Juvenile‐onset motor polyneuropathy in Siberian cats

Abstract Background Polyneuropathies are infrequently described in cats. There is a genetic predisposition in several breeds. Objective To clinically characterize a novel motor polyneuropathy in a family of Siberian cats. Animals Thirteen closely related Siberian cats, 4 clinically affected and 9 clinically unaffected individuals. Methods Retrospective study. Clinical data and pedigree information were obtained from the medical records and breeder. Electrodiagnostic testing and muscle and peripheral nerve biopsy samples were obtained from 1 affected cat. Follow‐up information was obtained for all affected cats. Results Onset of signs was 4 to 10 months in affected cats. Clinical signs were progressive or waxing/waning neuromuscular weakness (4/4), normal sensory function (4/4), and variably decreased withdrawal reflexes (3/4). All cats returned to normal neurologic function within 1 to 4 weeks. All cats had a recurrence of weakness (3/4 had 1 recurrent episode, 1/4 had 3 relapses) from which they recovered fully. In 1 cat, electromyography and motor nerve conduction studies showed multicentric spontaneous activity, normal motor nerve conduction velocity, reduced compound muscle action potential amplitude, and polyphasia. Histologic evaluation of muscle and nerve in that cat showed mild muscle atrophy consistent with recent denervation, endoneurial and perineurial edema, and mild mononuclear cell infiltration within intramuscular nerve branches and a peripheral nerve. Pedigree analysis suggests an autosomal recessive mode of inheritance, although neither a genetically complex/polygenic condition nor an acquired inflammatory polyneuropathy can be ruled‐out. Conclusions and Clinical Importance We describe a motor polyneuropathy in juvenile Siberian cats characterized by self‐limiting weakness with potential relapse.


| INTRODUCTION
Acquired and congenital or inherited polyneuropathies are infrequently described in cats. [1][2][3] Acquired forms are attributed to infectious agents, intoxications, metabolic, immune-mediated, inflammatory, neoplastic, or paraneoplastic conditions, although a definitive cause is not identified in most cases. 1,[3][4][5][6][7][8][9][10][11][12][13] There is a genetic predisposition to disease affecting young cats of several breeds including Snowshoe, Abyssinian, and Bengal cats. 2,[14][15][16][17] Clinical presentations among the published cases are variable, but consistent findings include progressive neuromuscular weakness in young animals with potential for relapse of signs and no consistent response to, or recommendation for, specific therapy. 7,9,14,[16][17][18] Electrodiagnostic testing and nerve and muscle biopsies are intermittently performed with variable results between specific reports. In the largest published case series, which described affected Bengal cats, findings are consistent with recurrent demyelination and remyelination as the pathophysiological underpinning of clinical signs of weakness and the chronic relapsing course of disease. 14 However, the underlying cause of neuropathy in Bengal cats has not been identified. A motor neuropathy of unknown cause is described in a group of 5 unrelated cats of various breeds. 18 While all cats had a juvenile onset and potential for recurrence or progression of signs, the heterogeneity in breed, presentation, and diagnostic findings suggest there might be multiple etiologies. 18 Among the published reports, many cases are described as having self-limiting signs but with the possibility of recurrence. Various specific treatments are employed including nonsteroidal anti-inflammatories or corticosteroids, but evidence is lacking on the efficacy or role for such medications with these conditions. For those cats in which a hereditary component is suspected, an underlying genetic variant has not been identified.
We recently noted a progressive or waxing and waning neuromuscular weakness in several related Siberian Forest cats which share some clinical characteristics with the motor polyneuropathy of young cats. To the best of the authors' knowledge, a polyneuropathy has not been previously reported in this breed. Our objective was to characterize a novel motor polyneuropathy in a family of related Siberian cats.  29 The fixed muscle biopsies were processed routinely into paraffin. A fixed biopsy from the common peroneal nerve was embedded in epoxy resin, cut into 1 μm thick sections, and stained with toluidine blue.

| Clinicopathological and imaging findings
Results of routine CBC and biochemical analyses were available for all affected cats. Results were within normal limits, with the exception of mild thrombocytopenia (147 000/L; reference range, 300 000-800 000/L) in 1 cat and mild hyperphosphatemia (7.5 mg/dL; reference range, 2.9-6.3 mg/dL) in another cat. Creatine kinase activities were available for 2 cats and both showed mild increases

