COVID-19 AND MYASTHENIA GRAVIS
As with many other diseases, coronavirus disease 2019 (COVID-19) has led to challenges in managing patients with neuromuscular junction disorders. Early in the pandemic, the International Myasthenia Gravis (MG)/COVID-19 Working Group provided guidance on the management of MG.1 Highlights of their treatment recommendations include continuing current MG therapies in most situations, considering home as opposed to hospital-based sites for intravenous immunoglobulin (IVIG) infusions, and possibly delaying B-cell depletion therapy if it is being considered. The use of alternatives to in-person consultations was recommended, and we have certainly seen a massive increase in telemedicine use. Other logical recommendations were that patients should be very careful about exposures, use extra vigilant social distancing, and avoid vaccinations involving live virus. The guidelines also address what to do if patients contract COVID-19. They include continuing current standard of care for mild-to-moderate MG and individualizing treatment based on COVID- 19 features and MG illness severity.
By late Autumn 2020, cases and small series of patients with MG and COVID-19 were published. In most patients, MG was preexisting. In a few, MG started after COVID-19 infection. For example, Sriwastava et al2 reported a patient with acetylcholine receptor (AChR) antibody (Ab)-positive MG with ocular manifestations presenting 2 weeks after the onset of cough, fever, and diarrhea. The patient had a positive COVID-19 nasopharyngeal reverse transcriptase polymerase chain reaction swab test. She developed respiratory compromise thought to be due to COVID-19 and eventually improved after a stormy course that included prone positioning and intravenous corticosteroid therapy.
These authors also reviewed 10 other reports of MG and COVID-19, including a larger series of 15 subjects.2,3 Restivo et al reported another patient with a new-onset of MG with COVID-19.4 In the other articles, MG was preexisting. Most patients were AChR Ab-positive, but several had muscle-specific kinase (MuSK) Abs. Treatment of those with preexisting MG generally included continuing the same medical regimen and sometimes providing extra doses of corticosteroids or IVIG. The larger series enrolled 15 consecutive MG adults admitted with COVID-19 at 4 hospitals in Sao Paulo, Brazil.3 Overall, they tended to have severe disease, and most were admitted to the intensive care unit. Four patients died. Seventy-three percent required mechanical ventilation. All received antibiotics. Four received plasma exchange, and one received IVIG. These treatments were well tolerated. The patients who died were not on preexisting higher levels of immunosuppressive therapy, and they did not receive IVIG or plasma exchange during hospitalization. All were men older than 50 years. Three had only ocular symptoms before admission. Two had other comorbidities.
At this point, we do not have a clear understanding of whether COVID-19 triggers the onset of or unmasks MG. Although there is concern that patients with MG on immunosuppressants may be at higher risk from COVID-19, there are no data that suggest that is the case. Furthermore, complement inhibition might be a target for COVID-19 therapy,5 so eculizumab could theoretically be of benefit for COVID-19 as well as MG.6 It does seem fair to say that patients with MG who contract COVID-19 have highly variable courses.7 Hopefully, physicians who manage patients with MG and COVID-19 will use the COVID -19 Associated Risks and Effects in MG (Care-MG) registry (https://myasthenia.org/Professionals/Resources-for-Professionals/CARE-MG). This registry can be mined to aid understanding of the epidemiologic, clinical, immunologic, management, and outcome aspects of patients with new-onset and preexisting MG and COVID-19.8
THYMECTOMY IN MG
Based on the results of the MGTX Study Group randomized trial of thymectomy in adults younger than 65 years of age with generalized, nonthymomatous, AChR Ab-positive MG of <5 years duration,9 a practice advisory for thymectomy in MG was promulgated by Gronseth et al10 for the American Academy of Neurology. In the MGTX study, patients who underwent extended transsternal thymectomy in addition to oral prednisone therapy had better outcomes versus those on prednisone alone as measured by quantitative MG scores. They also required less prednisone. The recommendations from the practice advisory were that “clinicians should discuss thymectomy treatment with patients with AChR Ab-positive generalized MG (level B). Clinicians should counsel patients with AChR Ab-positive generalized MG considering minimally invasive thymectomy techniques that it is uncertain whether the benefit attained by extended transsternal thymectomy will also be obtained from minimally invasive approaches (level B).”
