Myasthenia Gravis-like Syndrome in a Hereford Heifer
Version of Record online: 14 FEB 2008
Copyright © 2008 by the American College of Veterinary Internal Medicine
Journal of Veterinary Internal Medicine
Volume 22, Issue 1, pages 231–233, January–February 2008
How to Cite
Wise, L.N., Janke, J.J. and Washburn, K.E. (2008), Myasthenia Gravis-like Syndrome in a Hereford Heifer. Journal of Veterinary Internal Medicine, 22: 231–233. doi: 10.1111/j.1939-1676.2007.0004.x
- Issue online: 14 FEB 2008
- Version of Record online: 14 FEB 2008
- Submitted April 2, 2007; Revised May 28, 2007; Accepted July 25, 2007.
A 7-month-old 295 kg Hereford heifer was presented to the veterinary teaching hospital with a 5-day history of recumbency. The owner had manually raised the heifer several times a day since they noticed the recumbency to prevent pressure necrosis and provide physical therapy. The heifer reportedly would stand for 1 minute or less before “collapsing” in sternal recumbency. The owner had administered antibiotics, vitamin B12, and thiamine and despite their efforts, they observed no positive response to treatment. Beyond her inability to stand, the heifer appeared healthy and was in good body condition. Because of her potential genetic value as a future brood cow, she was referred for further evaluation.
Upon presentation, the heifer was bright and alert but unable to stand despite repeated stimulation. Upon stimulation, the heifer made attempts to rise, but collapsed in sternal recumbency after approximately 30 seconds. The patient's temperature, pulse, and respiratory rate were within normal reference ranges. The mucous membranes were pink and moist with a capillary refill time of less than 2 seconds. Auscultation of the heart and lungs was unremarkable. Rumen contractions were decreased but the heifer was noted to pass grossly normal urine and feces during the exam. Mild muscle tremors were evident in the hind limbs but no evidence of trauma was observed. Palpation of all joints, bones, and soft tissue structures of the hind limbs as well as the vertebrae revealed no significant findings. When offered feed and water, the heifer eagerly consumed both.
A neurologic exam was performed with the patient resting in sternal recumbency. All cranial nerves were observed to be intact with the exception of potential facial nerve deficits as bilateral, symmetrical upper eyelid ptosis was present. The panniculus reflex was present appropriately along the trunk. A response to superficial pain could be consistently elicited in all limbs. The patient was placed in lateral recumbency for spinal reflex evaluation. The withdrawal reflexes and patellar reflexes were intact, but mildly diminished. Muscle tone was generally diminished in all limbs. Tail and anal tone were decreased as well. The overall interpretation of physical and neurologic examination was recumbency caused by generalized weakness most likely caused by neuromuscular disease.
A packed cell volume, total solids, and a serum chemical profile were submitted. All values were within the normal reference intervals with the exception of a mild anemia (27%, reference interval 28–42), mildly elevated creatinine (1.9 mg/dL; ref 0.6–1.6 mg/dL), hypoalbuminemia (2.2 g/dL; ref 3.0–4.0), mildly elevated AST (178 U/L; ref 53–173), elevated creatinine kinase (604 U/L, ref 55–392), and mild hypokalemia (3.1 mmol/L; ref 3.3–4.6).
A lumbosacral cerebrospinal fluid collection was performed the following day with the patient in sternal recumbency. The fluid analysis revealed changes consistent with blood contamination only.
