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Eur J Neurol. 2024 Jan; 31(1): e16022.
Published online 2023 Aug 16. doi:10.1111/ene.16022
PMCID: PMC11235949
PMID: 37531447
Rodrigo Martinez‐Harms,1,2 Carolina Barnett,1,2 Monica Alcantara,1,2 and Vera Bril
1,2
Author information Article notes Copyright and License information PMC Disclaimer
Associated Data
- Supplementary Materials
- Data Availability Statement
Abstract
Background and purpose
Double‐seronegative myasthenia gravis (dSNMG) is defined as myasthenia gravis (MG) without detectable or low affinity antibodies to acetylcholine receptor (AChR) and muscle‐specific kinase (MuSK). There are limited data on detailed clinical features and outcomes after treatment in dSNMG patients. The aim was to describe the clinical characteristics and outcomes in dSNMG patients based on MG scales.
Methods
A retrospective study was performed of patients diagnosed with MG who had negative AChR or MuSK antibodies and they were compared with an AChR‐positive MG cohort. Correlations were made with data from the first and last clinic visits, between demographics, clinical characteristics, treatment and disease severity, based on the Myasthenia Gravis Foundation of America category, Myasthenia Gravis Impairment Index (MGII), Patient Acceptable Symptom State and simple single question (SSQ).
Results
Eighty patients met the inclusion criteria for dSNMG. The baseline MGII and SSQ scores in the dSNMG cohort showed no significant differences from the AChR group (p = 0.94 and p = 0.46). The dSNMG cohort MGII and SSQ scores improved significantly at the last clinical evaluation (p = 0.001 and p = 0.047). The MGII improvement in the AChR cohort was significantly better (p = 0.003).
Conclusions
The initial severity of dSNMG based on clinical scores is similar to antibody‐positive MG patients. There is significant clinical improvement in dSNMG patients after therapy, measured in the last clinical evaluation. This supports an immune pathophysiology of many dSNMG patients.
Keywords: double‐seronegative myasthenia gravis, myasthenia gravis, outcome, treatment
BACKGROUND
Myasthenia gravis (MG) is a chronic autoimmune disease that leads to impairment of neuromuscular transmission in skeletal muscles. Antibodies to the nicotinic acetylcholine receptor (AChR) are the most commonly identified autoantibodies followed by muscle‐specific kinase (MuSK) amongst seropositive MG patients [1, 2]. These autoantibodies are well established as sensitive and specific diagnostic markers, instrumental for patient classification and prognosis in MG [3, 4, 5].
Double‐seronegative MG (dSNMG) represents a heterogeneous group and includes patients with clinical and electrophysiological presentations consistent with MG but without detectable antibodies to AChR and MuSK [6, 7, 8]. Some patients have low affinity antibodies detected by specific assays or less common related antibodies such as lipoprotein related protein 4 associated MG [9, 10]. In dSNMG patients, in particular if there is no response to immunosuppressive therapy, alternative diagnoses should be considered such as other myasthenic syndromes (e.g., congenital MG) and other neuromuscular disorders [11, 12, 13]. Although dSNMG clinical features have been described in terms of muscle weakness distribution and disease severity in cross‐sectional studies, detailed disease characterization and treatment outcomes have not been described in larger series [6, 7, 8, 14].
Myasthenia gravis has significant implications for both patients and the healthcare system. There is a paucity of evidence on the detailed clinical features and prognosis in dSNMG patients. In addition, seronegative patients are commonly excluded from clinical trials, limiting the evidence of treatment efficacy in this group of patients. The present study aimed to describe the clinical characteristics and outcomes in dSNMG based on MG scales and compare them with an AChR‐positive MG population.
METHODS
A retrospective chart review was performed of patients with MG who attended the Prosserman Family Neuromuscular Clinic at the University Health Network, Toronto General Hospital, from January 2015 to November 2022. The study was approved by the University Health Network Research Ethics Board. Informed consent was waived.
