A4.5-year-old neutered male domestic ferret (Mustela putorius furo) was examined because of a 15-day history of anorexia, generalized weakness, and exercise intolerance. The animal lived indoors and was fed a commercially available dry diet formulated for ferrets. Routine vaccinationa had been performed a few days prior to the onset of clinical signs. On initial examination, the ferret was bright, alert, and in good body condition. Results of physical and neurologic examinations were unremarkable. When the animal was allowed to walk freely around the examination room, it initially displayed a normal gait and normal exploratory behavior. After a few seconds, however, generalized weakness became evident and rapidly progressed to nonambulatory tetraparesis. The ferret remained in sternal recumbency and was reluctant to move. Cervical ventroflexion was also observed, and the ferret was unable to maintain a normal head carriage. On repeated neurologic examination, hopping and muscle tone were decreased in all limbs. Withdrawal reflexes were mildly decreased in all limbs. Patellar reflexes were normal bilaterally, and mental status and results of cranial nerve examination were normal. There was no evidence of pain during palpation of the vertebral column or on flexion and extension of the head and neck. Results of hematologic testing, serum biochemical analyses, and abdominal and thoracic radiography were unremarkable, and a neuromuscular disorder was suspected.
General anesthesia was induced and maintained through administration of isoflurane by mask, and electrophysiologic assessment was performed with a portable electrodiagnostic machine.b Body temperature was maintained at > 37°C (98.6°F) during the examination. Electromyography was performed with an intramuscular, concentric needle electrode and sub-dermal, monopolar ground electrode. Electromyography revealed normal insertional activity and normal resting activity in all tested muscles. The distal and proximal compound muscle action potentials for the right sciatic-tibial nerve were recorded and were not reduced, compared with published values1 (26.5 and 16.6 mV, respectively; mean ± SD reference values, 10.79 ± 2.75 mV and 13.02 ± 3.41 mV, respectively). The motor nerve conduction velocity was calculated for this nerve and was found to be slightly decreased, compared with published values1 (53 m/s; mean ± SD reference value, 63.25 ± 7.56 m/s). This finding was considered to be clinically unimportant because of the relatively small number of individuals on which the reference value was based.1 Supramaximal repetitive nerve stimulation induced decrements in amplitude and area of compound muscle action potentials of 45% and 41% (mean ± SD reference values,1 0.3 ± 3.83% and 0.1 ± 3.51%, respectively, at 2 Hz; Figure 1). Findings were consistent with a presumptive diagnosis of MG. To further investigate, a single dose of neostigmine methylsulfate (0.04 mg/kg [0.018 mg/lb], IV) was administered once the ferret had recovered from general anesthesia. The clinical status of the animal improved markedly after the drug was administered, with effects lasting approximately 4 to 6 hours, as reported by the ferret's owner. Serologic testing for AChR antibodies was performed at the Comparative Neuromuscular Laboratory of the University of California–San Diego. The result was strongly positive (1.4 nmol/L; previously published value for healthy ferrets,2 < 0.06 nmol/L). On the basis of these results, a diagnosis of acquired MG was made, and treatment was started with pyridostigminec (1 mg/kg [0.45 mg/lb], PO, q 12 h) and prednisoloned (0.8 mg/kg [0.36 mg/lb], PO, q 12 h).
Tracings of compound muscle action potentials in the plantar interosseous muscle of a 4.5-year-old neutered male domestic ferret (Mustela putorius furo) with MG. Action potentials were elicited by means of supramaximal repetitive stimulation of the tibial nerve (stimulation rate, 1.5 Hz). Each horizontal division represents 2 milliseconds; each vertical division represents 2 mV. Notice the decremental decreases in both amplitude and area of the action potentials. Amp = Amplitude. Decr = Decrement. Stim = Stimulation.
Citation: Journal of the American Veterinary Medical Association 254, 10; 10.2460/javma.254.10.1192
Tracings of compound muscle action potentials in the plantar interosseous muscle of a 4.5-year-old neutered male domestic ferret (Mustela putorius furo) with MG. Action potentials were elicited by means of supramaximal repetitive stimulation of the tibial nerve (stimulation rate, 1.5 Hz). Each horizontal division represents 2 milliseconds; each vertical division represents 2 mV. Notice the decremental decreases in both amplitude and area of the action potentials. Amp = Amplitude. Decr = Decrement. Stim = Stimulation.
