Signalment:  

Five-month-old, female, Coton de Tulear, dog (Canis familiaris).The dog presented with ataxia evolving since the age of four months, with a rapid onset of clinical signs. Neurological examination oriented towards a cerebellar origin of the ataxia. Magnetic Resonance Imaging revealed a decreased size of the cerebellum, without signs of inflammation. The dog was euthanized after ataxia had worsened.

Gross Description:  

The only significant gross lesion at necropsy was a reduction in size of the cerebellum, with slight asymmetry between the two hemispheres. The gyri were diffusely sharply delineated and shrunken.

Histopathologic Description:

Diffusely, the cerebellar folia are slightly flattened. Severe loss of cells within the granular layer is present, multifocally leading to complete absence of this layer. Rarely, granular cells are swollen and vacuolated (degeneration), multifocally associated with empty baskets. Diffusely replacing this layer are glial cells (mainly astrocytes). A discrete population of microglial cells is also present. The molecular layer is mostly normal in thickness, or more rarely thinner. Purkinje cells do not show remarkable degenerative changes.

Morphologic Diagnosis:  

Cerebellum, Granular cell degeneration and loss, diffuse, severe, Coton de Tulear, canine.

Lab Results:  

N/A

Condition:  

Cerebellar abiotrophy

Contributor Comment:  

Cerebellar cortical abiotrophy is a spontaneous, premature and progressive degeneration and death of neurons without an intrinsically identifiable defect; it is well characterized in the dog and is described in several breeds. This condition is characterized by ongoing Purkinje neuronal cell degeneration and loss with reactive gliosis. Mostly, affected animals are healthy at the time of birth and develop clinical signs at several months of age, which worsen with time. In some breeds, a possible inherited genetic defect in the metabolism of the neurotransmitter glutamic acid has been proposed (or established).^2,11

This case is an unusual form of a cerebellar degeneration in the Coton de Tuléar breed, characterized by a severe depletion in the granular cell layer, hence the name “cerebellar granuloprival degeneration” for this condition.⁹ Rare cases of this condition in this breed have been published to date.⁹ Similar to this case, all differ from the Purkinje cell atrophy reported in many canine breeds.

Some similarity between this Coton de Tuléar and cerebellar granuloprival hypo-plasia in cats caused by intrauterine parvovirus infection has been proposed. However, in Coton de Tuléars, there is no disorganization of the cerebellar cortex and no lesions in the Purkinje cell layer. Parvovirus infection in dogs is not known to induce cerebellar changes.^9,12

Contrary to what has been published, in this case there is no significant inflammatory change in the cerebellum.⁹ The restriction of the disease specifically to Coton de Tuléar breed is favors a genetic basis for the lesions, but this hypothesis needs further analysis.

JPC Diagnosis:  

Cerebellum: Granular cell degeneration and loss, diffuse, severe, with spongiosis, and minimal multifocal Purkinje cell loss, Coton de Tulear, canine.

Conference Comment:  

The contributor provides a compelling example of an atypical form of cerebellar abiotrophy in the canine. Cerebellar abiotrophy, also known as cerebellar cortical degeneration, has been described as a hereditary defect in several breeds of dogs,^1,3,9 Arabian horses,⁸ rabbits,⁷ an alpaca,⁶ and recently in goats.⁵ Histologically, the characteristic distribution of lesions includes the marked loss and degeneration of the Purkinje cell neurons, often with retrograde degeneration in granular cells due to failure of synaptogenesis between parallel nerve fibers of the granular cell layer and Purkinje cells.^1,3,5 In this Coton de Tuléar dog, there is diffuse and severe degeneration and loss of the granular cell layer, with only scattered loss of Purkinje cells. This histomorphology has been rarely reported in the veterinary literature as cerebellar granuloprival de-generation in a number of different canine breeds, including the Coton de Tuléar, as discussed by the contributor.^3,4,9 Neonatal cerebellar ataxia in Coton de Tuléar dogs has also been reported as Bandera’s syndrome, suggesting a breed-related hereditary disease.³

