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Keywords:

  • Chronic-relapsing polyneuropathy;
  • Feline;
  • Neuromuscular;
  • Peripheral nerve

Abstract

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnotes
  7. Acknowledgments
  8. References

Background: With the exception of diabetic neuropathy, polyneuropathy associated with hyperchylomicronemia, and a few inherited polyneuropathies, peripheral neuropathies are poorly characterized in cats. A chronic polyneuropathy is described in a cohort of young Bengal cats.

Objective: To characterize the clinical and histopathological features of a chronic-relapsing peripheral neuropathy in young Bengal cats.

Animals: Thirty-seven young Bengal cats with clinical weakness consistent with peripheral neuropathy.

Methods: Bengal cats were included in this study after a diagnosis of polyneuropathy was confirmed by muscle and peripheral nerve biopsy specimens. Pathological changes were characterized at the light and electron microscopic level and by morphometry. Clinical information and long-term outcome from case records of Bengal cats with histologically confirmed peripheral neuropathy were then assessed.

Results: Nerve fiber loss within distal intramuscular nerve branches was a consistent finding in young Bengal cats with polyneuropathy. The most common abnormalities in peripheral nerve biopsies included inappropriately thin myelin sheaths and thinly myelinated fibers surrounded by supernumerary Schwann cell processes, indicative of repeated cycles of demyelination and remyelination. Recovery was common. Response to treatment could not be determined.

Conclusions and Clinical Importance: A chronic-relapsing form of polyneuropathy associated primarily with episodes of demyelination and remyelination was identified in young Bengal cats. The prognosis for recovery is good, although relapses are possible and there can be residual motor deficits.

Abbreviations:
CMAP

compound muscle action potential

EMG

electromyography

MNCV

motor nerve conduction velocity

Except for diabetic neuropathy and polyneuropathy associated with primary hyperchylomicronemia, which have been well characterized in cats,1–4 feline polyneuropathies are a complex and poorly understood group of diseases, with only a few case reports in the veterinary literature. Descriptions of inherited or breed-associated polyneuropathies in cats have generally been limited to those where the primary clinical sign might be referable to a more generalized central nervous system disease with concurrent pathological changes in the peripheral nerves. Specific examples include central-peripheral distal axonopathy in Birman cats,5 glycogenosis type IV in Norwegian Forest cats,6,7 alpha-mannosidosis in Persian cats,8,9 hyperoxaluria in domestic shorthaired cats,10 a variant of Niemann-Pick disease in Siamese cats,11 and a presumed congenital axonal neuropathy in young Snowshoe cats.12

The Bengal is a relatively new cat breed first introduced in 1983 in the United States as a result of a cross between an Asian leopard cat and a domestic cat.b We describe a syndrome of polyneuropathy in young Bengal cats with clinical signs localized to the peripheral nervous system. Available data suggest this disorder is a polyneuropathy with a chronic-relapsing course. A similar case was reported in the United Kingdom.13 The purpose of this study was to characterize this newly recognized polyneuropathy clinically and pathologically in a cohort of young Bengal cats from several geographic regions worldwide.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnotes
  7. Acknowledgments
  8. References

Case Selection

During the years 2001–2010, diagnostic muscle, peripheral nerve biopsy specimens, or both from 37 purebred Bengal cats located in the United States, United Kingdom, Australia, and Sweden were submitted to the Comparative Neuromuscular Laboratory at the University of California, San Diego. All cats showed clinical signs of lower motor neuron dysfunction and were subsequently confirmed to have polyneuropathy. Twenty-five cats had both muscle and nerve biopsies, 11 had muscle biopsy specimens only, and 1 cat had a nerve biopsy specimen only. Clinical information regarding each cat was obtained by evaluating medical records provided by the submitting veterinarian, in 34 of 37 cases a board-certified specialist. Additional case details and follow-up information were obtained through a questionnaire completed by the submitting veterinarian. When specific information including outcome was missing, either the primary or referring veterinarian or the owner was contacted. Case history, including timing of vaccinations and dietary information, was collected. Results of physical and neurological examinations, standard hematological and biochemical assays, infectious disease testing, cerebrospinal fluid (CSF) analysis, advanced imaging, electrodiagnostic testing, and pathological changes in muscle and peripheral nerve biopsies were compiled. Information was also collected regarding treatment, recovery, and long-term outcome.

Clinicopathologic Evaluation

Standard hematological and biochemical tests, including urinalysis, serum chemistry panel with creatine kinase (CK) activity, CBC, total T4, and CSF analysis, were evaluated. Results of testing for infectious diseases, including Toxoplasma gondii, feline leukemia virus, feline immunodeficiency virus (FIV), feline coronavirus, Neospora caninum, Anaplasma phagocytophylum, and Cryptococcus neoformans, were recorded. Additionally, serology for acetylcholine receptor antibodies and the response to edrophonium chloride challenge were noted when performed.

