Muscle Biopsy Could Help Secure MG Diagnosis for Unclear Cases
Patients without antibodies show buildup of certain immune proteins, lack of AChRs
Analyzing the motor end-plate (MEP) — the specialized muscle region that communicates with a nerve cell — using a muscle biopsy could help diagnose patients with myasthenia gravis (MG) who test negative for common disease-associated antibodies, a small study suggests.
Among patients with MG-like symptoms who were negative on standard tests, certain cellular features were observed in those ultimately found to have MG, but not those who ended up with a different diagnosis.
Specifically, MG patients showed a buildup of certain immune proteins and a lack of acetylcholine receptors (AChRs) at the MEP. About half of those ultimately diagnosed with MG had antibodies against AChRs that had clustered together at cell surfaces, which aren’t identified in standard tests.
“These results suggest the usefulness of MEP analysis of muscle biopsies in diagnosing immune-mediated MG … but, due to the invasiveness of the muscle biopsy procedure, clustered AChR [antibodies] should, if possible, be tested first,” the researchers wrote.
The study, “Motor end-plate analysis to diagnose immune-mediated myasthenia gravis in seronegative patients,” was published in the Journal of the Neurological Sciences.
MG is an autoimmune condition wherein self-reactive antibodies target the neuromuscular junction, where nerve cells and muscles communicate, leading to muscle weakness and wasting.
Because symptoms aren’t specific and can fluctuate, MG is typically diagnosed by the presence of disease-causing antibodies in the blood. These antibodies usually target AChRs, but less commonly attack a protein called muscle-specific kinase.
A repetitive nerve stimulation test can support an MG diagnosis. In it, doctors assess a nerve’s ability to transmit signals to a muscle. A hallmark of MG is when this capacity decreases with fatigue, known as the waning phenomenon.
Some patients may not exhibit these diagnostic markers, however, particularly those with ocular MG — a form of the condition wherein symptoms are restricted to the muscles controlling the eyes and eyelids. This makes a diagnosis more difficult.
Research suggests that a closer analysis of the MEP — the muscle “side” of the neuromuscular junction where AChRs reside — may reveal additional diagnostic markers.
Previous studies found that MEPs from patients positive for AChR antibodies had a low density of AChRs, as well as a buildup of C3, a protein of the complement system. The complement system is an immune signaling cascade that’s been implicated in inflammation and autoimmunity.
Making a diagnosis when typical MG antibodies are absent
The researchers sought to evaluate whether any of these changes could be observed in patients who tested negative for typical MG antibodies to help achieve a more definitive diagnosis.
They looked for a certain type of AChR antibody that only binds to AChRs that have clustered together on cell surfaces, as seen at the neuromuscular junction. These antibodies aren’t captured by routine blood tests.
The study involved 20 people with myasthenia-like symptoms, defined as at least eye muscle weakness with muscle fatigue.
All had a muscle biopsy at the researchers’ hospital in Japan between 1994 and 2015 after testing negative for MG antibodies and the waning phenomenon. Of these, 13 were women, with a mean age of 49 at symptom onset. Most patients (18) only had ocular symptoms, whereas two also had mild limb weakness.
Results showed five patients had C3 deposits at the MEP, four of whom also had reduced AChR densities — a finding similar to that seen in MG patients who are positive for AChR antibodies. The remaining 15 complement-negative patients didn’t show reductions in AChRs.
Clustered AChR antibodies were found in two of four people with complement deposition for whom data were available, and not in any without complement deposition.
During up to 10 years of follow-up, the five complement-positive patients developed ongoing MG symptoms and were determined to have immune-mediated MG. All responded to treatment.
All but one complement-negative patient were diagnosed with diseases other than MG. That patient later tested positive for AChR antibodies, when another biopsy revealed reduced AChR densities, complement deposits, and clustered AChR antibodies.
These findings suggest the “usefulness of MEP analysis and [cell-based analysis] for clustered AChR [antibodies] in diagnosing immune-mediated MG in patients with myasthenia-like symptoms,” the researchers wrote, noting “careful evaluation over time may help to provide a diagnosis for some cases.”