Biopsy Characteristics, Subtypes, and Prognostic Features in 107 Cases of Feline Presumed Immune-Mediated Polyneuropathy.

Inflammatory polyradiculoneuropathy (IMPN) is one of the causes of sudden onset of neuromuscular signs such as para-/tetraparesis in young cats. Even though most cases have a favorable outcome, persistent deficits, relapses, and progressive courses are occasionally seen. As clinical presentation does not always appear to predict outcome and risk of recurrence, this study was initiated to screen for prognostic biopsy findings in a large cohort of histologically confirmed IMPN cases with clinical follow-up. In total, nerve and muscle specimens of 107 cats with biopsy diagnosis of presumed autoreactive inflammatory polyneuropathy and 22 control cases were reviewed by two blinded raters for a set of 36 histological parameters. To identify patterns and subtypes of IMPN, hierarchical k-means clustering of 33 histologic variables was performed. Then, the impact of histological parameters on IMPN outcome was evaluated via an univariate analysis to identify variables for the final multivariate model. The data on immediate outcome and follow-up were collected from submitting neurologists using a purpose-designed questionnaire. Hierarchical k-means clustering sorted the tissues into 4 main categories: cluster 1 (44/129) represents a purely inflammatory IMPN picture, whereas cluster 2 (47/129) was accompanied by demyelinating features and cluster 3 (16/129) by Wallerian degeneration. Cluster 4 (22/129) reflects normal tissues from non-neuropathic control cats. Returned questionnaires provided detailed information on outcome in 63 animals. They were categorized into recovered and non-recovered. Thereby, fiber-invasive infiltrates by mononuclear cells and mild fiber loss in intramuscular nerve branches correlated with higher probabilities of recovery. Remyelination in semithin sections, on the other hand, is correlated with a less favorable outcome. Animals grouping in cluster 1 had a tendency to a higher probability of recovery compared to other clusters. In conclusion, diagnosis of feline IMPN from nerve and muscle biopsies allowed for the identification of histologic features that were positively or negatively correlated with outcome.

Clinical Course and Diagnostic Findings of Biopsy Controlled Presumed Immune-Mediated Polyneuropathy in 70 European Cats.

There is a paucity of information on the clinical course and outcome of young cats with polyneuropathy. The aim of the study was to describe the clinical features, diagnostic investigations, and outcome of a large cohort of cats with inflammatory polyneuropathy from several European countries. Seventy cats with inflammatory infiltrates in intramuscular nerves and/or peripheral nerve biopsies were retrospectively included. Information from medical records and follow up were acquired via questionnaires filled by veterinary neurologists who had submitted muscle and nerve biopsies (2011-2019). Median age at onset was 10 months (range: 4-120 months). The most common breed was British short hair (25.7%), followed by Domestic short hair (24.3%), Bengal cat (11.4%), Maine Coon (8.6%) and Persian cat (5.7%), and 14 other breeds. Male cats were predominantly affected (64.3%). Clinical signs were weakness (98.6%) and tetraparesis (75.7%) in association with decreased withdrawal reflexes (83.6%) and, less commonly, cranial nerve signs (17.1%), spinal pain/hyperesthesia (12.9%), and micturition/defecation problems (14.3%). Onset was sudden (30.1%) or insidious (69.1%), and an initial progressive phase was reported in 74.3%. Characteristic findings on electrodiagnostic examination were presence of generalized spontaneous electric muscle activity (89.6%), decreased motor nerve conduction velocity (52.3%), abnormal F-wave studies (72.4%), pattern of temporal dispersion (26.1%) and unremarkable sensory tests. The clinical course was mainly described as remittent (49.2%) or remittent-relapsing (34.9%), while stagnation, progressive course or waxing and waning were less frequently reported. Relapses were common and occurred in 35.7% of the cats' population. An overall favorable outcome was reported in 79.4% of patients. In conclusion, young age at the time of diagnosis and sudden onset of clinical signs were significantly associated with recovery (p < 0.05). Clinical and electrodiagnostic features and the remittent-relapsing clinical course resembles juvenile chronic inflammatory demyelinating polyneuropathy (CIDP), as seen in human (children/adolescents), in many aspects.

Cyclooxygenase-2 Inhibition as an Add-On Strategy in Drug Resistant Epilepsy-A Canine Translational Study.

