Ocular myasthenia gravis (OMG) is an autoimmune disorder associated with neuromuscular junction abnormality at the ocular muscle level. Although 40%–50% of myasthenia gravis (MG) patients initially present with ocular symptoms (1), even experienced clinicians can find the diagnosis of OMG difficult because many diseases mimic OMG (2,3). To address this diagnostic challenge, various testing methods have been developed to confirm the diagnosis of OMG. Ancillary tests for OMG include single-fiber electromyography (SFEMG), a diagnostic treatment that uses a cholinesterase inhibitor (pyridostigmine bromide: Mestinon) and immunosuppressants, and serological anti-acetylcholine receptor antibodies (AChR–Abs) testing. SFEMG of the facial muscles is a sensitive diagnostic tool for OMG; however, this method lacks specificity and a positive result can be seen in conditions other than OMG (4,5). Pyridostigmine bromide is widely used but there is a risk of bradycardia and hypotension (6). Conversely, AChR–Abs testing is a safe and simple ancillary method for confirming the diagnosis of OMG. However, despite this test's high sensitivity (85%–90%) for generalized MG (GMG), it has a low sensitivity (approximately 44%–66%) for OMG (7,8). This study was developed when the researcher's clinical experience brought into question the reportedly low sensitivity of AChR–Abs testing. It is hypothesized here that the sensitivity of AChR–Abs testing for diagnosing OMG has been underestimated, particularly in anti-acetylcholine receptor binding antibodies (AChR binding Abs) testing.
This study aimed to assess the effectiveness of AChR binding Abs testing for diagnosing OMG by evaluating the test's sensitivity, specificity, positive predictive value, and negative predictive value.
METHODS
This study was based on a retrospective and observational chart review of 114 patients suspected of having OMG. The patients underwent serum testing for the AChR binding Abs at the Royal Victorian Eye and Ear Hospital (RVEEH) in Victoria, Australia, between January 2, 2016, and December 30, 2017. All participants in the study initially presented to the RVEEH emergency department with predominantly ocular concerns, including diplopia, ptosis, or both diplopia and ptosis.
As the RVEEH is a specialized eye hospital, patients with signs and symptoms that suggested GMG were transferred to a nearby general hospital. Therefore, patients with systemic symptoms indicating GMG were excluded from this study.
The patients had an initial consultation with the ophthalmologists in the emergency department before being referred to the neuro-ophthalmology outpatient clinic, where they underwent serum testing for the AChR binding Abs. As per the hospital policy, AChR binding radioimmunoassay (RIA) was used, and AChR blocking RIA and acetylcholine receptor modulating antibodies were not used. The AChR binding Abs titer greater than 0.25 nmol/L was considered seropositive for the purpose of the study.
The progression of symptoms in the participants was checked longitudinally over an average of 2.8 months at the neuro-ophthalmology clinic. At the end of this period, participants were informed of the final diagnosis. The participants who tested seronegative for AChR binding Abs but were still regarded as likely to have OMG were further investigated to varying degrees with methods, such as muscle-specific kinase antibodies (MuSK–Abs) testing (n = 54), SFEMG (n = 3), a diagnostic treatment with a cholinesterase inhibitor (pyridostigmine bromide: Mestinon), and immunosuppressant therapy (n = 19).
Patients diagnosed with OMG met one of the following criterions: the patient was seropositive for AChR binding Abs and had a high clinical suspicion of OMG or the patient was seronegative for AChR binding Abs but was regarded as likely to have OMG clinically and responded to the diagnostic treatments (pyridostigmine bromide and immunosuppressant therapy).
Of the 114 participants, 13 AChR binding Abs seropositive patients and 2 AChR binding seronegative patients were diagnosed with OMG. One of the 2 seronegative patients diagnosed with OMG initially presented with both ptosis and diplopia and tested positive for lid fatigability and Cogan lid twitch. The MuSK–Abs testing also produced positive results from this patient. SFEMG was not administered. The patient was diagnosed with OMG after the diagnostic treatments resolved the patient's symptoms.
The other seronegative patient who was diagnosed with OMG initially presented with both ptosis and diplopia and tested positive during the ice pack test and the lid fatigability test. This patient was negative for MuSK–Abs testing and SFEMG, but the diagnostic treatments did resolve the patient's symptoms.
Notably, this study was approved by the hospital ethics committee on clinical research.
RESULTS
Of the 114 patients who initially presented to the RVEEH through the emergency department and underwent serum AChR binding Abs testing for OMG, 15 patients were eventually diagnosed with OMG and 99 patients received an alternative diagnosis.
Of the 15 patients diagnosed, 13 (86.7%) were AChR binding Abs seropositive and had a high clinical suspicion of OMG. The other 2 patients (13.3%) were AChR binding Abs seronegative but diagnosed based on the high clinical suspicion of OMG and the clinical improvement shown after the diagnostic treatments (Tables 1 and 2).
TABLE 1. -
Diagnostic evaluation of AChR–Abs testing on patients with OMG vs without OMG
|
AChR Binding Abs Testing |
| Patients With OMG |
Patients Without OMG |
Total |
| AChR binding Abs positive |
12 |
1 |
13 |
| AChR binding Abs negative |
3 |
98 |
101 |
| Total |
15 |
99 |
114 |
AChR–Abs, anti-acetylcholine receptor antibodies; OMG, ocular myasthenia gravis.
