First report of a novel 108 bp deletion and five novel SNPs in PRNP gene of stray cats and in silico analysis of their possible relation with feline spongiform encephalopathy.

Prion diseases are fatal neurodegenerative diseases affecting humans and animals. A relationship between variations in the prion gene of some species and susceptibility to prion diseases has been detected. However, variations in the prion protein of cats that have close contact with humans and their effect on prion protein are not well-known. Therefore, this study aimed to investigate the variations of prion protein-encoding gene (PRNP gene) in stray cats and to evaluate variants detected in terms of genetic factors associated with susceptibility or resistance to feline spongiform encephalopathy using bioinformatics tools. For this, cat DNA samples were amplified by a PCR targeting PRNP gene and then sequenced to reveal the variations. Finally, the effects of variants on prion protein were predicted by bioinformatics tools. According to the obtained results, a novel 108 bp deletion and nine SNPs were detected. Among SNPs, five (c314A>G, c.454T>A, c.579G>C, c.642G>C and c.672G>C) were detected for the first time in this study. Bioinformatics findings showed that c.579G>C (Q193H), c.454T>A (Y152N) and c.457G>A (E153K) variants have deleterious effects on prion protein and c.579G>C (Q193H) has high amyloid propensities. This study demonstrates prion protein variants of stray cats and their deleterious effects on prion protein for the first time.

Polioencephalopathy in Eurasier dogs.

BACKGROUND: Polioencephalopathies secondary to inborn errors of metabolism have been described in dogs, but few genetically characterized. OBJECTIVES: Clinically and genetically characterize polioencephalopathy in a family of Eurasier dogs. ANIMALS: Three Eurasier dogs (littermates) presented with early onset movement disorders (9 weeks in 2, 4-6 months in 1). Progressive gait abnormalities were detected in 2 of the dogs, persistent divergent strabismus in 1, whereas consciousness and behavior remained intact in all dogs. One dog was euthanized at 25 months. METHODS: Video footage was assessed in all dogs, and Dogs 1 and 2 had examinations and investigations performed. Whole genome sequencing of Dog 1 and further genetic analyses in the family were performed. A cohort of 115 Eurasier controls was genotyped for specific variants. RESULTS: Episodes were characterized by generalized ataxia, as well as a hypermetric thoracic limb gait, dystonia, and irregular flexion and extension movements of the thoracic limbs. Magnetic resonance imaging of the brain in Dogs 1 and 2 identified symmetrical, bilateral T2 and fluid attenuated inversion recovery hyperintense, T1 hypo to isointense, nonenhancing lesions of the caudate nucleus, lateral and medial geniculate nuclei, thalamus, hippocampus, rostral colliculus and mild generalized brain atrophy. Genetic analyses identified a homozygous mitochondrial trans-2-enoyl-CoA reductase (MECR) missense variant in all 3 dogs, and a homozygous autophagy-related gene 4D (ATG4D) missense variant in Dogs 1 and 2. CONCLUSIONS AND CLINICAL IMPORTANCE: We describe a presumed hereditary and progressive polioencephalopathy in a family of Eurasier dogs. Further research is needed to establish the role of the MECR gene in dogs and the pathogenic effects of the detected variants.

AFB1 induced free radicals cause encephalopathy in goat kids via intrinsic pathway of apoptosis: pathological and immunohistochemical confirmation of non-hepatic neuroaflatoxicosis.