Drug-resistant epilepsy is a common complaint in dogs and affects up to 30% of dogs with idiopathic epilepsy. Experimental data suggest that targeting cyclooxygenase-2 (COX-2) mediated signaling might limit excessive excitability and prevent ictogenesis. Moreover, the role of COX-2 signaling in the seizure-associated induction of P-glycoprotein has been described. Thus, targeting this pathway may improve seizure control based on disease-modifying effects as well as enhancement of brain access and efficacy of the co-administered antiseizure medication. The present open-label non-controlled pilot study investigated the efficacy and tolerability of a COX-2 inhibitor (firocoxib) add-on therapy in a translational natural occurring chronic epilepsy animal model (client-owned dogs with phenobarbital-resistant idiopathic epilepsy). The study cohort was characterized by frequent tonic-clonic seizures and cluster seizures despite adequate phenobarbital treatment. Enrolled dogs (n = 17) received a firocoxib add-on therapy for 6 months. Tonic-clonic seizure and cluster seizure frequencies were analyzed at baseline (6 months) months during the study (6 months). The responders were defined by a substantial reduction of tonic-clonic seizure and cluster seizure frequency (≥50%). In total, eleven dogs completed the study and were considered for the statistical analysis. Two dogs (18%, 2/11) were classified as responders based on their change in seizure frequency. Interestingly, those two dogs had the highest baseline seizure frequency. The overall tolerability was good. However, given the low percentage of responders, the present data do not support an overall considerable efficacy of COX-2 inhibitor add-on therapy to overcome naturally occurring phenobarbital-resistant epilepsy in dogs. Further translational evaluation should only be considered in the canine patients with a very high baseline seizure density.

A retrospective case series of clinical signs in 28 Beagles with Lafora disease.

BACKGROUND: Clinical signs and their progression in Beagles with Lafora disease are poorly described. OBJECTIVES: To describe clinical signs in Beagles with Lafora disease. ANIMALS: Twenty-eight Beagles with Lafora disease confirmed by genetic testing or histopathology. METHODS: Retrospective multicenter case series. Data regarding signalment, clinical signs, diagnostic tests and treatment were retrieved from hospital data files. A questionnaire was sent to owners asking about neurological deficits, changes in cognitive functions, behavioral changes, response to treatment and survival time. RESULTS: Onset of clinical signs was 8.3 years (mean; range, 6.3-13.3). All dogs had myoclonic episodes as an initial clinical sign with tonic-clonic seizures in n = 11/28 (39%) and n = 12/28 (43%) later developing tonic-clonic seizures. Deficits of coordination (n = 21/25; 84%), impaired vision (n = 15/26; 58%), and impaired hearing (n = 13/26; 50%) developed later. Mental decline was observed as loss of house training (urination; n = 8/25; 32%), difficulties performing learned tasks (n = 9/25; 36%), and difficulties learning new tasks (n = 7/23; 30%). Common behavioral changes were: increased photosensitivity (n = 20/26; 77%), staring into space (n = 16/25; 64%), reduced stress resistance (n = 15/26; 58%), increased noise sensitivity (n = 14/26; 54%), and separation anxiety (n = 11/25; 44%). Twenty-one dogs were alive (median age 11.9 years; range, 9.8-18.6), and 7 dogs were dead (mean age 12.1 years; SD: 1.3; range, 10.5-12.6) at time of writing. CONCLUSIONS AND CLINICAL IMPORTANCE: Lafora disease in Beagles causes significant behavioral changes, and mental decline as well as neurological deficits in addition to myoclonic episodes and generalized tonic-clonic seizures. Nevertheless, a relatively normal life span can be expected.

Mitochondrial PCK2 Missense Variant in Shetland Sheepdogs with Paroxysmal Exercise-Induced Dyskinesia (PED).

