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.

Gross Description:  

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.

Histopathologic Description:

Brain, 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 3–5 um thick, double contour, hyaline wall. Spherules are empty, or contain either granular to flocculent, basophilic material or 4–5 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.

Morphologic Diagnosis:  

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.

Lab Results:  



Pyogranulomatous meningoencephalitis/Coccidioides immitis

Contributor Comment:  

The dimorphic 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. 8 Coccidioidomycosis has been reported in a large variety of domestic animals including dogs2 , cats17, horses10, llamas4 , and wild animals including chimpanzee11, bottlenose dolphin13, free- living California sea lions7 , Przewalski’s horses16, and mountain lion. 1

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:
Successful host immunological response to Coccidioides spp. is dominated by cellmediated immunity9,12, 15, particularly Th1, and in general is related to the phase of the organism involved. 11 Due to the marked increase in size as the spherules mature, phagocytosis is restricted to initial yeast cells from germinated arthroconidia, and endospores released from ruptured spherules. 12 Inhaled arthroconidia elicit an initial response composed primarily of neutrophils with fewer macrophages and lymphocytes; in later stages, a granulomatous response predominates. 1,2

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

JPC Diagnosis:  

1. Cerebrum and meninges: Meningoencephalitis, pyogranulomatous and necrotizing, focally extensive severe with intra- and extracellular endosporulating yeasts, alpaca (Vicugna pacos).
2. Cerebrum, grey matter: Necrosis, focal, moderate.

Conference Comment:  

The contributor 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 infection. 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 infection.3,9

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 Masson’s 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.


1. Adaska JM. Peritoneal coccidioidomycosis in a mountain lion in California. J Wildl Dis. 1999; 35:75-77.

2. Ajithdoss DK, Trainor KE, Snyder KD, Bridges CH, Langohr IM, Kiupel M, Porter BE. Coccidioidomycosis presenting as a heart base mass in two dogs. J Comp Pathol. 2010; 145:132-137.

3. Caswell JL, Williams KJ: Respiratory system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer's Pathology of Domestic Animals. 6th ed. Vol 2. St. Louis, MO: Elsevier; 2016: 583-584.

4. Coster ME, Ramos-Vara J, Vemulapalli R, Stiles J, Krohne SG. Coccidioides posadasii keratouveitis in a llama (llama glama). Vet Ophthalmol. 2010; 13:53-57.

5. Diab S, Johnson S, et al. Case report: abortion and disseminated infection by Coccidioides posadasii in an alpaca (Vicugna pacos) fetus in Southern California. Med Mycol Case Rep. 2013; 2:159-162.

6. Dixon DM. Coccidioides immitis as a select agent of bioterrorism. J Appl Microbiol. 2001; 91:602-605.

7. Fauquier DA, Gulland FMD, Trupkiewicz JG, Spraker TR, Lowenstine LJ. Coccidioidomycosis in free-living California sea lions (Zalophus californianus) in Central California. J Wildl Dis. 1996; 32:707-710.

8. Fisher MC, Koening GL, White TJ, Taylor JW. Molecular and phenotypic description of 22 Coccidioides posadasii sp. previously recognized as the nonCalifornian population of Coccidioides immitis. Mycologia. 2002; 94:73-84.

9. Graupmann-Kuzma A, Valentine BA, Shubitz LF, Dial SM, Watrous B, Tornquist SJ. Coccidioidomycosis in dogs and cats: a review. J Am Anim Hosp Assoc. 2008; 44:226-235.

10. Higgins JC, Leith GS, Pappagianis D, Pusterla N. Treatment of Coccidioides immitis pneumonia in two horses with fluconazole. Vet Record. 2006; 159:349-351.

11. Hoffman K, Videan EN, Fritz J, Murphy J. Diagnosis and treatment of ocular coccidioidomycosis in a female captive chimpanzee (Pan troglodytes) a case study. Ann NY Acad Sci. 2007; 1111:404-410.

12. Hung C-Y, Xue J, Cole GT. Virulence mechanisms of Coccidioides. Ann NY Acad Sci. 2007; 1111:225-235.

13. Reidarson TH, Griner LA, PappagianisD, McBain J. Coccidioidomycosis in a bottlenose dolphin. J Wildl Dis. 1998; 34:629- 63, 1998.

14. Shubitz LF, Dial SM. Coccidioidomycosis: a diagnostic challenge. Clin Tech Small Anim Pract. 2005; 220:226.

15. Shubitz LF, Dial SM, Galgiani JN. T-lymphocyte predominance in lesions of canine coccidioidomycosis. Vet Pathol. 2010; 45:1008-1011.

16. Terio KA, Stalis IH, Allen JL et al. Coccidioidomycosis in Przewalski’s horses (Equus prewalskii). J Zoo Wildl Med. 2003; 34:339-345.

17. Tofflemire K, Betbeze C. Three cases of feline ocular coccidioidomycosis: presentation, clinical features, diagnosis and treatment. Vet Ophthalmol. 2010; 13:166-172.

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4-1. Cerebrum, alpaca

4-2. Cerebrum, alpaca

4-3. Cerebrum, alpaca

4-4. Cerebrum, alpaca

4-5. Cerebrum, alpaca

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