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ACQUIRED MYASTHENIA GRAVIS: AKITA DOG AT HIGHEST RELATIVE RISK BY G. Diane Shelton DVM, PhD Our knowledge of acquired myasthenia gravis (MG) in dogs has advanced significantly over the past ten years and it now is well established that MG is not an uncommon clinical problem in this species (1-3). In a recent study of 1154 dogs of 61 different breeds with acquired MG, the Akita dog was at highest relative risk (4). Since early recognition and correct treatment of MG is essential to a favorable clinical outcome, this article provides a brief description of the disease, presenting clinical signs, diagnosis, and treatment rationale for breeders and owners of Akita dogs. What is MG? Acquired MG is an autoimmune disease in which the body’s immune system mistakenly attacks and destroys special proteins (acetylcholine receptors) located on the muscle surface where the nerve attaches to the muscle. These proteins respond to the chemical acetylcholine, which is released by the stimulated nerve, and this response starts the process, which causes the muscles to contract. It is not known what initiates the autoimmune reaction, but if acetylcholine receptors are lost because of it, the response of the muscle to nerve impulses is poor and weakness may occur. The distinctive feature of MG is muscle weakness, made worse by use of those muscles and improved at least partially by rest of the same muscles. The muscles affected are called voluntary or striated muscles and include limb muscles involved with ambulation, pharyngeal, and esophageal muscles involved in swallowing and delivery of food into the stomach, laryngeal muscles involved in respiration and vocalizing, and extraocular muscles involved in eye movements. Involuntary heart muscle and smooth muscles of the gut, blood vessels, and uterus are not involved in MG. Different muscle groups may be affected in different dogs and clinical signs are not the same in all dogs. This makes the diagnosis of MG tricky for the inexperienced. There are certain clinical signs, however, that should alert owners and clinicians to test the dog for MG. While presenting clinical signs may vary between dogs, a common abnormality is regurgitation, which is the passive backward movement of undigested food as a result of a dilated esophagus with poor motility (megaesoophagus). The esophagus is composed of striated muscles in the dog. This needs to be distinguished from vomiting, which is an active process associated with retching and passage of digested food and usually bile. Excessive salivation of ropy saliva and multiple attempts at swallowing food also may be present. This may be the only abnormality (focal MG). A generalized form (generalized MG) may be present with weakness following normal activity. This may take the form of a stiff, stilted gait, or a hunched posture after very mild activity. Regurgitation may or may not be associated with generalized weakness. A high-pitched bark or an absence of a bark may be noted. The dog also may appear to “sleep with the eyes open” as the muscles involved with eyelid movements may be weak. A very severe form recently has been described in which there is a rapid onset of muscle weakness involving the esophagus and respiratory muscles associated with collapse. Treatment requires intensive care including ventilatory support. The prognosis is poor for this form of MG. How is the diagnosis of MG confirmed? A very sensitive and specific test for MG is a blood test to look for serum antibodies to the acetylcholine receptor. Ninety-eight percent of dogs with generalized MG have abnormally elevated serum levels of these antibodies. The percentage of positive tests in the focal form of MG may be slightly less, but currently there is no other way to diagnose this form of MG. This test is available through the Comparative Neuromuscular Laboratory at the University of California, San Diego, in LaJolla, CA (Companion Animal Diagnostics Section of the Comparative Neuromuscular Laboratories ). The acetylcholine receptor antibody assays are performed frequently with results are available in 5-7 working days. Serum (1-2 ml) should be collected prior to any corticosteroid therapy. A tentative diagnosis of acquired MG may be made by pharmacological testing, using the short-acting drug edrophonium chloride (brand-name “Tensilon”). This is a drug that is used intravenously to try to make the diagnosis of MG by reversing some obvious and measurable weakness, such as limb muscle strength or an absence of the ability to blink. A dramatic improvement in muscle strength usually is diagnostic; however, false positive and false negative results may occur. On rare occasions both of these tests are negative or equivocal in a dog whose history and physical examination still seem to point to a diagnosis of myasthenia gravis (seronegative MG). The positive clinical findings probably should take precedence over negative confirmatory tests and a diagnosis of “possible MG” should be made. If clinical signs were recent in onset, retesting in 1-2 weeks may confirm the diagnosis. How is MG treated? Supportive care and diligent owners are of primary importance in the treatment of canine MG. Elevation of food and water is critical if regurgitation resulting from megaesophagus is present. The dog should remain in an elevated position for at least 10 minutes after a meal. If regurgitation is the only clinical