transverse sectioning of the
rostral half of both cerebral hemispheres
revealed bilateral, moderate hydrocephalus
(dilated lateral ventricles / reduced thickness
of the cerebral grey and white matter).
Extending caudally from the optic chiasm to
the posterior extremity of the right cerebral
hemisphere, was an irregular, nodular,
roughly egg-shaped mass with approximate
dimensions of 5.5 cm [length] x 3-4 cm
[width] x 3.5-4 cm [height]. The mass
markedly expanded and distorted the right
lateral ventricle, and deformed/ partially
replaced the right thalamus. Further
caudally, there was partial replacement of
the right diencephalon / mesencephalon by
the mass. The left thalamus / mesencephalon
was laterally displaced and the left ventricle
was dilated (hydrocephalus) from the rostral to the caudal extremities.
On cross section, the mass was firm, slightly
gritty, and mottled, tank/pink/cream with
scattered yellow foci of approximately 0.2
cm in diameter.
cerebral cortex: Affecting approximately
90% of the white matter and disrupting the
normal architecture is a well-demarcated,
non-encapsulated inflammatory focus. The
focus consists of multiple, discrete to
coalescent, variably-sized cores of necrosis,
viable and degenerate neutrophils,
extravasated red cells and /or mineral,
interspersed with expanses of granulomatous
to mixed inflammation and plump reactive
astrocytes. Large numbers of fungal
spherules of varying sizes and stages of
development and occasional clusters of
endospores are scatted throughout the
necrotic cores, in few multinucleate giant
cells, or free amongst the mixed
inflammatory infiltrate. Spherules are round, range in size from 20-60 um in diameter,
and are surrounded by a 35 um thick,
double contour, hyaline wall. Spherules are
empty, or contain either granular to
flocculent, basophilic material or 45 um
oval endospores. In some sections, the
inflammatory focus regionally extends to
involve the meninges, while in others the
border is irregular with peripheral, discrete
pyogranulomas. Neuropil bordering the
inflammatory focus is either rarified
(malacic) with proteinaceous effusion
(edema), gitter cell infiltration and astrocyte
proliferation, or is irregularly infiltrated by
aggregates of lymphoplasmacytic cells.
In other sections (slides not submitted), there is marked dilation of the lateral ventricle accompanied by multifocal, mild to moderate cuffing of subependymal blood vessels by plasma cells. One section of the lateral ventricle contains clumps of cellular debris, purulent exudate, and several small spherules. A moderate lymphoplasmacytic infiltrate is present in the choroid plexus.
Brain, right cerebral cortex including the
lateral ventricles and meninges:
1. Meningoencephalitis, necrotizing and
pyogranulomatous, focally extensive,
chronic, severe, with numerous intralesional
fungal spherules and endospores, etiology
consistent with Coccidioides spp.
2. Hydrocephalus, bilateral, moderate.
Pyogranulomatous meningoencephalitis/Coccidioides immitis
soil fungi, Coccidioides immitis and C.
posadassi, are the causative agents of
coccidioidomycosis, a systemic fungal
disease in man and animals.
8 The disease is
endemic in arid regions of southwestern
USA, Mexico, Central and South America9
and is commonly known as desert fever,
valley fever, or San Joaquin Valley fever.
Coccidioidomycosis has been reported in a
large variety of domestic animals including
, cats17, horses10, llamas4
, and wild
animals including chimpanzee11, bottlenose
dolphin13, free- living California sea lions7
Przewalskis horses16, and mountain lion.