Aflatoxins, particularly AFB1, are the most common feed contaminants worldwide, causing significant economic losses to the livestock sector. The current paper describes an outbreak of aflatoxicosis in a herd of 160 male young goat kids (3-4 months), of which 68 young kids succumbed over a period of 25 days after showing neurological signs of abnormal gait, progressive paralysis and head pressing. The haematobiochemical investigation showed reduced haemoglobin, leucocyte count, PCV level, increased levels of AST, ALT, glucose, BUN, creatinine and reduced level of total protein. Grossly, kids had pale mucous membranes, pale and swollen liver; right apical lobe consolidation, and petechiation of the synovial membrane of the hock joints. The microscopic changes were characterized by multifocal hemorrhages, status spongiosus/ vacuolation, vasculitis, focal to diffuse gliosis, satellitosis, and ischemic apoptotic neurons in different parts of the brain and spinal cord. These changes corresponded well with strong immunoreactivity for AFB1 in neurons, glia cells (oligodendrocytes, astrocytes, and ependymal cells) in various anatomical sites of the brain. The higher values of LPO and reduced levels of antioxidant enzymes (Catalase, SOD, GSH) with strong immunoreactivity of 8-OHdG in the brain indicating high level of oxidative stress. Further, the higher immunosignaling of caspase-3 and caspase-9 in the brain points towards the association with intrinsic pathway of apoptosis. The toxicological analysis of feed samples detected high amounts of AFB1 (0.38ppm). These findings suggest that AFB1 in younger goat kids has more of neurotoxic effect mediated through caspase dependent intrinsic pathway.

Sporadic bovine encephalopathy caused by Chlamydia pecorum secondary to bovine viral diarrhoea virus infection in calves in South Australia.

BACKGROUND: Despite bovine viral diarrhoea virus and Chlamydia pecorum being important endemic diseases of cattle, there are limited reports of theirco-occurrence. CASE REPORT: Several 12-18-week-old, weaned Hereford calves presented with ill-thriftiness and neurological signs on a mixed cattle and sheep farm in South Australia in July 2021. Immune suppression resulting from transient infection with bovine viral diarrhoea virus (BVDV) is implicated in predisposing to infection with Chlamydia pecorum, the causative agent of sporadic bovine encephalopathy (SBE). Chlamydia spp. are difficult to culture in vitro or definitively identify based on current standard molecular based tests. In this case, diagnosis was confirmed by immunohistochemistry. CONCLUSION: To the authors' knowledge, this case report is the first to document BVDV transient infection occurring in conjunction with SBE. Given the current high prevalence of BVDV on Australian farms, such co-infections may have significant future clinical relevance. This case also highlights the need for appropriate tests, such as immunohistochemistry to demonstrate the causative organism in histological lesions and thus reduce the occurrence of false negative diagnosis.

Adeno-associated virus-vectored erythropoietin gene therapy for anemia in cats with chronic kidney disease.

BACKGROUND: A treatment of chronic kidney disease (CKD)-associated anemia in cats is needed. SB-001 is an adeno-associated virus-vectored (AAV)-based gene therapeutic agent that is administered intramuscularly, causing the expression of feline erythropoietin. HYPOTHESIS/OBJECTIVE: We hypothesized that SB-001 injection would lead to a sustained increase in PCV in cats with CKD-associated anemia. ANIMALS: Twenty-three cats with International Renal Interest Society (IRIS) Stage 2 to 4 CKD-associated anemia were enrolled at 4 veterinary clinics. METHODS: In a prospective clinical trial, cats were treated with 1 of 3 regimens of SB-001 (Lo 1.2 × 109 genome copies [GCs] on Day 0; Lo ± Hi [supplemental 2nd dose of 3.65 × 109 GC on Day 42]; Hi 3.65 × 109 GC IM on Day 0) and followed for 70 days. RESULTS: A response to SB-001 at any time between Day 28 and Day 70 was seen in 86% (95% confidence interval 65, 97%) of all cats. There was a significant (P < .003) increase in PCV from Day 0 to Day 28 (mean increase 6 ± 6 percentage points [pp]; n = 21), Day 42 (8 ± 9 pp; n = 21), Day 56 (10 ± 11 pp; n = 17), and Day 70 (13 ± 14 pp, n = 14). Twelve cats were hypertensive at baseline, 4 of which developed encephalopathy during the study. An additional 6 cats became hypertensive during the study. CONCLUSIONS AND CLINICAL IMPORTANCE: Results of this study suggest that SB-001 therapy represents a suitable single injection treatment that can address nonregenerative anemia in cats with CKD. It was generally well tolerated; however, hypertension and encephalopathy developed in some cats as previously described in association with erythropoiesis-stimulating agent therapy.