sign, alterations in feeding practices and evaluation of different food consistencies (liquid, solid, gruel) may be the only treatment required. If regurgitation remains uncontrollable, maintenance of nutrition and fluid requirements may require placement of a gastric feeding tube. If possible, certain things should be avoided including infections, fever, excessive heat or cold, and overexertion. In females, estrus cycles, pregnancy and delivery may exacerbate clinical signs of MG. A rule of thumb is to minimize stress of any kind. Many drugs can adversely affect dogs with MG. The most common offenders are the very medications used to treat MG (too much anticholinesterase, steroids), but anesthetic agents, muscle relaxants, magnesium salts, anticonvulsants, and other membrane stabilizers for irregular heart rate, as well as aminoglycoside antibiotics, are other drugs generally accepted to unmask or exacerbate MG. Anticholinesterase drugs are the cornerstone of therapy for MG, boosting the body’s neuromuscular transmitter acetylcholine by blocking the enzyme, which usually breaks it down. Pyridostigmine (brand-name “Mestinon”) and neostigmine (brand-name “Prostigmin”) commonly are used in the dog. These medicines do not cure MG, but they can provide a temporary crutch to help patients function better. Because muscle involvement and severity vary so much among patients with MG, there is no fixed dose or time schedule for anticholinesterases. The veterinarian will need to adjust dosages of these drugs based on the individual needs of the dog. If the clinical signs of MG are not completely relieved with anticholinesterase drugs, then immunosuppressive drug therapy can be initiated. These drug alternatives consist of a group of general suppressants of the body’s immune system and include prednisone and azathioprine. Prednisone is a synthetic drug taken by mouth that resembles natural hormones produced by the cortex of adrenal glands. The body depends on these hormones, called corticosteroids, during stress. Prednisone has a great many potential undesirable effects in dogs including suppression of adrenal gland function, marked muscle weakness, and muscle atrophy. Unique to MG is the possibility of increasing weakness during the first two weeks of prednisone therapy. This necessitates close medical supervision when prednisone is instituted, either on an outpatient or in-hospital basis. Azathioprine also may be of use in canine MG but side-effects require frequent monitoring of blood counts to detect rapid drops in the number of white and red cells in the blood, and periodic liver function tests to detect potential toxicity to the liver. Surgery may be required if MG is associated with a thymoma, which is a tumor of the thymus gland. Although most thymomas are benign, they usually are removed surgically. This occurs in <5% of cases of canine MG and usually in older dogs. Thymoma may be associated with an acute, fulminating form of MG. New information has shown that spontaneous remissions occur in canine MG (5) making the long term prognosis for recovery good if clinical signs are recognized early, an accurate diagnosis reached, and appropriate therapy given. Future directions In humans, autoimmune diseases such as MG, thyroid disease, lupus, and rheumatoid arthritis seem to run in families, and these families statistically (but not invariably) share certain tissue markers. New and promising experimental treatments for autoimmune diseases are based on the presence of such markers. In collaboration with Dr. John Angles at University College Dublin, Ireland, genetic markers are being evaluated for the Akita, Newfoundland, and Scottish Terrier, breeds at high relative risk for MG. The prognosis in canine MG still remains guarded since in many dogs an accurate diagnosis may be delayed and the dog succumbs to aspiration pneumonia resulting from megaesophagus. However, with early recognition of the aspiration pneumonia and appropriate treatment, the chances of spontaneous remission are good. Further studies on the mechanism of spontaneous remissions in canine MG may help to take the “gravis” out of MG for both our animal and human myasthenic patients. Note from Diane Shelton: “I would be interested in getting blood and pedigrees from any affected dogs that have been confirmed with MG by the antibody titer. …. Unfortunately due to legal constraints I cannot give direct advice to owners regarding specific treatment of their animals.” Diane Shelton, D.V.M., Ph.D. Email:
gshelton@ucsd.edu http://medicine.ucsd.edu/vet_neuromuscular
Selected references 1) Shelton GD, Willard MD, Cardinet III GH, Lindstrom J (1990) Acquired myasthenia gravis: Selective involvement of esophageal, pharyngeal, and facial muscles. J Vet Int Med 4:281-284. 2) Shelton GD (1992) Canine myasthenia gravis. In: Current Veterinary Therapy XI, Kirk RW and Bonagura JD (eds.), W.B. Saunders Co., Philadelphia 1039-1042. 3) Shelton GD (1992) Megaesophagus secondary to acquired myasthenia gravis. In: Current Veterinary Therapy XI, Kirk RW and Bonagura JD (eds.), W.B. Saunders Co. Philadelphia 580-583. 4) Shelton GD, Schule A, Kass PH (1998) Risk factors for acquired myasthenia gravis in dogs: 1, 154 cases (1991-1995). J Am Vet Med Assn 211: 1428-1431. 5) Shelton GD, Lindstrom JM (2001). Spontaneous remission in canine myasthenia gravis: Implications for assessing human MG therapies. Neurology 57:2139-2141. Updated on 09/18/2008 |
