Juvenile myasthenia gravis (JMG) is an autoimmune disorder that leads to dysfunction of acetylcholine receptors (AchR), defined as myasthenia gravis in children younger than 18 years of age (1). It is unclear whether the pathogenesis of JMG is the same as that of adults. While clinical phenotypes are similar to adults (2), JMG and adult MG still have many different characteristics, such as symptoms, clinical severity, antibody titer, and thymus histology (3). Current practice is taken from treatment guidelines for adult MG or individual experience, and it still has no standardized treatment guidelines (4, 5).

We performed a systematic review and meta-analysis to determine the clinical features, treatment, and outcomes of patients with JMG over the last 22 years.

Our search identified 181 articles, of which 11 studies remained after screening (Figure 1), covering 1,109 patients diagnosed between 2006 and 2021. All studies were retrospective studies (Table 1). The number of patients in each study varied between 40 and 327. Participants were followed for a period ranging from 0.2 to 67 years. Heterogeneity calculations for the data reported in pooled study results revealed significant heterogeneity (I²>50%) for 24 of the 40 study parameters (Supplementary file 1).

Our data show that juvenile myasthenia gravis is a rare autoimmune disease with more common ocular symptoms, and a relatively benign course, and a better prognosis than the adult disease (17). Although the data were not comprehensive enough, it can still summarize some clinical features of JMG.

In our review, a greater proportion of JMG patients had pre-pubertal onset. And pre-pubertal patients tended to have more ocular presentations (14, 15). Seronegative cases were also seen more frequently among them (8, 11). Generally, pre-pubertal JMG patients responded better to treatment than post-pubertal patients (8).

To better show the differences in clinical features between JMG and adult MG, we made a comparison with a large cohort of adult MG (17) in Table 4.

This review shows a female preponderance in the juvenile MG group, but not in the adult group. The fact is that estrogen reduces the expression of the autoimmune regulator gene in the thymus of young women, resulting in increased release of autoreactive T cells (18, 19). Seropositivity was almost similar to that observed in adults, both AchR and MUSK, similar to other studies (8, 16, 20). MUSK antibody positive is rare in both JMG and adult MG. Ocular symptoms were more common in the JMG group (9), but bulbar symptoms were less. The incidence of myasthenic crisis was similar in the two groups. However, the mortality rate of adult MG was significantly higher than that of JMG. It suggests that the cause of death in myasthenia gravis is not solely related to crisis. Thymoma can also lead to serious complications leading to death (19, 21). And thymoma is less common in JMG than in adults. This is one of the reasons for the low mortality in JMG. Consequently, the number of children achieving completely stable remission was also significantly higher than that of adults (9).

In our review, generalization of symptoms occurred in 21.9% of JMG patients. And the rate is lower than in the adult group, even much lower than in other study, where it reaches 50–80% (22, 23). This may explain the higher prevalence of isolated ocular MG among the juvenile population.

Juvenile MG has a relatively benign course. However, the treatment regimen guideline for children is not well-established. And current practice has been taken from adult guidelines and expert opinion based on individual experience (5, 24, 25). Typically, cholinesterase inhibitors and steroids are used first-line as symptomatic treatment in JMG (4, 26–28). Other immunosuppressants are the second-line therapy for both generalized MG and uncontrolled ocular MG when they failed to respond to anticholinesterase inhibitor therapy (12). Intravenous immunoglobulin (IVIG) and plasma exchange (PE) have also been used as maintenance therapy (29). Compared with the JMG group, adult patients more often received combinations of steroids and other immunosuppressive drugs, also IVIg, (Figure 5) but even so a lower proportion achieved completely stable remission.

In the JMG group, ocular MG and generalized MG have different prognosis. OMG typically has a higher remission rate than GMG (10, 15), and a lower incidence of myasthenic crisis (12). Most OMG patients could achieve remission with pyridostigmine alone, while GMG patients need combination treatment to achieve remission (12).

Autoimmune comorbidity is a known feature in patients with myasthenia gravis, and also in those with juvenile-onset (13, 30, 31). We also collected some data from other studies of MG patients in combination with other autoimmune diseases, and made statistics in Figure 3 (18, 32–35). 1,863 of 18,337 MG patients (10.2%) were found to have other autoimmune diseases, the incidence similar to the JMG group (13.6%). Thyroid disease was the most common autoimmune comorbidity in MG patients (6), also in the JMG group. There was no clear trend toward clustering in other autoimmune diseases (Figure 3).

Thymectomy is an important treatment option for adults with myasthenia gravis when medical therapy is refractory, but remains controversial in the juvenile myasthenia gravis population. Although several recent studies have shown the benefits of thymectomy in JMG patients (6, 36, 37), they are all retrospective and have limitations. And it was reported that some patients presented a crisis after thymectomy, requiring hospitalization and ventilatory support (38).

In our review, 41.8% of JMG patients performed thymectomy, and 36.5% of them were pure ocular MG. Despite the lack of prospective studies evaluating thymectomy in JMG, it is generally accepted that thymectomy is considered as part of the initial management of JMG patients with abnormal thymus pathology, such as thymoma and thymic hyperplasia. Meanwhile, thymectomy can also perform in AchR-Ab positive generalized JMG patients and JMG patients who do not respond well to medication (3). There is still a lack of large prospective cohort studies of JMG patients to standardize the use of thymectomy for JMG.

Our systematic review and meta-analysis found that JMG has some distinctive clinical features, such as better treatment outcome and lower generalization compared with adult. Nevertheless, it also has limitations. All studies were retrospective, introducing selection bias. JMG is a rare disease, and evidence-based guidelines are lacking. To standardize treatment guidelines, future prospective multicenter studies are needed for the best treatment outcome.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding authors.

QJ and YL designed the study. YL and QK conducted the literature search, collected, analyzed, interpreted the data, and drafted the first manuscript. HL, BL, and JL interpretation of data and revision of manuscript for intellectual content. QJ analysis and interpretation of data and revision of the manuscript for intellectual content. All authors have read and approved the final version of the manuscript.