Richard A. LeCouteur, BVSc, PhD, DACVIM (Neurology), DECVN
Numerous therapeutic options exist for acquired myasthenia gravis (MG). Treatment therefore needs to be customized for each dog's individual requirements.
Treatment goals include improving neuromuscular transmission and administering supportive care.
Optimal therapeutic approaches for dogs with acquired MG have not been established.
One confounding factor in the assessment of treatments for acquired MG is the frequent occurrence of spontaneous remission.
Early and accurate diagnosis is an essential aspect for obtaining a good clinical outcome in most cases of acquired MG. Experienced clinical judgment and cooperative, dedicated owners also are essential considerations.
Recognition of esophageal dilation and/or pharyngeal weakness prior to institution of therapy is mandatory.
Specific Therapeutic Considerations
Drugs available include pyridostigmine bromide (Mestinon®, 0.5–3 mg/kg, orally BID or TID) and neostigmine bromide (Prostigmin®, 2 mg/kg/d, orally in divided doses to effect).
Pyridostigmine bromide is preferred in most clinical situations because of its longer duration of action and fewer adverse effects.
Should dysphagia/regurgitation preclude oral medication, pyridostigmine bromide also may be given as a constant-rate infusion at 0.01–0.03 mg/kg/h IV.
Neostigmine (0.04 mg/kg SQ q 6 h) is an alternative to pyridostigmine.
Titrate dose based on weakness and adverse effects.
Some common adverse effects of pyridostigmine bromide in dogs include hypersalivation, increased gastrointestinal motility, vomiting, diarrhea, and apparent abdominal pain.
Adverse effects occur because muscarinic receptors located on the exocrine glands increase gastric acid secretion, salivation, and lacrimation.
Bradycardia may be seen due to excessive vagal activity.
Immunosuppressant therapy (acquired MG only) may be indicated when there is an inadequate response to anticholinesterase medication.
Use of immunosuppressive drugs is controversial, particularly as a "first-line" treatment, due to the high incidence of aspiration pneumonia (particularly in dogs) and the potential for glucocorticoids to exacerbate muscle weakness.
Prednisone is the initial drug of choice (start at 0.5 mg/kg PO q 24 h for 1–2 weeks, then increase to 2–4 mg/kg PO q 24 h if needed; gradual taper if possible based on clinical response).
Contraindications for glucocorticoid therapy include ongoing infections or aspiration pneumonia, diabetes mellitus, severe obesity, uncontrolled hypertension, and gastrointestinal ulcerations.
Other immunosuppressive agents (e.g., azathioprine, cyclosporine, cyclophosphamide, mycophenolate mofetil) may be recommended in dogs where use of glucocorticoids is contraindicated, should adverse effects of glucocorticoids become difficult to manage, or if there is an inadequate response to prednisone.
Avoid drugs that impair neuromuscular transmission, including ampicillin, aminoglycosides, and phenothiazines.
Organophosphates may increase toxicity of anticholinesterase drugs.
Aspiration pneumonia is the most common and serious complication in dogs with pharyngeal/esophageal weakness.
Respiratory failure may occur if respiratory muscle weakness is severe.
Endotracheal intubation and ventilatory support may be necessary for dogs with acute fulminating MG or for patients with severe aspiration pneumonia.
Complications may arise secondary to long-term immunosuppressant drug treatment.
Client monitors weakness and dysphagia/regurgitation at home daily.
Monitor anti-acetylcholinesterase receptor antibody titer every 8 weeks in patients with acquired myasthenia gravis, because the disease will spontaneously resolve in many patients, usually by 6 to 18 months.
Prevention and treatment of aspiration pneumonia are essential considerations in animals with acquired MG.
Frequent turning of recumbent animals, antibiotic therapy, nebulization and coupage are examples of treatment considerations for aspiration pneumonia.
Maintenance of adequate hydration is essential in animals with acquired MG.
Intravenous fluid therapy may be necessary in animals that regurgitate liquids.
Special feeding procedures (e.g., feeding food and water from elevated feed bowls or holding an animal in a vertical position for more than 20 minutes after feeding), placement of a gastrotomy tube, and in some cases parenteral nutrition, must be considered.
Construction of special chairs ("Bailey chair") to aid in upright feeding can be invaluable. www.caninemegaesophagus.org/support.htm
Intensive care and ventilatory support may be required in dogs with severe aspiration pneumonia or severe generalized weakness.
Modification of gastrointestinal tract function
Management of dysphagia and megaesophagus, with associated complications of aspiration pneumonia, regurgitation and esophagitis, is an essential consideration.
Drugs that may improve esophageal motility (e.g., metoclopramide), increase lower esophageal sphincter tone (e.g., cisapride), or increase the pH of gastrointestinal contents (e.g., cimetidine or ranitidine) should be considered.
