Managing myasthenia gravis (Proceedings)


Managing myasthenia gravis (Proceedings)

Apr 01, 2008

Acquired myasthenia gravis

Acquired myasthenia gravis is an immune-mediated disorder in which autoantibodies develop against the neuromuscular junction acetylcholine receptors (AChR). Binding of these antibodies results in failure of neuromuscular transmission. Mechanisms for antibody impairment of neuromuscular transmission is not entirely known, but may involve one or a combination of the following: direct interference and binding of ACh to the receptors, accelerated endocytosis of the crossed-linked receptors, complement-mediated destruction of the post-synaptic muscle cell membrane, and decreased synthesis and incorporation of new receptors into the membrane. The disease is most common in dogs and people. The mean age of dogs affected is 6.65 years, but there appears to be a bimodal age distribution of affected dogs of 3 and 10 years. There is a predilection to affect spayed female dogs. There appears to be a high relative risk in the golden and Labrador retriever, Akita, Miniature Dachshund, Scottish terrier, German shorthaired pointer, Shetland sheepdog, and collie. Dogs less than 1 year of age and intact males appear to have a decreased relative risk for acquiring the disease.

Table 1
The classical clinical signs have been reported to be exercise-induced weakness followed by resolution at rest. However, these signs appear to be the exception rather than the rule. There are 3 described forms in the dog (Table 1).

Myasthenia typically occurs in absence of some underlying disease, but it has been reported in conjunction with thymoma, osteosarcoma, and cholangiocellular carcinoma. MG is the most commonly reported paraneoplastic syndrome associated with thymoma, and MG patients with thymoma may have a higher likelihood to have the acute fulminating form of the disease. The relationship to thymoma is not known, but it is postulated that neoplastic thymic cells express antigenic epitopes similar to NMJ AChR and cytoskeletal proteins of skeletal muscles. The antineoplastic immune response to the epitopes results in high levels of circulating autoantibodies.

It is possible that focal MG may be an earlier manifestation of the generalized form. Although this is true in people, it has not been proven in dogs.

The risk factors for developing the acute fulminating form are not clear. In people with myasthenic crisis, infections (urinary or respiratory) or concurrent illness are found to be risk factors. Dogs typically have concurrent aspiration pneumonia, but it is not known if this is cause or effect. Regurgitation in this form is consistent and severe, and decreased cough reflex may result in "silent" aspiration.

Diagnosis is based on signalment, history, clinical, and laboratory testing. Administration of acetylcholinesterase medication, edrophonium chloride (Tensilon®) can result in rapid improvement in muscle strength and is suggestive for MG. However, false positive tests can occur and true positive tests may be seen in only 50-75% of MG cases. Partial responses are common and there is often a lack of response in cases with the acute fulminating form. Therefore, a negative Tensilon test does not rule out MG. The Tensilon test can still help in determining the potential value of using long acting acetylcholinesterase medications for therapy. Repetitive nerve stimulation reveals a classical response of detrimental amplitude of muscle action potential. However, nerve conduction studies require general anesthesia and this is contraindicated in animals with aspiration pneumonia or acute fulminating disease. The most definitive method of diagnosis is measurement of anti-AChR autoantibodies. The range of titers in affected dogs is reported as 0.74-34.1 nmol/L. Anti-AChR antibody titers are considered positive at levels > 0.6 nmol/L. Animals with the focal form have been reported with titers of 1.05-2.0 nmol/l. The range reported for generalized MG is 1.82-6.4 nmol/L. There is no statistical difference between the titer values for the focal and generalized form. The acute fulminating form of the disease is associated with statistically higher titer values reported as 12.0-34.1 nmol/L.