Scopolamine causes delirium-like brain network dysfunction and reversible cognitive impairment without neuronal loss.

Delirium is a severe acute neuropsychiatric syndrome that commonly occurs in the elderly and is considered an independent risk factor for later dementia. However, given its inherent complexity, few animal models of delirium have been established and the mechanism underlying the onset of delirium remains elusive. Here, we conducted a comparison of three mouse models of delirium induced by clinically relevant risk factors, including anesthesia with surgery (AS), systemic inflammation, and neurotransmission modulation. We found that both bacterial lipopolysaccharide (LPS) and cholinergic receptor antagonist scopolamine (Scop) induction reduced neuronal activities in the delirium-related brain network, with the latter presenting a similar pattern of reduction as found in delirium patients. Consistently, Scop injection resulted in reversible cognitive impairment with hyperactive behavior. No loss of cholinergic neurons was found with treatment, but hippocampal synaptic functions were affected. These findings provide further clues regarding the mechanism underlying delirium onset and demonstrate the successful application of the Scop injection model in mimicking delirium-like phenotypes in mice.

Atypically located arachnoid cyst in a five-year-old cat.

Arachnoid cysts are cystic lesions that occur in spinal or intracranial locations in the leptomeningeal space. Four intracranial cases have been described in cats, three of which were diagnosed by imaging techniques alone. We now report the clinical, gross and histopathological findings in a 5-year-old, male-neutered European Shorthair cat that presented with chronic, asymmetrical encephalopathy. Using magnetic resonance imaging, a focal, fluid-filled cavity that did not show contrast enhancement was identified in the left temporal and piriform lobes. Necropsy confirmed the presence of a cystic, meningeal cavity filled with clear, serous fluid. Histologically, the cyst had an irregular, hypereosinophilic surface and single psammoma bodies with moderate perivascular oedema in the adjacent neuroparenchyma. Immunohistochemical evidence of meningeal tissue surrounding the cyst confirmed the diagnosis of an arachnoid cyst, which should be considered as a differential diagnosis of intracranial, fluid-filled cavities.

Mitochondrial fission factor (MFF) frameshift variant in Bullmastiffs with mitochondrial fission encephalopathy.

Familial cerebellar ataxia with hydrocephalus in Bullmastiffs was described almost 40 years ago as a monogenic autosomal recessive trait. We investigated two young Bullmastiffs showing similar clinical signs. They developed progressive gait and behavioural abnormalities with an onset at around 6 months of age. Neurological assessment was consistent with a multifocal brain disease. Magnetic resonance imaging of the brain showed intra-axial bilateral symmetrical focal lesions localised to the cerebellar nuclei. Based on the juvenile age, nature of neurological deficits and imaging findings, an inherited disorder of the brain was suspected. We sequenced the genome of one affected Bullmastiff. The data were compared with 782 control genomes of dogs from diverse breeds. This search revealed a private homozygous frameshift variant in the MFF gene in the affected dog, XM_038574000.1:c.471_475delinsCGCTCT, that is predicted to truncate 55% of the wild type MFF open reading frame, XP_038429928.1: p.(Glu158Alafs*14). Human patients with pathogenic MFF variants suffer from 'encephalopathy due to defective mitochondrial and peroxisomal fission 2'. Archived samples from two additional affected Bullmastiffs related to the originally described cases were obtained. Genotypes in a cohort of four affected and 70 unaffected Bullmastiffs showed perfect segregation with the disease phenotype. The available data together with information from previous disease reports allow classification of the investigated MFF frameshift variant as pathogenic and probably causative defect of the observed neurological phenotype. In analogy to the human phenotype, we propose to rename this disease 'mitochondrial fission encephalopathy (MFE)'.

Neurologic Disorders of the Foal.