More recently, Lee et al11 presented a post hoc analysis of data from the randomized trial mentioned above. The original trial spanned 3 years, and there was a voluntary 2-year extension. Sixty-eight patients entered the extension study, and 50 completed the month 60 visit. The investigators found that subjects in the thymectomy plus prednisone group achieved sustained minimal manifestation status (MMS) with complete discontinuation of prednisone more often (64% vs. 38%, P < 0.001) than those in the prednisone alone group, and MMS was reached faster—at a median of 30 months—in the thymectomy group. There were more prednisone-associated adverse symptoms in the prednisone alone group, and steroid-sparing immunosuppressant agents were used more frequently in the prednisone alone group (35% vs. 5% in the thymectomy plus prednisone group).
The authors noted that most patients who achieved MMS and completed withdrawal of prednisone remained stable. In addition, if patients developed symptoms and signs of MG after steroid discontinuation, they usually regained MMS after reintroducing lower doses of prednisone. This scenario may be reassuring to clinicians who plan total steroid withdrawal in their patients with MG. The authors do point out that weaknesses of the study include some of the restrictions that were in place regarding the use of other immunosuppressive therapy, use of alternate day rather than daily prednisone, the post hoc analysis, and potential selection bias.
Following the American Academy of Neurology advisory on thymectomy in MG, an even more recent statement comes from an international group of MG experts.12 Because there was no difference in outcome in the relatively small number of patients older than 50 years treated with thymectomy and prednisone versus prednisone alone in the randomized MGTX trial,9 their consensus was that “in nonthymomatous generalized MG patients with AChR Abs, aged 18–50 years, thymectomy should be considered early in the disease to improve clinical outcomes and to minimize immunotherapy requirements and need for hospitalizations for disease exacerbations.” There was no guidance statement regarding thymectomy after age 50 years. The group also importantly emphasizes that thymectomy is an elective procedure and should only be performed after the patient is stable and deemed safe to undergo the operation. As previously written, they again note that endoscopic and robotic approaches have a good track record and seem to yield similar results to more aggressive approaches. Thymectomy may be considered in AChR Ab-negative patients depending on the clinical course, and there is no current evidence to support thymectomy for patients with MuSK, low-density lipoprotein receptor-related protein-4 (LRP4), or agrin antibodies.12
On the topic of less invasive thymectomy, Li et al13 reported a case series of robotic-extended rethymectomy for refractory MG. These authors reported 6 patients with AChR-seropositive MG who had refractory MG despite undergoing previous thymectomies. One underwent a transcervical approach, 2 underwent video-assisted thoracoscopic surgeries, and 3 had sternotomies. All required immunosuppressants, and 5 of the 6 patients required IVIG and/or plasma exchange to control symptoms. The patients selected for rethymectomy all had MG Foundation of America (MGFA) class IIb-V MG. The median observation time before rethymectomy was 108 months, and the median follow-up time after rethymectomy was 46.5 months (range 13–155 months). After rethymectomy, MGFA postintervention status was improved in 3 and unchanged in 3 patients. The median daily corticosteroid dose was significantly decreased without change in azathioprine use. There was no morbidity or mortality in patients who underwent rethymectomy. Histopathologic studies showed residual thymic tissue in 5 of the 6 patients.
It is pertinent to note that this surgical group at the Charite University Hospital in Berlin was experienced and had performed 597 robotic-extended thymectomies for MG over a 15-year period. Their indications for robotic-extended rethymectomy are as follows: (1) improvement after the original thymectomy, followed by a deterioration and then an observation period of more than 2 years, (2) evidence of previous incomplete resection from the review of specimen or video documentation of the procedure, and (3) evidence of “unexpected” thymic tissue from imaging studies after what was thought to be a complete resection. The study design does not allow one to prove the benefit for rethymectomy in patients with refractory MG, but the methods used and their criteria for rethymectomy and results are certainly of interest to clinicians.
