Standard treatments help many people with rare double-seronegative MG

Standard treatments helped many people with myasthenia gravis (MG) who lack the most common disease-causing antibodies, according to a new review study.

The findings shed new light on how so-called double-seronegative MG (dSNMG) compares with more common forms of the disease and highlight the need for careful monitoring, particularly in cancer patients receiving newer immune-based therapies that may trigger MG.

The study, “Double-seronegative myasthenia gravis: clinical characteristics, treatment, and outcomes – a systematic review of case reports and case series,” was published in BMC Neurology. 

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What makes double-seronegative MG different

MG is an autoimmune disease in which self-reactive antibodies disrupt communication between nerves and muscles, leading to symptoms such as muscle weakness and fatigue. Most MG cases are caused by antibodies that target one of two key proteins: acetylcholine receptor (AChR) or muscle-specific kinase (MuSK).

However, about 10% of MG patients lack antibodies against either AChR or MuSK and are classified as double-seronegative. Some of these patients, up to half, may instead have self-reactive antibodies against another protein called low-density lipoprotein receptor-related protein 4 (LRP4).

Recent research suggests that people with dSNMG may have different clinical features than those with the more common MG-driving antibodies.

“Nonetheless, the available data on dSNMG remains limited and sometimes inconsistent, making the characterization and optimal management of these patients unclear,” the researchers wrote.

Review examines clinical features and outcomes in rare MG subtype

To better understand dSNMG, scientists in Palestine reviewed previously published studies and identified 40 reports describing clinical outcomes in 45 people with this rare form of MG.

The mean age when symptoms began was 50.7 years, and just more than half of patients (51.1%) were women. There was a roughly even split between men and women across ages, which differs somewhat from AChR-related MG, which is more often seen in younger women and older men, the researchers noted.

The most common early symptoms involved the eyes, such as drooping eyelid and/or double vision, affecting 82.2% of patients. Limb weakness was also common, reported in 53.3%. At diagnosis, about 29% had symptoms limited to the eyes (ocular MG), while 71% experienced more widespread muscle weakness affecting other parts of the body (generalized MG).

Myasthenic crisis, a life-threatening complication in which breathing muscles become too weak, occurred in 17.7% of cases. This is “similar to the rate in AChR-positive MG (15-20%) and … considerably lower than the crisis rate often reported in MuSK-positive MG which is around 40%,” the team wrote.

“This symptom profile is similar to that seen in AChR-positive MG but less severe than MuSK-positive MG, where [difficulty speaking, swallowing, and/or breathing] are typically more prominent,” the researchers wrote. “dSNMG appears to occupy an intermediate space between AChR-positive and MuSK-positive MG less aggressive than the latter but still requiring timely and tailored intervention.”

LRP4 antibodies and cancer linked to worse clinical outcomes

Nine patients (20%) tested positive for antibodies against LRP4, and ocular MG appeared to be more common in this group. However, only 12 people (26.7%) were tested for LRP4 antibodies, making it difficult to determine how these antibodies affect disease progression.

Fifteen patients (33.3%) also had cancer, which is higher than the 10%-15% typically reported in MG overall, the researchers noted. These patients were generally older at MG diagnosis and tended to have worse outcomes.

Of those with cancer, five had a thymoma — a tumor of the thymus gland that is a known risk factor for MG. The other 10 had cancers outside the thymus, referred to as extrathymic malignancy.

“Thymoma-related dSNMG was more frequently seen in younger women and involved generalized weakness, while extrathymic malignancy tended to be older with a higher occurrence of ocular MG and myasthenic crisis,” the team wrote.

Among the 10 patients with cancers outside the thymus, eight (all older adults) developed MG after treatment with immune checkpoint inhibitors (ICIs). These cancer therapies work by stimulating the immune system to attack cancer, but in some cases may also trigger autoimmune side effects such as MG.

Findings highlight treatment response and monitoring needs

These findings “highlight the need for thorough malignancy screening in dSNMG patients as well as neuromuscular monitoring in cancer patients on ICIs,” the researchers wrote.

The most commonly used treatments were Mestinon (pyridostigmine bromide; 84.4%) and corticosteroids (75.5%), which are standard therapies for MG patients testing positive for common antibodies. The “majority of patients achieved complete or substantial clinical improvement,” the team wrote.

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

The researchers said their findings highlight the wide range of ways dSNMG can present and respond to treatment, and emphasize the need for larger, long-term studies to better understand this rare form of MG.