Neurologic disease of foals is a diagnostic and therapeutic challenge for veterinarians. Disease conditions such as neonatal encephalopathy are seen as well as developmental and congenital defects, bacterial infections, and trauma. Neonatal encephalopathy can be considered a "syndrome" with a variety of causes resulting in a similar clinical presentation. These causes can be categorized as maladaptation, hypoxic/ischemic encephalopathy, and metabolic abnormalities, all leading to signs of cerebral and brainstem disease. Spinal cord signs may occasionally be seen, but these signs are usually overshadowed by cerebral disease. Treatment in most cases involves supportive care and outcome is favorable in most cases.

Mild Encephalitis/Encephalopathy with Reversible Splenial Lesion Associated with Scrub Typhus in a Child: A Case Report.

Background: Mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) is a rare clinicoradiological syndrome characterized by transient mild encephalopathy and magnetic resonance imaging (MRI) findings of a reversible lesion in the splenium of the corpus callosum (SCC). Multiple causes have been proposed for the pathogenesis of MERS, with infection as the most pre-eminent. Case Presentation: We report the case of a 10-year-old girl with MERS due to scrub typhus. Her clinical manifestations of headache and drowsiness, together with lesions involving the SCC, as shown by MRI, and their complete resolution upon follow-up fulfilled the diagnosis of MERS. At the same time, the characteristic eschar of the skin and the positive Weil-Felix test result confirmed the existence of scrub typhus infection. Conclusions: To the best of our knowledge, we described the first pediatric case of MERS associated with scrub typhus. The case indicated that an MERS patient with fever should be considered as possibly having a scrub typhus infection. The characteristic black eschar of scrub typhus generally occurs after bite of mite that is important and useful to the doctor for making proper diagnosis.

Encephalopathy caused by Talisia esculenta intoxication in pregnant ewes and their newborn lambs.

An outbreak of acute encephalopathy occurred in pregnant ewes and their newborn lambs associated with consumption of Talisia esculenta fruits and bark. Clinical signs in 5 adult pregnant ewes included drooling, bloat, tachypnea, depression, ataxia, body shaking, difficulty in rising, and recumbency. Three neonatal lambs born to some of those ewes had similar clinical signs. No significant gross abnormalities were observed on autopsy. Histologically, neuronal necrosis, axonal and dendritic swelling, and loss of Purkinje neurons were observed in the cerebellum. The observation of similar neurologic clinical signs and lesions in pregnant ewes and their neonatal lambs suggests that the toxic principle of T. esculenta crosses the placenta and reaches the fetus.

Selective symmetrical necrotizing encephalopathy secondary to primary mitochondrial disorder in a cat.

A 2-year-old female cat was referred for progressive neurological signs indicative of involvement of the prosencephalon, cerebellum, and brainstem. Magnetic resonance imaging identified multifocal, bilateral, symmetrical lesions with strong contrast enhancement, affecting multiple areas of the brain. Neuropathology at necropsy showed demyelination, necrotic lesions, spongiosis, and neuropil edema with reactive astrogliosis and neovascularization. Ultrastructural study indicated mitochondrial polymorphism. Genetic investigations outlined 2 polymorphisms within the tRNA-Leu(UUR) gene of mitochondrial DNA. Imaging and neuropathological findings were consistent with selective symmetrical necrotizing encephalopathy, for which genetic investigations support mitochondrial pathogenesis.

NK-lysin peptides ameliorate viral encephalopathy and retinopathy disease signs and provide partial protection against nodavirus infection in European sea bass.

