Ronald Johnson, DVM, ACVIM
GVS Neurology/Neurosurgery Services

Acquired Myasthenia Gravis is, an immune-mediated neuromuscular disease. It is a disease in which antibodies are directed against the nicotinic acetylcholine receptors (on skeletal muscle) at the neuromuscular junction. The origin of the immune response is unknown and may be variable. Some possibilities include the thymus, lymph nodes, infectious agents and genetic factors. There are three primary forms of this disease, and they include Focal, Generalized and Acute fulminating forms. The focal form includes megaesophagus alone, megaesophagus with facial, pharyngeal and/or laryngeal muscle weakness, or facial, pharyngeal and/or laryngeal muscle weakness alone. The generalized form is characterized by appendicular muscle weakness with or without focal signs. Acute fulminating myasthenia gravis is a rapid onset of appendicular muscle weakness with respiratory distress.

Clinical Signs:
The clinical signs are dependent upon the form of the disease (as described above). The signs may include limb weakness (possibly exercise-induced), regurgitation, ptyalism, voice change, labored respirations, dysphagia, or dysfunction of palpebral reflexes (may be weak, fatigable or absent). The tendon reflexes are usually normal, however, they may be fatigable in some cases. In the acute fulminating form, the patient may present with rapidly progressing appendicular weakness (possibly non-ambulatory tetraparesis) and respiratory failure. Due to the variability in clinical presentations, Myasthenia Gravis (MG) should be included in the differential list of most lower motor neuron diseases.

Diagnostic Tests:
The minimum database typically includes a complete blood count (CBC), biochemical profile, urinalysis, creatine phosphokinase (CPK), and thoracic radiographs. The CPK can be useful, as other diseases (ie; Polymyositis) , may mimic the signs of MG. Thoracic radiographs help evaluate for aspiration pneumonia, a cranial mediastinal mass, and megaesophagus. Thyroid testing is also advised, as hypothyroidism has been associated with Myasthenia. Attention to cardiac status (specifically with thoracic ausculation and EKG) is also suggested, as third degree heart block has been identified in some dogs. The 'gold standard' test in both dogs and cats is the demonstration of circulating AchR antibodies by immunoprecipitation radioimmunoassay. This assay is both sensitive and -specific, and may detect up to 98% of generalized myasthenics. An AchR Ab titer of greater than 0.6 nmol/L and 0.3 nmol/L in dogs and cats respectively, is considered diagnostic. The edrophonium chloride (Tensilon) challenge test may be helpful as a clinical test. Tensilon is an ultrashort acting anticholinesterase which will provide, more Ach for interaction with the AchR. A positive response (ie. improvement in muscle strength) is suggestive of Myasthenia but is not specific, as other various neuromuscular diseases may show a slight improvement with Tensilon. The doses typically used are 0.1-0.2 mg/kg IV for dogs and 0.25-0.5 mg total dose IV in cats. Cats are relatively sensitive to the effects of Tensilon, therefore pretreatment with Atropine (0.02-0.04 mg/kg) is recommended. This will help reduce the muscarinic effects of the Tensilon, without an impact on the desired nicotinic effects. Electrodiagnostic testing can also be useful in -the diagnosis. Specifically, repetitive nerve stimulation and single fiber electromyography are the tests of choice. A decrement in amplitude of the compound muscle action potential (M Wave) upon repetitive nerve stimulation may help provide a presumptive diagnosis. However, this test lacks sensitivity and specificity and also requires general anesthesia.

