Immune‐mediated polyneuropathy in cats: Clinical description, electrodiagnostic assessment, and treatment

Abstract Background Suspected immune‐mediated polyneuropathy has been increasingly reported in cats, especially in the last decade, but the condition remains poorly understood. Objectives Refine the clinical description and review the classification of this condition based on electrodiagnostic investigation and evaluate the benefit of corticosteroid treatment and L‐carnitine supplementation. Animals Fifty‐five cats presented with signs of muscular weakness and electrodiagnostic findings consistent with polyneuropathy of unknown origin. Methods Retrospective, multicenter study. Data from the medical records were reviewed. The owners were contacted by phone for follow‐up at the time of the study. Results The male‐to‐female ratio was 2.2. The median age of onset was 10 months, with 91% of affected cats being <3 years of age. Fourteen breeds were represented in the study. The electrodiagnostic findings supported purely motor axonal polyneuropathy. Histological findings from nerve biopsies were consistent with immune‐mediated neuropathy in 87% of the tested cats. The overall prognosis for recovery was good to excellent, as all but 1 cat achieved clinical recovery, with 12% having mild sequelae and 28% having multiple episodes during their lifetime. The outcome was similar in cats with no treatment when compared with cats receiving corticosteroids or L‐carnitine supplementation. Conclusions and Clinical Importance Immune‐mediated motor axonal polyneuropathy should be considered in young cats with muscle weakness. This condition may be similar to acute motor axonal neuropathy in Guillain‐Barré syndrome patients. Based on our results, diagnostic criteria have been proposed.

in various breeds, including domestic shorthair cats. 4,5,7,9 Although electrodiagnostic data generally were incomplete, they were consistent with a motor, axonal, [1][2][3]8 demyelinating, 6,9 or mixed axonal and demyelinating polyneuropathy. 5,7 However, involvement of a sensory component has not been evaluated in most published cases. 1,2,8,9 The origin of the disease is still unknown. Early reports have considered it an idiopathic polyneuropathy, 1,3,5 whereas more recent reports indicate an immune-mediated polyneuropathy (IMPN). 2,4,6,8,9 Various treatment modalities have been described, including corticosteroids, L-carnitine supplementation, and physical therapy alone. To date, insufficient data is available to allow specific treatment recommendations.
Our primary objective was to refine the classification of this condition based on a large case series with comprehensive electrodiagnostic investigation. In particular, similarities among Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and acute canine polyradiculoneuritis (ACP) are discussed. Our secondary objective was to investigate the potential benefits of corticosteroid treatment and L-carnitine supplementation in our cohort.

| Electromyography
A disposable bipolar concentric needle electrode (40 mm length, 0.45 mm width, 0.068 mm 2 sampling area) and a SC ground electrode were used for electromyography. Abnormal spontaneous electromyographic activity (e.g., fibrillation potentials, positive sharp waves, complex repetitive discharges) was graded from 1+ to 3+ (mild to severe) in all cats, according to a published grading scale. 10

| Motor and sensory nerve conduction studies
For the following assessments, polytetrafluoroethylene-coated stainless-steel monopolar electrodes of different lengths with 3 mm bare tips were used for stimulation and recording. A ground electrode was placed SC between the stimulation and recording electrodes.
At least 3 nerves were tested in all cats. Compound muscle action potentials (CMAP) were obtained with supramaximal stimuli of 0.1 ms duration, delivered at a frequency of 1 Hz. The sciatic-tibial CMAP was recorded from the plantar interosseous muscle after stimulation of the sciatic notch and hock. The sciatic-fibular CMAP was recorded from the tibialis cranialis muscle after stimulation of the sciatic notch and stifle. Ulnar CMAP was recorded from the palmar interosseous muscle after stimulation of the elbow and carpus. Radial CMAP was recorded from the extensor carpi radialis muscle after stimulation of the brachial plexus and distal third of the humerus. Conduction block was defined by >50% reduction of CMAP area when stimulating proximally as compared to distally. 11 Sensory nerve action potentials (SNAP) were obtained with electrical stimulation applied as a rectangular wave of 0.1 ms duration at a frequency of 5 Hz at supramaximal intensity without motor interference. At least 100 consecutive recordings were averaged for interpretation purposes. The sciatic-fibular SNAP was recorded from the proximal sciatic-fibular nerve after SC stimulation of the dorsal part of the paw. Ulnar SNAP was recorded from the proximal ulnar nerve after SC stimulation of the lateral part of the fifth digit. Radial SNAP was recorded from the proximal radial nerve after SC stimulation of the dorsal part of the paw.

