3.1 Patient characteristics
One hundred twelve JMG patients (42 males, 70 females, male-to-female ratio 0.6) were identified. The average age of onset was 8.5 years (range 0-20 years). The peak age of onset was biphasic: one peak was before the age of 5 and the other peak occurred during adolescence.
The most common symptoms were ptosis in 108 (96.4%) patients followed by diurnal symptom change in 61 (54.5%), muscle weakness in 24 (21.4%), double vision in 23 (20.5%), bulbar palsy in 18 (16.1%), respiratory symptoms in 10 (8.9%), head deviation in 3 (2.7%), ophthalmoplegia in 2 (1.8%), and facial palsy in 1 (0.9%) patient.
Clinical classification of the disease severity at onset was evaluated as class I in 88 (78.6%), class II in 13 (11.64%), class III in 3 (2.7%), class IV in 4 (3.6%) and class V in 4 (3.6%) patients. The age of onset for ocular type MG (n= 88) was younger than that for systemic type (n= 24) (7.29 ± 6.17 vs. 13.07 ± 4.71, P=0.001). Four patients had a family history of MG. Three patients had a family history of thyroid diseases.
Serologic tests were performed in 107 (95.5%) patients. Peak anti-acetylcholine receptor antibodies were ≥ 0.5 nmol/L in 60 (56%), 0.2-0.5 nmol/L in 11 (10%), and < 0.2 nmol/L in 35 patients (33%). Nine seronegative patients with onset of symptoms younger than the age of two were believed to have congenital MG. One seronegative patient had autoantibodies against MuSK and presented with systemic type and bulbar palsy.
Repetitive stimulation tests were performed in 47 patients, and 32 patients exhibited a typical decremental change. No correlation was observed between the anti-acetylcholine receptor value and repetitive stimulation test results.
3.2 Outcome at two years and last outpatient clinic follow-up
After excluding patients without serum antibody data and one patient positive for anti-MuSK antibodies, a total of 54 patients followed up for over two years (range 24 to 258 months, mean 112 months) (Fig. 1). We compared the demographic data of JMG patients with different levels of anti-acetylcholine receptor antibodies, and no difference was observed (Table 1). In total, 42 patients (80%) were ocular type and 12 patients (20%) were generalized type. Nine (9/54, 16.7%) achieved complete remission without medication use at two years after diagnosis. Thirteen (24.1%) patients achieved complete remission during later follow-up periods. Thirty-two (59.3%) patients had improved symptoms but were maintained on oral medication, 5 (9.3%) patients were maintained on a high dosage of immunosuppressant, and 4 (7.3%) patients had worse symptoms. Fifty-two of 106 (49%) patients had incomplete follow-up over two years. No gender, age, disease severity, and intervention differences were observed between patients followed up for two years and those without.
3.3 Outcome versus anti-acetylcholine receptor antibody levels
We compared two-year outcomes among 54 JMG patients using receiver operating characteristic curve (ROC) curves with anti-acetylcholine receptor antibodies at different levels. ROC curves of primary and secondary outcomes are presented in Fig. 2 and 3. Analyses revealed that a serum cut-off level of 0.2 nmol/L serves as an optimal predictive value at two years after diagnosis (sensitivity: 80%, specificity: 66%, PPV: 92%, NPV: 40%) (Table 2) and at last outpatient clinic (sensitivity: 83%, specificity: 57%, PPV: 85%, NPV: 53%) (Table 3). JMG patients with negative anti-acetylcholine receptor antibodies (< 0.2 nmol/L) were significantly more likely to achieve complete remission compared with those with antibodies ≥ 0.2 nmol/L at two years (6/15 [40%] vs. 3/39 [7.7%], 95% confidence interval [CI] 1.670 to 38.323) (Table 2, Fig. 4). In addition, JMG patients with anti-acetylcholine receptor antibodies less than 0.2 nmol/L exhibited a higher rate of complete remission compared with those with antibody > 0.2 nmol/L at last out-patient visit (8/15 [53.3%] vs. 5/39 [12.8%], 95% CI 2.367 to 20.704) (Table 3, Fig. 4). After adjustment for age, gender, classification and thymectomy operation, the clinical outcome exhibited a significant difference if we used a serum level of 0.2 nmol/L as a cut-off (Table 4).
3.4 Clinical fluctuations
Four boys (aged 0.5 years, 1.5 years, 2.5 years and 7.3 years) with initial anti-acetylcholine levels less than 0.2 nmol/L became positive later (0.25 nmol/L, 12.5 nmol/L, 2.19 nmol/L and 11.1 nmol/L). The occurrence of seroconversion was detected 11, 19, 107, and 85 months after clinical onset, respectively. One of the 4 patients achieved complete remission at 2 years but developed symptom relapse, and the other 3 were maintained on oral medication throughout the study course.
3.5 Comorbidity
Comorbid diseases included Graves’ disease in 11 (9.8%) patients, Hashimoto disease in 2 (1.8%), systemic lupus erythematous in 1 (0.9%), and rheumatic arthritis in 1 (0.9%) patient.
We analyzed the characteristics of 13 patients with comorbid autoimmune thyroid disease. Nine (69%) patients were females, and the mean onset age was older than JMG patients without comorbid autoimmune thyroid disease (11.8 ± 5.8 years old vs. 8.0 ± 6.3 years old, 95% CI 0.018 to 7.33). Ten (77%) patients had ocular type MG. Two had a family history of hyperthyroidism, and two had a family history of MG. In 10 (77%) patients, comorbid autoimmune thyroid diseases were diagnosed at or after the JMG diagnosis was made. Patients with anti-acetylcholine antibody serum levels < 0.2 nmol/L were less likely to have autoimmune thyroid disease (1/35 [2.9%] vs. 12/71 [16.9%], 95% CI 0.018 to 1.161). No correlation found using a cut-off level of 0.5 nmol/L.
3.6 Pharmacologic and surgical treatment
Forty-six of 112 (41.1%) patients received both cholinesterase inhibitors and steroids, 35 (31.3%) patients received cholinesterase inhibitors only, 5 (4.5%) patients received steroids only, and 8 (7.1%) patients did not receive any medication.
Eighteen of 112 (11%) patients received thymectomy, and 16 (16/18, 90%) were female. Patients manifesting with initial systemic MG were more likely to require thymectomy than those with initial ocular MG (12/24 [50%] vs. 6/88 [6.8%], 95% CI 4.31 to 43.49). No difference in the primary and secondary outcomes was observed between patients who received both or either cholinesterase inhibitors and steroids or who underwent thymectomy.