Treatment:
There is considerable controversy over the appropriate treatment regimens for this disease, owing to the lack of well-controlled clinical trials in veterinary medicine. The primary treatment options include cholinesterase inhibitors, immunomodulatory therapy, and thymectomy. The cholinesterase inhibitors have been the cornerstone of therapy. This class of drugs prolongs the action of Ach at the neuromuscular junction, thereby enhancing neuromuscular transmission. The primary drug used for maintenance therapy is Pyridostigmine Bromide (Mestinon) at 1-3 mg/kg po bid-tid. In severely debilitated patients, where oral therapy is problematic, Neostigmine (Pro,stigmin) can be used at 0.04 mg/kg 1M tid-qid. Another option for critical patients is a constant rate infusion of Pyridostigmine Bromide (0.01-0.03 mg/kg/h). Immunomodulatqry therapy includes prednisone, azathioprine, cyclosporine, plasmapheresis, or IV immunoglobulin. If an appropriate response is not gained with the cholinesterate inhibitors, then prednisone may be used. Typically, immunosuppressive doses are not recommended, as there may be an exacerbation of muscle weakness. In humans, about 48% will have a worsening of muscle weakness in the initial 1-2 weeks of prednisone therapy. Similar observations have been made in dogs, occasionally resulting in respiratory arrest (Shelton-unpublished reports). A low dose, alternate day treatment plan (0.5 mg/kg every other day) is recommended. In some cases of severe, g'eneralized disease (acute fulminating form), without evidence of aspiration pneumonia, a high dose methylprednisolone protocol may be useful. Azathioprine is another option for immunomodulation. It is a cytotoxic antimetabolite drug. The mode of action includes interference with DNA synthesis, a reduction in lymphocyte and immunoglobulin production, and an inhibition of T-cell proliferation. Azathioprine is frequently used as an adjunct in human medicine. In human studies, there is an improvement in about 70-90% of cases when used as a sole agent, and in 50-70% of cases which are steroid resistant. One drawback is a delayed respon~e of about 4-8 months. Cyclosporine can also be used in some cases. It causes an inhibition of T -lymphocyte dependent immune responses. Cyclosporine can be used alone or with prednisone. In humans, improvement is typically noted in 1-2 months with a maximal response in 3-4 months. Reports on cyclosporine in dogs are limited. Plasmapheresis is another treatment consideration. The concept behind plasmapheresis is the removal of plasma and adverse components (ie AchR Ab, complement). Indications for its use include a sudden worsening of signs, before thymectomy, or in chronic non-responsive cases. Due to the expense and technical difficulty of this procedure, this is not commonly utilized in veterinary medicine. IV Immunoglobulin can be quite useful as an adjunctive therapy in humans. It's mechanism of action includes binding circulating antibodies, blocking Fe receptors, interfering with complement, and increasing suppressor T-cell activity. Currently, there are no reports in dogs. One other important aspect. of treatment is an appropriate feeding protocol for megaesophagus cases. Elevation of food and water or placement of a PEG tube (depending on the particular case) is recommended.

Thymectomy can also be an important part of the treatment, especially in cats. This procedure may help to remove a potential source of antibodies or its paraneoplastic effects. A cranial mediastinal mass (thymoma) has been reported commonly in feline myasthenics. However, the incidence of cranial mediastinal masses in dogs is less than 5%.

An early diagnosis, appropriate treatment protocol, and patient-committed clients are important in the successful treatment of this disease. In the absence of aspiration pneumonia, acute fulminating disease or pharyngeal weakness, the prognosis is typically quite good. Spontaneous remission can also occur in some cases, and it is recommended to repeat AchR Ab levels every 6-8 weeks to evaluate for remission. Clinical response to treatment may also be monitored (in an individual patient) through recheck of AchR Ab levels.

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Robert Schick, DVM, ACVD
Dermatology Services

As winter approaches, many allergic pets actually have an increase in their pruitus. House dust mite and indoor aeroallergens are common causes of atopic signs in dogs and cats. these allergens actually increase in the winter as the house is closed and the furnaces are blowing through the ductwork. In a recent university study. on nonseasonal pruritic dogs, 93% were proven to be atopic. Food allergy was again shown to be a rare cause of nonseasonal pruritus. In fact when these remaining 7% were further evaluated, 50% of them were shown to be food allergic with concurrent atopy. The clinical signs of these pets include pruritus of the face, paws, and axillae as well as recurrent otitis externa. Secondary bacterial and Malassezia infections of the skin and ears are common. Diagnosis is made on a careful history, physical examination, and intradermal allergy testing. Allergy vaccine therapy is effective in 75% of canine and 80% of feline atopic patients.