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Home arrow Environment arrow Inflammatory Disorders of the Nervous System: Pathogenesis, Immunology, and Clinical Management
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Diagnosis

Serological Testing

MG is a condition which fulfills all the major criteria for a disorder mediated by autoantibodies against the acetylcholine receptor (AChR-Ab) or against a receptor- associated protein, muscle-specific tyrosine kinase (MuSK-Ab).

Patients with positive AChR-Ab or MuSK-Ab assays have seropositive myasthenia gravis (SPMG). Demonstration of these antibodies is possible in approximately 90% of patients with generalized MG and provides the laboratory confirmation of the disease [1, 2]. In those patients with purely ocular MG, the sensitivity of AChR-Ab testing is considerably lower, detectable in about half of patients. There are rare cases of ocular myasthenia that are MuSK-Ab positive, but most large case series of ocular myasthenia gravis have not found patients who are MuSK-Ab positive.

Acetylcholine receptor antibodies Immunologic assay to detect the presence of circulating AChR-Ab is the first step in the laboratory confirmation of MG. There are three AChR-Ab assays: binding, blocking, and modulating. Most authors use the term AChR-Ab as synonymous with the binding antibodies, and these are what are referenced in most studies that report the diagnostic sensitivity of these tests in MG for the reasons discussed below. These antibodies are polyclonal and are present in approximately 85% of patients with generalized disease. Essentially all patients (98 to 100%) with myasthenia gravis and thymoma are seropositive for these antibodies [7, 8]. The negative predictive value of thymoma in the absence of acetylcholine antibodies (binding) is high at 99.7% [8].

The assay for the binding antibody is the most sensitive. One study found these antibodies in 93, 88, and 71% of individuals with moderate to severe generalized myasthenia gravis, mild generalized myasthenia, and ocular myasthenia, respectively [9]. Others have found binding AChR-Ab in 80 to 90% of those with generalized disease [2, 10, 11] and in 40 to 55% of those with ocular myasthenia. Binding AChR antibodies are measured by standard radioimmunoassay and are highly specific for MG. There are virtually no false-positive results in healthy or disease- matched populations [12-14]. There are rare false positives in low titers in Lambert-Eaton myasthenic syndrome (5%), motor neuron disease (3-5%), and polymyositis (<1%) [9, 14, 15]. They are also rarely seen in some disorders that are not usually confused with myasthenia: primary biliary cholangitis, systemic lupus erythematosus, thymoma without myasthenia, and in first-degree relatives of patients with myasthenia gravis [16, 17].

Blocking AChR-Ab are present in about half of patients with generalized disease. They are present in fewer than 1% of patients with negative binding antibodies, but they have no significant false positives.

Assays for modulating AChR-Ab increase the sensitivity by <5% when added to the binding studies [11], and false-positive results are more of a problem [17].

Binding antibody studies are sufficient in most circumstances. The blocking and modulating antibody assays add relatively little to the diagnostic sensitivity [14]. However, the demonstration of blocking antibodies may be helpful if a possible false-positive binding antibody result is suspected.

AChR-Ab titers correlated poorly with disease severity between patients. A low- titer or even antibody-negative patient may have much more severe clinical disease than a patient with high titers. However, in an individual patient, the titers tend to fall with successful immunotherapy, and they parallel clinical improvement.

Ideally, serologic testing for AChR-Ab should be performed prior to initiating immunomodulating therapy for myasthenia gravis, as such therapy can sometimes lead to apparent seronegativity [11]. In one cohort of 143 seropositive patients, 9% became seronegative after treatment when retested in clinical remission. In addition, repeat serologic testing 6-12 months after initial testing has been reported to detect positive seroconversion in approximately 15% of patients with myasthenia gravis who were initially seronegative [11, 18].

MuSK antibodies Antibodies to the muscle-specific receptor tyrosine kinase (MuSK) are present in 38-50% of those with generalized myasthenia gravis who are AChR-Ab negative [11, 19-25]. MuSK is a receptor tyrosine kinase that mediates agrin-dependent AChR clustering and neuromuscular junction formation during development. MuSK antibody-positive MG may have a different cause and pathologic mechanism than AChR-Ab-positive disease [19, 26].

MuSK antibodies are generally not present in those with well-established ocular MG, but they have been detected in a few cases [27, 28]. Although nearly half of patients with AChR-Ab-negative myasthenia gravis will have MuSK antibodies, those with AChR-Ab-positive myasthenia do not have antibodies to MuSK in most studies to date [19-24]. However, one group found that 11% of patients with AChR- Ab-positive myasthenia did have antibodies to MuSK as well [29]. MuSK antibodies appear to be much less common in some AChR-Ab-negative myasthenia populations, being found in only 1 of 27 Taiwanese patients [30] and 0 of 17 Scandinavian patients [31].

One consistent finding is that patients with AChR-Ab-negative MG and MuSK antibodies have a much lower frequency of thymic pathology than patients with AChR-Ab-positive MG [32-35]. Thymic hyperplasia is frequent in AChR-Ab- positive myasthenia, but this pathology is much less frequent in the MuSK-Ab- positive group.

In the appropriate clinical setting (i.e., a patient with the typical clinical features of myasthenia gravis (see “Clinical features” below) who is AChR-Ab negative), MuSK antibody testing can clarify the diagnosis and perhaps direct treatment [20]. However, the initial management of clinically apparent MG should be the same for patients with or without AChR antibodies. This would change only if future studies find additional therapeutic differences related to MuSK antibody status.

Seronegative myasthenia The term seronegative MG, also called antibodynegative MG, refers to the 6-12% of patients with myasthenia who have negative standard assays for both AChR antibodies and MuSK antibodies. The term was previously used only for those who were AChR antibody negative, regardless of MuSK antibody status.

Patients with seronegative MG are more likely to have purely ocular disease than those who are seropositive. There is also a trend for those with generalized seronegative MG to have a better outcome after treatment [25].

Seronegative MG is an autoimmune disorder with most of the same features as seropositive myasthenia gravis [18, 25]. The electrophysiologic findings are identical. Patients with seronegative MG respond in a similar fashion to pyridostigmine, plasma exchange, glucocorticoids, and immunosuppressive therapies, as well as thymectomy.

Newer diagnostic antibody assays may further reduce the percentage of patients that are considered seronegative. As an example, approximately 50% of patients with seronegative MG have low-affinity AChR antibodies (also called clustered AChR antibodies) when tested by a specialized cell-based immunofluorescence assay. Other studies have demonstrated antibodies against LRP4, an agrin receptor required for agrin-induced activation of MuSK and AChR clustering and neuromuscular junction formation. These antibodies have been found in 2-50% of patients with seronegative MG. These assays are not commercially available and are not yet in widespread clinical use.

 
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