Central Nervous System Of Cat Research Articles

A Histopathological Study on the Changes in the Central Nervous System of Dead Cats With Neurological Symptoms

Background: Neurological conditions constitute approximately 10% of feline cases referred to veterinary clinics. Such cases often present manifestations of central nervous system (CNS) damage, including inflammatory lesions, neoplastic growth and structural and cellular transformations. Objectives: This study aimed at identifying histopathological changes in the CNS of cats that had succumbed to neurological symptoms. Methods: Microscopic evaluation of different sections within the CNS was conducted on 20 cats that had either died naturally or were euthanized due to neurological signs. After performing a necropsy, we examined the CNS tissues and conducted PCR testing to screen for possible viral infections, including feline infectious peritonitis (FIP), feline immunodeficiency virus (FIV) and feline leukemia virus (FeLV). Results: The majority of cases showed characteristic histopathologic lesions, notably mononuclear and suppurative meningoencephalitis, perivascular cuffing, disseminated intravascular coagulation (DIC), granulomatous meningoencephalitis, acute neuronal necrosis, liquefactive necrosis, epididymitis, thrombosis and demyelination. Among the 20 cats studied, 12 tested positive for FIP by PCR analysis, while 5 cats exhibited positive results for FIV. Also, FeLV PCR tests displayed positive results in 4 cats. No evidence of feline spongiform encephalopathy (FSE) was observed. Conclusion: This study is the first of its kind conducted in Iran. Based on the results, the most prevalent viral agents infecting cats’ CNS were FIP, FIV and FeLV. The investigation revealed no evidence of FSE in cats with neurological signs.

Identification of Prototheca from the Cerebrospinal Fluid of a Cat with Neurological Signs.

Prototheca infections are rare in cats, and they are usually associated with cutaneous or subcutaneous infections by P. wickerhamii, with no evidence of neurological signs or systemic disease. In this study, we report the identification of prototheca in the cerebrospinal fluid (CSF) of a cat with neurological symptoms. Fourteen CSF samples were gathered from cats presented with neurological disease between 2012 and 2014. The inclusion criteria for the samples were an increase in CSF protein and cell number (pleocytosis), suggestive of an infectious inflammatory status of the central nervous system (CNS). Nine samples fulfilled the inclusion criteria (inflammatory samples), while five samples, used as control, did not (non-inflammatory samples). All the samples were screened molecularly for different pathogens associated with CNS disease in cats, including prototheca. Out of 14 CSF samples, only one inflammatory sample tested positive for prototheca. Upon sequence and phylogenetic analysis of the amplicon, the strain was characterized as P. bovis. This report is the first documented evidence of prototheca in the cerebrospinal fluid of a cat with neurological signs. Prototheca should be considered in the diagnostics procedures on the CNS of cats presented with infectious diseases.

Central nervous system development of cats (Felis catus L. 1758)

The morphological similarities of vertebrates' embryonic development are used as a criterion for choosing animal models that can be used in biomedical research. This study describes the embryonic and fetal development of the domestic cat's central nervous system from 15 days after conception until birth. In total, fifty-seven samples of embryos and fetuses were carefully dissected and analyzed microscopically. The closure of the neural tube was observed between 14-15th days of gestation. The differentiation of the primordial cerebral vesicles was observed from the 17th day of gestation. On the 19th day of gestation, the formation of the choroid plexus began, and on the 20th day of gestation, the brain and brainstem were well-identified macroscopically. On the 24th day of gestation, four layers of cells from the cerebral cortex were described, and on the 60th day, six layers of cells were present. The cerebellar cortex had the three classic cortical layers at this stage. The morphological aspects of embryonic and fetal development in cats were very similar to the stages of development of the human nervous system. As such, this study provided relevant information that highlights the domestic cat as an animal model option for preclinical research on infectious and non-infectious neurological diseases in humans.

