Treatment of Autoimmune Myasthenia Gravis

Chapter 239

Treatment of Autoimmune Myasthenia Gravis

The name myasthenia gravis (MG) originally was given to a human disease that was frequently fatal. As recently as 40 years ago, 25% of human MG patients died of the disease. Canine MG also has been associated with a high death rate and, according to many older textbooks of veterinary medicine, a poor prognosis for recovery. We now know that, with early recognition of the disease, a correct diagnosis, and appropriate treatment, the prognosis for a relatively normal quality of life and life span is favorable in both human and canine patients with MG.

Canine MG is the most common neuromuscular disease diagnosed in my laboratory. Feline autoimmune MG occurs much less frequently but is associated with a higher incidence of a cranial mediastinal mass (25.7%) than canine MG (3.4%).

Diagnosis of Myasthenia Gravis

The spectrum of clinical presentations in both cats and dogs is broad and variable; thus autoimmune MG should be high on the list of differential diagnoses for any dog or cat with focal or generalized neuromuscular weakness, acquired megaesophagus, or dysphagia. In-depth discussions of the diversity of clinical presentations in canine and feline MG can be found in the literature (Dewey et al, 1997; Shelton, 2002; Shelton, Ho, and Kass, 2000; Shelton and Lindstrom, 2001; Shelton, Schule, and Kass, 1997). The onset of clinical signs commonly is acute, occurring only a few days to a few weeks before presentation. Because of the propensity of dogs with MG to develop aspiration pneumonia, autoimmune MG is one disease in which a delay in obtaining a diagnosis or assumption of the wrong diagnosis can result in a fatal outcome.

When MG is suspected, ideally a serum sample should be collected for acetylcholine receptor (AChR) antibody testing and the diagnosis confirmed before initiation of therapy. The gold standard for the diagnosis of autoimmune MG continues to be the demonstration of autoantibodies against muscle AChRs by immunoprecipitation radioimmunoassay. The assay is specific and sensitive and documents an autoimmune response against muscle AChRs. Although seronegative MG occurs in approximately 2% of dogs with generalized MG, false-positive results are rare.

The edrophonium chloride challenge test (Tensilon or Enlon, 0.1 to 0.2 mg/kg in dogs and 0.25 to 0.5 mg total dose in cats IV) also should be performed since dramatic positive test results give a presumptive diagnosis of MG and allow initiation of therapy before serologic confirmation. A negative edrophonium chloride challenge result does not rule out a diagnosis of MG. In addition, a subjective improvement in muscle strength may be found in other neuromuscular diseases; thus, unless the response is dramatic, the edrophonium chloride challenge test should not be used alone to confirm a diagnosis.

Treatment of Focal and Generalized Myasthenia Gravis

No single treatment regimen is ideal for all cases of MG. Choices must be made among the therapeutic options, with the goal of obtaining the best result while keeping the risks and adverse effects as low as possible. Each case needs an individualized treatment plan, which may have to be changed from time to time depending on the stage of the disease and response to treatments. Relative to discussion of available treatments, autoimmune MG can be divided into focal (group 1), generalized (group 2), acute fulminating (group 3), and paraneoplastic (group 4) forms. Unlike humans with MG, in whom treatment is usually lifelong, dogs with MG routinely experience spontaneous remission if they survive the initial month following onset of clinical signs and do not have a thymoma (Shelton and Lindstrom, 2001).

Supportive Care

General supportive care and dedicated owners are integral parts of treatment for all groups of MG patients. The owners should be advised that treatment for MG may be as short as a few months or may need to be continued for several months to a couple of years, depending on the severity of disease.

Differentiation of vomiting from regurgitation and recognition of esophageal dilation or pharyngeal weakness are critical. Aspiration pneumonia should be treated aggressively (see Chapter 162). In cases of acute fulminating MG, referral of patients to centers with intensive care facilities is optimal. As for any dog with esophageal dilation, altered feeding procedures, including elevation of food and water or placement of a gastrostomy tube, should be used to facilitate adequate hydration, nutrition, and drug delivery. If there is a delay in recognition of megaesophagus, inadequate nutrition and poor hydration may occur, which could worsen the clinical status of the animal. Nutritional support can be expected to decrease morbidity and improve immune status.

Cholinesterase Inhibitors

Cholinesterase inhibitors are the cornerstone of treatment for MG and are advised for all patient groups. These drugs result in improved muscle strength by decreasing the hydrolysis of acetylcholine (ACh) at the neuromuscular junction. This allows a greater number of ACh molecules to bind to and activate AChRs on the postsynaptic membrane, prolongs the action of ACh, and enhances neuromuscular transmission. Cholinesterase inhibitors do not treat the underlying aberrant immune response and thus do not modify the course of the disease, but they do control the clinical signs. In canine nonthymomatous MG, this is not a problem since the natural course of the disease is to go into remission in the absence of immunosuppression. If an optimal response to therapy is obtained and normal limb muscle strength returns and regurgitation decreases or resolves, supportive care and management of megaesophagus, anticholinesterase therapy, and time may be all that is required.

Pyridostigmine bromide (Mestinon, 1 to 3 mg/kg q8-12h PO) and neostigmine bromide (Prostigmin, 2 mg/kg/day PO administered in divided doses to effect) are the most commonly used cholinesterase inhibitors; the former is preferred in most clinical situations because of its longer duration of action and fewer cholinergic adverse effects. The dosage must be adjusted individually for each animal, depending on the response to the drug and tolerance of the adverse effects.

Pyridostigmine bromide is available in syrup, tablet, and time-release forms. The syrup form may be optimal for dosing in smaller breeds of dogs but should be diluted 50 : 50 in water before use because gastric irritation may result if it is given straight. In animals in critical condition in which oral dosing is not possible, constant-rate infusion of pyridostigmine bromide (0.01 to 0.03 mg/kg/hr) may be used until oral feedings are resumed or a feeding tube is placed. For dosing in cats, pyridostigmine bromide (0.1 to 0.25 mg/kg IV q24h) has been recommended.

Adverse effects of cholinesterase inhibitors result from excessive cholinergic stimulation following the accumulation of ACh at muscarinic receptors of smooth muscle, autonomic glands, the central nervous system, and nicotinic receptors of skeletal muscle. Bradycardia, which results from excessive vagal activity, is seen almost exclusively after parenteral injections of ACh inhibitors. Gastrointestinal adverse effects may occur after administration by any route and include nausea, vomiting, abdominal cramping, loose stools, or overt diarrhea. Increased bronchial and oral secretions may be a problem if dysphagia is present. Adverse effects may be reduced by administering small doses of atropine or having the animal take medication after meals when feasible.

Overtreatment with cholinesterase inhibitors can result in excessive accumulation of ACh at the neuromuscular junction, with worsening of weakness as a result of depolarization or desensitization of the postsynaptic membrane. Any increase in anticholinesterase medication that does not produce clear-cut improvement in muscle strength should be reversed promptly.

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Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Treatment of Autoimmune Myasthenia Gravis
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