Fungal mycelia survive well in dry, hot conditions; grow after intense rainfall and release arthroconidia which are disseminated by the wind.3,9 Inhalation of airborne arthroconidia is the most common route of infection, although local traumatic inoculation has been associated with cutaneous and subcutaneous lesions. 3 The arthroconidia migrate to bronchi and alveoli and transform to yeast forms (immature spherules) of 10-20 um in diameter. As spherules mature they enlarge up to 100 um in diameter and are surrounded by a double contour, 4-5 um hyaline wall. Spherules undergo endosporulation forming numerous uninucleated endospores 2-5 um in diameter. Mature spherules rupture to release endospores that form new spherules in tissue or mycelia if released to the environment.3,14 Dissemination to other organs is through blood or lymphatics, and fungi are believed to reach the central nervous system through leukocytic trafficking and hematogenous spread from primary sites of infection. 3,12
Three main virulence mechanisms by which Coccidiodes spp. survive in host environment have been described.12 These include:
- 1. Production of dominant spherule outer wall glycoprotein (SOWgp) which modulates the host immune response resulting in compromised cell-mediated immunity
- 2. Depletion of SOWgp presentation on endospore surface preventing host recognition of the pathogen
- 3. Induction of host arginase 1 (decreased nitric oxide production) and coccidial urease which contribute to tissue damage at sites of infection.
Although the spherule form shed from lesions is not readily infectious, arthroconidia from mature cultures are easily aerosolized and are highly infectious. 14 As such, Coccidioides immitis is designated as Biosafety Level 3, and is classed as a select agent of bioterrorism in the United States due to its high virulence and infectious nature. 6
1. Cerebrum and meninges:
and necrotizing, focally extensive severe
with intra- and extracellular endosporulating
yeasts, alpaca (Vicugna pacos).
2. Cerebrum, grey matter: Necrosis, focal,
provides a striking example and a concise
review of the epidemiology, pathogenesis,
and virulence factors of these dimorphic,
endosporulating fungi. South American
camelids, such as llamas and alpacas, are
exquisitely susceptible to coccidioidal infection
and clinical cases usually present
with severe respiratory and/or disseminated
9 In any species, disseminated
disease can occur either early, or several
months after initial infection.3,9 In dogs, up
to 22% can have disseminated systemic
infection without a history of respiratory
disease. However, cases of systemic lesions
without pulmonary involvement are
theorized to reflect clinical resolution of the
lung, rather than extra-pulmonary
The most common presentation of disseminated disease is lameness due to osteomyelitis.9,10 This typically occurs late in the disease and is characterized by osteolytic granulomas surrounded by proliferative new bone growth. Painful draining tracts in the overlying skin, palpable bone swelling, and enlarged and reactive regional lymph nodes are additional signs of disseminated disease.3 However, generalized lymphadenopathy is uncommon in this disease.3,9 Other clinical signs of disseminated disease are variable and are usually dependent on the organ infected. Animals with central nervous system (CNS) disease, such as this case, typically have seizures, progressive ataxia, and are comatose in severe cases. Other organs affected include: eyes, liver, spleen, kidney, and testes.3,9 Abortion has also been reported in both horses and an alpaca in Southern California. 5
This case generated enthusiastic debate among conference participants regarding whether the profound pyogranulomatous inflammation effacing 90% of the histologic section originated from the cerebrum or the meninges. Participants favoring cerebral origin argued that the cerebrum is lost and replaced by an astrocytic scar with spindled and palisading epithelioid macrophages. Participants favoring meningeal origin noted that the spindled cells are birefringent and likely represent collagen and fibrous connective tissue deposition secondary to chronic pyogranulomatous inflammation. A Massons trichrome stain revealed abundant blue staining collagen within the granuloma. Given that fibrocytes are not a normal component of the neuropil, it is likely that fibrocytes penetrated into the granuloma from the adjacent meninges. The granuloma was also diffusely immune-negative for glial fibrillary acidic protein (GFAP), supporting a meningeal origin of the granuloma rather than an astrocytic scar in the cerebrum.
Several conference participants also noted a focal area of cavitary necrosis within the cerebrum adjacent to the pyogranuloma. This is likely due to thrombosis of a vessel adjacent to the large granulomatous nodule, creating an infarct in the section of the cerebrum. Unfortunately, none of the conference participants noted vascular thrombi within their tissue sections. The vascular thrombi may be out of the plane of section.
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