Signalment:  

A male, adult (exact age not known) European hedgehog (Erinaceus europaeus) from a wildlife park The hedgehog was found in lateral position with tremors. There was a short improvement of the symptoms with medical treatment (Dexamethasone, Baytril and Levamisol). Euthanasia was performed because of vestibular ataxia four days later.

Gross Description:  

At necropsy, the hedgehog was in poor general body condition. There was severe lung edema and all lung lobes were mottled in dark and light red. There was no macroscopic lesion in the tympanic bullae or the brain

Histopathologic Description:

Brain: Diffusely, the meninges, plexus choroideus, cerebrospinal fluid in the lateral ventricles, Virchow-Robbins space and surrounding brain tissue of the white and grey matter are massively thickened and infiltrated by intra- and extracellular fungal yeasts of 5-20 um in diameter, ovoid to spherical with a 1-2 um basophilic cell wall and a non-staining thick capsule observed as a clear circular halo up to 10 um in thickness. There is rare narrow-based budding. The yeasts are accompanied by a severe infiltrate of macrophages, lymphocytes, plasma cells, fewer eosinophils and neutrophils. Predominantly perivascular located and multifocal pallisading are large numbers of multinucleated giant cells of the foreign body type and Langhans cell type. They contain up to 20 nuclei and intracytoplasmic fungal yeast (phagocytosis). The meningeal and encephalic vessel walls, predominantly of the veins, are severely infiltrated by the above mentioned inflammatory cells, giant cells and yeasts and slightly homogenous and hypereosinophilic (vasculitis and fibrinoid degeneration). Multifocal in the inflammatory areas are moderate numbers of extravasated erythrocytes (hemorrhage). Within the grey and white matter, there is a severe, diffuse increase of glial cells (gliosis) predominantly astrocytes (astrocytosis) which have an elongated or glassy, rounded nuclei (activation), often surrounding neurons (satellitosis). At the white-grey matter junction, the neuropil is loosely arranged and vacuolated, mostly around the affected vessels (edema). Additionally, the epithelium of the ventricle is multifocally thickened and composed of two or three cell layers (hyperplasia). 

Morphologic Diagnosis:  

Brain: granulomatous and lymphoplasmocytic meningoencephalitis and vasculitis, severe, diffuse, chronic with intralesional yeasts consistent with Cryptococcus sp. 

Lab Results:  

PCR Result: Cryptococcus neoformans var. gattii

Condition:  

Cryptococcus neoformans

Contributor Comment:  

The disease cryptococcosis is caused by the genus Cryptcoccus (C.), including over 37 species, the majority of which do not cause disease in mammals.(7) The disease-causing Cryptococcus sp. are referred to as the C. neoformans C. gattii species complex, which includes C. neoformans var. neoformans, C. neoformans var. grubii and C. gattii.(7) The classification was originally based on serotype, determined by capsular antigens.(3,7) Nowadays, genotyping has replaced serologic typing and divided Cryptococcus in two different species, C. neoformans and C. gattii, and in molecular types VNI and VNII, (C. neoformans var. grubii, serotype A), VNIV (C. neoformans var. neoformans, serotype D), VNIII (hybrid serotype AD), VGI, VGII, VGIII and VGIV (C.gatti, serotype B and C).(3,7)

In our case, the PCR resulted as Cryptococcus neoformans var. gattii. 

Cryptococcosis is the most common systemic mycotic disease of cats worldwide, but has been described in other domestic species (ferrets, horses, cattle, goats, sheep and llamas) and non-domestic species (parrots, elk, koalas and dolphins).(1,7) The disease is sporadic and the infection is neither contagious nor zoonotic.(1) To our knowledge, Cryptococcus has not been described in hedgehogs. This animal was kept in an open wildlife park environment. The immune status was unknown. Similar lesions containing yeasts were also found in the lung and kidney, the infection was considered as systemic. Clinical presentations of cryptococcosis are similar in all described animals; althought C. gattii appears to be more virulent and has a greater propensity to infect the CNS.(7) The route of entry is considered by inhalation of basidiospores (yeast cells).(1) CNS penetration is a consequence of the number of organisms inhaled, the virulence of the isolate and the ease of penetration of the nasal and frontal bones and the cribiform plate.(7) It is described that dogs, in comparison to cats, develop a marked inflammatory response, primarily mixed cellular or granulomatous, whereas cats develop a mild, primarily neutrophilic response.(9) In the present case of the hedgehog, there is a moderate to severe granulomatous meningoencephalitis, similar to the described lesions in dogs. Reports of cerebral cryptococcosis without respiratory involvement in domestic animals are scarce, though described in cats(6), horses(2) and in cows.(5)

Recent reports of CNS cryptococcosis include single reports in a bull from Brazil(8) and smaller series of animals as in dogs and cats from California.(9) A special variant of CNS cryptococcosis is the so called cryptococcoma, a single gelatinous pseudocyst in the CNS, often suggested as neoplasia with MRI.(9) The cyst is histologically composed of cryptococcal organisms surrounded by a pyogranulomatous inflammatory reaction and necrosis.(5,6) In people, neurocryptococcosis is linked to immunosuppression, often seen in HIV-infected patients. Whether the same is true in animals remains the subject of debate.(6)

Here, diagnosis was based on H&E histology, supported by special stains and a PCR investigation: The wall of the yeasts stained positive with Periodic acid Schiff (PAS) and Grocott and the capsule stained positive with Mayers mucicarmine. PCR: Cryptococcus neoformans var. gattii. 