Electrodiagnostic Testing

When available, results of electromyography (EMG) were categorized as increased insertional activity and spontaneous activity (fibrillation potentials, positive sharp waves, and complex repetitive discharges). Compound muscle action potential (CMAP) amplitudes and morphology were recorded when reported. Measurements of motor and sensory nerve conduction velocities were recorded as normal or reduced and referenced to published reference ranges1 when numerical values for velocity were provided.

Imaging

When performed, results of various imaging modalities, including magnetic resonance imaging (MRI), radiography, ultrasonography, and myelography, were recorded.

Histopathology, Electron Microscopy, and Morphometry

Muscle and nerve biopsy specimens submitted by various clinicians were obtained under general anesthesia by an open biopsy procedure.14 Muscles most commonly biopsied included the cranial tibial, gastrocnemius, and triceps and quadriceps groups. Less frequently, the biceps femoris, extensor carpi radialis, lateral digital extensor, and semitendinosus muscles were sampled. Peripheral nerve biopsies were most commonly obtained from the common peroneal nerve. Nerves biopsied less frequently included the tibial and caudal cutaneous sural nerves.

All biopsies were submitted to the laboratory by an overnight express service under refrigeration. Unfixed biopsy specimens were flash frozen in isopentane precooled in liquid nitrogen and stored at −80°C until further processed.15 Formalin-fixed muscle biopsy specimens were embedded in paraffin by standard methods. Muscle cryosections were processed with a standard panel of histochemical stains and reactions as described by Dubowitz and Sewry.15 Unfixed nerve biopsy specimens were flash frozen in the same manner as the unfixed muscle specimens. Fixed nerve biopsy specimens (fixed in 10% neutral buffered formalin or in 2.5% glutaraldehyde) were postfixed in osmium tetroxide and dehydrated in serial alcohol solutions and propylene oxide before embedding in araldite resin as described previously.2 Thick sections (1 μm) were cut and stained with toluidine blue-basic fuschin or paraphenylediamine before light microscopic examination. Thin sections (60–90 nm) were cut and stained with uranyl acetate and lead citrate before examination in a Zeiss 10 electron microscope (Carl Zeiss NTS, Peabody, MA).

For quantitative assessment, peroneal nerve specimens free of artifact were chosen from 6 Bengal cats with moderate to marked pathological changes and from 6 Bengal cats with normal-appearing nerves. By point counting techniques16 and a grid with a magnified distance of 0.08 mm between intersection points, fascicular area, defined as the number of points falling on the endoneurium of nerve fascicles, was determined. The total number of myelinated fibers (MF), the number of fibers with inappropriately thin myelin sheaths as well as those with myelin splitting and ballooning, and the number of probable regenerative clusters were assessed in each nerve specimen and normalized to fascicular area.

Clinical Outcome

Time to improvement was defined as the time from diagnosis until ambulation was perceived to improve by the owner and veterinarian, but not necessarily with resolution of clinical signs. Time to resolution of clinical signs was defined as the time elapsed from diagnosis until the cat was first clinically normal and off all medications. A relapse was defined as a return of clinical signs of muscle weakness and difficulty ambulating.

Statistical Analysis

Numerical clinical data are presented as the mean ± SD (range) or median. For morphometry, data are presented as mean ± SD (range) and were analyzed by a 2-tailed, unpaired t-test. When variances were unequal, a t-test with Welch's correction was used.

Results

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnotes
  7. Acknowledgments
  8. References

Signalment, History, and Clinical Signs

Muscle or peripheral nerve biopsies or both were received from 37 Bengal cats evaluated for lower motor neuron dysfunction by various clinicians from the United States (27), the United Kingdom (8), Sweden (1), and Australia (1). Of these cats, 28 were evaluated by veterinary neurologists, 4 by specialists in veterinary internal medicine, 2 by veterinary surgeons, and 3 by general practitioners. The mean age of onset was 10.6 ± 7.9 months (3–44 months). The mean duration of clinical signs before presentation was 2.9 ± 8.1 months (0–48 months). Of the 37 cats, 24 (65%) were male. Vaccination history was available for 17 cats and was variable. Nine cats were not vaccinated during the 2-month time period before onset of clinical signs, while the remaining cats were vaccinated at various time points, ranging from 2 months before onset to the time of onset. Dietary information was available for 20 cats. Various commercial cat foods were fed exclusively in 14 cats, with the remaining cats fed combinations of commercial cat food, table scraps, and raw food. Illnesses such as gastrointestinal or upper respiratory infections, or prior stressful events such as hospitalization, were only reported in 3 cases.

