Hereditary cerebellar degenerative disease (cerebellar cortical abiotrophy) in rabbits

A pair of rabbits gave birth to a set of littermates (F1) with symptoms of early-onset ataxia. Microscopic examination revealed cerebellar degenerative disease in 5 of 6 littermates. Light microscopy was used to compare the thickness of each cerebellar layer in affected animals in contrast to a normal control. Affected animals showed narrowing of the molecular layer of the vermis, reduced density of Purkinje cell dendrites and irregular thickness in their branchlets, and reduced density of granular cells and scattered pyknotic cells in the granular layer. Pyknotic cells were apoptotic granular cells, confirmed by positive staining using the TUNEL method. Electron microscopy confirmed the thinning of the molecular layer seen by light microscopy and also showed a reduced number of parallel fibers, which indicate granular cells axons, and a reduced number of synaptic junctions between Purkinje and granular cells. Purkinje cells had electron-dense, irregularly shaped cytoplasm with irregularly shaped nuclei, and some of these cells had a central chromatolysis-like region. These findings support a diagnosis of cerebellar cortical abiotrophy, a hereditary condition that causes nerve function impairment leading to early-onset progressive degeneration of the cerebellar cortex.     

Cerebellar abiotrophy in a family of Border Collie dogs

Cerebellar abiotrophies have a nonsex-linked, autosomal, recessively inherited basis in a number of species, and lesions typically reflect profound and progressive loss of Purkinje cells. In this report, an unusual form of abiotrophy is described for two sibling Border Collies. Extensive loss of the cerebellar granular cell layer was present with relative sparing of Purkinje cells of two female pups. The biochemical basis for this form of cerebellar abiotrophy is unknown, but the lack of disease in other siblings supports an autosomal recessive mode of inheritance.     

Neuronal apoptosis in the developing cerebellum

The following study analysed apoptosis in proliferative cells and migrating neurons of the developing cerebellum. The external granular layer, Purkinje cell layer and internal granular layer in the developing mouse cerebellar cortex were analysed by active caspase-3 immunohistochemistry, Hoechst 33258 staining and Western blot analysis. Immunocytochemistry results indicated that the peak of apoptosis appeared at postnatal days P8, P5 and P9 in the external granular layer, Purkinje cell layer and internal granular layer, respectively. Subsequently, in each region, the rate of apoptosis decreased with increasing age. In contrast, Western blot results demonstrated the highest expression of activated caspase-3 in the cerebellum at P5, followed by a subsequent decline and disappearance of expression by P14. Activated caspase-8 was expressed maximally at P10, and subsequently disappeared by P30. The results of this study suggest that the key period of neuronal apoptosis in the cerebellar cortex is between P0 and P14, indicating that this developmental period could be susceptible to treatment for congenital neurodegenerative diseases.     

Cerebellar cortical abiotrophy in American Staffordshire terriers: clinical and pathological description of 3 cases

Three American Staffordshire Terriers were presented with gait abnormalities and loss of balance at the age of 4.5 (female) and 6 years (2 males). The onset varied between 3 and 5 years of age and the clinical signs were slowly progressive. The neurological examination revealed symmetrical generalized cerebellar ataxia with hypermetria, stiffness, and loss of balance with no evidence of paresis. The menace reflex was decreased in one dog and absent in another. A positional nystagmus was found in two dogs. The dogs were euthanized and a histopathological examination of each brain was performed. Pathological changes were confined to the cerebellum. The main finding was loss of Purkinje cells, as well as depletion of granular cell bodies and shrinkage of the granular and molecular cell layer. These findings are consistent with cerebellar cortical abiotrophy. A genetic basis is supposed, but the mode of inheritance is not determined yet. In contrast to some spinocerebellar ataxias in humans, the cause of Purkinje cell degeneration in cerebellar cortical abiotrophy of dogs is not known.     