Antimicrobial peptides (AMP) comprise a wide range of small molecules with direct antibacterial activity and immunostimulatory role and are proposed as promising substitutes of the antibiotics. Additionally, they also exert a role against other pathogens such as viruses and fungi less evaluated. NK-lysin, a human granulysin orthologue, possess a double function, taking part in the innate immunity as AMP and also as direct effector in the cell-mediated cytotoxic (CMC) response. This molecule is suggested as a pivotal molecule involved in the defence upon nervous necrosis virus (NNV), an epizootic virus provoking serious problems in welfare and health status in Asian and Mediterranean fish destined to human consumption. Having proved that NK-lysin derived peptides (NKLPs) have a direct antiviral activity against NNV in vitro, we aimed to evaluate their potential use as a prophylactic treatment for European sea bass (Dicentrarchus labrax), one of the most susceptible cultured-fish species. Thus, intramuscular injection of synthetic NKLPs resulted in a very low transcriptional response of some innate and adaptive immune markers. However, the injection of NKLPs ameliorated disease signs and increased fish survival upon challenge with pathogenic NNV. Although NKLPs showed promising results in treatments against NNV, more efforts are needed to understand their mechanisms of action and their applicability to the aquaculture industry.

Nutritional Management of Behavior and Brain Disorders in Dogs and Cats.

There are several natural products and functional ingredients that, either alone or in combination with other ingredients, have shown evidence for decreasing signs associated with cognitive dysfunction and anxiety in dogs and cats, and in management of seizures in dogs with epilepsy. The evidence supporting the role that a healthy gastrointestinal tract plays in behavior is also growing as more is learned about the gut-brain axis. Nutritional support may play an important role in therapy for certain brain disorders and behavioral problems, in conjunction with other aspects of management. A multimodal approach provides the greatest likelihood of success.

PEA15 loss of function and defective cerebral development in the domestic cat.

Cerebral cortical size and organization are critical features of neurodevelopment and human evolution, for which genetic investigation in model organisms can provide insight into developmental mechanisms and the causes of cerebral malformations. However, some abnormalities in cerebral cortical proliferation and folding are challenging to study in laboratory mice due to the absence of gyri and sulci in rodents. We report an autosomal recessive allele in domestic cats associated with impaired cerebral cortical expansion and folding, giving rise to a smooth, lissencephalic brain, and that appears to be caused by homozygosity for a frameshift in PEA15 (phosphoprotein expressed in astrocytes-15). Notably, previous studies of a Pea15 targeted mutation in mice did not reveal structural brain abnormalities. Affected cats, however, present with a non-progressive hypermetric gait and tremors, develop dissociative behavioral defects and aggression with age, and exhibit profound malformation of the cerebrum, with a 45% average decrease in overall brain weight, and reduction or absence of the ectosylvian, sylvian and anterior cingulate gyrus. Histologically, the cerebral cortical layers are disorganized, there is substantial loss of white matter in tracts such as the corona radiata and internal capsule, but the cerebellum is relatively spared. RNA-seq and immunohistochemical analysis reveal astrocytosis. Fibroblasts cultured from affected cats exhibit increased TNFα-mediated apoptosis, and increased FGFb-induced proliferation, consistent with previous studies implicating PEA15 as an intracellular adapter protein, and suggesting an underlying pathophysiology in which increased death of neurons accompanied by increased proliferation of astrocytes gives rise to abnormal organization of neuronal layers and loss of white matter. Taken together, our work points to a new role for PEA15 in development of a complex cerebral cortex that is only apparent in gyrencephalic species.

Fibrocartilaginous Embolic Encephalopathy in a Pig.

A 1-year-old boar was investigated after presenting with acute onset collapse and obtundance. No significant gross lesions were observed at post-mortem examination. Histopathological investigation revealed a severe bilateral and multifocal necrotizing encephalopathy with an amorphous material, which obstructed neuroparenchymal vessels in the metencephalon and mesencephalon. Alcian blue staining identified the material as of cartilaginous origin and a diagnosis of cerebral fibrocartilaginous embolism was established. No gross evidence of vertebral disc disease was detected and the origin of the embolic material was not found. Although cerebral fibrocartilaginous embolism has been reported in a human, and rarely in animals, it has not been reported previously in the pig.

Cortical laminar necrosis detected by diffusion-weighted imaging in a dog suspected of having hypoglycemic encephalopathy.