It is well known that thymectomy is indicated in all patients with MG and thymoma. However, approximately 50% of patients with thymoma do not have MG. Neurologists are sometimes consulted to evaluate patients with thymoma for the presence of MG before thymectomy. In those who are seronegative and have normal examinations, it may still be of interest to determine if there is a molecular marker of thymoma that indicates propensity toward MG. Lee et al14 investigated molecular profiling of thymoma based on RNA sequencing (RNA-seq). They studied 16 patients with both thymoma and MG and 18 patients with thymoma without known MG. Unfortunately, the clinical features of the patients are not provided, and it is unclear if any of the patients who were not known to have MG were assessed for AChR or striated muscle Abs.
They identified 4 genes that were differentially expressed in patients with thymoma and MG versus thymoma without MG. They validated their findings by quantitative polymerase chain reaction and concluded that hypoxia-inducible factor 3 alpha (HIF3A) was abnormally expressed in patients with MG and thymoma and that this gene may be important in the development of MG in patients with thymoma. However, the role of HIF3A in this regard is unclear. HIF3A was upregulated in an amyotrophic lateral sclerosis mouse model, so the authors believe that it could facilitate neuromuscular disease development and therefore be important in MG progression.14 Confirmation of the investigators' findings is certainly warranted. One should be cautious in assuming HIF3A in thymoma predicts MG based on a cross-sectional study. A longitudinal study to determine if patients with HIF3A and thymoma without serologic or clinical features of MG develop clinical or serologic features would be of interest.
LRP4/AGRIN AB-POSITIVE MG
Approximately 10% of patients with generalized MG are double seronegative for AChR and MuSK Abs. Some of these patients have LRP4 Abs, agrin Abs, or both. These proteins are found at the neuromuscular junction. Agrin binds to LRP4 and activates MuSK. The prevalence of these Abs, clinical features of those harboring these Abs, and the associated prognosis is not particularly well known. Because of these shortcomings, Rivner et al15 performed a multicenter study at 16 sites in the United States on 181 patients with double seronegative MG to find that 27 (15%) patients were positive for either LRP4 or agrin Abs. Twenty-three of the 27 patients had both Abs. Three patients were positive for only agrin Abs, and one patients was positive for only LRP4 Abs. Because most patients had both Abs, they lumped the 27 patients into the study group. Normal control samples were obtained from 106 random blood donors.
Fifty-nine percent of Ab-positive patients were women. The average age of onset was 44 years. Thirty-one percent had ocular onset. Seventy-eight percent were White, 15% were Black, and 7% were Asian. Bulbar features occurred in 41% at disease onset and in 59% at the time of the study visit. As far as disease classification, 22% were MGFA Class I, whereas 36% of the quadruple seronegative cohort of 154 subjects were MGFA Class I. More Ab-positive patients presented with generalized symptoms compared with Ab-negative patients (69% vs. 43% P< =0.02). The MGFA classification in general was higher in Ab-positive patients with 70% versus 39% being MGFA class III–V. Despite greater severity of disease, LRP4/agrin Ab patients tended to have good responses to treatment with 22 of the 27 (81.5%) patients improving to MGFA class I or II during the mean follow-up period of 11 years. Most patients received pyridostigmine and prednisone while a little less than half received mycophenolate mofetil. Plasma exchange was used in 8 (29.6%) patients, and IVIG was given to 4 (14.8%) patients. Azathioprine, methotrexate, and rituximab were also used in smaller numbers of patients.
In summary, approximately 15% of patients with double seronegative MG had Abs to either LRP4 or agrin. These patients usually had generalized MG and overall were somewhat worse than Ab-negative patients. Most Ab-positive patients improved with standard immunotherapies. The study design did not allow for conclusions regarding the best therapy.