Cerebellar hypoplasia associated with an avian leukosis virus inducing fowl glioma

Fowl glioma-inducing virus (FGV), which belongs to subgroup A of avian leukosis virus (ALV), shows tumorigenicity and pathogenicity, mainly in the nervous system, and causes astrocytoma and perineurioma. Apart from these neoplasms, cerebellar anomaly was found in chickens infected with FGV in ovo. The study reported here describes the morphologic characteristics of the affected cerebellum. Specific-pathogen-free chickens (C/O) were inoculated with FGV through the yolk sac on the 7th day of incubation. The cerebellar anomaly included diffuse depletion of granular cells of the internal granular layer (IGL), remnants of the external granular layer (EGL), and disorganization of the Purkinje cell layer. These cerebellar changes were observed in all birds except one. In the infected embryos, the EGL was thicker and had an irregular arrangement with a thin molecular layer (ML) and IGL, compared with the control. The granular cells were immunohistochemically positive for ALV common antigen. Immunohistochemical analysis for vimentin revealed disarrangement and decreased number of Bergmann's fibers. Use of the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling method and electron microscopy indicated that apoptotic granular cells were frequently observed in the EGL and ML. These results suggested that the cerebellar anomaly was hypoplasia, principally resulting from the apoptosis of granular cells in the EGL and ML caused by FGV infection and that the cell loss induced obstruction of granular cell migration and disarrangement of Bergmann's fibers in the ML.     

神经肽Y免疫反应神经元在鸽小脑中的定位--SABC 法研究

采用石蜡切片和免疫组化SABC法（链霉亲合素-生物素-过氧化物酶连结法），对10只肉鸽小脑内神经肽Y免疫反应神经元的分布状况进行了研究．并与北京鸭、鸟鸡、肉鸡及大鼠的相关结果进行了比较。在光镜下观察分析了阳性神经元的分布状况．并用图像分析软件进行了半定量分析。结果显示：（1）小脑内神经肽Y（neuropeptide Y，NPY）阳性神经元主要存在于小脑皮质的蒲肯野氏细胞层，且以小叶顶端的蒲肯野氏细胞阳性明显；（2）小脑白质中央核可见到少量阳性神经元．不同于鸟鸡、肉鸡及大鼠；（3）分子层、颗粒层未见阳性反应细胞。表明：鸽小脑NPY阳性神经元的分布在皮质中与鸡、大鼠大体相似；在白质中与鸡、大鼠有差异。     

Two cases of hereditary quadriplegia and amblyopia in a litter of Irish setters

Two, one-month-old male Irish setters from the same litter showed incoordination, rotary nystagmus and motor and visual impairment. No abnormalities were found in either the blood, urine or cerebrospinal fluid. Radiographs of the head, chest and abdomen were normal. Histopathology revealed degeneration and necrosis of the granular layer and Purkinje cells of the cerebellar cortex. On electron microscopic examination, the granular cells showed dilated endoplasmic reticulum and vacuolated mitochondrial cristae. There was also serious destruction of Purkinje cells.     

Lysosomal storage disease caused by Sida carpinifolia poisoning in goats

A neurologic disease characterized by ataxia, hypermetria, hyperesthesia, and muscle tremors of the head and neck was observed for 2 years in a flock of 28 Anglo-Nubian and Saanen goats on a farm with 5 ha of pasture. Six newborns died during the first week of life, and five abortions were recorded. The predominant plant in the pasture was Sida carpinifolia. The disease was reproduced experimentally in two goats by administration of this plant. Three goats with spontaneous disease and the two experimental animals were euthanatized and necropsied. No significant gross lesions were observed. Fragments of several organs, including the central nervous system, were processed for histopathology. Small fragments of the cerebellar cortex, liver, and pancreas of two spontaneously poisoned goats and two experimentally poisoned goats were processed for electron microscopy. Multiple cytoplasm vacuoles in hepatocytes, acinar pancreatic cells, and neurons, especially Purkinje cells, were the most striking microscopic lesions in the five animals. Ultrastructural changes included membrane-bound vacuoles in hepatocytes, Kupffer cells, acinar pancreatic cells, Purkinje cells, and the small neurons of the granular cell layer of the cerebellum. Paraffin-embedded sections of the cerebellum and pancreas were submitted for lectin histochemical analysis. The vacuoles in different cerebellar and acinar pancreatic cells reacted strongly to the following lectins: Concanavalia ensiformis, Triticum vulgaris, and succinylated Triticum vulgaris. The pattern of staining, analyzed in Purkinje cells and acinar pancreatic cells coincides with results reported for both swainsonine toxicosis and inherited mannosidosis.     