Presenting clinical signs in affected cats included pelvic and thoracic limb weakness, exercise intolerance, a stiff or stilted gait, a plantigrade stance, and decreased jumping ability. Clinical signs involved all 4 limbs in 8 cats, were initially restricted to the pelvic limbs in 25 cats, but progressed to involve all 4 limbs in 7 of the cats. Muscle atrophy, weight loss, or stunted growth was reported in 8 cats.

Physical and Neurological Examination

With the exception of neurological dysfunction, physical examination was unremarkable in 22 cats for which information was available. Results of neurological examinations were available for 35 cats and were consistent with neuromuscular disease. Mentation was generally appropriate, although 3 cats were described as listless or lethargic. Cranial nerve abnormalities were limited to a decreased or absent palpebral reflex in 7 cats and difficulty prehending food in 1 cat. Gait and postural abnormalities involving all limbs or just the pelvic limbs were common, and included a plantigrade stance (14), tetraparesis (11), paraparesis (5), weakness (12), a stiff or stilted gait (5), ataxia (10), decreased jumping ability (3), and weakness that worsened after exercise (3). Six cats were nonambulatory. Tremors were reported in 3 cats and cervical ventroflexion in 1 cat. Spinal reflexes were reduced in all 4 limbs or only in the pelvic limbs in most cats, with only 5 cats reported as having normal reflexes. Decreased perineal reflexes or tail tone was reported in 3 cats. Reduced superficial sensation and nociception was also reported in 3 cats. Hyperesthesia was described in 14 cats that could be localized to the muscles in 3 cats, the joints or limbs in 4 cats, and during spinal palpation in 7 cats. Diffuse muscle atrophy or atrophy most pronounced in the pelvic limbs was reported in 18 cats. A normal muscle mass was reported in 4 cats, and enlarged or abnormally firm muscles reported in 2 cats.

Clinicopathologic Findings

CBC, serum biochemical analysis, and urinalysis were reported in 28, 29, and 14 cats, respectively. CK activities were mildly increased in 21 cats (1,072 ± 367 U/L, 146–7,888 U/L) or were simply reported as normal without a numeric value in 5 cats. Serum total T4 concentration and acetylcholine receptor antibody titers were normal in 8 and 7 cats, respectively. Response to edrophonium chloride challenge was negative in 2 cats and equivocal in 1 cat. CSF was collected in 15 cats for analysis. A CSF protein concentration was reported for 13 cases and was increased in 4 of 10 collected after cerebellomedullary cisternal puncture (33.5 ± 9.5 mg/dL, 5–100 mg/dL) and in 2 of 3 collected after lumbar subarachnoid space puncture (52.7 ± 12.7 mg/dL, 39–64 mg/dL).17 Nucleated cell count was normal (<5 nucleated cells/μL)17 in 10 of 10 cats evaluated. Three of 8 cats tested for feline coronavirus had an equivocal or low-positive titer, 1 of 25 cats tested for feline leukemia virus was positive on bone marrow immunofluorescent assay, and 1 of 25 cats tested for FIV had an equivocal result. Two of 21 cats tested for T. gondii infection showed low-positive titers. One cat each was tested for A. phagocytophylum, C. neoformans, and N. caninum with negative results.

Imaging

Several different imaging procedures were performed at various veterinary hospitals. Radiography of the spine, thorax, abdomen, or limbs was performed in 19 cats. Cardiomegaly was identified in 3 cats, hip dysplasia in 1 cat, and 1 cat had evidence of both renomegaly and hepatomegaly. Myelography was performed on 1 cat and was normal. Echocardiography was performed on 3 cats, which revealed evidence of hypertrophic cardiomyopathy. Results of abdominal ultrasonography were reported in 3 cats with a normal scan in 1 and mesenteric lymphadenopathy in 2 cats. MRI of the spine was performed in an additional 3 cats and revealed paraspinal muscle atrophy in 1 cat, mild meningeal enhancement in the caudal third of the lumbar spine in the second cat, and was normal in the third cat. Another cat underwent an MRI of the brain, which did not reveal any abnormalities.

Electrodiagnostics

EMG was performed in 28 cats. Increased insertional activity and spontaneous activity, including either positive sharp waves and fibrillation potentials (22 of 28) or complex repetitive discharges (2 of 28), were reported. Spontaneous activity was described as diffuse in 10 cats, most severe in the pelvic limb musculature in 8 cats, more severe in the distal thoracic and pelvic limb muscles in 3 cats, and affecting all limbs in 7 cats. Motor nerve conduction velocity (MNCV) was determined in 22 of 28 cats that underwent electrodiagnostic evaluation. Measurement of the sciatic nerve conduction in entirety, in segments, or in the peroneal or tibial branches was reported as decreased in 17 cases. The mean sciatic MNCV was 53 ± 17 m/s (28–81 m/s; reference 93.7 ± 9.4 m/s) in 13 cats for which numerical results were provided. The ulnar MNCV was reduced in 3 of 4 cats when that nerve was evaluated, with a mean velocity of 29 ± 4.4 m/s (20–34 m/s; reference 82.1 ± 11.1 m/s). MNCV was reported only as decreased without nerve designation in 2 cats and equivocal in 1 cat. Only 3 of 22 cats had normal MNCV in all nerves tested. Sensory nerve conduction velocity and repetitive nerve stimulation of the CMAP were normal in 1 cat. Compound motor action potential amplitudes were reported reduced in 6 of 10 cases, showed temporal dispersion in 5 cases, and were polyphasic in 3 cases.