Cholesteatoma and hydrocephalus associated to a third ventricle meningioma in a cat

ABSTRACT: Meningiomas are neoplasms that commonly involve the central nervous system of cats, while cholesteatomas are nodular granulomatous chronic lesions within the choroid plexus that are rarely reported in cats. This study described a case of cholesteatoma and non-communicating hydrocephalus associated to a third ventricle meningioma in a cat. Clinically, the cat had a 2-year history of behavioral changes, photophobia and motor incoordination. At the necropsy, a tan-brown mass totally occluded the third ventricle, causing a severe dilation of the lateral ventricles (non-communicating hydrocephalus). Microscopically, the mass was composed by a neoplastic proliferation of spindle cells arranged in bundles, containing in the center psammomatous bodies (meningioma), while in the adjacent areas a cholesteatoma was observed, which was characterized by multiple cholesterol cleft formation, hemosiderosis and associated granulomatous inflammation. At immunohistochemistry (IHC), neoplastic cells had a marked immunostaining for vimentin, while were negative for cytokeratin and S100. The diagnosis of transitional meningioma occurring in association to cholesteatoma and non-communicating hydrocephalus in a cat was obtained mainly by the histological and IHC features. These are important methods to distinguish this condition from other neurological disorders in cats.

Glial response in the central nervous system of cats with feline infectious peritonitis.

The aim of the study was to evaluate central nervous system (CNS) lesions in non-effusive and effusive cases of feline infectious peritonitis (FIP) regarding aspects related to astrocytic and microglial reactions. Five necropsied cats that were naturally infected with FIP virus, confirmed by reverse transcriptase polymerase chain reaction and immunohistochemistry, with different intensities of CNS lesions, were studied. Brain and cerebellum were evaluated by light microscopy and immunohistochemistry for glial fibrillary acidic protein (GFAP) and vimentin to assess astrocytic morphology, and lectin histochemistry for Ricinus communis agglutinin-I (RCA-I) to detect microglia was performed to evaluate the glial response in the CNS of cats with FIP. An important astrocytic response in many areas of the CNS of all cats, including the periventricular areas of lateral ventricles and fourth ventricle, the molecular layer of the cerebellum and cerebral cortex, was visualized. This astrocytic reactivity was associated with areas of granulomatous or pyogranulomatous vasculitis/perivasculitis in most cases, and it was characterized by multifocal to coalescing astrocytosis and astrogliosis with an increase in the expression of intermediate filaments, such as GFAP. However, astrocytes exhibited strong vimentin expression in neuroparenchyma with severe inflammatory and necrotic changes, but GFAP expression was mild or absent in these cases. A microglial response was present only in severe lesions, and RCA-I expression was detected primarily in gitter cells and resting microglia. The present study indicates a strong astrocytic response, including the presence of many less differentiated vimentin-positive astrocytes and gitter cells positive for RCA-1 in severe lesions in the CNS of cats with FIP.

Intracisternal delivery of AAV9 results in oligodendrocyte and motor neuron transduction in the whole central nervous system of cats

Systemic and intracerebrospinal fluid delivery of adeno-associated virus serotype 9 (AAV9) has been shown to achieve widespread gene delivery to the central nervous system (CNS). However, after systemic injection, the neurotropism of the vector has been reported to vary according to age at injection, with greater neuronal transduction in newborns and preferential glial cell tropism in adults. This difference has not yet been reported after cerebrospinal fluid (CSF) delivery. The present study analyzed both neuronal and glial cell transduction in the CNS of cats according to age of AAV9 CSF injection. In both newborns and young cats, administration of AAV9-GFP in the cisterna magna resulted in high levels of motor neurons (MNs) transduction from the cervical (84±5%) to the lumbar (99±1%) spinal cord, demonstrating that the remarkable tropism of AAV9 for MNs is not affected by age at CSF delivery. Surprisingly, numerous oligodendrocytes were also transduced in the brain and in the spinal cord white matter of young cats, but not of neonates, indicating that (i) age of CSF delivery influences the tropism of AAV9 for glial cells and (ii) AAV9 intracisternal delivery could be relevant for both the treatment of MN and demyelinating disorders.