Morphometric analysis of progressive changes in hereditary cerebellar cortical degenerative disease (abiotrophy) in rabbits caused by abnormal synaptogenesis

We previously investigated rabbit hereditary cerebellar cortical degenerative disease, called cerebellar cortical abiotrophy in the veterinary field, and determined that the pathogenesis of this disease is the result of failed synaptogenesis between parallel fibers and Purkinje cells. In this study, longitudinal changes in the development and atrophy of the cerebellum of rabbits with hereditary abiotrophy after birth were morphometrically examined (postnatal day [PD] 15 and 42) using image analysis. Although development of the cerebellum in rabbits with abiotrophy was observed from PD 15 to PD 42, the growth rate of the cerebellum was less than that in normal rabbits. In rabbits with abiotrophy, the number of granular cells undergoing apoptosis was significantly higher at PD 15 and dramatically decreased at PD 42. The number of granular cells did not increase from PD 15 to 42. The synaptogenesis peak at PD 15 occurred when the largest number of apoptotic granular cells in rabbits with abiotrophy was observed. Although 26% to 36% of parallel fiber terminals formed synaptic junctions with Purkinje cell spines, the remainder did not at PD 15 and 42. The rate of failure of synaptogenesis in the present study might be specific to this case of abiotrophy. Morphometric analysis revealed detailed changes in development and atrophy in animals with postnatal cerebellar disease occurring soon after birth.     

Cerebellar abiotrophy in a 6‐year‐old Arabian mare

Cerebellar abiotrophy (CA) is an uncommon neurological disease that most commonly affects Arabian horses. Affected horses are typically identified within the first 6 months of life. Intention tremor, wide based stance and ataxia are common clinical signs observed in affected individuals. No treatment is available for resolution of clinical signs. Definitive diagnosis is based on histopathological examination of cerebellar tissue, which is characterised by loss of Purkinje cell layer. This report describes a case of cerebellar abiotrophy that had a delayed diagnosis until 6 years of age.     

Cerebellar degeneration in a mature Staffordshire terrier

A 5-year-old Staffordshire terrier exhibited slowly progressive signs of cerebellar disease, including nystagmus and dysmetria. After a 30-month course, the dog was euthanized. Grossly, the cerebellum was small and comprised only 5% of the brain weight. Histopathological examination of the brain documented diffuse degeneration. Purkinje cells were most depleted, but granular cells and the molecular layer of cerebellum were also depleted. The history and necropsy examination were evidence of late-onset primary cerebellar degeneration.     

Inositol 1,4,5-triphosphate receptor protein immunohistochemistry of cerebellar Purkinje cells in two dogs with hypoglycemia

Immunohistochemical study was performed on cerebellar Purkinje cells of two dogs with hypoglycemia using an antibody against the inositol 1,4,5-triphosphate receptor that is identical to the cerebellar Purkinje cell glycoprotein P(400) (P(400)/InsP(3)R). In the cerebellar neocortex of an acute case of hypoglycemia, the P(400)/InsP(3)R staining of hypoglycemic Purkinje cells was heterogeneous: some peripheral dendrites, including spiny branchlets, were negative and others were stained with various intensities, although Purkinje cells were morphologically intact by hematoxylin and eosin (HE) stain. In a chronic case of hypoglycemia, almost all the dendrites of Purkinje cells of both the neo- and archicortex of the cerebellum were not stained with the P(400)/InsP(3)R antibody. This is in contrast to the normal dog where Purkinje cell bodies, axons, and dendrites, including spiny branchlets, are intensely stained by the P(400)/InsP(3)R antibody. These results suggest that P(400)/InsP(3)R immunolabeling of Purkinje cells decreased, despite their morphology being preserved by HE stain, and that the function of P(400)/InsP(3)R, especially in spiny branchlets that receive inputs originating from axon terminals of parallel fibers, may be impaired in hypoglycemia.     

Kernicterus in a neonatal foal.

A 5-day-old Thoroughbred foal was submitted to the necropsy service at the University of Kentucky Livestock Disease Diagnostic Center. The foal had a clinical history of seizure activity and severe icterus. A complete blood count and serum chemistry analysis indicated that the foal was anemic (hematocrit, 16%), hyperbilirubinemic (45 mg/dl), and hypoglycemic. At necropsy, all tissues were discolored various shades of yellow. Microscopically, there was degeneration and necrosis of cerebral neurons and cerebellar Purkinje cells; severe hepatocellular degeneration and necrosis; and deposition of amorphous golden-yellow material in the cerebellar granular cell layer, pulmonary alveoli, renal tubular epithelium, splenic trabecula, and the lamina propria of the small and large intestine. The golden-yellow material in the brain, lung, spleen, and small intestine was identified as bilirubin by histochemistry. Based on the macroscopic and microscopic findings, a diagnosis of kernicterus (bilirubin encephalopathy) was made. This report describes a rare case of equine neonatal kernicterus.     