Histological differential diagnoses based on similar morphology: Blastomyces dermatitidis, Histoplasma capsulatum, Candida albicans, Sporothrix schenkii and Prototheca spp.(5)

JPC Diagnosis:  

Cerebrum, meninges: Meningoencephalitis, granulomatous, multifocal to coalescing, moderate, with granulomatous ventriculitis and choroiditis, moderate hydrocephalus and numerous intrahistiocytic and extracellular yeasts. 

Conference Comment:  

The contributor introduced recent literature discussing the updated nomenclature of this organism. Cryptococcus gattii, identified in this case, occurs in immunocompetent mammals and is thus considered a primary pathogen, while C. neoformans var. neoformans and C. neoformans var. grubii are often opportunistic pathogens linked with immunosuppression.(7) Although considered a primary pathogen, the sheer number of organisms present within the meninges and outnumbering the inflammatory cells in this case led conference participants to speculate whether the administration of steroids permitted this organism to proliferate further prior to necropsy. However, glucocorticoid therapy has successfully achieved favorable clinical responses in some cases of cryptococcosis.(9) Contrarily, it may be the yeast capsules ability to inhibit leukocyte recognition and chemotaxis that accounts for the lack of inflammation.(1) Cryptococcus spp. are readily identifiable by this large negatively-staining but carminophilic capsule, which also aids it in prevention of phagocytosis by macrophages and neutrophils. The organisms also utilize superoxide dismutase and catalase in addition to being one of the many species which produce melanin, all to provide protection from oxidative damage by host mechanisms. Utilizing dopamine as a substrate for melanin production may facilitate its affinity for the CNS.(7)

The thick polysaccharide capsule gives lesions a gross gelatinous appearance, and in the cerebrum these often characteristically develop into cystic spaces as mentioned by the contributor. This is most commonly observed in cats and occurs through a repetitive process of macrophage phagocytosis, cell lysis and subsequent chemotaxis of additional macrophages allowing an expansive accumulation of the polysaccharide capsule.(10) The pathogenesis of this infection is curious, and largely still unexplained as to why the variability in inflammatory responses and lesion development occurs. Findings such as large cryptococcomas being more commonly reported in immunocompetent patients(9), and the lack of increased susceptibility in cats with retrovirus infections(7) seem to be counterintuitive. Overall, cryptococcosis is a disease often associated with a poor prognosis, as median survival time (MST) for all cats was just 19 days in one study despite treatment with antifungal drugs.(9) But when excluding the rapidly deteriorating patients, or those which didnt survive the first three days following diagnosis, the MST is much longer with many cats surviving past the conclusion of the study.(9)

The presentation of Cryptococcus in a hedgehog is unique, and conference participants discussed other known diseases within this species as they are becoming increasingly popular as pets. Hedgehogs seem to have a high incidence of neoplasia, with its prevalence at necropsy being as high as 53%.(4) Another condition first described in the mid-1990s is a progressive paralysis called Wobbly hedgehog syndrome with an incidence of 10% in pet hedgehogs in North America.(4) This is characterized histologically as vacuolation of the white matter tracts without an inflammatory infiltrate,(4) similar to degenerative myelopathy which occurs commonly in German Shepherd Dogs.

References:

1. Caswell JL, Williams KJ. The respiratory system In: Maxie, MG ed. Jubb, Kennedy and Palmers Pathology of Domestic Animals. 5th ed. Edinburgh, Scotland: Elsevier; 2007:642-644. 

2. Cho DY, Pace LW, Beadle RE. Cerebral crytococcosis in a horse. Vet Pathol. 1986;23:207-209. 

3. Fragnello J, Dutra V, Schrank A, et al. Identification of genomic differences between Cryptococcus neoformans and Cryptococcus gattii by representational differences analysis (RDA). Med Mycol. 2009;47:584-591. 

4. Gibson CJ, Parry NA, Jakowski RM, Eshar D. Anaplastic astrocytoma in the spinal cord of an African pygmy hedgehog (Atelerix albiventris). Vet Pathol. 2008;45:934-938.

5. Magalhaes GM, Elsen Saut JP, Beninati T, et al. Cerebral cryptococcomas in a cow. J Comp Path. 2012;147:106-110. 

6. Mandrioli L, Bettini G, Marcato, OS, et al. Central nervous system Cryptococcoma in a cat. J Vet Med A. 2002;49:526-530. 

7. Lester SJ, Malik R, Bartlett KH, et al. Cryptococcosis: update and emergence of Cryptococcus gattii. Vet Clin Pathol. 2011;40:4-17. 

8. Riet-Correa F, Krockenberger M, Dantas AFM, et al. Bovine cryptococcal meningoencephalitis. J Vet Diagn Invest. 2011;23:1056-1060. 

9. Sykes JE, Sturges BK, Cannon MS, et al. Clinical signs, imagin features, neuropathology, and outcome in cats and dogs with central nervous system cryptococcosis from California. J Vet Intern Med. 2010;24:1427-1438. 

10. Zachary JF. Mechanisms of microbial infections. In: Zachary JF, McGavin MD, eds.Pathologic Basis of Veterinary Disease. v5th ed. St. Louis, MO: Elsevier Mosby; 2012:237.