Histopathology and Electron Microscopy of Muscle and Nerve Biopsies

Muscle biopsies were submitted from 36 affected Bengal cats. Angular to anguloid atrophy occurring in small and large groups was identified in 27 muscle biopsy samples (Fig 1a). Fiber-type grouping was not observed. Intramuscular nerve branches within the muscle biopsy specimens showed variable loss of MF in 23 cases (Fig 1a,b) with diffuse mononuclear infiltration and fiber loss in 6 cases. Other abnormalities in muscle were rare but included necrotic fibers undergoing phagocytosis (2), excessive intramyofiber lipid droplets (2), mild lymphocytic infiltration having an endomysial distribution (1), single or multiple internal nuclei within myofibers (1), and rare myofiber-containing blue-rimmed vacuoles (1).

image

Figure 1.  Muscle biopsies from Bengal cats with polyneuropathy were evaluated in serial cryosections. The most frequent pathological changes observed with the H&E (a) and modified Gomori trichrome (b) stains included the presence of atrophic fibers having an angular to anguloid shape (a, arrows) and occurring in small (a, b) and large (not shown) groups, and variable loss of myelinated fibers in intramuscular nerve branches (a, b) with some nerve branches showing marked fiber loss and fibrosis (asterisks). Peripheral nerve biopsies from Bengal cats with polyneuropathy were evaluated in frozen sections with the modified Gomori trichrome stain (c) and in plastic sections (d) stained with toluidine blue-basic fuschin. Variability in severity of pathological changes between nerve fascicles was commonly observed in both frozen (c) and resin sections (d) with some fascicles relatively normal in appearance adjacent to other fascicles showing pathological changes (asterisks highlight abnormal fascicles in c and d). Bar = 50 μm for (a), (b) ,(c) and 100 μm for (d).

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Peripheral nerve biopsies were submitted from 26 affected Bengal cats and abnormalities were identified in 17. The extent of pathological changes between individual nerve fascicles within the same biopsy specimen was highly variable, with fascicles normal in appearance adjacent to abnormal-appearing fascicles (Fig 1c,d). The most common abnormalities included MF with inappropriately thin myelin sheaths (11 nerves) indicating demyelination and subsequent remyelination, and thin MF surrounded by supernumerary Schwann cell processes, indicative of repeated cycles of demyelination and remyelination (11 nerves, Fig 2a). Axonal degeneration was only observed in 4 cases and clusters of small-caliber nerve fibers, suggestive of regeneration, were rarely observed (Fig 2a). Subperineurial and endoneurial edema were found in 12 nerve biopsies. Ultrastructural evaluation confirmed the presence of supernumerary Schwann cell processes surrounding thin MF (Fig 2b, onion-bulb formations), inappropriately thin MF containing intratubal macrophages (Fig 2c), and regenerative clusters surrounded by a single basal lamina (Fig 2d).

image

Figure 2.  By light microscopy, the most common pathological changes in affected nerve fascicles included myelinated fibers with inappropriately thin myelin sheaths, some with supernumerary Schwann cell processes suggestive of repeated demyelination and remyelination (a, onion-bulb formations, arrows), subperineurial edema, nerve fiber loss, and occasionally, clusters of small-sized fibers consistent with regeneration (a, circle). Ultrastructural evaluation confirmed the presence of supernumerary Schwann cell processes surrounding thinly myelinated fibers (b, arrows indicate basal laminae of Schwann cell processes), thinly myelinated fibers containing intratubal macrophages (c; m, macrophage), and regenerative clusters surrounded by a single basal lamina (d, arrows). White bar on section fold in (d) = 20 μm for (a), 0.59 μm for (b), 0.87 μm for (c), and 0.95 μm for (d).

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Morphometry

Abnormal and normal-appearing nerve fascicles from Bengal cats with polyneuropathy were compared with respect to MF density, the number and percentages of split and thin MF, and the number and density of regenerating clusters (Table 1). Although trends were observed in abnormal versus normal nerves, including a decrease in MF density, an increased percentage of split MFs, and an increased density and percentage of thin MFs, no significant differences were found among the groups. However, when comparing normal and abnormal fascicles within the same nerves from 3 affected cats (Table 2), a statistically significant difference in MF density (P= .004) was evident in the abnormal fascicles, likely reflecting increased edema in these fascicles and not extensive fiber loss as regenerating clusters were rare.