Naturally occurring parvovirus-associated feline hypogranular cerebellar hypoplasia-- A comparison to experimentally-induced lesions using immunohistology

Three cases of feline cerebellar hypoplasia are presented. At the time of examination, the ages of the cats ranged from 2 months to 1 year. Necropsy revealed cerebellar and pons hypoplasia. Polymerase chain reaction for parvoviral deoxyribonucleic acid was positive in cerebellar tissue. Cell-specific immunolabeling was used to characterize the lesions, which were characterized into 2 types. In type 1 lesions, the cortex was nearly agranular, with an extremely thin molecular layer; the Purkinje cells were randomly placed and oriented, and their stunted main dendrite produced a thorn-covered atrophic dendritic tree; the basket cell axons ran randomly and had dysmorphic endings; and myelinated fibers were severely reduced in folia axes. In type 2 lesions, the cortex was hypogranular; the Purkinje cells were linearly organized, but their main dendrite extended too far in the molecular layer before giving up smooth, bent secondary dendrites; many basket cells were located along the cerebellar surface, and their axons ran at right angle to the surface; myelinated fibers were moderately reduced. Defects in climbing fiber synapse translocation and elimination were evident in both types of lesion. This immunohistologic study allowed a comparison between lesions in these spontaneous cerebellar hypoplasia cases with those documented when using silver impregnation studies after perinatal experimental cerebellar damage. Such a comparison is consistent with viral infection that occurs before birth in all 3 cases. Progress in parvovirus biology knowledge suggests that viral NS1 protein cytotoxicity might explain degenerative changes in the Purkinje cells that were present, in addition to the development defect.     

Cerebellar hypoplasia in three sibling cats after intrauterine or early postnatal parvovirus infection

The present report describes the case of an intrauterine or early postnatal parvovirus infection with subsequent cerebellar hypoplasia in three kittens from the same litter. Clinical examination of affected cats revealed neurologic signs indicative of cerebellar ataxia. Due to poor prognosis, animals were euthanised and submitted for necropsy. Post mortem examination demonstrated variable degrees of cerebellar hypoplasia. Histologically, brain lesions were characterised by segmental loss of the external and internal granular layer and decreased numbers of Purkinje cells. Reactive proliferation of astrocytes in the central nervous system was verified by the detection of GFAP-expressing glial cells in affected areas using immunohistochemistry. Furthermore, parvovirus antigen was detected immunohistochemically in neuronal cells of the cerebellum, but not in other parts of the brain and spinal cord or non-neuronal tissues. The present report demonstrates the usefulness of post mortem examination and detection of viral antigen by immunohistochemistry for the discrimination of neurologic disorders in feline species. Neurologic deficiencies due to cerebellar hypoplasia caused by in utero or perinatal feline parvovirus infection should be taken into consideration as differential diagnoses for ataxia in neonatal and juvenile cats.     

Cerebellar granuloprival degeneration in an Italian hound

A severe atrophy of the cerebellum was observed in a 7-month-old male Italian hound with a history of progressive ataxia and head tremor from the age of 3 months. On clinical examination, signs included severe hypermetric gait, head tremors and proprioception deficits in all limbs. At necropsy, a pronounced symmetrical reduction in size of the cerebellum was the only gross lesion observed. Histological examination of the cerebellum revealed marked thinning of the granular and molecular layers with almost complete loss of granule cells. Purkinje cells had normal morphology and distribution. These findings differ from those of previous reports of cerebellar cortical abiotrophy in dogs, which were mainly characterized by prominent Purkinje cell degeneration and loss.     