Patients
Myasthenia gravis patients who had clinical manifestations of MG and had abnormal repetitive nerve stimulation (RNS) and/or single fibre electromyography in keeping with a post‐synaptic neuromuscular junction disorder, and with negative results for AChR or MuSK antibodies were included. Patients with pure ocular and generalized disease were included. All patients were tested at the first clinical visit for AChR and MuSK antibodies by radioimmunoprecipitation assay and in the case of negative results through cell‐based assay at BC Neuroimmunology in British Columbia [5].
A random patient cohort of patients with AChR‐positive MG seen during the same study period was also selected. Patients with congenital myasthenic syndromes or patients diagnosed after their baseline, in the follow‐up visit, with an alternative diagnosis such as Lambert−Eaton syndrome, congenital myopathy, chronic progressive external ophthalmoplegia or oculopharyngeal muscular dystrophy were excluded.
All patients were routinely assessed with validated measures at each visit, including the Myasthenia Gravis Impairment Index (MGII) [15, 16], the single simple question (SSQ) [17] and Patient Acceptable Symptom State (PASS) scales [18]. The following data were abstracted at baseline: demographics, clinical presentation, MG scales (Myasthenia Gravis Foundation of America [MGFA], SSQ, MGII and PASS response), serological status, thymoma status, electrophysiological test results and medical treatment. The data abstracted at the last visit included MGII, SSQ, MGFA post‐intervention status (MGFA‐PIS) and PASS response. In addition, the medication history was collected during the study and in the follow‐up period.
Measures
The patients were classified using MG scales, which reliably describe disease severity. They were categorized using the MGFA [19] status, MGFA‐PIS [20, 21], MGII, SSQ and PASS.
The MGFA classification is a categorical scale based on MG severity [19]. In order of increasing severity, the MGFA categories include complete stable remission (no signs or symptoms for >1 year), pharmacological remission (remission, except that the patient continues on some form of therapy) and minimal manifestations (patients with few or mild symptoms). The patients are classified into class I (pure ocular symptoms), class II (mild generalized symptoms), class III (moderate generalized symptoms) and class IV (severe generalized symptoms).
The MGII is a measure of MG severity that has demonstrated feasibility, reliability and construct validity as well as disease responsiveness [22]. It consists of 22 patient‐reported and six examination items. Total scores for the MGII can range from 0 to 84; higher scores represent worse disease severity. A reduction of ≥6 points is considered significant improvement (MGII responders) [16].
To assess PASS, patients answered the following question: ‘Considering all the ways you are affected by myasthenia, if you had to stay in your current state for the next months, would you say that your current disease status is satisfactory?’, with a dichotomous response ‘Yes’/‘No’ [18].
The single simple question (SSQ) rates how patients perceive their MG disease status as a continuous variable. The SSQ is a broad disease impact scale that measures overall disease status and can be used to assess treatment efficacy in longitudinal follow‐up. Quantification of the clinical status is done by asking what percentage of normal patients are with respect to their overall MG status, 0% being the worst and 100% being normal [17, 23].
Statistical analysis
All statistical analyses were conducted with R statistical software and RStudio (version 2022.07.2+576). Clinical and demographic data are reported by means and standard deviations for continuous variables or percentages for categorical variables. Comparisons of the baseline and last evaluation characteristics were done between the cohorts, with independent t tests for continuous variables and Fisher's exact test for categorical variables. Multivariable linear regression modelling was done for the MGII score change from the first to the last visit. The regression analysis included age, sex, antibody status, MGFA at baseline and follow‐up time. p values <0.05 were considered statistically significant.
RESULTS
A total of 153 patients were included, 80 in the dSNMG group and 73 AChR positive. The details of the demographic and treatment data of both groups are shown in Table1. Fifty‐six patients (70%) in the dSNMG cohort had a disease onset over 50 years of age, similar to the AChR group. In this older age group, 36 were female (64.3%) in the dSNMG cohort and 28 (48.3%) in the AChR‐positive group. In the subgroup of young patients diagnosed with MG (<50 years old), 15 (62.5%) were female in the dSNMG cohort, and this proportion was similar between groups.