Use of anti-coronavirus antibody testing of cerebrospinal fluid for diagnosis of feline infectious peritonitis involving the central nervous system in cats

To assess the use of measuring anti-coronavirus IgG in CSF for the diagnosis of feline infectious peritonitis (FIP) involving the CNS in cats. Prospective study. CSF and serum samples from 67 cats. CSF and serum samples were allocated into 4 groups: cats with FIP involving the CNS (n = 10), cats with FIP not involving the CNS (13), cats with CNS disorders caused by diseases other than FIP (29), and cats with diseases other than FIP and not involving the CNS (15). Cerebrospinal fluid was evaluated for concentrations of erythrocytes, leukocytes, and total protein. Anti-coronavirus IgG was measured in CSF and serum by indirect immunofluorescence assay. CSF IgG (range of titers, 1:32 to 1:4,096) was detected in 12 cats, including 6 cats with neurologic manifestation of FIP, 4 cats with FIP not involving the CNS, and 2 cats with brain tumors. Cerebrospinal fluid IgG was detected only in cats with correspondingly high serum IgG titers (range, 1:4,096 to 1:16,384) and was positively correlated with serum IgG titers (r = 0.652; P < 0.01), but not with any other CSF parameter. Blood contamination of CSF resulted in < or = 333 erythrocytes/microL in cats with CSF IgG. The correlation between serum and CSF IgG and the fact that CSF IgG was detected only in strongly seropositive cats suggested that CSF anti-coronavirus IgG was derived from blood. Measurement of anti-coronavirus IgG in CSF was of equivocal clinical use.

Abnormal neuronal metabolism and storage in mucopolysaccharidosis type VI (Maroteaux–Lamy) disease

Mucopolysaccharidosis (MPS) type VI, also known as Maroteaux-Lamy disease, is an inherited disorder of glycosaminoglycan catabolism caused by deficient activity of the lysosomal hydrolase, N-acetylgalactosamine 4-sulphatase (4S). A variety of prominent visceral and skeletal defects are characteristic, but primary neurological involvement has generally been considered absent. We report here that the feline model of MPS VI exhibits abnormal lysosomal storage in occasional neurones and glia distributed throughout the cerebral cortex. Abnormal lysosomal inclusions were pleiomorphic with some resembling zebra bodies and dense core inclusions typical of other MPS diseases or the membranous storage bodies characteristic of the gangliosidoses. Pyramidal neurones were shown to contain abnormal amounts of GM2 and GM3 gangliosides by immunocytochemical staining and unesterified cholesterol by histochemical (filipin) staining. Further, Golgi staining of pyramidal neurones revealed that some possessed ectopic axon hillock neurites and meganeurites similar to those described in Tay-Sachs and other neuronal storage diseases with ganglioside storage. Some animals evaluated in this study also received allogeneic bone marrow transplants, but no significant differences in neuronal storage were noted between treated and untreated individuals. These studies demonstrate that deficiency of 4S activity can lead to metabolic abnormalities in the neurones of central nervous system in cats, and that these changes may not be readily amenable to correction by bone marrow transplantation. Given the close pathological and biochemical similarities between feline and human MPS VI, it is conceivable that children with this disease have similar neuronal involvement.

Elimination of phenolsulfonphthalein from the cerebrospinal fluid via capillaries in central nervous system in cats by active transport

It was recently proposed that organic anions, such as cerebral acidic metabolites and phenolsulfonphthalein (PSP), are eliminated from cerebrospinal fluid (CSF) by diffusion into the central nervous system (CNS) and further by active transport into capillaries. To test this hypothesis, PSP was injected into cisternal CSF and its distribution into various parts of the CNS was measured 1 and 3 h later in control cats and those pretreated with probenecid, which blocks active transport of organic anions into capillaries. PSP in tissue shows an intensive pink color when exposed to 1 N NaOH. Planimetric analysis of color pictures of coronal CNS slices showed that at the first hour, diffusion and distribution of PSP into the CNS in both groups of animals was similar, while at the third hour, a great reduction of PSP distribution in the CNS in control and only a slight reduction in probenecid pretreated cats was observed. The results support the hypothesis that active transport across the capillary wall in the CNS is the main avenue for elimination of cerebral acidic metabolites from both CSF and CNS and in such a way that central homeostasis is maintained.

A Review of Coronavirus Infection in the Central Nervous System of Cats and Mice

Feline infectious peritonitis (FIP) is a common cause of death in cats. Management of this disease has been hampered by difficulties identifying the infection and determining the immunological status of affected cats and by high variability in the clinical, pathological, and immunological characteristics of affected cats. Neurological FIP, which is much more homogeneous than systemic effusive or noneffusive FIP, appears to be a good model for establishing the basic features of FIP immunopathogenesis. Very little information is available about the immunopathogenesis of neurologic FIP, and it is reasonable to use research from the well‐characterized mouse hepatitis virus (MHV) immune‐mediated encephalitis system, as a template for FIP investigation, and to contrast findings from the MHV model with those of FIP. It is expected that the immunopathogenic mechanisms will have important similarities. Such comparative research may lead to better understanding of FIP immunopathogenesis and rational prospects for management of this frustrating disease.

