Andrea Tipold

International veterinary epilepsy task force consensus report on epilepsy definition, classification and terminology in companion animals

Dogs with epilepsy are among the commonest neurological patients in veterinary practice and therefore have historically attracted much attention with regard to definitions, clinical approach and management. A number of classification proposals for canine epilepsy have been published during the years reflecting always in parts the current proposals coming from the human epilepsy organisation the International League Against Epilepsy (ILAE). It has however not been possible to gain agreed consensus, “a common language”, for the classification and terminology used between veterinary and human neurologists and neuroscientists, practitioners, neuropharmacologists and neuropathologists. This has led to an unfortunate situation where different veterinary publications and textbook chapters on epilepsy merely reflect individual author preferences with respect to terminology, which can be confusing to the readers and influence the definition and diagnosis of epilepsy in first line practice and research studies.In this document the International Veterinary Epilepsy Task Force (IVETF) discusses current understanding of canine epilepsy and presents our 2015 proposal for terminology and classification of epilepsy and epileptic seizures. We propose a classification system which reflects new thoughts from the human ILAE but also roots in former well accepted terminology. We think that this classification system can be used by all stakeholders.

Neuroimmunological studies in steroid-responsive meningitis-arteritis in dogs.

The clinical and pathological expression of steroid-responsive meningitis-arteritis (SRMA) is predominantly neurological and the present study was therefore mostly concerned with the intrathecal humoral immune responses of 13 dogs suffering from the disease. All the dogs synthesised IgG intrathecally, indicating that the immune response in SRMA is in part specifically directed towards the central nervous system (CNS). Half of the dogs also had high levels of IgM only in the cerebrospinal fluid (CSF) and nearly all of them had high levels of IgA in the CSF as well as in the serum. Six of the dogs had circulating immune complexes in the serum, but not in the CSF. Neither IgM nor IgA rheumatoid factors were found. A chemotaxis assay revealed enhanced migration of neutrophils into the CSF in three cases. All the dogs had marked meningeal inflammation and arterial lesions of the meningeal blood vessels. Only one dog had arterial involvement outside the CNS. The acute vascular lesions consisted mostly of degenerative changes of the media and periarterial inflammation, and there was no evidence of immune complex deposition. Chronic lesions were mostly characterised by stenosis, adventitial thickening and periarteritis. Focal deposits of IgA were found in the vascular wall of one chronic case. It was concluded that the meningeal lesions in SRMA are a primary event, rather than the result of a generalised immune complex disease. These lesions are associated with an intrathecal humoral immune response, in which IgA appears to play a central role.(ABSTRACT TRUNCATED AT 250 WORDS)

Prominent microglial activation in the early proinflammatory immune response in naturally occurring canine spinal cord injury.

Better understanding of the pathogenesis of spinal cord injury (SCI) is needed for the development of new therapeutic strategies. Spinal cord injury has been investigated in various rodent models, but extrapolation to humans requires the use of a large animal model that more closely mimics human SCI. Dogs frequently develop spontaneous SCI with features that bear a striking resemblance to the human counterpart. We investigated the temporal course of the immuneresponse during naturally occurring canine SCI and in organotypic canine spinal cord slice cultures that are devoid of peripheral immune cells. By immunohistochemistry, the inflammatory response in subacute canine SCI was largely restricted to resident immune cells as demonstrated by activation of major histocompatibility complex class II-expressing microglia/macrophages. By quantitative polymerase chain reaction, there was parallel upregulation of proinflammatorycytokine gene expression (i.e. of interleukin 6 [IL-6] and IL-8 witha trend toward upregulation of tumor necrosis factor) in acute canine SCI. Expression of neuroprotective cytokines (e.g. IL-10) remained unchanged, and transforming growth factor &bgr; upregulationwas delayed. In organotypic spinal cord slices, there was similar activation of major histocompatibility complex class II-positive microglia and prolonged upregulation of inflammatory cytokines, indicating that resident rather than infiltrating cells play major roles in the postinjury immune response. Thus, canine SCI represents a bridge between rodent models and human SCI that may be relevant for clinical and preclinical treatment studies.