Table 1.   MF changes in peripheral nerves of Bengal cats with polyneuropathy.
 Normal Nerve (n = 5)Abnormal Nerve (n = 4)
  1. Data are presented as mean ± SD and were analyzed with a 2-tailed, unpaired t-test or, where variances were different, with a Welch-corrected t-test. Where shown, range is indicated by values in parentheses. None of the values were significantly (P < .05) different between normal and affected nerves.

  2. NS, not significant; MF, myelinated fiber; split MF, fibers with split and ballooned myelin sheaths, indicative of demyelination; thin MF, fibers with myelin sheaths that are inappropriately thin relative to their axonal diameter, indicative of remyelination.

MF density (#/mm2)6,923 ± 1,791 (4,788–9,113)4,686 ± 1,757 (2,219–6,070)
Split MF density (#/mm2)32 ± 37 (0–65)63 ± 35 (33–94)
% Split MF0.4 ± 0.51.8 ± 1.7
Thin MF density (#/mm2)202 ± 150 (30–368)290 ± 282 (55–660)
% Thin MF2.7 ± 1.810.0 ± 13.6
Cluster density (#/mm2)00
# Myelinated sprouts/cluster00
Table 2.   Variability of nerve fiber changes between nerve fascicles of the same nerve in 3 Bengal cats with polyneuropathy.
 Normal Fascicles (n = 5)Abnormal Fascicles (n = 9)
  • Data are presented as mean ± SD and were analyzed with a 2-tailed, unpaired t-test or, where variances were different, with a Welch-corrected t-test. Where shown, range is indicated by values in parentheses.

  • NS, not significant; MF, myelinated fiber; split MF, fibers with split and ballooned myelin sheaths, indicative of demyelination; thin MF, fibers with myelin sheaths that are inappropriately thin relative to their axonal diameter, indicative of remyelination.

  • *

    P= .004, for all others P > .05.

MF density (#/mm2)14,385 ± 3,619 (9,599–18,955)5,186 ± 1,443 (3,040–7,256)*
Split MF density (#/mm2)16 ± 23 (0–56)43 ± 40 (0–134)
% Split MF0.1 ± 0.20.8 ± 0.7
Thin MF density (#/mm2)504 ± 228 (263–835)720 ± 467 (168–1,373)
% Thin MF3.7 ± 2.016.7 ± 13.8
Cluster density (#/mm2)02 ± 5
# Myelinated sprouts/cluster00 ± 1

Treatment and Outcome

Information regarding treatment and outcome was available for 35 and 33 cats, respectively. Twenty-one cats were treated with varying dosages of a glucocorticoid with or without additional medications and supplements. Eight cats were treated with various medications including oral antibiotics, nonsteroidal anti-inflammatory drugs, and therapies for heart disease. Six cats received no treatment. Vitamin supplements and nutraceuticals were variably administered. There was no standardization of dosage, drug formulation, or duration of treatment. Regardless of treatment, the time from diagnosis to the onset of recovery was 2 days to 52 weeks (median 1.5 weeks). A complete recovery was reported in 17 of 33 cats (51%) with the mean time elapsed until the cats were considered clinically normal of 3.5 ± 4.5 months (0.6–16 months, median 1.5 months). A partial recovery with some residual weakness was reported in 12 (36%) cats. Four of 33 cats (12%) were euthanized at or shortly after the time of diagnosis. At least one relapse was reported in 12 of 27 cats, and 7 had more than one relapse. Two additional cats were euthanized at the time of relapse. Seven cats with a complete recovery did not have further relapse. Four of the 6 cats that received no treatment were alive at the end of the study. Two of the untreated cats were clinically normal, and the other 2 had minimal residual deficits (weak jumping, persistent muscle atrophy) but were reported to be functional with a good quality of life. In total, 6 of 33 cats were euthanized either at the time of diagnosis or during a relapse, but the remainder of the cats were alive at last follow-up. In none of the cats could death be attributed to the disease.

Discussion

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnotes
  7. Acknowledgments
  8. References

This study describes the clinical and pathological characteristics of a polyneuropathy in young Bengal cats. Based on our results, polyneuropathy in Bengal cats can have a chronic and relapsing course, although cats with only single episodes of weakness were described. Central nervous system signs were not reported. The pattern of muscle fiber atrophy was consistent with denervation, including angular atrophied fibers, as well as small and large groups of atrophic fibers in the absence of myopathic changes. A striking abnormality in the muscle biopsies was the marked loss of myelinated nerve fibers and fibrosis within intramuscular nerve branches in 24 cats. When observed, only 6 cats had normal-appearing intramuscular nerve branches. In 6 of the cats with abnormal intramuscular nerve branches, mononuclear cell infiltrates were identified. Denervation resulting from nerve fiber loss within intramuscular nerve branches is the most likely cause of the spontaneous EMG activity, as only minimal evidence of axonal degeneration and regeneration was present in peripheral nerve biopsies.