We describe a 5-year-old castrated male dog suspected hypoglycemic encephalopathy that was evaluated by using diffusion-weighted imaging (DWI). The dog experienced hypoglycemia after prolonged generalized and continued partial seizures. In the acute phase, DWI showed hyperintensity in the left temporal lobe. After about a month, DWI maintained hyperintensity, and left middle cerebral artery dilation was noted on magnetic resonance angiography (MRA). In the chronic phase, the left temporal lobe lesion was replaced by cerebrospinal fluid. In humans, it was reported that cortical laminar necrosis (CLN) with hypoglycemic encephalopathy presents hyperintensity in the cerebral cortex on DWI and increased vascularity of the middle cerebral artery branches on MRA. In conclusion, DWI has detected CLN in a dog suspected hypoglycemic encephalopathy.

Uraemic Encephalopathy in a Persian Cat with Chronic Kidney Disease.

Uraemic encephalopathy (UE) is rarely associated with acute kidney injury or chronic kidney disease in domestic animals, and we now report the first case in a cat. The animal presented with hypothermia, apathy, lethargy, depression, severe dehydration, uraemic breath, elevated serum urea nitrogen and creatine concentrations, and eventual seizures and coma prior to death. Gross necropsy findings included severe bilateral renal scarring, ulcerative stomatitis and glossitis, and uraemic gastropathy. Microscopic lesions of diffuse interstitial fibrosis, multifocal mineralization and lymphoplasmacytic interstitial nephritis were seen in the kidneys. There was symmetrical, bilateral spongy vacuolation of the white matter of the basal nuclei and cerebellum and Alzheimer type II astrocytes in the cerebral cortex and hippocampus. Glial fibrillary acid protein immunolabelling was absent or faint in astrocytes of the cerebral grey matter. UE should be included in the differential diagnosis in animals with chronic kidney disease and neurological signs.

Investigation of routes of entry and dispersal pattern of RGNNV in tissues of European sea bass, Dicentrarchus labrax.

Viral encephalopathy and retinopathy (VER) is a serious neuropathological fish disease affecting in the Mediterranean aquaculture mainly European sea bass, Dicentrarchus labrax. It is well known that betanodaviruses are neurotropic viruses that replicate in nerve tissues, preferentially brain and retina. However, routes of entry and progression of the virus in the central nervous system (CNS) remain unclear. The role of four tissues-eye, oesophagus, gills and skin-as possible gateways of a betanodavirus, the redspotted grouper nervous necrosis virus (RGNNV), was investigated after experimental challenges performed on European seabass juveniles. The dispersal pattern of Betanodavirus at primarily stages of the disease was also assessed, using a real-time qPCR assay. The development of typical clinical signs of VER, the presence of characteristic histopathological lesions in the brain and retina and the detection of viral RNA in the tissues of all experimental groups ascertained that successful invasion of RGNNV under all experimental routes was achieved. Transneuronal spread along pathways known to be connected to the initial site of entry seems to be the predominant scenario of viral progression in the CNS. Furthermore, viraemia appeared only after the installation of the infection in the brain.

Is there a link between bacteriuria and a reversible encephalopathy in dogs and cats?

Bacteriuria has been associated with abnormal neurological status in humans, especially geriatric patients. In this report, we review 11 cases (seven dogs and four cats) that suggest an association between bacteriuria and abnormal neurological status in veterinary medicine. These cases showed diffuse forebrain signs with or without brainstem signs, but primary brain disease was excluded by MRI and cerebrospinal fluid analysis. Bacteriological culture of urine was positive in each animal and neurological deficits improved or resolved with initiation of antibiosis ± fluid therapy and levetiracetam. While further studies are needed to definitively confirm or refute the link between bacteriuria and a reversible encephalopathy, urine bacteriological culture should be considered in veterinary patients presented with acute onset forebrain neuro-anatomical localisation, even in the absence of clinical signs of lower urinary tract inflammation.