Late onset cerebellar degeneration in a middle-aged cat

Cerebellar degeneration (abiotrophy) (CD) is a spontaneous and accelerated degeneration of one or several mature cerebellar neuronal cell populations and has been described in many domestic animals, especially in dogs, with numerous breed-related cases. In cats, CD is mentioned as a rare sporadic entity. Late onset CDs are exceptionally uncommon and only two cases are reported in young adults, both aged 18 months. This report describes clinical and pathological findings of a late onset feline CD in a 9-year-old male Persian cat. The cat was presented with a history of progressive ataxia lasting 2 years. Neurological examination revealed severe neurological deficits such as generalised and severe ataxia, hypermetria in all four limbs, and bilateral absence of menace response. The lesion was diffusely localised in cerebellum. On gross pathology, the cerebellum appeared of normal size and shape and kidneys were characterised by mild hyperaemia. Histologically, lesions were limited to the cerebellum and kidneys. In the cerebellum, all cerebellar folia of both hemispheres and the vermis were affected. Changes were characterised by severe and diffuse loss of Purkinje cells, loss of cellularity in the granular layer, mild astrogliosis associated with moderate hypertrophy of Bergmann's glia. Immunohistochemistry for feline parvovirus antigen revealed a negative result. Renal lesions consisted of chronic fibrosis associated with chronic interstitial nephritis. CD is a rare disease and occurs commonly in puppies or young animals, who are clinically normal at birth and usually develop neurological signs within a few weeks or months after birth. This report represents the first case of CD in a middle-aged cat.     

Immunohistochemical demonstration of cytochrome oxidase in different parts of the central nervous system: a comparative experimental study

Cytochrome oxidase, the terminal enzyme of the electron transport chain, is a marker of the functional activity of the cell. In this study; localization of cytochrome oxidase in cerebrum, cerebellum, hippocampus, substantia nigra and choroid plexus of adult rats was investigated using immunohistochemical methods. Neural bodies were immunoreactive while neuroglial cells and axonal areas did not show significant immunostaining. The cerebral cortical substantia grisea region was stained almost homogeneously with cytochrome oxidase. In the cerebellar cortex, immunolabelling was more intense in the granular layer than the molecular layer. There was significant immunostaining in Purkinje cells. White matter, both in cerebrum and cerebellum, did not show immunoreactivity for cytochrome oxidase. Neurones in the hippocampus showed variable immunostaining; some of them were negative while others revealed high immunoreactivity. The neurones in substantia nigra were heavily labelled. Immunostaining for cytochrome oxidase in plexus choroideus epithelial cells was also remarkable. The morphological findings demonstrate the regions which most require and produce energy and reflect the differences in cellular activity in these parts of the central nervous system.     

Lesions in bovine progressive degenerative myeloencephalopathy ("Weaver") of Brown Swiss cattle

Gross changes and other necropsy findings in 36 purebred Brown Swiss cattle affected with bovine progressive degenerative myeloencephalopathy were nonspecific. Primary microscopic lesions were confined to the central nervous system, specifically the white matter of the spinal cord, axons in some brainstem nuclei, and Purkinje cells of the cerebellar cortex. Spinal cord lesions involved only the white matter and consisted of axonal degeneration, loss of axons and myelin, and status spongiosus. Axonal degeneration was characterized by swelling and fragmentation of the axoplasm or formation of large, discontinuous swellings referred to as spheroids. Lesions were qualitatively similar at all levels, but quantitatively dissimilar in the same funiculi at different levels. Both ascending and descending fibers were involved but correlation to specific fasciculi was not evident. Lesions always were most severe in thoracic spinal cord segments. Little or no astroglial response, no inflammatory response, and no involvement of gray matter were observed in the spinal cord. Cerebellar lesions were limited to selective degeneration and loss of Purkinje cells and occasional swelling of Purkinje cell axons (torpedos) in the granular layer of the cerebellar cortex. Brainstem lesions were inconsistent and limited to occasional axonal swelling in brainstem nuclei. The pathogenesis of bovine progressive degenerative myeloencephalopathy is unknown and possible mechanisms were discussed. The disease exhibits a familial pattern in Brown Swiss cattle and may be hereditary. Extraneural lesions were considered secondary to central nervous system lesions.     

Cerebellar granuloprival degeneration in an Australian kelpie and a Labrador retriever dog

A 7-month-old Australian kelpie dog and a 14-month-old Labrador retriever dog were diagnosed with an uncommon form of cerebellar abiotrophy called cerebellar granuloprival degeneration. This was characterized by a loss of the granular neurons with relative sparing of the Purkinje neurons.