Citation: Journal of the American Veterinary Medical Association 254, 10; 10.2460/javma.254.10.1192
Tracings of compound muscle action potentials in the plantar interosseous muscle of a 4.5-year-old neutered male domestic ferret (Mustela putorius furo) with MG. Action potentials were elicited by means of supramaximal repetitive stimulation of the tibial nerve (stimulation rate, 1.5 Hz). Each horizontal division represents 2 milliseconds; each vertical division represents 2 mV. Notice the decremental decreases in both amplitude and area of the action potentials. Amp = Amplitude. Decr = Decrement. Stim = Stimulation.
Citation: Journal of the American Veterinary Medical Association 254, 10; 10.2460/javma.254.10.1192
Two weeks later, the ferret was reexamined. No clinical improvement had been noted by the owners since the onset of treatment. However, the treatment was well tolerated, and only a few episodes of mild diarrhea had been observed. The animal also had had continuous mild body tremors since the onset of treatment. Clinical and neurologic examinations revealed persistent marked exercise intolerance, and the owners were advised to administer pyridostigmine and prednisolone 3 times daily, rather than twice daily. Esomeprazolee (1.5 mg/kg [0.68 mg/lb], PO, q 24 h) was added to the treatment regimen because of adverse gastrointestinal effects.
Approximately 2 months after treatment had been initiated, the owners observed the first signs of improvement. The ferret was able to leave its cage and walk around following administration of pyridostigmine; however, the effect of the drug lasted only approximately 30 minutes. Treatment was maintained unchanged.
A follow-up examination was performed 10 months after the onset of treatment. At that time, the owner reported better exercise tolerance, and physical examination revealed a marked improvement in the ferret's clinical status. The ferret was able to walk around the examination room without evident weakness, and only mild generalized tremors persisted. Follow-up serologic testing for AChR antibodies was performed, and the titer (0.08 nmol/L) was substantially lower, compared with the initial value. In view of the clinical improvement and decreased AChR antibody titer, the prednisolone dosage was tapered over the next 4 months, followed by discontinuation of pyridostigmine administration. No clinical signs of relapse were observed, and a follow-up AChR antibody titer measured after treatment was discontinued (0.01 nmol/L) was low. Thirty months after initial examination, the ferret was reportedly healthy and not receiving any medications.
Discussion
Myasthenia gravis is a disorder of neuromuscular transmission that can be either congenital (ie, resulting from a deficiency in or functional disorder of AChRs) or acquired (ie, resulting from an autoimmune attack against AChRs).3 The acquired, autoimmune form is relatively common in dogs and also occurs in cats.3 To our knowledge, there has to date been only 1 reported case of autoimmune MG involving a ferret.2 In that report, the animal was euthanized shortly after diagnosis because of a lack of sustained response to treatment.2 To the authors’ knowledge, long-term follow-up and outcome of the disease in this species have not been reported previously.
The acquired form of MG affects dogs and cats of all breeds and both sexes.4,5 The age at diagnosis for both of these species ranges from approximately 4 months to 15 years, although a bimodal age distribution in dogs has been suggested, with peaks in incidence at 2 to 3 and 9 to 10 years of age.5–9 The previously described ferret2 was substantially younger than the ferret described in the present report, indicating that in ferrets, as in cats and dogs, age at diagnosis could vary widely.
In humans, treatment with certain drugs, particularly d-penicillamine, has been associated with the development of acquired MG,10 and a similar connection has been identified in a few hyperthyroid cats treated with methimazole.11,f In cats, no association between vaccination and the onset or exacerbation of clinical signs could be established.5 The ferret described in the present report had received a routine vaccination just a few days prior to the onset of clinical signs. However, there is no evidence that vaccination can trigger development of MG in ferrets, and the association between vaccination and the onset of clinical signs may have been merely a coincidence. Interestingly, even though vaccination has not been reported as a trigger for development of MG in dogs, it has been associated with relapse of clinical signs in a dog with MG that was in clinical remission.12
Muscle weakness is a major sign of MG in humans and other animals. In companion animals, initial clinical signs may include generalized weakness and regurgitation secondary to esophageal dilatation.6 Acute fulminating MG has also been reported in dogs.6 The previously reported ferret with MG2 and the ferret described in the present report both had generalized weakness without evidence of dysphagia or regurgitation. The previously reported ferret had mild esophageal enlargement on thoracic radiographs, but thoracic radiographs for the ferret described in the present report were considered normal.