TABLE 2. -
Statistical evaluation of AChR–Abs testing
|
Sensitivity |
Specificity |
Positive Predictive Value |
Negative Predictive Value |
| AChR binding Abs test |
80% (95% CI, 51.91–95.67%) |
98.99% (95% CI, 94.50–99.97%) |
92.31% (95% CI 62.68–98.85%) |
97.03% (95% CI, 92.23–98.90%) |
One AChR binding Abs positive patient did not meet the standard for OMG diagnosis because of the low clinical suspicion of OMG. This patient presented with horizontal binocular diplopia with a left temporal headache and tender left globe. On examination, a mild esotropia in the left eye was observed. As pain is not a manifestation of MG and the clinical presentation indicated vascular factors, OMG was excluded from the possible diagnoses. The patient's diplopia resolved spontaneously after 10 days and the patient was diagnosed with microvascular sixth nerve palsy.
CONCLUSIONS
AChR binding Abs testing was assessed as a possible binary test for the diagnosis of OMG because a reliable test with high sensitivity, specificity, and positive predictive value is necessary to compensate for the poor predictive power of the clinical features when differentiating the pathology. Of the suspected patients with OMG, the percentage that were diagnosed was low at 13.16% (statistics have been rounded to 2 decimal places). However, 80% of those diagnosed with OMG were AChR binding Abs seropositive. Conventionally, AChR–Abs testing is considered to have a low sensitivity for diagnosing OMG, with some studies suggesting approximately 44%–66% and other studies suggesting 14.1% (7–9).
However, a recent, large observational cohort study demonstrated 70.9% sensitivity in AChR binding Abs testing (2). Similarly, this study found that AChR binding Abs testing was highly sensitive (80%; 95% CI, 51.91%–95.67%), indicating that AChR binding Abs testing may be more useful for diagnosing OMG than previously reported. In addition, AChR binding Abs testing showed a high specificity (98.99%; 95% CI, 94.50%–99.97%) and positive predictive value (92.31%; 95% CI, 62.68%–98.85%) when used for diagnosing OMG.
Vincent and Newsom-Davis (10) suggested that recent onset MG patients may not be AChR binding Abs seropositive because the high affinity of AChR binding Abs to the endplate receptors impedes the free AChR binding Abs in the serum. This may explain the higher sensitivity of the AChR binding Abs that is reflected in this study. This study was completed at a tertiary, largely referral-based eye center in Victoria, Australia, and many participants were referred from the community. As such, the participants may have seroconverted during the referral period, allowing a higher proportion of seropositive OMG patients to be detected at the center.
Of 114 patients, one did not meet the criteria for the OMG diagnosis despite AChR binding Abs seropositivity because of the low-index clinical suspicion of OMG. The patient was given the final diagnosis of microvascular sixth cranial nerve palsy. The high level of AChR–Abs in non-MG patients may be explainable by the presence of mitochondrial myopathies. Mitsikostas et al suggested that the acetylcholine receptor antibody and ophthalmoplegia correlate with mitochondrial myopathies because the mitochondrial DNA abnormality may cause the immune destruction associated with the acetylcholine receptor antibody (11). Suzuki et al (12) further explained that the ophthalmoplegia may be prompted by vascular events associated with a proliferation of abnormal mitochondria in vascular smooth muscle cells.
This study had 4 limitations. First, the retrospective study of the patient population was rarified because patients were included based on the serological testing after their initial presentation in the emergency department. Setting presentation to the emergency department as an inclusion criterion may have introduced selection bias that could account for the higher than expected sensitivity of AChR binding Abs when diagnosing OMG. The patients who first presented to the emergency department may have more severe clinical manifestations and, therefore, higher probability of AChR binding Abs seropositivity.
Second, the high sensitivity of AChR binding Abs testing may have been observed because AChR binding Abs testing was a diagnostic criterion for OMG. Therefore, the seropositivity of the AChR binding Abs could not be evaluated independently.
Third, only a small number of patients underwent SFEMG (n = 3). SFEMG is known to have high sensitivity for neuromuscular junction diseases, including seronegative OMG and GMG. If more AChR binding Abs seronegative patients had undergone SFEMG, perhaps more patients would have been diagnosed with OMG, which would lower the sensitivity and positive predictive value of AChR binding Abs.
Fourth, the study had a relatively small number (n = 15) of OMG confirmed patients who attended a longitudinal neuro-ophthalmology follow-up after 2.8 months (on average). Another follow-up and a larger pool of positive OMG patients may have revealed different factors in the diagnosis and affected the estimates of sensitivity, specificity, and predictive value.
In conclusion, the study demonstrated a higher sensitivity of AChR binding Abs testing (80%; 95% CI, 51.91%–95.67%) in diagnosing OMG than previously reported (44%–66%). The AChR binding Abs test had a high specificity (98.99%; 95% CI, 94.50%–99.97%) and positive predictive value (92.31%; 95% CI, 62.68%–98.85%). This suggests that the AChR binding Abs serology test is more useful than previously suggested for diagnosing OMG, especially in the setting of the complexities and uncertainties inherent in the clinical diagnosis of OMG.
STATEMENT OF AUTHORSHIP
Category 1: a. Conception and design: S. Sheth and K. Wells; b. Acquisition of data: S. Sheth, K. Wells, and T. Campbell; c. Analysis and interpretation of data: I. Y. Chung; Category 2: a. Drafting the manuscript: I. Y. Chung; b. Revising it for intellectual content: I. Y. Chung and T. Campbell. Category 3: a. Final approval of the completed manuscript: I. Y. Chung, S. Sheth, K. Wells, and T. Campbell.
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