| Late waves
Monopolar electrodes were positioned similar to distal CMAP recording to record the H-reflex and F wave. The H-reflex was obtained for the sciatic-tibial and ulnar nerves with a submaximal stimulus of 0.1 ms duration. The H-reflex was identified as the most prominent wave with a submaximal stimulus for the M-wave or in the absence of an M-wave. The latency rate was calculated using a previously described equation: limb length/(H latency À M latency). 12 The F-wave was obtained for sciatic-fibular and radial nerves with a supramaximal stimuli of 0.1 ms duration. The F-ratio was calculated using the equation: (F latency À M latency À 1)/(2 Â M latency). 13

| Repetitive nerve stimulation
Repetitive supramaximal stimulation of the sciatic-fibular nerve was performed with trains of 10 supramaximal stimuli of 0.1 ms duration for each stimulus rate, delivered at different frequencies from 0.1 to 3 Hz. A minimum of 1 minute of recovery time elapsed between trains of stimuli. Compound muscle action potential amplitude and area under the curve were compared among the first, fourth, fifth, and tenth potentials to assess decremental responses.

| Muscle and nerve biopsies
Under general inhalation anesthesia, biopsy specimens were collected from the right triceps brachii, biceps femoris, cranial tibialis muscles, and right superficial sciatic-fibular nerve at the level of the stifle joint as previously described. 14,15 Cats received analgesia with methadone at 0.3 mg/kg IV and antibiotic prophylaxis with ampicillin-sulbactam at 20 mg/kg IV.

| Treatments and follow-up
All owners were contacted by phone at the time of the study. Recovery status, time from examination to recovery, treatments prescribed, and residual neurological deficits (referred to as sequelae) were reviewed. If multiple episodes were mentioned, only data from the episode for which the electrodiagnostic study was performed (referred to as the studied episode) were used. Time from examination to recovery was defined as the time between the electrodiagnostic study and stabilization of clinical signs (complete recovery or recovery with sequelae). The duration of the studied episode was defined as the sum of the duration of clinical signs at presentation and the time from examination to recovery. If corticosteroid treatment was started later in the absence of improvement with or without another treatment, the cat was considered to be treated with corticosteroids, the time from examination to recovery started from corticosteroid treatment initiation, and the duration of the studied episode included the time from presentation to initiation of corticosteroids.
A cat was considered lost to follow-up if no data were available regarding clinical examination at least 1 month after the electrodiagnostic study and the owners could not be reached after that time, unless the cat returned to normal during that period.

| Statistical description
Because all variables were non-normally distributed, data are presented as medians and interquartile ranges (IQR). Statistical analysis was performed using R software (version 3.6.3, R Foundation for Statistical Computing, Vienna, Austria) and Excel software (version 2202, Microsoft, USA).

| Motor and sensory nerve conduction
All cats had abnormal motor nerve conduction in the tested nerves  (Table 2). In a few cases (7%), sensory nerve conduction velocity was mildly decreased compared to the reference interval, but SNAP amplitude was normal.
F I G U R E 1 Animal ages at the time of the electrodiagnostic study.
T A B L E 1 Motor nerve conduction for sciatic-tibial, sciatic-fibular, ulnar, and radial nerves.