TABLE 1
Baseline profile of MG patients.
| dSNMG (80) | AChR + MG (73) | Statistical difference (p) | |
|---|---|---|---|
| Mean ± SD (range)/number (percentage) | Mean ± SD (range)/number (percentage) | ||
| Age of onset (years) | 57.5 ± 15.5 (23–88) Median age 57.5 | 60 ± 14.8 (26–85) Median age 63 | 0.31 |
| Female | 52 (65%) | 37 (50.7%) | 0.051 |
| History of thymoma | 2 (2.5%) | 20 (27%) | 0.001 |
| Positive RNS | 18 (22.5%) | 30 (41%) | 0.015 |
| Positive RNS in only GMG | 12 of 44 (27.3%) | 24 of 58 (41.4%) | 0.15 |
| Positive SFEMG | 80 (100%) | 70 (95.9%) | 0.11 |
| MGFA I | 37 (46.3%) | 14 (19.1%) | 0.001 |
| MGFA II | 30 (37.5%) | 51 (69.9%) | 0.001 |
| MGFA III | 13 (16.3%) | 8 (11%) | 0.35 |
| Treatment | |||
| Pred + NSIST | 35 (43.7%) | 29 (39.7%) | 0.63 |
| Pred only | 16 (20%) | 20 (27.4%) | 0.34 |
| Mestinon only | 12 (15%) | 13 (17.8%) | 0.67 |
| NSIST only | 11 (13.8%) | 9 (12.3%) | 0.81 |
| No treatment | 6 (7.5%) | 2 (2.7%) | 0.28 |
| IVIG treatment | 8 (10%) | 13 (17.8%) | 0.24 |
Open in a separate window
Note: Bold values are p<0.05.
Abbreviations: AChR, acetylcholine receptor; dSNMG, double‐seronegative myasthenia gravis; GMG, generalized myasthenia gravis, IVIG, intravenous immunoglobulin; MG, myasthenia gravis; MGFA, Myasthenia Gravis Foundation of America; NSIST, non‐steroidal immunosuppressant treatment; Pred, prednisone; RNS, repetitive nerve stimulation; SFEMG, single fibre electromyography.
Thirty‐seven dSNMG patients (46.3%) presented with only ocular symptoms (MGFA class I), which was significantly higher than in the AChR‐positive cohort (p < 0.001), and in the last clinical evaluation 28 dSNMG patients (23%) remained with restricted ocular involvement.
There were two patients (2.5%) with a history of thymoma in the dSNMG cohort. The treatment selection was similar in both groups (Table1). Eight dSNMG patients (10%) were on intravenous immunoglobulin treatment, all of them combined with an immunosuppressant therapy.
The baseline MGII and SSQ scores in the total dSNMG cohort were 21.3 ± 13.3 (4–60) and 65.6% ± 21.8% (25–100), respectively, with no significant differences from the AChR group (Table2). In those with generalized MG (removing purely ocular MG patients), the MGII and SSQ scores at diagnosis were similar in the AChR and seronegative patients (p = 0.15 and p = 0.71, respectively).
TABLE 2
Clinical characteristics at baseline and last clinical evaluation of MG patients.
| dSNMG (80) | AChR + MG (73) | Statistical difference (p) | |
|---|---|---|---|
| Mean ± SD (range)/number (percentage) | Mean ± SD (range)/number (percentage) | ||
| Follow‐up time | 42.8 ± 23.4 (8–90) | 36.2 ± 21.2 (7–89) | 0.08 |
| MGII at diagnosis | 21.3 ± 13.3 (4–60) | 21.2 ± 14.4 (0–75) | 0.94 |
| MGII at last evaluation | 13.6 ± 14.8 (0–61) | 7.5 ± 9.2 (0–41) | 0.003 |
| MGII responders | 47 (59.8%) | 54 (74%) | 0.06 |
| SSQ at diagnosis | 65.6 ± 21.8 (25–100) | 61.9 ± 23.3 (10–100) | 0.46 |
| SSQ at last evaluation | 74.3 ± 21.7 (10–100) | 78.4 ± 21.2 (3–100) | 0.25 |
| PASS ‘Yes’ at last evaluation | 52 (68.4%) | 56 (76.7%) | 0.15 |
| MGFA change in status | |||
| Improved | 41 (51.3%) | 57 (78.1%) | 0.001a |
| Unchanged | 24 (30%) | 10 (13.7%) | |
| Worse | 13 (16.5%) | 5 (6.8%) | |
| Exacerbated | 2 (2.5%) | 1 (1.4%) | |
Open in a separate window
Note: Bold values are p<0.05.