| Electrodiagnostic testing
Electrodiagnostic testing was performed in 1 affected cat. Electromyography demonstrated moderate, multifocal spontaneous activity consisting of fibrillation potentials and positive sharp waves in multiple appendicular muscles (Figure 1). Electromyographic abnormalities varied from 1+ to 2+ (mild to moderate) according to a published grading scale. 19 Changes were subjectively more severe in distal compared to proximal musculature. Changes were also more prominent in pelvic limb muscles than thoracic limb muscles, consistent with this cat's neurologic examination.
Motor nerve conduction studies of the ulnar and sciatic/tibial nerves were abnormal ( Figure 1). For the sciatic/tibial nerves, compound muscle action potential peak to peak amplitude was reduced There was normal conduction velocity, reduced compound muscle action potential amplitude and, for sciatic/tibial nerve, polyphasia edema, mild regional depletion of myelinated nerve fibers, and mild scattered mononuclear cell infiltrates (Figure 2A). Nerve biopsy showed subjectively normal nerve fiber density with numerous collagenous bundles in the subperineurium and endoneurium consistent with resolving edema ( Figure 2B). Neither axonal nor myelin abnormalities were identified. Minimal mononuclear cell infiltrations were present in the endoneurium with some proximity to nerve fibers ( Figure 2B). The changes in the intramuscular nerve branches and common peroneal nerve were consistent with an early or mild predominantly distal polyneuropathy with associated inflammation. to be neurologically normal 1 to 2 years after their initial presentation with no further episodes of weakness. One cat (whose first relapse occurred at 3 months after initial signs of weakness) was reported to have had 2 additional episodes of mild weakness characterized by being less active and mild difficulty jumping. These were noted by the owner at approximately 6 months and 20 months after the initial episode. The cat was not evaluated by a veterinarian during these additional occurrences, no treatment was instituted, and signs resolved gradually over several months. At the time of writing, this cat was reported to be normal at home with no residual weakness.

| Pedigree analysis
All affected cats were closely related; specifically, 3 were half-siblings (#12177, 12301, and 12311; sharing the same sire) and the fourth's (#12311) mother was also produced by that same sire. Cat #12177 underwent the thorough diagnostic evaluation for neuromuscular disease as outlined above. All 9 control cats (#12178, 12310, 12340, 12341, 12342, 12375, 12376, 12377, and 12388) were healthy with no history of neuromuscular weakness and were also closely related to the cases. Control status was confirmed for these 9 cats through owner-supplied answers to a health questionnaire. Other related cats were reported as clinically normal via the health questionnaires completed by the owners of the affected or control cats who knew that the remainder of the litter and parents were healthy. Therefore, they were presumed to be unaffected but specific confirmation of health status was not available for these additional cats. A pedigree was assembled unlikely. While neuromuscular weakness is an uncommon presentation overall, immune-mediated polyradiculoneuritis is relatively frequently identified as a cause in young cats. 1,6,8,9,11,16 Therefore, acquired idiopathic or immune-mediated polyradiculoneuritis or polyneuritis were considered possible and explain some of the biopsy, electrodiagnostic, and cerebrospinal fluid analysis findings. Albuminocytologic dissociation is reported with inflammatory conditions, including Guillain-Barre syndrome in people and acute polyradiculoneuritis in dogs and cats. 9,30,33,34 Additionally, biopsy samples in the affected cat reported here demonstrated mild mononuclear cell infiltration consistent with an inflammatory cause but could not confirm if such inflammation was present at the level of the ventral nerve roots, as would be expected with polyradiculoneuritis. Acute polyradiculoneuritis presents suddenly with rapid progression from paraparesis to tetraparesis or tetraplegia, often with respiratory fatigue. 30 45 Further, in Newfoundlands with an early-onset immunemediated Myasthenia Gravis, a genotype association exists within the canine major histocompatibility complex, specifically the dog leukocyte antigen class I. 44 However, a P 0 (myelin structural protein in the peripheral nervous system) knockout mouse model produces a neuropathy resembling chronic inflammatory demyelinating polyneuropathy. 46 This raises the possibility that some patients with We also lacked extensive health information for additional "unaffected" littermates and parents of the affected cats that were used when constructing the pedigree. However, these were typically described as "normal" by the breeder or the owner of affected or control cats mentioning that the remainder of the kittens in the litter were normal. We feel it is unlikely that any of these cats were misclassified given the young age of onset and overt nature of the weakness displayed by affected cats.

ACKNOWLEDGMENTS
Funding provided by U.S. Department of Health and Human Services, National Institutes of Health, Office of the Director, award number KOI-OD027051, for Kari J. Ekenstedt. This work was presented as an ePoster at the 2020 ACVIM Forum On Demand.

CONFLICT OF INTEREST DECLARATION
Authors declare no conflict of interest.

OFF-LABEL ANTIMICROBIAL DECLARATION
Authors declare no off-label use of antimicrobials.

INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE (IACUC) OR OTHER APPROVAL DECLARATION
Approved by the Purdue University IACUC, protocol #1812001840.

HUMAN ETHICS APPROVAL DECLARATION
Authors declare human ethics approval was not needed for this study.