| Histopathological evaluation of muscle and nerve biopsies
Muscle biopsies were performed in 43 cats (78%), including 42 biceps femoris, 18 tibialis cranial, and 11 triceps brachii. Diffuse variability in muscle fiber size was observed in all muscles, with scattered or clustered atrophic and angular fibers within the same fascicle ( Figure 4A).
Other abnormalities were rarely observed and, when present, were focal and not prominent. When an IM nerve was present, axons often were depleted: 15/19 in biceps femoris, 9/9 in tibialis cranial, and 5/5 in triceps brachii muscles ( Figure 4B). For cases from ENVA, the semiquantitative evaluation of the severity of myofiber atrophy is presented in Table 3. Depending on the fascicle, a predominance of type 2 myofibers, type 1 myofibers, or both type 2 and type 1 myofibers

| Comparison between cats with and without IMPN histological diagnosis
The results of motor and sensory nerve conduction studies (not detailed) and follow-up (Table 4) were similar in the overall cohort and in the cats with and without a nerve biopsy consistent with IMPN.

| Relationship between treatment and outcome
Of the 43 cats with follow-up, complete recovery was reported in   Figure 6B).

| DISCUSSION
Our study refines the clinical description of IMPN in cats, with recurrent episodes in young cats, especially males. Similar to the most recent studies, our results do not support a breed-related disease. 4,7,9 Some cats had a history of similar episodes that resolved without treatment before presentation. All limbs, or only the pelvic limbs, were symmetrically involved. Electrodiagnostic studies were consistent with motor axonal polyneuropathy, with minimal or no sensory involvement. The overall prognosis with or without treatment was good to excellent, and all but 1 cat achieved clinical recovery. However, our study showed relapse in 28% of cats and sequelae in 12% of cats, which remained mild. The rate of sequelae was lower than noted in previous studies. 6,9 The time of recovery may be shorter in cats with previous episodes before presentation, but this result should be confirmed in future studies.