Abbreviations: AChR, acetylcholine receptor; dSNMG, double‐seronegative myasthenia gravis; MG, myasthenia gravis; MGFA, Myasthenia Gravis Foundation of America; MGII, Myasthenia Gravis Impairment Index; PASS, Patient Acceptable Symptom State; SSQ, single simple question.
ap value of the MGFA improved group.
The total follow‐up time was 42.8 ± 23.4 (8–90) months in the dSNMG group and did not differ significantly between groups (p = 0.06). All patients had a minimum follow‐up of 8 months from the date of diagnosis and had completed the MGII, SSQ and PASS responses. Forty‐seven dSNMG patients (59.8%) had a significant improvement in the MGII score measure by ≥6 points difference from the first clinic visit to the last clinical evaluation (Table2). In the dSNMG cohort, the MGII and SSQ scores had significantly improved at the last clinic evaluation (p = 0.001 and p = 0.047, respectively) compared to the baseline. The dSNMG MGII individual change was −7.4 ± 12.3 and in the AChR‐positive cohort was −14.2 ± 15.4 (p = 0.005). However, patients in the AChR‐positive cohort had significantly greater improvement in mean MGII scores than the dSNMG group (p = 0.003) (Figure1).
FIGURE 1
Mean MGII score at baseline (1) and last clinical evaluation (2) in the AChR‐antibody‐positive MG and dSNMG cohorts. AChR, acetylcholine receptor; dSNMG, double‐seronegative myasthenia gravis; MG, myasthenia gravis; MGII, Myasthenia Gravis Impairment Index.
In a secondary analysis, on removing patients with MGFA class I (pure ocular symptoms), there was still significant improvement of the MGII scores in the dSNMG group at the last clinic evaluation, with MGII improving from 28.4 ± 13.8 at baseline to 13.6 ± 14.8 at last visit (p = 0.006).
The multivariable linear regression analysis of the MGII improvement factoring in antibody status, baseline MGFA stage, age, sex and follow‐up time showed that the AChR antibody status and initial MFGA stage were the only significant factors associated with improvement of the MGII score (p = 0.014 and p = 0.001, respectively) (TableS1).
Fifty‐two dSNMG patients (68.4%) reached a PASS ‘Yes’ response in the last evaluation, compared to 56 (78%) in the AChR‐positive group (p = 0.15). In the last evaluation, 17 dSNMG patients (21.2%) reached minimal manifestations status, six (7.5%) pharmacological remission and two (2.5%) complete remission. In the AChR‐positive cohort, 27 (37%) reached minimal manifestations, two (2.7%) pharmacological remission and four (5.4%) complete remission (Figure2). Forty‐one dSNMG patients (51%) had an improved MGFA status in the last clinical evaluation, compared to 57 (78.1%) in the AChR‐positive group (p < 0.01). Details of the clinical characteristics at baseline and last clinical evaluation in both groups are presented in Table2.
FIGURE 2
MGFA‐PIS status of last clinical evaluation in the dSNMG and AChR‐antibody‐positive cohorts. AChR, acetylcholine receptor; dSNMG, double‐seronegative myasthenia gravis; MGFA‐PIS, Myasthenia Gravis Foundation of America post‐intervention status.
DISCUSSION
Our study is novel in describing the clinical outcomes of a large cohort of dSNMG patients after treatment. It was found that a high proportion of patients with dSNMG had significant clinical improvement after therapy, measured in the last clinical evaluation, with a good response to immunosuppressive treatment. The improvement was substantial across all the scores, MGII, SSQ, PASS and MGFA change in status. This finding remained the same after analysing patients with only generalized dSNMG at diagnosis, after excluding patients with only ocular manifestations. Although the improvement was significant in the dSNMG and AChR groups, the improvement measured by the MGII and MGFA change in status was significantly better in the AChR group. The MGII improvement was only associated with the initial MGFA stage and the antibody status, analysed by linear regression modelling. The age, sex and follow‐up time were not correlated to the change in the MGII [24, 25, 26]. The distinct clinical outcomes found between our study cohorts may be related to a different immune pathogenesis in the dSNMG group. It is possible that new antibodies, not yet described in this condition, might respond less effectively to classical first‐line MG treatments.