Myasthenia gravis has been associated with other diseases, such as hypothyroidism, hypoadrenocorticism, thrombocytopenia, hemolytic anemia, and tumors.3,13,14 Thymoma-associated MG is a well-recognized entity in human and veterinary medicine and is particularly common in cats.5,15–17 In the ferret described in the present report, no concurrent diseases were identified at the time of initial evaluation or developed during the follow-up period.
A presumptive diagnosis of MG can be made on the basis of clinical signs in conjunction with results of electrophysiologic and pharmacological testing.3 Administration of a single dose of neostigmine methylsulfate can be used to help strengthen a presumptive diagnosis of MG, but a negative response does not preclude this diagnosis.3,10
Electrophysiologic evidence of a > 10% decrement in the amplitude of compound muscle action potentials in response to repetitive nerve stimulation can help support a diagnosis of MG.3,18 As with the previously reported ferret, such testing proved to be useful in the ferret described in the present report, especially in conjunction with a positive response to neostigmine administration.2 The current standard for the diagnosis of acquired MG remains demonstration of serum AChR antibodies by means of a radio-immunoprecipitation assay.19 This assay is specific and sensitive, and a positive result reflects an autoimmune response against muscle AChRs. Canine or feline muscle extract is used in the assay, and values < 0.06 nmol/L were previously found in 4 clinically normal ferrets.2 Both the previously reported ferret suspected to have MG and the ferret described in the present report had high AChR titers, compared with this value, suggesting that, as in other species, quantification of AChR antibodies can help confirm a diagnosis of acquired MG. However, whether seronegative MG can occur in ferrets is unknown.
To date, both in human and veterinary medicine, there are no well-controlled studies as to the best treatment protocol for MG.3,15 The cornerstone of treatment is drugs that increase the amount of acetylcholine at the level of the neuromuscular junction.15 Pyridostigmine, an acetylcholinesterase inhibitor that reduces acetylcholine breakdown at the level of the neuromuscular junction, is the preferred drug for symptomatic treatment in humans and is also used in companion animals.3,20 When a satisfactory response cannot be achieved with this treatment alone, immunosuppressive drugs should be administered.3,15 For the ferret described in the present report, pyridostigmine seemed to alleviate clinical signs but had a very short duration of action. Mild generalized muscle tremors were observed after treatment was initiated and may have represented an unusual adverse effect of pyridostigmine. Importantly, what role, if any, pharmacological treatment had in our patient could not be evaluated because long-lasting clinical improvement was apparent only after several months, making it impossible to determine whether improvement represented a response to treatment or spontaneous remission.
In human and companion animal medicine, the value of repeated measurement of AChR antibody titers is debated, but changes in antibody titers might support treatment decisions.3,14,21 If repeated testing is performed, treatment should be continued as long as the AChR antibody titer is still high.3
In dogs with acquired MG, high rates of spontaneous clinical remission have been reported, although some relapses may be seen.12 In contrast, few cats have been reported to have spontaneous remission.5 In the patient described in the present report, both clinical and serologic remission were documented. Treatment for MG may need to be continued for several months to years depending on the clinical form,3 and this was the case for our patient, which received pharmacological treatment for 14 months. Owner compliance, dedication, and willingness to provide supportive treatment during the first months had a substantial impact on the outcome of this patient, as did the owner's decision to not euthanize the ferret despite the initial lack of response to treatment.
Findings for the ferret described in the present report suggested that MG should be considered in the differential diagnosis for ferrets with generalized weakness and that clinical and serologic remission can potentially be achieved in affected ferrets. Importantly, sustained clinical improvement was not evident for several months after the initiation of treatment. This may have possibly reflected a species-specific response in ferrets, and more information is needed regarding disease course in ferrets with MG.
Acknowledgments
No third-party funding or support was received in connection with this study or the writing or publication of the manuscript. The authors declare that there were no conflicts of interest.
ABBREVIATIONS
| AChR | Acetylcholine receptor |
| MG | Myasthenia gravis |
Footnotes
Canigen CHPPi, Virbac, Carros Cedex, France.
Nicolet Viking Quest, Natus Medical Inc, San Carlos, Calif.
Mestinon, Meda Pharma GmbH, Wangen-Bruttisellen, Switzerland.
Microsolone, Merial, Lyon, France.
Inexium, AstraZeneca, Courbevoie, France.
Shelton GD, Joseph R, Richter K, et al. Acquired myasthenia gravis in hyperthyroid cats on Tapazole therapy (abstr), in Proceedings. 15th Annu Meet Am Coll Vet Intern Med. J Vet Intern Med 1997;11:120.
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