A review of coronavirus infection in the central nervous system of cats and mice.

Feline infectious peritonitis (FIP) is a common cause of death in cats. Management of this disease has been hampered by difficulties identifying the infection and determining the immunological status of affected cats and by high variability in the clinical, pathological, and immunological characteristics of affected cats. Neurological FIP, which is much more homogeneous than systemic effusive or noneffusive FIP, appears to be a good model for establishing the basic features of FIP immunopathogenesis. Very little information is available about the immunopathogenesis of neurologic FIP, and it is reasonable to use research from the well-characterized mouse hepatitis virus (MHV) immune-mediated encephalitis system, as a template for FIP investigation, and to contrast findings from the MHV model with those of FIP. It is expected that the immunopathogenic mechanisms will have important similarities. Such comparative research may lead to better understanding of FIP immunopathogenesis and rational prospects for management of this frustrating disease.

In Vivo Infection of Ramified Microglia from Adult Cat Central Nervous System by Feline Immunodeficiency Virus

Infection of microglial cells by the human immunodeficiency virus (HIV) is supposed to play an important role in the pathogenesis of AIDS-related central nervous system (CNS) complications. So far, however, experimental data about interactions between HIV and ramified microglia from the adult CNS were only occasionally reported, making it difficult to understand the exact nature of pathogenic events contributing to HIV-encephalopathy. Therefore, we used the animal model of feline immunodeficiency virus (FIV) infection of domestic cats to establish an experimental system which is suitable for studying the relationships between an immunodeficiency virus and the mature ramified microglia of the central nervous system. By means of density gradient centrifugation approximately 95% pure microglial cells could be isolated from adult feline brain that were characterized by their CD45low phenotype. Resident microglia extracted from the CNS of experimentally infected cats harbored FIV-specific DNA and cocultivation with mitogen-activated, but uninfected peripheral blood mononuclear cells (PBMC) resulted in recovery of high-titered infectious virus. Double labeling of brain cell monocultures explanted from persistently infected animals for both microglia and FIV markers disclosed less than 1% of viral antigen expressing microglial cells. This suggests that during the subclinical phase of the infection only a small number of brain-resident macrophages are productively infected. However, interaction of FIV-infected microglia and inflammatory lymphocytes may promote viral replication, thus supporting viral spread in brain tissue.

Feline immunodeficiency virus envelope protein (FIVgp120) causes electrophysiological alterations in rats

Close to 20% of the patients infected with the AIDS virus develops neurological deficit; eventhough HIV does not invade neurons. Consistently with the neurological deficit, HIV + subjects show abnormalities in brainstem auditory and visual evoked potentials (BSAEP and VEP) and in sleep patterns. The HIV-derived glycoprotein 120 has been postulated as a neurotoxic; therefore, it may be playing a crucial role in the generation of BSAEP and VEP, as well as in sleep disturbances. To study the role of the virus-derived proteins on the development of these electrophysiological signals' alterations, we have used the feline immunodeficiency virus (FIV)-derived gp120 and evaluated the changes in these electrophysiological signals. We employed 15 adult male Sprague–Dawley rats (250–350 g), chronically implanted for evoked potential and sleep recordings. Results showed that the i.c.v. administration of FIVgp120 (5 ng/10 μl) produces changes in the latency of both cortical auditory evoked potentials (CAEPs) and VEPs and a decrease in both REM sleep and SWS. These data support the notion that FIVgp120 is neurotoxic to the central nervous system of cats and rats and that this protein suffices to cause electrophysiological alterations. In addition, it suggests that a similar effect may be occurring in humans as a result of HIVgp120's neurotoxic effects.

Tumor necrosis factor-alpha and virus expression in the central nervous system of cats infected with feline immunodeficiency virus.