In a single case report, a 9-month-old, female, domestic shorthaired cat was described with a chronic-relapsing polyneuropathy with depletion of MF in intramuscular nerve branches.18 Other reported cases of polyneuropathy in cats differ and include central nervous system involvement with exaggerated spinal reflexes,19 concurrent hemolytic anemia and myositis,20 or severe polymyositis and neuritis.21 Recently, a 16-month-old, male, neutered Bengal cat with a relapsing tetraparesis beginning in the pelvic limbs was described.13 Although muscle and peripheral nerve biopsies were not performed in this case, extensive electrodiagnostic evaluation including residual M-wave latencies, F-wave latencies, and F-ratios showed evidence of a proximal neuropathy primarily affecting the nerve root, suggesting a disease process similar to Guillain-Barre' syndrome. The cat was reported to have had 2 relapses, which were treated with physiotherapy after which the cat was clinically normal. The clinical description in this case was very similar to the Bengal cats in our study. Unfortunately, extensive electrodiagnostics were only performed on one of our cases and biopsies were not performed in the published case report for comparison. An axonal neuropathy in 2 young Snowshoe cats has also recently been described in which clinical signs as well as electrodiagnostic changes were suggestive of lower motor neuron dysfunction, more prominent in the pelvic limbs.12 In addition, inconsistent evidence of vestibular system dysfunction was described. The histopathological changes in peripheral nerve biopsies were consistent with an axonopathy. Similar to some of the Bengal cats in our cohort, both cats recovered clinically without treatment.

There are many histologic similarities between this polyneuropathy in young Bengal cats and chronic inflammatory demyelinating polyneuropathy in people.22 Inclusion criteria include evidence of demyelination, remyelination, nerve fiber loss, onion-bulb formation, and inflammation. Subperineurial and endoneurial edema are also consistent with inflammation. The mononuclear cell infiltrates within intramuscular nerve branches and edema within the peripheral nerve biopsies suggest this polyneuropathy is inflammatory in nature and the onion-bulb formations are indicative of repeated episodes of demyelination and remyelination.

Other specific causes of peripheral nerve dysfunction were not identified in our cohort of Bengal cats. A phenylalanine- and tyrosine-deficient diet has been shown to cause a distal sensory polyneuropathy in specific pathogen-free black cats.23 However, most Bengal cats in this study were fed balanced commercial diets and rarely showed decreased or abnormal sensation. Moreover, the sensory nerve conduction velocity performed on 1 cat in this study was normal. Intoxication with various substances, including organophosphates, salinomycin, and acrylamide, might cause peripheral nerve disease. However, such intoxications are usually associated with signs of autonomic dysfunction.24 Further, a chronic, frequently relapsing course and the breed tendency in this study is less consistent with intoxication. Endocrine disorders such as diabetes mellitus and hyperthyroidism that can result in neuromuscular weakness were ruled out by routine laboratory evaluations. The clinical presentations, laboratory findings, and pathologic changes in nerve biopsies were inconsistent with disorders such as primary hyperoxaluria,10 hyperchylomicronemia,4 globoid-cell leukodystrophy,25 or central and peripheral distal axonopathy.5 Neoplastic and infectious etiologies can be associated with a paraneoplastic, inflammatory, or infiltrative neuropathy.24 However, primary or metastatic neoplasia was not identified in any of the Bengal cats in our study and even mild indications of infection were rare. Infection with feline leukemia virus was identified in only a single cat using a bone-marrow aspirate. One cat was identified as having an equivocal FIV test result, but inflammatory disorders secondary to FIV are usually associated with intracranial signs and were not evident in our cats. Motor neuron disease can have an early onset26 or occur in adult cats.27 However, in motor neuron diseases, reflexes are initially normal and become depressed with advanced disease. In this cohort of Bengal cats, spinal reflexes were decreased at the onset. Similarly, pathologic changes in peripheral nerves may be normal early in the course of the disease but become evident with advanced disease. Finally, the clinical course in motor neuron diseases is chronic and progressive, as opposed to periods of remission and relapses with ultimate improvement, or full remission, as in these Bengal cats with polyneuropathy.