Should a concurrent thymic mass or other neoplasm be present, then surgical removal, with or without radiation therapy, should be considered.
As a majority of dogs with thymoma and acquired MG also have megaesophagus and aspiration pneumonia, and because mortality rate after thymectomy in these dogs is high, it is recommended to delay thymectomy until clinical signs of MG are controlled by means of medical management.
Treatment of Acute Fulminating Myasthenia Gravis
Management of severe generalized acquired MG is difficult.
Affected animals should be managed in an intensive care unit.
Anticholinesterase therapy and ventilatory support provide the basis for therapy.
Ventilatory support usually is required due to weakness of intercostal muscles and diaphragm, or due to concurrent pulmonary infection (often resulting from aspiration pneumonia).
Plasmapheresis and human IV immunoglobulin have been used to treat dogs with acute fulminating MG.
Monitoring the Response to Treatment
In the absence of immunosuppression, determination of serial AChR antibody titers may aid in determination of both disease status and duration of treatment.
The overall goal in dogs is to improve muscle strength and minimize the adverse effects of medications until the disease goes into remission.
In general, the treatment plan may need to be altered based on response and severity of the disease.
For mild disease, anticholinesterase agents and altered feeding procedures may be sufficient.
For more severe disease, early use of immunosuppressants or immunomodulators (a substance that has some effect on the immune system) may be required.
There are many considerations in the management and care of dogs with MG, including anesthesia, ways to avoid aspiration pneumonia, and concurrent diseases.
If an animal with MG must undergo anesthesia for a life-threatening condition, there needs to be a detailed preanesthetic and postanesthetic evaluation.
Preoperatively, an animal that is poorly controlled may benefit from other modalities such as plasmapheresis or human IV immunoglobulin therapy.
An animal may require mechanical ventilation during recovery or if it has significant aspiration pneumonia.
Drugs that may worsen MG by blocking action at the neuromuscular junction include: aminoglycosides, ampicillin, lidocaine, propranolol, and other β blockers, quinidine, procainamide, penicillamine, magnesium, and contrast agents.
Immunosuppressant and Immunomodulatory Agents
Of immunosuppressant agents, prednisone often is the first drug of choice.
Immunosuppressants such as azathioprine, cyclosporine, mycophenolate mofetil, cyclophosphamide and tacrolimus may help to improve muscle strength by suppressing the production of autoantibodies, but have many potential adverse effects associated with their use.
Immunosuppressant drugs used for treatment of MG may be classified, based on mechanisms of action, into the following groups:
Inhibition of the cell cycle:
Drugs that inhibit the cell cycle include leflunomide, azathioprine, cyclophosphamide, and mycophenolate mofetil.
Immunosuppression of T cells:
Glucocorticoids, cyclosporine A, and tacrolimus are immunosuppressors of T cells
Depletion of B cells
Rituximab depletes B cells
Drugs that interfere with the cell cycle block both T and B cell proliferation and exhibit their effects on the resting (G1) and DNA synthesis (S) phases of the cell cycle.
Those that suppress T cells act specifically in the T cells on specific sites and receptors.
Note: There are no controlled clinical studies in dogs that show benefit of any one drug over another in the treatment of MG.
If used, immunosuppressant drugs may be of value early in the course of MG in dogs when clinical signs may be most severe and difficult to control.
Thymomas can be associated with a myasthenic paraneoplastic syndrome in dogs.
In dogs that have thymomas, 30–50% have MG.
In a retrospective study of 1,154 cases of confirmed acquired MG dogs, 3.4% had an anterior mediastinal mass.
A more severe form of MG may be seen in dogs with a thymoma.
Human IV Immunoglobulin
There is documented use of hIVIG in 2 dogs with MG using a dosage of 0.5 g/kg IV over 6 hours.
To date, sufficient data do not exist in veterinary medicine to comment on any benefits of hIVIG in canine MG.
hIVIG must be used with caution in repeated doses due to anaphylaxis.
An extracorporeal procedure that separates blood into its components for removal or specific alteration prior to return to the patient.
Therapeutic plasma exchange (TPE) is an apheresis treatment in which plasma (containing pathologic antibodies) is removed and exchanged with donor plasma.
TPE is not routinely used in veterinary medicine due to the high cost, specialized equipment, and specialty training involved.
TPE provides only a temporary improvement in clinical signs and must be repeated.
It may be of use early in the course of MG, or in the most severe cases of MG, such as fulminant MG.
While treatment with TPE is expensive, its use may result in more rapid recovery, and decrease secondary complications, such as recurrent aspiration and/or respiratory compromise, thereby significantly decreasing hospital stays and associated costs.