Abiotrophy is a spontaneous cerebellar degenerative disease process characterized by premature loss of neurons in the cerebellum.² Conference participants discussed how this differs from cerebellar hypoplasia, a condition in which the cerebellum does not completely form during embryogenesis due to in-utero viral infections from parvoviruses or pestiviruses. Examples include feline parvovirus (pan-leukopenia), bovine pestivirus (bovine viral diarrhea virus), classical swine fever (hog cholera/pestivirus), sheep and goat pestivirus (Border disease), and rat parvovirus (Kilham rat virus).² Additionally, certain toxicities, such as organophosphates, and malnutrition can also cause cerebellar hypoplasia.³ In contrast to animals born with cerebellar hypoplasia, those affected with abiotrophy are neurologically normal at birth and develop early-onset progressive cerebellar proprioceptive deficits during the post-natal period, in the case of this dog at four to five months.^1,3,5 Typical neurologic deficits include ataxia, head tremor, intention tremors, symmetrical hypermetria, broad-based stance, and loss of balance.²

In addition to the diffuse and severe degeneration and loss of the cerebellar molecular cell layer, the conference moderator noted an increase in the number of hypertrophic astrocytes with large vesicular nuclei within the Purkinje cell layer, interpreted as Bergmann gliosis. This astrocytic reaction occurs predominantly in areas where Purkinje cells are lost, described by several conference participants as empty baskets.⁴ Bergmann glial cells are astrocytes with cell bodies located in the Purkinje cell layer with long radial processes that surround the synapses on Purkinje cell dendrites and extend to the molecular layer, terminating on the pial surface of the cerebellum;¹⁰ they are essential for the normal differentiation, migration and maturation of Purkinje cell and granular cell neurons. The immunohistochemical stain, glial fibrillary acidic protein (GFAP), is useful in demonstrating the empty baskets surrounded by Bergmann gliosis in cases of cerebellar abiotrophy.¹⁰

The confounding aspect of this case is the severe selective depletion of granular cells with only scattered loss of Purkinje cells. The pathogenesis of cerebellar granuloprival degeneration in this breed has not yet been elucidated; it is hypothesized to be the result of an inherited disorder of granular cell development, but most Purkinje cells survive since their main excitatory input is from the olivary nucleus.⁴ However, some authors suggest that Purkinje cells can be lost as result of granular cell depletion in chronically affected dogs.⁴

References:

1. Berry ML, Machado UB. Cerebellar abiotrophy in a miniature schnauzer. Can Vet J. 2003; 44:657-659.
2. Cantile C, Youssef S. Nervous system. Maxie MG ed. In: Jubb Kennedy and Palmer's Pathology of Domestic Animals. Vol 1. 6th ed. Philadelphia, PA:  Elsevier Saunders; 2016:275-276.
3. Coates JR, O’Brien DP, Kline KL, et al. Neonatal cerebellar ataxia in Coton de Tulear dogs. J Vet Intern Med. 2002; 680-689.
4. Huska J, Gaitero L, Heindrich SN, et al. Cerebellar granuloprival degeneration in an Australian kelpie and a Labrador retriever dog. Can Vet J. 2013; 54:55-60.
5. Koehler JW, Newcomer BW, Holland M, Caldwell JM. A novel inherited cerebellar abiotrophy in a cohort of goats. J Comp Path. 153:135-139.
6. Mouser P, Levy M, Sojka JE, Ramos-Vara JA. Cerebellar abiotrophy in an alpaca (Lama pacos). Vet Pathol. 2009; 46:1133-1137.
7. Sato J, Yamada N, Kobayashi R, et al. Morphometric analysis of progressive changes in hereditary cerebellar cortical degenerative disease (abiotrophy) in rabbits caused by abnormal synap-togenesis. J Toxicol Pathol. 2015; 28:73-78.
8. Scott EY, Penedo MC, Murray JD, Finno CJ. Defining trends in global gene expression in Arabian horses with cerebellar abiotrophy. Cerebellum. 2016; Oct 5. [Epub ahead of print].
9. Tipold A, Fatzer R, Jaggy A, Moore P, Vanevelde M. Presumed immune-mediated cerebellar granuloprival de-generation in the Coton de Tuléar breed. J neuroimmunol. 2010; 110:130-133.
10. Yamada K, Watanabe M. Cyto-differentiation of Bergmann glia and its relationship with Purkinje cells. Anat Sci Int.
11. Zachary JF, McGavin DM. Nervous system. In: Pathologic Basis of Veterinary Disease. 5th ed. St. Louis, MO: Mosby; 2012:816, 856-857.