Four female Shetland Sheepdogs with hypertonic paroxysmal dyskinesia, mainly triggered by exercise and stress, were investigated in a retrospective multi-center investigation aiming to characterize the clinical phenotype and its underlying molecular etiology. Three dogs were closely related and their pedigree suggested autosomal dominant inheritance. Laboratory diagnostic findings included mild lactic acidosis and lactaturia, mild intermittent serum creatine kinase (CK) elevation and hypoglycemia. Electrophysiological tests and magnetic resonance imaging of the brain were unremarkable. A muscle/nerve biopsy revealed a mild type II fiber predominant muscle atrophy. While treatment with phenobarbital, diazepam or levetiracetam did not alter the clinical course, treatment with a gluten-free, home-made fresh meat diet in three dogs or a tryptophan-rich, gluten-free, seafood-based diet, stress-reduction, and acetazolamide or zonisamide in the fourth dog correlated with a partial reduction in, or even a complete absence of, dystonic episodes. The genomes of two cases were sequenced and compared to 654 control genomes. The analysis revealed a case-specific missense variant, c.1658G>A or p.Arg553Gln, in the PCK2 gene encoding the mitochondrial phosphoenolpyruvate carboxykinase 2. Sanger sequencing confirmed that all four cases carried the mutant allele in a heterozygous state. The mutant allele was not found in 117 Shetland Sheepdog controls and more than 500 additionally genotyped dogs from various other breeds. The p.Arg553Gln substitution affects a highly conserved residue in close proximity to the GTP-binding site of PCK2. Taken together, we describe a new form of paroxysmal exercise-induced dyskinesia (PED) in dogs. The genetic findings suggest that PCK2:p.Arg553Gln should be further investigated as putative candidate causal variant.

Steroid-responsive meningitis-arteritis in dogs in Germany: Are there epidemiological or clinical factors influencing recurrence rate?

OBJECTIVE: Steroid-responsive meningitis arteritis (SRMA) is one of the most common inflammatory diseases of the central nervous system in dogs. The present study examined breed and sex predisposition factors based on the population of dogs in Germany as well as epidemiological and clinical factors regarding the relapse rate of SRMA. MATERIAL AND METHODS: Data of 153 dogs with SRMA (SRMA) were analysed retrospectively in this multicentre study. It was investigated whether some dog breeds that suffer from SRMA were disproportionately more often (n ≥ 5) represented when compared to the total population of dogs in Germany. Furthermore it was examined which sex is affected more often. Data provided by "Verband für das deutsche Hundewesen" (VDH) and "Tasso e. V." was used as reference data of the total population. The following factors were investigated with regard to the occurrence of one or more relapses: signalment; body weight; age at first presentation; time period between last vaccination and onset of clinical signs; clinical signs and timepoint of the first SRMA manifestation; results of cerebrospinal fluid (CSF) analysis at first presentation (nucleated cell count and differentiation, protein concentration); immunglobulin A and C-reactive protein (CRP) concentrations in serum and CSF; immunosuppressive medication; follow-up data including response to therapy, occurrence of relapses and mortality including reasons, i. e. due to the disease, therapy or euthanasia. RESULTS: The breed had a statistically significant influence on the development of SRMA (p < 0.05). Beagles and Boxers were affected more often by SRMA than other breeds in relation to the total population in Germany. Relapses occurred in 29.4 % of the 153 dogs of this study. In contrast to the development of SRMA, in which male dogs have a significantly increased risk of developing SRMA (p < 0.05), female dogs are more likely to relapse (p = 0.02). Patients on prednisolone monotherapy had fewer relapses than those with prednisolone and azathioprine in combination (p < 0.05). Younger age (p = 0.071) und lower CRP concentrations (p = 0.081) at first presentation were tentatively associated with a higher incidence of relapses. CONCLUSION: The determined breed and sex predispositions support the diagnosis of SRMA arteritis and confirm previous observations. This study allows a more accurate explanation to owners about the risk of relapse.

[Follow-up study in German Hunting Terrier dogs with exercise induced metabolic myopathy]. / Verlaufsuntersuchungen bei Deutschen Jagdterriern mit belastungsabhängiger metabolischer Myopathie.