GENERALIZATION OF OCULAR MG
This important topic has been retrospectively studied by a number of investigators over the past 37 years. There has been variability in diagnostic criteria, and several studies have concluded that immunosuppressive agents, especially prednisone, are protective for generalization of ocular MG.16–18 Recently Apinyawasisuk et al19 examined this occurrence in a Thai population. They performed a retrospective cohort study of 71 patients with ocular MG who were seropositive for AChR Abs who came from a population of 184 patients with seropositive MG seen by experienced neuroophthalmologists or neurologists. Seventy-nine of the 184 patients had generalized symptoms, unknown time of onset, or missing records and were excluded; 34 patients with ocular MG were excluded because of incomplete information on risk factors. Patients were seen over a 7-year period with a median follow-up of 4.91 years.
Thirty-six (51%) of the enrolled patients converted to generalized MG. At 2 years, the probability of conversion was 0.37 [95% confidence interval (CI) 0.27–0.49]. The median conversion time was 4.97 years. The authors found 3 risk factors for conversion to generalized MG. First was female sex [odds ratio (OR) 2.15]. Second, there was an increased risk with a history of smoking (OR 2.64). Finally, the presence of thymic abnormalities (hyperplasia or thymoma) carried an OR of 3.82. On the other hand, receiving immunosuppressive agents and pyridostigmine was both associated with a lower rate of conversion (OR for immunosuppressive agents was 0.29, and OR for pyridostigmine was 0.16). The age of onset, which occurred at a mean of 52.4 years, was not associated with conversion to generalized MG. The results of a COX proportional hazard model were in agreement with those of logistic regression models.
Like the other reports, this study is limited by its retrospective nature and potential selection bias, but the diagnosis is more secure than in studies that included seronegative patients. In addition, the role of thymectomy was not addressed in patients with thymic abnormalities. Of interest are the novel aspects of an association of smoking with disease generalization and pyridostigmine as a protective factor. The authors hypothesize that smoking could increase autoimmune activity, and they postulate that pyridostigmine might exhibit activity in anti-inflammatory pathways in addition to its main effect of inhibiting acetylcholinesterase.
TREATMENT: IGS AND RITUXIMAB
IVIG is an accepted rescue medication for MG, and it is also used as a bridge to immunosuppressive therapies with delayed action. Its role in maintenance therapy is less clear. For example, a relatively large retrospective study of 52 patients with refractory MG receiving maintenance IVIG disclosed that 37 (71%) had mild or moderate improvement in disease activity, but none achieved a full remission.20 Alcantara et al21 recently provided an updated retrospective analysis of Ig maintenance therapy in MG that included subcutaneous IG (SCIG) as well as IVIG. Their 34 patients had moderate-to-severe symptoms (MGFA Class III or IV) while on immunosuppressant medications. Sixty-six percent were AChR Ab-positive. Twenty-three (68%) had thymectomies, and 11 (32% overall) of the 23 had thymomas.
Thirty received IVIG and transitioned to SCIG, 3 received SCIG alone, and one received IVIG alone. Treatment periods averaged 20–22 months. Maintenance therapy for IVIG was usually 1 gram/kg every 4 weeks, and SCIG infusions were administered weekly at 31.4 ± 13.8 grams, (range 15–80 grams per week). The primary outcome measure was the mean change in MG impairment index after Ig therapy compared with pretreatment. Secondary outcomes included change in pyridostigmine and immunosuppressive medications and patient-reported “percentage of normal.”