Because treatment protocols were so variable and 6 cats received no treatment, it is not clear whether immunosuppression or other therapies were effective. Recovery times and the extent of recovery varied widely from cat to cat. Further studies by defined-treatment protocols are necessary to determine whether immunosuppression may be of benefit in accelerating the time to remission, preventing relapses, or improving long-term outcome. An inflammatory, possibly immune-mediated cause is supported by the histopathological analysis but a specific inciting cause is not yet known. While some of the cats showed signs of systemic inflammatory disease, such as fever, respiratory signs, lethargy, anorexia, and leukocytosis, these were not consistent findings. Some cats developed initial signs of the disease or experienced a relapse without exposure to a vaccination, so it is unclear what role nonspecific immune stimulation plays in this disease. Although similar early-onset polyneuropathies with recovery and relapses have been recognized in other purebred and domestic shorthair cats,c a genetic breed predisposition is suspected in the Bengal cats. Unknown environmental triggers may initiate an immune-mediated inflammatory response against specific, but as yet unidentified, peripheral nerve antigens.

Although much useful information was gained from this study, there are many limitations, most of which are the commonly reported pitfalls of a multicenter, retrospective, record-based analysis where animals are evaluated by many different clinicians with different levels of training using variable terminology in the interpretation of clinical findings. There was no standardization of what was reported in any of the clinical examinations including physical and neurological evaluations, or electrodiagnostic testing. The use of imaging studies varied widely. Many of these limitations may be because of equipment availability and costs of the testing procedures. However, histopathological evaluations were standardized throughout the study, with muscle biopsies evaluated by histologic and histochemical methods in cryosections and peripheral nerve biopsies in resin sections. Even with the limitations noted above, there is clear evidence of muscle weakness, absence of upper motor neuron signs, and histopathological confirmation of peripheral nerve disease.

In conclusion, a polyneuropathy has been identified in young Bengal cats and, although relapses did occur, the prognosis for a functional, if not complete, recovery is good. Aside from describing this disorder, a key finding is that this disease is not directly fatal. The clinical signs can be quite dramatic and, in a young cat where infectious disease has been ruled out, a degenerative disease could easily be suspected and prompt the recommendation for euthanasia. Additionally, by increasing awareness of this disease, a more organized approach to diagnosis and determination of any benefits after treatments can be investigated. Because chronic and relapsing polyneuropathy has been reported in other cat breeds, the possibility exists that, rather than a separate disease entity, the Bengal cat is predisposed to developing chronic and relapsing polyneuropathy more commonly than other breeds.

Footnotes

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnotes
  7. Acknowledgments
  8. References

a Bensfield AC, Evans J, Shelton GD. Lower motor neuron dysfunction consistent with a peripheral neuropathy in young Bengal cats. J Vet Intern Med 2010;24:699 (abstract)

b Becker J. The Bengal Cat, Nixa, MO: American Cat Fanciers Association, http://www.acfacat.com/bengal_synopsis.htm

c Pettigrew R, Kent M, Berry WL, Shelton GD. Muscle and nerve biopsies in 138 cats: Diagnosis and outcome. J Vet Intern Med 2005;19:422 (abstract)

Acknowledgments

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnotes
  7. Acknowledgments
  8. References

The authors thank the following veterinarians for submitting muscle and peripheral nerve biopsy specimens to the Comparative Neuromuscular Laboratory for diagnosis: Drs Filippo Adamo, Sebastien Behr, Robert Bergman, Melanie Campbell, Rodolfo Capello, Anne Chauvet, Betsy Dayrell-Hart, Jerry Demuth, Dominik Faissler, Rita Goncalves, Gillian Irving, Ronald Johnson, Bud Keller, Michael Knoeckel, Robert Kroll, Stephen Lane, Timothy Lenehan, Donald Levesque, David Lipsitz, Randy Longshore, Peter Maguire, Alistir McVey, John Meeks, Natasha Olby, Simon Platt, Michael Podell, Cecilia Rohdin, Timothy Sellmeyer, Kerry Simpson, Mark Soderstrom, Karen Sullivan, Stacy Sullivan, Mary Thompson, Annette Wessmann, Sheila Wills, and Sean Yoshimoto. The authors also thank Colette Williams for review of the electrodiagnostic descriptions and the Bengal cat owners who provided information and follow-up for this study.

Support for studies in the Comparative Neuromuscular Laboratory is from the Muscular Dystrophy Association and the Jain Foundation.