OBJECTIVE: Exercise induced metabolic myopathy in German Hunting Terrier dogs is an autosomal-recessively inherited disorder, caused by a nonsense variant of the gene encoding for the very long-chain acyl-CoA-dehydrogenase (VLCAD) enzyme. Clinical signs include exercise- induced fatigue, muscle pain and weakness. In the present study, the long-term course of this disease was investigated over a period of 1 year in 9 affected German Hunting Terriers. The dogs were treated symptomatically with oral L-carnitine, coenzyme Q10 and a special diet characterized by a low content of long-chain fatty acids and a high proportion of carbohydrates. MATERIAL AND METHODS: In 9 affected dogs, the phenotype as well as clinical, laboratory parameters, and histopathological findings are described (time point 1) and compared to follow-up examinations 1 year later (time point 2). At both time points clinical and neurological examinations, complete blood cell count, clinical chemistry profile and the concentration of brain natriuretic peptide (NT-proBNP) were investigated. RESULTS: In the follow-up examinations, the same post-exercise clinical signs were present as in the initial presentation of the homozygous dogs. Dark-brownish discoloration of the urine, weakness, myalgia as well as stiff and tetraparetic gait were apparant. All hematological values and the concentration of NT-proBNP were within the relevant reference ranges. Plasma CK and ALT activities were compared between the first presentation and the follow- up examination and no significant differences were detected (pCK = 0.31, pALT = 0.64). Signs of myopathy remained unchanged throughout the examination period. CONCLUSION AND CLINICAL RELEVANCE: Oral supplementation with L-carnitine, coenzyme Q10 and the special dietary management did not result in any improvement of clinical signs or laboratory parameters. No progression of the disease was observed. The prognosis for affected dogs remains cautious as long-term observations of affected dogs over several years are lacking. Our findings provide further important information on inherited disorders of mitochondrial ß-oxidation in dogs, especially focused on the exercise induced metabolic myopathy in the German Hunting Terrier. This may provide new insights for novel treatment modalities in conjuntion with the development of improved breeding guidelines.

A Nonsense Variant in the ACADVL Gene in German Hunting Terriers with Exercise Induced Metabolic Myopathy.

Several enzymes are involved in fatty acid oxidation, which is a key process in mitochondrial energy production. Inherited defects affecting any step of fatty acid oxidation can result in clinical disease. We present here an extended family of German Hunting Terriers with 10 dogs affected by clinical signs of exercise induced weakness, muscle pain, and suspected rhabdomyolysis. The combination of clinical signs, muscle histopathology and acylcarnitine analysis with an elevated tetradecenoylcarnitine (C14:1) peak suggested a possible diagnosis of acyl-CoA dehydrogenase very long chain deficiency (ACADVLD). Whole genome sequence analysis of one affected dog and 191 controls revealed a nonsense variant in the ACADVL gene encoding acyl-CoA dehydrogenase very long chain, c.1728C>A or p.(Tyr576*). The variant showed perfect association with the phenotype in the 10 affected and more than 500 control dogs of various breeds. Pathogenic variants in the ACADVL gene have been reported in humans with similar myopathic phenotypes. We therefore considered the detected variant to be the most likely candidate causative variant for the observed exercise induced myopathy. To our knowledge, this is the first description of this disease in dogs, which we propose to name exercise induced metabolic myopathy (EIMM), and the identification of the first canine pathogenic ACADVL variant. Our findings provide a large animal model for a known human disease and will enable genetic testing to avoid the unintentional breeding of affected offspring.

Generalized myoclonic epilepsy with photosensitivity in juvenile dogs caused by a defective DIRAS family GTPase 1.

The clinical and electroencephalographic features of a canine generalized myoclonic epilepsy with photosensitivity and onset in young Rhodesian Ridgeback dogs (6 wk to 18 mo) are described. A fully penetrant recessive 4-bp deletion was identified in the DIRAS family GTPase 1 (DIRAS1) gene with an altered expression pattern of DIRAS1 protein in the affected brain. This neuronal DIRAS1 gene with a proposed role in cholinergic transmission provides not only a candidate for human myoclonic epilepsy but also insights into the disease etiology, while establishing a spontaneous model for future intervention studies and functional characterization.

Nodo-paranodopathy, internodopathy and cleftopathy: Target-based reclassification of Guillain-Barré-like immune-mediated polyradiculoneuropathies in dogs and cats.

Recent views on Guillain-Barré syndrome (GBS) question the accuracy of classification into axonal and demyelinating subtypes that represent convergent neurophysiological phenotypes rather than immunological targets. Instead it has been proposed to clarify the primarily affected fibre subunit in nerve biopsies. As nerve biopsies rarely are part of routine work-up in human patients we evaluated tissues taken from companion animals affected by GBS-like polyradiculoneuropathy to screen for distribution of immune cells, targeted fibre components and segregating non-inflammatory lesions. We identified that immune responses were directed either at Schmidt-Lanterman clefts, the paranode-node complex or both. Based on infiltrative and non-inflammatory changes, four subtypes and/or stages were distinguished, some of which indicate localisation of primary target antigens while others represent convergent late stage pictures, as a consequence to epitope spreading. The impact of histological subtyping onto clinical management and prognosis remains to be evaluated in future clinical trials. Natural development and clinical manifestation of large animal dysimmune neuropathy may reflect human Guillain-Barré syndrome more accurately than experimental models and therefore provide complementary clues for translational research.