The results were that there was a significant reduction in MG impairment index scores—denoting improvement—in patients who received IVIG and SCIG. In addition, there was a reduction in pyridostigmine and immunosuppressant use, and patients reported a significant “percentage of normal” improvement with Ig therapy. Three patients achieved MMS at the end of follow-up. As far as adverse events, only minor side effects were reported with SCIG. They included headache, chills, and infusion site reactions. The authors concluded that chronic treatment with IVIG or SCIG improves outcomes in patients with generalized MG. They demonstrated successful transition from IVIG to SCIG with only mild treatment side effects. Therefore, this study provides additional evidence that maintenance IVIG and SCIG may be useful in a subset of patients with generalized MG. A prospective, randomized study of Ig versus other treatments with consideration of costs and availability as well as efficacy and adverse events is warranted.21
The utility of rituximab in treating non-MuSK Ab+ MG also remains somewhat unclear. A phase II randomized controlled trial of rituximab (Beat-MG) that enrolled 52 patients with generalized AChR-Ab-positive MG did not show benefit in patients on a stable regimen of prednisone for 4 weeks or prednisone plus another immunosuppressive agent for 6 months. The main outcome measure was a steroid-sparing effect.22 More recently, Brauner et al reported the results of a retrospective cohort study performed on prospectively collected data from patients with non-MuSK Ab+ MG treated with rituximab at the Karolinska University Hospital.23 They compared rituximab treatment for new-onset, generalized MG with refractory generalized MG, and they also used a comparison group of 26 conventionally treated, new-onset cases. Time to remission was the main outcome measure, and the use of rescue therapies or additional immune therapies and time in remission were secondary measures.
The authors identified 113 patients who received rituximab from 2010 to 2018. Twenty-four patients had new-onset MG, and 34 patients were refractory to immunotherapy. The remainder did not meet entry criteria. The rituximab study population consisted of 43% women. The mean age at treatment start was 60 years. The comparison group had only 12% women, and the mean age was 68 years. Twenty-four patients received rituximab within 12 months of disease onset, whereas 34 of the 48 patients who received rituximab at a later time were considered to have refractory disease. Eighty-three percent of the rituximab group had AChR Abs. Patients with refractory disease had an inadequate response to therapy with one or more immunosuppressants and 12 or more months since disease onset. New-onset generalized MG was defined as no immunosuppressant exposure and less than 12 months since generalized disease onset. Typical dosing of rituximab was 500 mg every 6 months. A 12-month observation after treatment was the minimum.
The median time to remission was shorter for patients with new-onset MG versus refractory MG (7 vs. 16 months; P = 0.009). Those who received rituximab achieved remission in 7 months versus 11 months in those receiving conventional immunosuppressant therapies (P = 0.004). There was also a statistically significant lower need for rescue therapy in the first 24 months in the rituximab group.
In summary, it seems that MG outcomes with rituximab therapy may be better with newer onset (<12 months) versus refractory disease, and there may also be benefit in comparison to conventional immunosuppressant therapies in newer onset disease. A placebo control randomized study is still necessary to prove benefit, and a randomized double-blind, placebo-controlled multicenter study of rituximab in new-onset generalized MG is underway (NCT02950155).23
FATIGUE AND DEPRESSION IN MG
We commonly encounter fatigue in patients with MG. It is reasonable to attempt to separate fatigue into peripheral fatigue, including muscle fatiguability due to neuromuscular junction dysfunction from the more vague central fatigue that is characterized by a feeling of lack of energy, either physically or mentally. In some patients, fatigue can be intertwined with depression. Ruiter et al24 provide a systematic review of central fatigue in MG. Twenty-one publications were analyzed. Fatigue was reported in 44%–82% of patients with MG compared with 18%–40% in control groups. The prevalence of fatigue increased with MG severity, and it seemed to improve with treatment of MG, but data are limited regarding treatment. IVIG, plasma exchange, or prednisone may lead to a reduction in fatigue scores. Eculizumab reduced fatigue in the phase III Regain study.25 Even patients with no signs of MG complained of fatigue, but less often than with active disease. Thirty-two percent of patients in pharmacologic remission had fatigue, whereas 72% with generalized MG reported fatigue. Higher scores on depression scales significantly correlated with higher patient-reported fatigue. Most studies also found that female sex was associated with higher fatigue rates. Results associating sleep and fatigue varied. After controlling for depression, restriction of physical activity was the best predictor of fatigue severity. Those with restricted physical activity did not necessarily have differing quantitative MG scores compared with those who were more active.
