Clinical Characteristics and Treatment Management of Seronegative Myasthenia Gravis: A Systematic Review of the Literature

Seronegative myasthenia gravis (SNMG) is characterized by the absence of detectable autoantibodies against known MG targets, despite clinical and electrophysiological evidence of a postsynaptic neuromuscular junction disorder. The aim of this systematic review was to better define clinical features, diagnostic clues and treatment outcome of SNMG patients. We conducted a systematic review following PRISMA guidelines, analyzing studies published from 2001 to August 2024 through MEDLINE, Embase, and Cochrane databases. A total of 31 studies (712 patients) with SNMG diagnoses based on clinical features, electrophysiology, pharmacological testing, or treatment response were included. The cohort was predominantly female (473/712, 67%) with a mean age at onset of 42 years. Isolated ocular symptoms were present in 281/500 (56%) patients, with progression to generalized MG in 113/262 (43%) within 2 years from onset. Regarding diagnostic strategies, some studies combined clinical findings consistent with MG and both electrophysiology and pharmacological testing, while others applied a less stringent diagnostic approach, leading to variability in case definitions. Moreover, only 213/448 (48%) patients underwent cell-based assays to confirm the seronegative results after antibody screening, raising concerns of misclassification. Immunotherapy was administered to 271/333 (81%) patients, most commonly corticosteroids combined with immunosuppressants (173/271, 74%). Despite treatment, only 153/394 (39%) achieved the minimal manifestations status, and 52/220 (24%) were classified as refractory. In conclusion, SNMG is a heterogeneous condition with significant diagnostic and therapeutic challenges. Standardized diagnostic criteria, including the use of highly sensitive antibody assays, are needed to improve immunological stratification and optimize therapeutic management.