References

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnotes
  7. Acknowledgments
  8. References
  • 1
    Mizisin AP, Shelton GD, Burgers ML, et al. Neurological complications associated with spontaneously occurring feline diabetes mellitus. J Neuropath Exp Neurol 2002;61:872884.
  • 2
    Mizisin AP, Nelson RW, Sturges BK, et al. Comparable myelinated nerve pathology in feline and human diabetes mellitus. Acta Neuropathol 2007;113:431442.
  • 3
    Estrella JS, Nelson RN, Sturges BK, et al. Endoneurial microvascular pathology in feline diabetic neuropathy. Microvasc Res 2008;75:403410.
  • 4
    Jones BR, Johnstone AC, Cahill JI, Hancock WS. Peripheral neuropathy in cats with inherited primary hyperchylomicronaemia. Vet Rec 1986;119:268272.
  • 5
    Moreau PM, Vallat JM, Hugon J, et al. Peripheral and central distal axonopathy of suspected inherited origin in Birman cats. Acta Neuropathol (Berlin) 1991;82:143146.
  • 6
    Fyfe JC, Giger U, Va Winkle TJ, et al. Glycogen storage disease type IV: Inherited deficiency of branching enzyme activity in cats. Pediatr Res 1992;32:719725.
  • 7
    Coates JR, Paxton R, Cox NR, et al. A case presentation and discussion of type IV glycogen storage disease in a Norwegian Forest cat. Prog Vet Neurol 1996;7:511.
  • 8
    Jezyk PF, Haskins ME, Newman LR. Alpha-mannosidosis in a Persian cat. J Am Vet Med Assoc 1986;189:14831485.
  • 9
    Vite CH, McGowan JC, Braund KG, et al. Histopathology, electrodiagnostic testing, and magnetic resonance imaging shows significant peripheral and central nervous system myelin abnormalities in the cat model of alpha-mannosidosis. J Neuropathol Exp Neurol 2001;60:817828.
  • 10
    McKerrell RE, Blakemore WR, Heath MF, et al. Primary hyperoxaluria (l-glyceric aciduria) in the cat: A newly recognized inherited disorder. Vet Rec 1989;125:3134.
  • 11
    Cuddon PA, Higgins RJ, Duncan ID, et al. Polyneuropathy in feline Niemann-Pick disease. Brain 1989;112:14291443.
  • 12
    Matiasek LA, Feliu-Pascual AL, Shelton GD, et al. Axonal neuropathy with unusual clinical course in young Snowshoe cats. J Feline Med Surg 2009;11:10051010.
  • 13
    Granger N, Stalin CE, Harcourt-Brown TB, Jeffery ND. Idiopathic polyradiculonuropathy in a Bengal cat: Electrophysiological findings and 1 year follow-up. J Feline Med Surg 2008;10:603607.
  • 14
    Dickinson PJ, LeCouteur RA. Muscle and nerve biopsy. Vet Clin N Am Small Anim Pract 2002;32:63102.
  • 15
    Dubowitz V, Sewry CA. Histological and histochemical stains and reactions. In: DubowitzV, SewryCA, eds. Muscle Biopsy: A Practical Approach, 3rd ed. St. Louis, MO: Saunders Elsevier; 2007:2139.
  • 16
    Weibel ER. Stereological Methods. New York: Academic Press; 1979.
  • 17
    Wamsley H, Alleman R. Clinical pathology. In: PlattSR, OlbyNJ, eds. BSAVA Manual of Canine and Feline Neurology, 3rd ed. Quedgeley, Gloucester: BSAVA; 2004:3553.
  • 18
    Shores A, Braund KG, McDonald RK. Chronic relapsing polyneuropathy in a cat. J Am Anim Hosp Assoc 1987;23:569573.
  • 19
    Flecknell PA, Lucke VM. Chronic relapsing polyradiculoneuritis in a cat. Acta Neuropathol 1978;41:8184.
  • 20
    Lane JR, deLahunta A. Polyneuritis in a cat. J Am Anim Hosp Assoc 1984;20:10061008.
  • 21
    Ginman AA, Kline KL, Shelton GD. Severe polymyositis and neuritis in a cat. J Am Vet Med Assoc 2009;235:172175.
  • 22
    Dyck PJ, Prineas J, Pollard J. Chronic inflammatory demyelinating polyneuropathy. In: DyckPJ, ThomasPK, eds. Peripheral Neuropathy, 3rd ed. Philadelphia, PA: WB Saunders Co; 1993:14981517.
  • 23
    Dickinson PJ, Anderson PJG, Williams DC, et al. Assessment of the neurologic effects of dietary deficiencies of phenylalanine and tyrosine in cats. Am J Vet Res 2004;65:671680.
  • 24
    Dickinson P, LeCouteur R. Feline neuromuscular disorders. Vet Clin N Am Small Anim Pract 2003;34:13071359.
  • 25
    Sigurdson CJ, Basaraba RJ, Mazzaferro EM, Gould DH. Globoid cell-like leukodystrophy in a domestic longhaired cat. Vet Pathol 2002;39:494496.
  • 26
    He Q, Lowrie C, Shelton GD, et al. Inherited motor neuron disease in domestic cats: A model of spinal muscular atrophy. Pediatr Res 2005;57:324330.
  • 27
    Shelton GD, Hopkins AL, Ginn PE, et al. Adult-onset motor neuron disease in three cats. J Am Vet Med Assoc 1998;212:12711275.