The authors point out that it would be useful to have a potential biomarker for fatigue in MG. Larger randomized trials on aerobic exercise and cognitive behavioral therapy, which may be of benefit, are also desirable. Empiric treatment could be worthwhile. Depression, when present, should also be targeted for therapy in addition to other treatable comorbidities that can cause fatigue.
Focusing on depression, Gavrilov et al26 performed a study to examine depression phenotypes and determinants of depressive symptoms in MG including overlap with fatigue. Using the Beck Depression Inventory (BDI),27 they evaluated cognitive-affective and somatic depression in 68 patients with consecutive MG. Items on the somatic domain of the BDI are those involving body image, work inhibition, sleep disturbance, fatigability, loss of appetite, weight loss, somatic preoccupation, and loss of libido. Cognitive-affective domain items involve mood, feelings of guilt or satisfaction, self-hate, crying spells, irritability, and social withdrawal. Fatigue was measured through the Fatigue Severity Scale and Fatigue Impact Scale. The Epworth Sleepiness Scale was used to measure daytime sleepiness.
The authors found that depression was mild in 30 patients with MG (44%), moderate in 12 (18%), and severe in 2 (3%). There was no difference in age, sex, body mass index, or MG disease severity or disease duration in patients who were depressed versus nondepressed. However, fatigue was more prevalent in depressed than nondepressed patients (84% vs. 46%). There was also a large overlap between depression and fatigue with both occurring in 54.4%. Fatigue did increase with MG severity. The Epworth Sleepiness Scale findings correlated only with cognitive-affective BDI measures, and younger age was independently associated with cognitive-affective BDI domains. Female sex and thymectomy were associated with somatic BDI. Thymectomy was independently associated with lower BDI scores, but it had no apparent impact on fatigue. Daytime sleepiness, which is covered in the somatic subscale, correlated only with the cognitive-affective BDI scores.
In conclusion, depression symptoms and fatigue overlapped in a large proportion of patients with MG, but fatigue correlated with disease severity while depression symptoms did not. However, the study may not have separated peripheral from central fatigue. The nature of depression in MG is unclear. It does not seem to be related to somatic features because the somatic BDI subscale findings did not correlate with MG disease severity. Given this relatively small study without a control group, it is unclear how generalizable the findings are, but it does underscore the frequency of depression in MG as well as its overlap with fatigue. The study did not address targeting therapies to the depression phenotype, a topic that would be of interest to clinicians.
1. International MG/COVID-19 Working Group, Jacob S, Muppidi S, Guidon A, et al. Guidance for the management of myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS) during the COVID-19 pandemic. J Neurol Sci. 2020;412:116803.
2. Sriwastava S, Tandon M, Kataria S, et al. New onset of ocular myasthenia gravis in a patient with COVID-19: a novel case report and literature review. J Neurol. 2020;12:1–7.
3. Camelo-Filho A, Silva A, Estephan E, et al. Myasthenia gravis and coivd-19: clinical characteristics and outcomes. Front Neurol. 2020;11:1053.
4. Restivo DA, Centonze D, Alesina A, et al. Myasthenia gravis associated with SARS-CoV-2 infection. Ann Intern Med. 2020;173:1027–1028.
5. Risitano AM, Mastellos DC, Huber-Lang M, et al. Complement as a target in COVID-19? Nat Rev Immunol. 2020;6:343–344.
6. Dalakas M. Progress in the therapy of myasthenia gravis: getting closer to effective targeted immunotherapies. Curr Opin Neurol. 2020;33:545–552.
7. Anand P, Slama M, Kaku M, et al. COVID-19 in patients with myasthenia gravis. Muscle Nerve. 2020;62:254–271.
8. Muppidi S, Guptill J, Jacob S, et al. COVID-19- associated risks and effects in myasthenia gravis (Care-MG). Lancet Neurol. 2020;12:970–971.