Based on clinical and preliminary laboratory findings, differential diagnoses for neuromuscular dysfunction included diseases affecting either the ventral horns of the spinal cord, nerves, muscle, or neuromuscular junctions. Differentials considered for dysfunction of the spinal cord and spinal nerve roots included trauma, a space-occupying lesion of the spinal column, and vertebral body infection. Generalized neuropathy rule outs included delayed organophosphate toxicity and copper deficiency, whereas nutritional myopathy and toxic plant ingestion were considered for diffuse myopathy. Disorders considered as potential causes of generalized weakness included botulism, tick paralysis, and, at the level of the neuromuscular junction, myasthenia gravis. Although spinal radiographs were not performed because of an unlikely ability to obtain diagnostic plain films, traumatic lesions were considered unlikely because of the lack of external evidence of insult. A space occupying mass such as lymphoma and vertebral body abscessation were considered unlikely because of the age of the heifer and CSF analysis results, respectively. There was no known exposure to organophosphates. The fact that the heifer was for exhibition on a balanced ration and in a controlled environment made exposure to Clostridium botulinum, toxic plants, and development of nutritional myopathy unlikely. Additionally, although creatine kinase levels were increased in this heifer, values were considered not high enough to be the result of a primary myopathy. Copper deficiency also was unlikely because of the lack of supporting accompanying signs of chronic diarrhea and hypochromotrichia. The heifer was examined thoroughly for ticks and none were discovered.
The heifer was administered an intravenous dose of tripelennamine HCL at 1 mg/kg as a central nervous system stimulant to determine if the heifer was recumbent as the result of a clinically unapparent central lesion. She remained unable to rise following administration despite vigorous stimulation.
Based on the remaining diseases on the rule-out list, a neuromuscular junction disorder, particularly myasthenia gravis, was suspected. An edrophonium chloride response test was performed by intravenous administration of edrophonium at a dose of 0.1 mg/kg. The upper eyelid ptosis resolved immediately, and within 1 minute of administration, the heifer stood with no assistance. Muscle tremors were still evident throughout the trunk but were concentrated to the hindquarters and subsided within 2 minutes of administration. The heifer remained standing and was able to ambulate with mild gait deficits throughout day. During this time, she also was observed to lie down and stand again unassisted. Twenty-four hours following injection, the patient had returned to recumbent status and was unable to stand despite vigorous stimulation.
Further diagnostics and treatment of the heifer were pursued with a working diagnosis of an edrophonium responsive neuromuscular junction disorder similar, if not identical, to myasthenia gravis. An acetylcholine receptor antibody titer yielded a result of 0.1 nmol/L. This result was considered a normal titer, but pointed out one of many problems associated with diagnosis of myasthenia gravis in species other than canine or feline. The relatively species-specific nature of the acetylcholine receptor antibody test lends itself to misleading results. The species supplying the muscle antigen is most commonly canine or feline; therefore, circulating bovine acetylcholine receptor antibodies do not cross react, potentially resulting in a falsely normal or low titer.
Muscle biopsies were taken from the external intercostal and semitendinosus muscles in 3 cm sections and submitted both as fresh and fixed tissue. The sections were stained with H&E, modified trichrome, PAS, ATPases, esterase, NADH-TR, acid Pase, alkaline Pase, oil red O, and SPA-HRPO. No specific abnormalities were identified within the muscle. None of the submitted samples contained sections of intramuscular nerve branches or motor end plates; however, the observations were considered not to be the underlying cause of the disease.a
Because of economic constraints and a poor prognosis for return to function, additional diagnostics such as an electromyogram and nerve conduction velocities were not pursued. Twenty-four hours after the first injection of edrophonium chloride, a second dose was administered. Again, within 1 minute of injection the heifer was able to rise on her own and ambulate. This time, she remained functional for approximately 48 hours. Finally, an additional dose was administered to facilitate discharge. Because of the increasing periods of normalcy with each dose of edrophonium, and the high estimated cost for maintenance with a longer acting acetylcholine esterase inhibitor such as pyridostigmine, it was determined to discharge the calf with two additional doses of edrophonium chloride. The owners were instructed that they should use these doses as necessary, but should not salvage the animal for food within 30 days of the last dose due to an unknown withdrawal time. Further, in the event that the myasthenia gravis was, in fact, of the immune mediated type, dexamethasone was discharged with the owners to be given at the rate of 20 mg IM once daily for 3 days and 10 mg IM once daily for 2 days.
Long-term followup with the owners revealed that the heifer relapsed twice approximately 4 days and 1 week after discharge. In both instances, she responded to a dose of edrophonium chloride at 0.1 mg/kg intravenously. Following recovery from the 2nd relapse, the heifer remained weak in comparison to the other cattle but did not relapse again. Four months following initial admission, she was slaughtered because of the possibility of having a disease with a heritable component.
