Ocular Symptoms, Malignancy Common in Double Seronegative MG

Patients with double seronegative myasthenia gravis (dSNMG) had similar clinical characteristics across the board, according to a review published in BMC Neurology.1 Ocular symptoms and malignancy were the most common characteristics reported, highlighting the need for screening in patients with dSNMG.

Patients with dSNMG, a subgroup of SNMG, are those without acetylcholine receptor or muscle-specific kinase antibodies in their bodies. This subgroup makes up about 10% of all cases of MG. Although seropositive MG often presents with similar clinical characteristics, like muscle weakness distribution, SNMG is usually associated with bulbar and ocular weakness rather than limb fatigue.2 However, the data are limited. The review aimed to evaluate the literature on dSNMG patients to describe clinical characteristics, outcomes, and treatments for those with the condition.1

Ocular symptoms were common in patients with double seronegative MG | Image credit: Serg Zastavkin - stock.adobe.com

PubMed and Google Scholar were used to search for literature written in English, with the search lasting through October 31, 2022. Case reports and series with extractable data were eligible to be included, whereas any articles not written in English, cases of unclear or disproven MG diagnosis, cases without proof of seronegative MG, cases with other neuromuscular disorders, and reports without any confirmation of MG were excluded.

There were 40 articles included in this study, which included 35 individual case reports and 5 small case series that included 45 patients with dSNMG. Mean (SD) age at diagnosis was 52.4 (20.5) years and mean age of symptom onset was 50.7 (21.4) years. There were more women included in the study overall (51.1%).

Generalized MG occurred in 71.1% of the patients, whereas 28.8% presented with isolated ocular MG. Ocular symptoms were the most common symptoms (82.2%), with limb weakness (53.3%) and dysphagia (26.6%) also reported. A total of 17.7% of the cases had experienced a myasthenic crisis.. Patients with malignancy had a mean age of 68.5 (13.2) years compared with 48.6 (21.1) years in those without. The malignancy group were less likely to have favorable outcomes compared with those without (37.5% vs 78.6%).

Ocular MG was more common in those who were lipoprotein receptor-related protein 4 (LRP4)-positive but did not reach statistical significance. The groups also did not have significantly different treatment outcomes across the 3 therapies included in the evaluation. Rituximab produced favorable outcomes in 66.7% of the patients, intravenous immunoglobulin had favorable outcomes in 90.9%, and tacrolimus had favorable outcomes in 83.3%.

Patients with dSNMG related to immune checkpoint inhibitors had a higher mean age (70.9 [9.1] years) compared with those whose dSNMG was related to thymoma (63.3 [14.4] years) or was idiopathic (47.0 [19.7] years).

There were a few limitations to this review. There were a limited number of patients who were tested for LRP4 and require further testing to confirm the results. Rituximab was only taken by 3 patients, which limits the interpretation of its efficacy. The reporting quality in the case reports varied and could have introduced information bias. Unusual presentations or favorable outcomes are more likely to be reported, introducing publication bias and limiting the generalizability.

The authors concluded that “younger individuals frequently exhibited ocular symptoms and LRP4 positivity, often responding well to standard immunotherapy. In contrast, older patients, particularly those with malignancies or immune checkpoint inhibitor exposure, more commonly presented with generalized MG and had less favorable outcomes.”

References

1. Abuhammad A, Ayyad M, Albandak M, et al. Double-seronegative myasthenia gravis: clinical characteristics, treatment, and outcomes – a systematic review of case reports and case series. BMC Neurol. Published online January 20, 2026. doi:10.1186/s12883-026-04644-8
2. Sundaram S. Seronegative myasthenia gravis. EyeWiki. November 23, 2025. Accessed January 21, 2026. https://eyewiki.org/Seronegative_Myasthenia_Gravis