Concentrations of acute-phase proteins in dogs with steroid responsive meningitis-arteritis.

BACKGROUND Measurement of concentrations of acute-phase proteins (APPs) is used as an aid in the diagnosis of a variety of diseases in animals. OBJECTIVE To determine the concentration of APPs in dogs with steroid responsive meningitis-arteritis (SRMA) and other neurologic diseases. ANIMALS One hundred and thirty-three dogs with neurologic diseases, 6 dogs with sepsis, and 8 healthy dogs were included in the study. Thirty-six dogs had SRMA (31 of which had monitoring), 14 dogs had other meningoencephalitides (ME), 32 had disk disease (IVDD/DLSS), 26 had tumors affecting the central nervous system (TCNS), and 25 had idiopathic epilepsy (IE). METHODS Prospective, observational study: C-reactive protein (CRP), alpha(2)-macroglobulin (AMG), and albumin concentrations were determined in the serum or plasma. CRP was also measured in the cerebrospinal fluid. RESULTS Serum CRP was significantly higher in dogs with SRMA (x=142 microg/mL+/-75) and sepsis (x=114 microg/mL+/-67) in comparison with dogs with other neurologic diseases (x=2.3-21 microg/mL; P< .001). There was no significant difference detected in AMG between groups. Serum albumin concentration was significantly lower (P< .01) in dogs with SRMA (x=3.2 g/dL+/-0.41) than in other groups (x=3.6-3.9 g/dL). Serum CRP concentration of SRMA dogs correlated with alkaline phosphatase levels (r=0.515, P= .003). CONCLUSIONS AND CLINICAL IMPORTANCE CRP concentrations in serum are useful in diagnosis of dogs with SRMA. Serum CRP could be used as a monitoring parameter in treatment management of these dogs.

Intrathecal synthesis of major immunoglobulin classes in inflammatory diseases of the canine CNS

The IgG index, IgM and IgA contents in cerebrospinal fluid and serum were examined retrospectively using an enzyme-linked immunosorbent assay (ELISA) in 69 dogs with inflammatory central nervous system (CNS) diseases of various aetiologies. Fifteen normal dogs were used as controls. After measuring IgG and albumin contents in serum and cerebrospinal fluid (CSF), the IgG index was calculated according to the formula of Link and Tibbling to demonstrate intrathecal immunoglobulin synthesis. A surprisingly high number of animals with encephalitis, including dogs with protracted diseases such as chronic distemper encephalitis and granulomatous meningoencephalomyelitis, showed in addition to an elevated IgG production evidence of intrathecal IgM and IgA production. The highest values of intrathecal as well as systemic IgA levels were found in dogs suffering from steroid responsive meningitis-arteritis. It was concluded that the control of the humoral immune response in the brain differs from that in other tissues. Because of striking similarities between dogs and humans in respect to humoral neuroimmunological reactions, the dog can be considered to be a useful animal model for the study of the intrathecal humoral immune response.

Anticonvulsant Efficacy of the Low-affinity Partial Benzodiazepine Receptor Agonist ELB 138 in a Dog Seizure Model and in Epileptic Dogs with Spontaneously Recurrent Seizures

Summary:  Purpose:Ataxia, sedation, amnesia, ethanol and barbiturate potentiation, loss of efficacy (tolerance), development of dependence, and the potential for drug abuse limit the clinical use of benzodiazepines (BZDs) for long‐term treatment of epilepsy or anxiety. BZD ligands that are in current use act as full allosteric modulators of γ‐aminobutyric acid (GABA)‐gated chloride channels and, on long‐term administration, trigger a functional uncoupling between the GABAA and BZD recognition sites. Partial allosteric modulators, which have a low intrinsic activity at the BZD recognition site of the GABAA receptor, might eventually overcome the limitations of full agonists such as diazepam (DZP).

