Background <p>Myasthenia gravis (MG) is an autoimmune condition characterized by muscle weakness caused by antibodies targeting the postsynaptic neuromuscular junction. The majority of patients test positive for antibodies against the acetylcholine receptor (AChR) or muscle-specific kinase (MuSK). A minority of patients test negative for these antibodies and are referred to as double-seronegative MG (dSNMG), a condition that remains inadequately studied and incompletely characterized.</p> Methods <p>We conducted a systematic review in accordance with PRISMA guidelines (PROSPERO registration: CRD42022368329). We performed a thorough search of PubMed and Google Scholar through October 2022 for English-written studies reporting confirmed dSNMG cases. Inclusion criteria required confirmed MG diagnosis with negative testing for AChR and MuSK antibodies. Abstract and full-text screening was performed independently by two reviewers. This was followed by data extraction, descriptive analyses, and assessment of the quality of the selected reports.</p> Results <p>We included 40 articles (35 case reports and five case series) accounting for 45 patients with dSNMG. The mean age at diagnosis was 52.4 ± 20.5 years, and the mean age at symptom onset was 50.7 ± 21.4 years, with 51% being female. The most common initial manifestations were ocular (ptosis and/or diplopia) accounting for 82% of cases. Of these, 29% had purely ocular MG, whereas 71% showed generalized MG at onset. Nine patients (20%) were positive for low-density lipoprotein receptor-related protein 4 (LRP4) antibodies. Malignancy was observed in 15 patients (33%), including five cases with thymoma and 10 cases with extrathymic malignancies. Among the latter, eight had been previously treated with immune checkpoint inhibitors (ICIs). Thymoma patients tended to be younger (mean 55.6 years) and more frequently female (60%) compared to patients with extrathymic cancers (mean 69.2 years, 30% female). Those with extrathymic malignancies had higher rates of ocular presentation and myasthenic crisis (40% vs. 20%) for each compared with the thymoma group. Standard MG treatments were administered to all patients, most frequently acetylcholinesterase inhibitors (84%) and corticosteroids (76%), often combined with other immunosuppressants and/or IVIG. Overall outcomes were favorable, especially among those treated with plasmapheresis, rituximab, or tacrolimus. No severe treatment-related adverse events were reported.</p> Conclusions <p>Patients with dSNMG often present with ocular symptoms and typically respond well to conventional MG therapies. Some patients classified as seronegative may harbor LRP4 or other antibodies. Malignancy, particularly following ICI therapy, was a prevalent comorbidity. Thymoma-related dSNMG was more frequently seen in younger women and involved generalized weakness, while extrathymic malignancy cases tended to occur in older patients with a higher occurrence of ocular MG and myasthenic crisis. These differences highlight the need for thorough malignancy screening in dSNMG patients as well as neuromuscular monitoring in cancer patients on ICIs. Further investigation is warranted to validate these observations and clarify specific clinical implications related to the management of dSNMG.</p>