Some authors have proposed an analogy between GBS in humans
and ACP and IMPN in cats. 4,6 The diagnostic criteria for GBS are broad, and include progressive muscular weakness in the legs and arms (or only in the legs) and areflexia (or decreased tendon reflexes) in the weak limbs. Additional clinical signs that strongly support the diagnosis include a progressive phase that lasts from days to 4 weeks, relative symmetry, and cranial nerve involvement, especially bilateral facial paralysis. 16 Except for bilateral facial paralysis in only 11% of the cats, and normal tendon reflexes in weak limbs in a few cats, all criteria were met in our study. We found a predominance of males over females (2.2-fold). Considering all previously published cases, the ratio of males to females in IMPN affected cats was estimated to be 2.0 (129/63), which is very close to the relative risk of male GBS patients, estimated to be 1.8. 1,3-9,17 Similar to GBS patients and ACP affected dogs, treatment with corticosteroids and L-carnitine supplementation in our cohort did not have any obvious effect on the recovery latency, total duration of the episode, relapse rate, or the sequelae rate compared to the untreated cats. 18,19 Because 3 cats achieved clinical recovery only after the addition of corticosteroids, we cannot rule out a benefit for a subgroup of cats, although it is possible these cats would have recovered without treatment. No data in the literature support the use of L-carnitine in these diseases. Similarly, our results did not support its use in cats. Reference treatments currently are IV immunoglobulin therapy and plasma exchange in GBS patients. 16,20 A recent study found that IV immunoglobulin therapy tended to decrease the time to recover ambulation in dogs with ACP. 21 This treatment could be investigated in future studies in IMPN-affected cats, but its value may be limited by the rapid recovery in most cats.
Interestingly, important differences were found in the clinical presentation among IMPN-affected cats, GBS patients, and ACP-affected dogs. Guillain-Barré syndrome typically affects adults and elderly people, with an increased incidence of 20% for every 10 years increase in age. 17 In dogs with ACP, the trend is similar with a mean age of 7-8 years. [22][23][24][25] Conversely, the incidence decreased with age in IMPN-affected cats: 91% were <3 years old in our study. According to previously published data, the youngest cat was 3.0 months old and the oldest cat was 10.4 years old. 1,3-9 Albuminocytological dissociation is another key feature in the diagnosis of GBS. 16 Another study reported albuminocytological dissociation in 6/13 (46%) cats. 6 Considering the low prevalence of albuminocytological dissociation and the absence of abnormal spontaneous electromyographic activity in the paraspinal muscles of most cats, nerve root involvement is questionable. Late wave studies are poorly described in this disease. 1,2,8,9 The latency rate allows the assessment of the latency of the H-reflex considering the length of the limbs. The decreased latency rate for the sciatic-tibial and ulnar nerves is consistent with neuropathy and radiculopathy. The decreased F-ratio in our cohort compared to that in control cats was consistent with distal nerve involvement. Thus, we suggest that the term motor polyneuropathy might be preferred to polyradiculoneuropathy. Finally, the relapse rate was higher in the IMPN-affected cats than in the GBS patients. In a recent study, only 5% of GBS patients had a relapse with a median time of 18 weeks between onset of the disease and relapse. 26 However, approximately 10% of GBS patients had treatment-related fluctuations defined as disease progression within 2 months after initial treatment-induced clinical improvement or stabilization. 20 In IMPN-affected cats, we cannot exclude that relapses and treatment-related fluctuations are not confounded.
Classic sensorimotor GBS is the most frequent variant, affecting 30%-86% of GBS patients. A purely motor variant was reported in 5%-15% of patients and can occur in patients with acute motor axonal neuropathy (AMAN) or acute inflammatory demyelinating polyneuropathy (AIDP) subtypes. 16,20 The absence of sensory nerve conduction abnormalities is much more frequent in AMAN patients (94%) than in AIDP patients (15%). 27 The differentiation between these subtypes is based on their associated previous infections, neurological features, electrodiagnostic results, and serum antibodies. The correct classification of GBS subtypes can be difficult to achieve, especially during the early phase. In a study, 14%-16% of initial diagnoses were equivocal, and subtype classification changed in 24% of patients at follow-up, with an increase in the proportion of axonal GBS. 28 This result may be because of motor nerve conduction slowing and conduction block in the IgG anti-GM1 AMAN subtype, known as reversible conduction failure (RCF). This feature rapidly may resolve with restoration of conduction velocity and CMAP amplitudes without evidence of temporal dispersion, as would be the case in remyelination. 29 Moreover, segmental conduction block may be noted in an early phase in AMAN patients. Thus, electrodiagnosis appears to be more reliable between 3 and 6 weeks rather than within the first 2 weeks after GBS onset. 30 In which is the opposite of the motor polyneuropathy found in IMPNaffected cats. 40 Third, in the previous study, only 52% of cats had decreased MNCV, and CMAP amplitude was not detailed, making it difficult to interpret the decrease in MNCV. 9 In CIDP patients, a decrease of MNCV ≥30% below the lower limit of normal (defined as mean À 2 SD) in 2 nerves is required to be considered demyelinating. 40 In veterinary medicine, it is currently impossible to establish these thresholds in the absence of reliable reference values. Thus, it could be difficult to draw this conclusion with these results regarding demyelinating polyneuropathy. Fourth, as in GBS, albuminocytological dissociation is a major finding in CIDP (93% of patients), which differs from IMPN-affected cats. 41 Finally, corticosteroids are superior to no treatment in CIDP patients, which also differs from our results. [35][36][37]40,41 Our study had some limitations based on its retrospective nature.
There was no standardization of clinical data reported by different cli- T A B L E 5 Diagnostic criteria for immune-mediated polyneuropathy in cats, adapted from GBS consensus statement. 20

Diagnostic criteria
Features required for the diagnosis Progressive muscular weakness involving all limbs or just the pelvic limbs with relative symmetry.
Features that strongly support the diagnosis (1) Young age (juvenile or young adult); (2) History of similar episodes that resolved without treatment; (3) Decreased or absent tendon reflexes in weak limbs; (4) Absence of sensory deficit; (5) Cranial nerve involvement, especially bilateral weakness of facial muscles; (6) Electrodiagnostic examination consistent with motor axonal polyneuropathy; (7) Nerve biopsy with abnormalities consistent with nodo-paranodopathy.