Cytokine disregulation has been implicated in the pathogenesis of lentivirus-induced diseases. In the present study, 18 specific pathogen free (SPF) cats were inoculated with feline immunodeficiency virus (FIV) Petaluma strain and sacrificed at different times post-infection. Five additional SPF cats were used as controls. The cell localization of the cytokine tumor necrosis factor alpha (TNF-alpha) in the central nervous system (CNS) was determined by immunohistochemical and morphometric analyses with a polyclonal rabbit anti-human TNF-alpha antibody. TNF-alpha and FIV RNA were measured using competitive reverse transcriptase polymerase chain reaction (PCR) assays and the number of proviral genomes was estimated by competitive PCR. Portions of frontal cortex were collected from each animal and both formalin-fixed and snap-frozen and stored at -80 degrees C until used. The results showed that TNF-alpha is present mainly in astrocytes and microglial cells. Morphometric analysis showed that areas of TNF-alpha production increased in the early phases of infection. Molecular analyses demonstrated that the kinetics of proviral loads in the CNS were comparable to what observed in lymph nodes and peripheral blood mononuclear cells, with the peaks in the early and late stages of infection. A positive correlation was found between viral parameters and TNF-alpha transcription, the strongest relationship was found between the transcription of the cytokine and viral RNA load. These results confirm that invasion of CNS by FIV occurs soon after virus exposure and that during this phase there is an increase of local viral loads with concomitant up-regulation of TNF-alpha expression. During the asymptomatic phase viral replication remains low in spite of the progression of CNS alterations. The dissociation between the viral load and the lesions observed suggests the importance of an indirect mechanism for the progression of these lesions, even if TNF-alpha seems to play a role particularly in the early phase of infection.

Experimental infection of swine and cat central nervous systems by the pig paramyxovirus of the blue eye disease.

This study analyses whether the pig paramyxovirus of blue eye disease (PPBED) infects the central nervous system (CNS) utilizing anterograde and retrograde peripheral nerve transport systems. The virus was injected into muscle and skin, and inoculated per nasum. The presence of PPBED was detected by an immunohistochemical method using polyclonal mouse antibodies against the whole inactivated virus, and was revealed with polyclonal rabbit antibodies against mouse immunoglobulin G (IgG) labelled with peroxidase. The PPBED injected into the pig medial gastrocnemius (MG) muscle was detected in a terminal branch innervating the MG muscle, in neural fibres of the sciatic nerve, in fibres of the ventral and dorsal spinal roots and in ventral horn neurones of the spinal cord. When PPBED was injected into the skin area innervated by the sural nerve, it was detected in neural fibres of the sural and sciatic nerves and in spinal cord dorsal horn neurones. The per nasum inoculum rapidly invaded the CNS through the olfactory nerve. The study concluded that, in order to invade the CNS, PPBED was transported retrogradely by peripheral cutaneous and muscular nerves, and anterogradely by the olfactory nerve. No PPBED was detected in either cat peripheral nerves or in cat CNS.

Regional distribution of lesions in the central nervous system of cats infected with feline immunodeficiency virus.

Neuropathological examination of the central nervous system of 13 naturally and 13 experimentally feline immunodeficiency virus (FIV)-infected cats revealed diffuse gliosis of gray and white matter and vacuolar myelinopathy in a large proportion of infected animals, sometimes associated with lymphocytic meningitis. Multinucleated giant cell formation, the hallmark of multifocal giant cell encephalitis in HIV infection, was never observed. Morphometric analysis confirmed a marked increase of GFAP reactivity in infected cats. Gliosis was mainly present in cortical structures of frontal, parietal, and occipital lobes. Only one naturally infected animal evidenced clinical symptoms of neurological damage. This study confirms that FIV provides an interesting model for studying HIV-induced cortical and subcortical brain pathology believed to be the cause of the neurological manifestations frequently observed in AIDS patients.

Immunoreactivity of the central nervous system in cats with a Borna disease-like meningoencephalomyelitis (staggering disease).

The inflammatory cell composition and the expression of major histocompatibility complex (MHC) antigens in the central nervous system (CNS) of 13 cats with a spontaneous, Borna disease-like meningoencephalomyelitis (staggering disease) was investigated by immunohistochemistry with a panel of monoclonal and polyclonal antibodies. T lymphocytes were the predominating inflammatory cells within the adventitial space. CD4+ T cells were more abundant than CD8+ T cells. Scattered IgG-, IgA- and IgM-containing cells were found in the adventitial space and surrounding neuropil, often adjacent to neurons. There was a markedly increased MHC class II expression in cells morphologically resembling microglia. In several cats, Borna disease virus specific antigen was detected, but only in a few cells, mainly of macrophage character. Our findings indicate a long-standing inflammatory reaction in the CNS of cats with staggering disease, possibly triggered and sustained by a persistent viral infection.