The PASS response was similar in both groups, with a large positive satisfactory response at the last clinical evaluation. These results confirm previous data from our centre on the association of PASS with the MGII score and the SSQ score [18, 23].
The baseline clinical scores were similar in both groups measured by the MGII and SSQ scores with the exception of the MGFA stage. When analysing only generalized dSNMG at onset, the disease severity was similar to the AChR group.
Our results align with the experience that dSNMG patients present more as ocular MG [4, 6]. In contrast with generalized MG, approximately 40%–70% of ocular MG have detectable AChR antibodies [4, 27]. This probably explains the higher incidence of an ocular presentation in our dSNMG group. In addition, the lower RNS positivity found in the dSNMG group was related to the greater number of ocular patients at diagnosis in this group; when analysing only generalized MG the RNS test results were no different between cohorts [28].
Most of the dSNMG patients in our cohort had disease onset after 50 years of age similar to previous population studies in Europe [29]. In our cohort of dSNMG, there was a female preponderance with a sex ratio of 1.8:1, compared to the AChR‐positive group, similar to previous published data[4, 6, 8]. In contrast, the AChR group was similar to previous population studies with a sex ratio close to 1:1 [2]. Young patients diagnosed with MG (<50 years old) had a female preponderance in both cohorts and patients over 50 years old had an equal sex distribution in the AChR‐antibody‐positive cohort and female preponderance in the dSNMG cohort.
Thymoma is strongly related to AChR‐positive MG and it is highly valuable to perform chest imaging to rule out this condition. In our study only two dSNMG patients had a history of thymoma and these patients had negative testing for AChR by radioimmunoprecipitation assay and cell‐based assay. A few cases of thymoma without detectable AChR antibodies have been reported in the literature [25, 30]. The cases of thymoma found in our dSNMG cohort could be explained as due to the reduction of AChR levels after thymectomy or to non‐detectable antibody levels [31]. Our findings reinforce the importance of ruling out thymoma in all MG patients, even in dSNMG cases, and that many patients with seronegative MG may have undetectable antibody levels.
The immunosuppressant drug selection in dSNMG patients did not differ from the patients with AChR‐positive MG. Patients were predominantly on combined prednisone and non‐steroidal immunosuppressive treatment. The most frequent non‐steroidal immunosuppressive drugs in our cohort were azathioprine, mycophenolic acid and mycophenolate mofetil. Intravenous immunoglobulin was also used in this cohort with a positive response.
A weakness of our study is that it is a retrospective review, and future prospective studies on outcomes in dSNMG are required. Secondly, the serology status included only AChR and MuSK testing and adding lipoprotein related protein 4 antibody serology might have reduced the numbers considered to be dSNMG.
CONCLUSION
Double‐seronegative MG is a diverse group with limited clinical characterization. It was found that the initial severity based on clinical scores is similar to that in antibody‐positive MG patients, and there is significant clinical improvement in dSNMG patients after treatment, supporting an immune pathophysiology in this cohort and encouraging efforts to improve response to treatment.
AUTHOR CONTRIBUTIONS
Rodrigo Martinez‐Harms: conceptualization; investigation; writing—original draft; methodology; validation; visualization; writing—review and editing; formal analysis; data curation; supervision; project administration; software. Carolina Barnett: conceptualization; writing—original draft; methodology; validation; visualization; writing—review and editing; supervision. Monica Alcantara: methodology; writing—review and editing; writing—original draft; investigation; visualization. Vera Bril: conceptualization; investigation; writing—original draft; methodology; validation; visualization; writing—review and editing; project administration; supervision; resources.
CONFLICT OF INTEREST STATEMENT
None.
Supporting information
Table S1.
Click here to view.(13K, docx)
Notes
Martinez‐Harms R, Barnett C, Alcantara M, Bril V. Clinical characteristics and treatment outcomes in patients with double‐seronegative myasthenia gravis. Eur J Neurol. 2024;31:e16022. doi: 10.1111/ene.16022 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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