Acquired Myasthenia Gravis in Companion Animals

Acquired myasthenia gravis is among the more common neuromuscular diseases of dogs; it can also affect cats, although rarely, and typically affects purebred cats (e.g., Abyssinian, Somali). Acquired myasthenia gravis is an immune-mediated disease of the neuromuscular junction characterized by the presence of autoantibodies to the nicotinic acetylcholine receptor, located on the postsynaptic membrane of the neuromuscular junction. Thus, fewer receptors are available for acetylcholine to attach to, resulting in weakness of striated muscle.¹ Affected muscles are in the appendicular and axial musculoskeletal systems, along with the oropharynx and most of the esophagus in dogs. Megaesophagus rarely occurs in cats with myasthenia gravis because their esophagus lacks striated muscle.

Myasthenia gravis can be primarily immune-mediated, or it can be secondary to a cranial mediastinal mass, most commonly a thymoma, although other types of tumors have also been associated. Among cats with myasthenia gravis, the condition is secondary to a cranial mediastinal mass in approximately 50%.^2,3 Although congenital myasthenia gravis is a concern for dogs and cats, it is rare and is not covered in this article.

The 3 main forms of acquired myasthenia gravis are focal, generalized, and fulminant. The focal form is largely localized to the oroesophageal muscles; the generalized form includes appendicular muscle weakness along with megaesophagus; and the fulminant form is an acute, severe generalized form that can result in the need for ventilatory support.^3,4

How is acquired myasthenia gravis diagnosed?

The standard for diagnosing myasthenia gravis is based on finding definitive evidence of an elevated serum titer of acetylcholine receptor antibodies, determined by radioimmunoprecipitation assay (RIPA). Sensitivity and specificity of the RIPA are quite high, although seronegative myasthenia gravis is possible; studies suggest that the rate is approximately 2%.⁵ Presumptive diagnosis, based on clinical signs and response to a short-acting anticholinesterase medication, is often made while awaiting titer results. Patients with myasthenia gravis experience decrementation of their compound muscle action during repetitive nerve stimulation, which is typically identified during a neurologic consultation with electrophysiologic testing and not in a general practitioner’s clinic.

The clinical signs associated with myasthenia gravis are lower motor neuron or diffuse neuromuscular signs. For patients with focal myasthenia gravis, the only clinical signs may be associated with regurgitation and/or dysphagia because the striated muscles of the esophagus and oropharynx are the main muscles affected. For patients with generalized myasthenia gravis, there is commonly a gradation of clinical signs, from mild exercise intolerance to severe generalized appendicular weakness with a short, choppy gait in all 4 limbs (FIGURE 1), reduced tone, spinal reflexes, and a fatigable palpebral reflex. These patients can and often do experience regurgitation secondary to megaesophagus. Patients with fulminant myasthenia gravis are laterally recumbent and not strong enough to stand or walk, and the weakness can progress to ventilatory failure.⁴

Figure 1. Two-year-old spayed female golden retriever demonstrating generalized weakness and inability to fully extend all 4 limbs, consistent with lower motor neuron weakness.

Unfortunately, the short-acting anticholinesterase medication edrophonium (Tensilon), which was commonly used to perform presumptive testing for myasthenia gravis, was discontinued in the United States and is no longer available. A study of dogs and cats with myasthenia gravis details use of neostigmine as a substitute for edrophonium.⁶ In this study, the medication was given subcutaneously, intravenously, or intramuscularly, and the patients were monitored for 30 minutes to determine if they had a positive response. Approximately 80% of the patients that had a positive acetylcholine receptor antibody titer had a positive response to the neostigmine challenge. Use of neostigmine can be helpful for arriving at a presumptive diagnosis in the clinic, but caution should be taken because other disease processes (e.g., polymyositis) can also respond positively to anticholinesterases.

Another diagnostic test that should be used is thoracic radiography because many patients also have megaesophagus and are at greater risk for aspiration pneumonia. Some patients have acquired myasthenia gravis secondary to a cranial mediastinal mass; therefore, thorough evaluation of the mediastinum is recommended.

How is acquired myasthenia gravis treated?

Acquired myasthenia gravis is primarily treated with an anticholinesterase medication (e.g., pyridostigmine, neostigmine). These medications work by preventing the breakdown of acetylcholine in the synaptic cleft, allowing extended time for acetylcholine to attach to unaffected receptors. If patients experience return of regurgitation, hypersalivation, or weakness while receiving therapy, it can be unclear whether the dose should be increased or decreased because signs of anticholinesterase medication toxicity can often mimic the initial presenting signs (e.g., regurgitation, hypersalivation, urinary accidents, diarrhea, lacrimation, weakness).^1,7

If an anticholinesterase alone is not working, immunosuppression with steroids, mycophenolate, and/or cyclosporine should be considered.^1,8,9 However, immunosuppressants should be used with caution in patients with aspiration pneumonia because immunosuppression can cause complications with regard to response to therapy for the aspiration pneumonia.