9. Wolfe GI, Kaminski HJ, Aban IB, et al. On behalf of the MGTX study group. Randomized trial of thymectomy
in myasthenia gravis. N Engl J Med. 2016;375:511–522.
10. Gronseth G, Barohn R, Narauamaswami P, et al. Practice advisory: thymectomy
for myasthenia gravis (practice parameter update). Neurol 2020;94:705–709.
11. Lee I, Juo HC, Aban B, et al. Minimal manifestation status and prednisone withdrawal in the MGTX trial. Neurol. 2020;95:755–766.
12. Narayanaswami P, Sanders DB, Gil W, et al. International consensus guidance for management of myasthenia gravis. 2020 update. Neurol. 2020;3:2020.
13. Li F, Li Z, Taahashi R, et al. Robotic-extended rethymectomy for refractory myasthenia gravis: a case series. Semin Thorac Surg. 2020;32:593–602.
14. Lee MC, Hsiao TH, Chuang HN, et al. Molecular profiling of thymoma with myasthenia gravis. Risk factors of developing myasthenia gravis in thymoma patients. Lung Cancer. 2020;139:157–164.
15. Rivner M, Quarles BM, Pan JX, et al. Clinical features of LRP4/agrin-antibody-positive myasthenia gravis. A multicenter study. Muscle Nerve. 2020;62:33–343.
16. Li F, Hotter B, Swierzy M, et al. Generalization after ocular onset in myasthenia gravis: a case series in Germany. J Neurol. 2018;265:2773–2782.
17. Hong YH, Kwon SB, Kim BJ, et al. Prognosis of ocular myasthenia in Korea: a retrospective multicenter analysis of 202 patients. J Neurol Sci. 2008;273:10–14.
18. Kupersmith MJ, Larkany R, Homel P. Development of generalized disease at 2 years in patients with ocular myasthenia gravis. Arch Neurol. 2003;60:243–248.
19. Apinyawasisuk S, Chongpison Y, Thitisaksakul C, et al. Factors affecting generalization of ocular myasthenia gravis in patients with positive acetylcholine receptor antibody. Am J Ophthalmol. 2020;209:10–17.
20. Hellmann MA, Mosberg-Galili R, Lotan I, et al. Maintenance IVIg therapy in myasthenia gravis does not affect disease activity. J Neurol Sci. 2014;338:39–42.
21. Alcantara M, Sarpong E, Barnett C, et al. Chronic immunoglobulin maintenance therapy in myasthenia gravis. Eur J Neurol. 2020;0:1–8.
22. Nowak RJ, Coffey C, Goldstein J. AAN 2018 Emerging science abstracts: B-cell targeted treatment in myasthenia gravis (BeatMG)- a phase 2 trial of rituximab in myasthenia gravis: topline results. Neurology. 2018;90:e2182–e2194.
23. A study evaluating the safety and efficacy of rituximab in patients with myasthenia gravis (Rinomax). ClinicalTrials.gov.Identifier:NCT02950155. Available at: https://clinicaltrials.gov/ct2/show/NCT02950155
. Accessed March 27, 2020.
24. Ruiter AM, Verschuuren JGM, Tanemaat MR. Fatigue in patients with myasthenia gravis. A systemic review of the literature. Neuromusc Dis. 2020;30:631–639.
25. Anderson H, Mantegazza R, Wang JJ, et al. Eculizumab improves fatigue in refractory generalized myasthenia gravis. Qual Life Res. 2019;28:2247–2254.
26. Gavrilov YV, Alekseeva TM, Kreis OA, et al. Depression in myasthenia gravis: a heterogeneous and intriguing entity. J Neurol. 2020;267:1802–1811.
27. Beck AT, Ward CH, Mendelson M, et al. An inventory for measuring depression. Arch Gen Psychiatry. 1961;4:561–571.