The results of definitive diagnostics for myasthenia gravis were inconclusive in this case and allowed only a diagnosis of an edrophonium responsive myasthenia gravis-like disorder.
Myasthenia gravis, a disorder of neuromuscular transmission, is a common disease of domestic animals, especially dogs and cats. The disease can present itself in both a rare congenital form and an acquired form for which the causes are numerous. The congenital form can be caused by a deficiency or dysfunction of the acetylcholine receptors at the neuromuscular junction. The acquired form is typically caused by an autoimmune disorder that affects these receptors. Regardless of the cause, the main presenting clinical sign is generalized muscle weakness. In small animals, after completion of a minimum database and imaging studies, diagnostics to classify or diagnose suspected myasthenia gravis are performed. These include edrophonium response tests, electrophysiology studies, examination of muscle samples for morphology, and evaluation of the neuromuscular junctions. For cases of suspected congenital myasthenia, a few specialized muscle laboratories offer direct evaluation of the motor end plates as well as in vitro electrophysiologic testing of muscle sections. The “gold standard” test for the immune mediated form is the confirmation of serum autoantibodies against muscle acetylcholine receptors by radioimmunoassay.1
A congenital myasthenia gravis-like syndrome has previously been described in related Brahman calves in South Africa. In this report, 4 calves, aged 3 to 4 weeks, were identified but only 1 was subjected to diagnostics and treatment. These calves, which shared a common sire, presented much like the heifer in this case and responded transiently to administration of edrophonium chloride. The hospitalized calf was subjected to an EMG and muscle biopsies, which were both normal. A serum acetylcholine antibody test was not performed in this case most likely because given the young age of onset, immune mediated myasthenia gravis was unlikely. The calf was treated with the long-acting acetylcholinesterase inhibitor pyridiostigmine, responded transiently, but later died of an unrelated illness.2
Documentation of these 4 calves led to further research that elucidated the cause of their disorder as a homozygous mutation in the acetylcholine receptor gene.3 These researchers continued the pursuit of this syndrome by identifying the carrier bulls from affected herds. From this information, they developed a screening test for this genetic mutation, which is currently being used to establish the prevalence of the heterozygous carriers within Brahman cattle in South Africa.4,5
The older age of the heifer in this case, as compared to the Brahman calves, makes it unlikely that she had a congenital form of myasthenia gravis; however, it may indicate that this congenital disorder is not limited to Brahman cattle and could be later in onset. Based on the follow-up of this heifer, it is also possible this case was immune mediated myasthenia gravis because of the decreased frequency of clinical signs coinciding with the tapering dexamethasone therapy prescribed postdischarge. Although diagnostic tests performed to determine if this case was immune mediated were not supportive, as mentioned previously, the source of the antigen for the acetylcholine receptor antibody test was most likely canine or feline. The methods used to collect and prepare the muscle in this case may have also hindered the ability to determine if this case was truly immune mediated because no intramuscular nerve branches or motor end plates were observed. Although collection recommendations vary according to laboratory, in general, samples should include a fresh, intact muscle from origin to insertion as well as fresh frozen and fixed sections measuring at least 0.5 × 0.5 × 1.0 cm.1a
For cattle presented with generalized weakness, following rule-out of more common diseases, this syndrome should be considered in the differential diagnoses list, and edrophonium chloride can be used as an inexpensive diagnostic aid.
The research performed in South Africa indicates that myasthenia gravis may be a source of economic loss for their country. The researchers speculate that many calves in the past that were either found dead or perhaps deemed “weak” with no known etiologic explanation may instead have suffered from this disease. If a similar genetic mutation exists in the American-bred Herefords, a similar process may be present in the United States. This case represents a general lack of knowledge in this area of bovine medicine and emphasizes potential difficulties in diagnosing myasthenia gravis in species other than canine or feline.
aAcetylcholine receptor antibody serology, muscle profile, and partial collection guidelines provided by the Comparative Neuromuscular Laboratory University of California, San Diego, CA