For patients with myasthenia gravis secondary to a cranial mediastinal mass, surgical removal of the mass is recommended, although some patients experience worsening of clinical signs after surgery.¹

In human medicine, intravenous immunoglobulin (IVIG) therapy and therapeutic plasma exchange (TPE, also known as plasmapheresis) are used frequently in addition to pyridostigmine. The mechanism of action for IVIG is inhibiting immunoglobulin G receptors on phagocytic and antigen-presenting cells; blocking autoantibodies by targeting cytokines, chemokines, B and T cells, and the complement system; and suppressing antibody production. The mechanism of action for TPE is that filtration or removal of the plasma that holds the circulating autoantibodies lessens the circulating population of antibodies available to attach to acetylcholine receptors, but it does not help replenish the receptors that have already attached to the antibodies.^1,10 Few papers in veterinary medicine describe evaluation of the benefits of IVIG or TPE for patients with myasthenia gravis, but the published studies have shown positive results with use of these treatments.^1,11,12 Because IVIG is typically of human origin, transfusion reaction is a risk. Many clinics do not have a plasmapheresis machine, but other versions of TPE exist that involve use of a central line and blood bags with a centrifuge (large enough to fit the blood bags). This technique could prove to be beneficial for patients that do not respond to traditional therapies, have aspiration pneumonia and are at risk with immunosuppression, or are severely affected and in need of a more rapid therapeutic response.^1,12

What other treatment modalities are used?

The nursing/at-home care required for patients with megaesophagus secondary to myasthenia gravis is quite intense due to the increased risk for regurgitation and aspiration. Patients with megaesophagus need to be maintained in an upright position while eating and drinking, remaining in this position for approximately 15 minutes afterwards. This positioning allows for gravity to help food and liquid travel down the esophagus and enter the stomach. The usefulness of a Bailey chair or other device is recommended, but some clients manually hold their pet upright. Frequent, small feedings minimize the amount of food sitting in the esophagus. Typically, forming small “meatballs” of food helps with prehension, although some patients do better with a “gruel” for their food. Some patients do poorly with liquid, so the use of Thick-It powder (thickit.com) mixed in water or hydrogel cubes can be used for hydration. It takes time to determine the best situation for each patient’s eating and drinking habits and the optimal schedule and food/hydration type.

Promotility medications have been used to try to help prevent regurgitation; however, use them with caution because many increase the tone of the lower esophageal sphincter, which can prevent flow of substance from the esophagus to the stomach. Sildenafil may be another medication to consider. It has been identified as beneficial for puppies with congenital megaesophagus because it relaxes the tone of the lower esophageal sphincter; however, there are no current published studies about use of sildenafil for veterinary patients with myasthenia gravis. Hyoscyamine has also been intermittently used to help reduce oral secretions for patients that hypersalivate, whether from side effects of the pyridostigmine or from the disease process.

For patients with evidence of aspiration pneumonia, treatment with antibiotics (and oxygen supplementation if needed) should be included in their therapy. Last, surgery to address a cranial mediastinal mass should be considered for patients in which the myasthenia gravis is secondary to the mass.

What is the prognosis for acquired myasthenia gravis?

Unfortunately, the prognosis associated with myasthenia gravis is guarded. A recent publication that evaluated 94 patients with myasthenia gravis and their response to treatment noted that only 31% of patients experienced clinical remission, 15% were clinical responders, 26% clinically improved with therapy, and 29% exhibited no improvement. Regurgitation was negatively associated with outcome.⁷ Clinically, the outcomes fit closely with these statistics. There is also concern that megaesophagus may not resolve with treatment of myasthenia gravis; therefore, patients with megaesophagus are at increased risk for lifelong regurgitation and aspiration pneumonia.

Summary

Acquired myasthenia gravis is a common neuromuscular disease of dogs and some cats. Basic diagnosis and treatment involve thoracic radiography, acetylcholine receptor antibody titers, anticholinesterase medications, and feeding modifications; treatment can also include immunosuppressants. For some patients, alternative therapies may be needed. Acquired myasthenia gravis is a frustrating disease to treat because patients respond to therapy variably and often experience setbacks consisting of aspiration pneumonia or relapse of their clinical signs.