Disease Progression and Treatment Response of Idiopathic Epilepsy in Australian Shepherd Dogs

BACKGROUND Idiopathic epilepsy (IE) in Australian Shepherds (ASs) occurs worldwide but there is a lack of description of the epilepsy syndrome in this breed. The ABCB1-1Δ mutation is more prevalent in ASs than in many other dog breeds. HYPOTHESIS Australian Shepherds suffer from a poorly controlled IE syndrome with prevailing severe courses. Seizure control and ABCB1-1Δ mutation might be related in this breed. ANIMALS Fifty ASs diagnosed with IE and 50 unaffected ASs. METHODS Predominant study design is a longitudinal cohort study. Pedigrees, medical records, seizure, and treatment data of ASs with IE were analyzed descriptively. Sex, color, and the ABCB1-1Δ genotype were compared between case and control groups and ASs with poorly or well-controlled seizures. Differences in survival times were assessed by logrank tests and Cox regression analysis. RESULTS Idiopathic epilepsy in ASs is dominated by moderate and severe clinical courses with the occurrence of cluster seizures and status epilepticus and a high seizure frequency. Poor seizure control and a high initial seizure frequency (≥10 seizure days/first 6 months) are associated with shorter survival times (P < .05). Poor seizure control, unrelated to the ABCB1(MDR1) genotype, is evident in 56% of epileptic ASs. Pedigree analysis suggests a genetic basis. CONCLUSION AND CLINICAL IMPORTANCE Frequent severe clinical courses, poor seizure control unrelated to the ABCB1(MDR1) genotype, and a young age at death compromise animal welfare and warrant further genetic studies to unravel the underlaying molecular mechanisms of IE and seizure control in the breed.

Microglial cell activation in demyelinating canine distemper lesions

Microglia cells are the principal immune effector elements of the brain responding to any pathological event. To elucidate the possible role of microglia in initial non-inflammatory demyelination in canine distemper virus (CDV) infection, microglia from experimentally CDV infected dogs were isolated ex vivo by density gradient centrifugation and characterized immunophenotypically and functionally using flow cytometry. Results from dogs with demyelinating lesions were compared to results from recovered dogs and two healthy controls. CDV antigen could be detected in microglia of dogs with histopathologically confirmed demyelination. Microglia of these dogs showed marked upregulation of the surface molecules CD18, CD11b, CD11c, CD1c, MHC class I and MHC class II and a tendency for increased expression intensity of ICAM-1 (CD54), B7-1 (CD80), B7-2 (CD86), whereas no increased expression was found for CD44 and CD45. Functionally, microglia exhibited distinctly enhanced phagocytosis and generation of reactive oxygen species (ROS). It was concluded that in CDV infection, there is a clear association between microglial activation and demyelination. This strongly suggests that microglia contribute to acute myelin destruction in distemper.

DNA vaccine encoding nucleocapsid and surface proteins of wild type canine distemper virus protects its natural host against distemper

Canine distemper virus (CDV), a member of the genus Morbillivirus induces a highly infectious, frequently lethal disease in dogs and other carnivores. Current vaccines against canine distemper consisting of attenuated viruses have been in use for many years and have greatly reduced the incidence of distemper in the dog population. However, certain strains may not guarantee adequate protection and others can induce post vaccinal encephalitis. We tested a DNA vaccine for its ability to protect dogs, the natural host of CDV, against distemper. We constructed plasmids containing the nucleocapsid, the fusion, and the attachment protein genes of a virulent canine distemper virus strain. Mice inoculated with these plasmids developed humoral and cellular immune responses against CDV antigens. Dogs immunized with the expression plasmids developed virus-neutralizing antibodies. Significantly, vaccinated dogs were protected against challenge with virulent CDV, whereas unvaccinated animals succumbed to distemper.

Epilepsy after head injury in dogs: A natural model of posttraumatic epilepsy

In humans, traumatic brain injury (TBI) is one of the most common causes of acquired (symptomatic) epilepsy, but as yet there is no treatment to prevent the development of epilepsy after TBI. Animal models of posttraumatic epilepsy (PTE) are important to characterize epileptogenic mechanisms of TBI and to identify clinically effective antiepileptogenic treatments. The prevalence and phenomenology of naturally occurring canine epilepsy are similar to those in human epilepsy. However, the risk of epilepsy after TBI has not been systemically studied in dogs. We therefore performed a large retrospective study in 1,000 dogs referred to our clinical department over a period of 11.5 years with the aim to determine the incidence of early and late seizures after head trauma in this species.