Immunoreactivity of the central nervous system in cats with a Borna disease-like meningoencephalomyelitis (staggering disease)

The inflammatory cell composition and the expression of major histocompatibility complex (MHC) antigens in the central nervous system (CNS) of 13 cats with a spontaneous, Borna disease-like meningoencephalomyelitis (staggering disease) was investigated by immunohistochemistry with a panel of monoclonal and polyclonal antibodies. T lymphocytes were the predominating inflammatory cells within the adventitial space. CD4+ T cells were more abundant than CD8+ T cells. Scattered IgG-, IgA- and IgM-containing cells were found in the adventitial space and surrounding neuropil, often adjacent to neurons. There was a markedly increased MHC class II expression in cells morphologically resembling microglia. In several cats, Borna disease virus specific antigen was detected, but only in a few cells, mainly of macrophage character. Our findings indicate a long-standing inflammatory reaction in the CNS of cats with staggering disease, possibly triggered and sustained by a persistent viral infection.

The divergent actions of volatile anaesthetics on background neuronal activity and reactive capability in the central nervous system in cats.

The effects of halothane, isoflurane, and enflurane on background neuronal activity and reactive capability in the central nervous system were studied in cats. The background neuronal activity was assessed by midbrain reticular cell firing, which was measured by the method of multi-unit activity, and the EEG in the cortex, amygdala, and hippocampus. The reactive capability was assessed by evoked responses in the visual neuronal pathway. All anaesthetics studied suppressed reticular cell firing in a dose-dependent manner, and the suppression by halothane (43.8 +/- 10.3% of control, mean +/- SD) was less than isoflurane (66.5 +/- 5.8%, P < 0.01) and enflurane (73.1 +/- 8.8%, P < 0.05) at 1 MAC. Spontaneous EEG spikes developed at 4.8% isoflurane and 3.6% enflurane anaesthesia. Phasic activation of reticular cell firing was associated with EEG spikes during isoflurane and enflurane anaesthesia, and the activation during enflurane anaesthesia was greater than during isoflurane anaesthesia (P < 0.01). Photic stimulation provoked EEG spikes and repetitive stimulation induced seizure activity only at 3.6% enflurane anaesthesia. Halothane and isoflurane suppressed stimulation induced responses in the visual neuronal pathway. The amplitudes of N1 in visual cortical evoked responses induced by photic stimulation were suppressed to 70.1 +/- 24.5% of control at 2.4% halothane and 39.3 +/- 27.3% at 4.8% isoflurane. Enflurane, at 3.6%, augmented the evoked response induced by photic stimulation (398.4 +/- 83.0% of control in the amplitude of N1). These results indicate that all the agents studied had suppressive actions on background neuronal activity in the order halothane < isoflurane = enflurane. The effects on reactive capability were divergent among agents, e.g., enflurane enhanced, halothane suppressed, and the actions of isoflurane were intermediate. We conclude that the anaesthetic effects on background activity and on reactive capability are divergent and that suppression of reactive capability is a factor in determining the ease of clinical application of the anaesthetics.

The extracellular matrix of cerebral gray matter: Golgi's pericellular net and nissl's nervösen Grau revisited

Glial hyaluronate-binding protein (GHAP) and a large aggregating chondroitin sulfate proteoglycan (Ag-Pg) similar to a fibroblast proteoglycan (versican) were localized in bovine, dog and cat central nervous system (CNS) gray matter by indirect immunofluorescence. The distribution of the two hyaluronate-binding proteins was identical with that of hyaluronate, an extracellular glycosaminoglycan. All substances formed a finely reticulated mesh in the neuropil with a condensation of the stain around large neurons. It is concluded that in gray matter, as in white matter, the extracellular matrix (ECM) contains hyaluronate-protein aggregates. We suggest that the hyaluronate-protein aggregates correspond to the pericellular network first described by Golgi.