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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 38  |  Issue : 2  |  Page : 127-134

Late-onset myasthenia gravis: Is it a different clinical entity?


Department of Neurology, Haydarpasa Numune Training and Research Hospital, University of Health Sciences, Istanbul, Turkey

Date of Submission12-Nov-2020
Date of Decision18-Dec-2020
Date of Acceptance13-Feb-2021
Date of Web Publication15-Jun-2021

Correspondence Address:
Hulya Tireli
Department of Neurology, Haydarpasa Numune Training and Research Hospital, University of Health Sciences, Istanbul
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/nsn.nsn_201_20

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  Abstract 


Objective: The increase in the average life expectancy of humans has resulted in an increased occurrence of late-onset myasthenia gravis (LOMG). It is noticeable that the clinical, immunologic, and prognostic features of patients with LOMG are different than those of the patients with early-onset myasthenia gravis (EOMG). The present study aimed to establish the dissimilar features of patients with EOMG and LOMG. Subjects and Methods: The study retrospectively compared 93 patients with EOMG and LOMG in terms of clinical and immunologic features and response to medical treatment and thymectomy. Results: Of the 93 patients with MG, 56 had EOMG and 37 had LOMG. The EOMG group was dominated by female patients and generalized MG, whereas male patients and ocular MG were predominant in the LOMG group. Both groups tested positive for acetyl choline receptors antibodies. The number of patients undergoing thymectomy was higher in the EOMG group than in LOMG group. Responses to thymectomy and immunosuppressive treatment in LOMG group were lower compared with the EOMG group. Conclusion: The present study concludes that the clinical prognosis of patients with LOMG is better, and thymectomy may not be quite necessary for patients in this group who do not have thymomas (nonthymomatous patients).

Keywords: Early-onset myasthenia gravis, late-onset myasthenia gravis, thymectomy


How to cite this article:
Tireli H, Yuksel G, Tutkavul K. Late-onset myasthenia gravis: Is it a different clinical entity?. Neurol Sci Neurophysiol 2021;38:127-34

How to cite this URL:
Tireli H, Yuksel G, Tutkavul K. Late-onset myasthenia gravis: Is it a different clinical entity?. Neurol Sci Neurophysiol [serial online] 2021 [cited 2021 Sep 18];38:127-34. Available from: http://www.nsnjournal.org/text.asp?2021/38/2/127/318497




  Introduction Top


Myasthenia gravis (MG) is an autoimmune disease characterized by impaired transmission in the neuromuscular junction and the presence of antibodies against postsynaptic antigens mainly toward acetyl choline receptors (AChR). The main symptom of the disease is pathologic weakness of the skeletal muscle, which fluctuates during the day.[1] The majority of patients respond to therapy well, but 10%–20% of patients with MG are refractory to all conventional treatment modalities. Myasthenic crisis, caused by bulbar and respiratory muscle involvement, has frequently been seen among this refractory MG group.[2],[3] Anti-AChR antibodies are present in the majority and anti-MuSK antibodies in a minority of patients. In addition, anti-titin and anti-LRP4 antibodies may be present less frequently.

There have recently been more MG diagnoses than in the past. This increase is essentially due to the diagnosis of patients aged over 50 years. While reports from early 20th century specify the age of onset as the second or third decade, epidemiologic studies indicate that patients with late-onset MG (LOMG) age over 50 years have become more prevalent over the last decades and that the ratio of patients who are AChR antibody positive has increased in this group. This, to some extent, is due to the increase in average life expectancy.[4],[5]

Patients with MG are categorized into subgroups for treatment approaches and assessment of prognosis. The subgroups are formed based on serum antibodies, clinical findings (ocular/generalized), age of onset (early/late-onset), presence of thymomas, presence of anti-AChR and anti-MuSK antibodies, or seronegativity.[6] These subgroups are thought to display different clinical findings and probably different pathogenesis. Treatment strategies and prognoses may vary across the subgroups.[7] If these subgroups are known well enough, patients can receive the treatments suitable for their respective subgroups, which in turn may increase treatment success.[8]

As in many other conditions, old age is an independent risk factor for mortality and development of immunotherapy complications in MG; thus, treatment of patients with LOMG requires special care and diligence.[9] As our knowledge about this patient group increases, it becomes more prominent and visible that the clinical prognoses, immunologic features, and treatment requirements of patients with LOMG differ from those with early-onset MG (EOMG).

Some researchers define LOMG as the age of onset over 40 years. However, others accept the age limit of 50 years to distinguish LOMG from EOMG.[10],[11],[12]

Consequently, as they encounter older patients with MG, neurologists create larger datasets concerning the clinical, immunologic, and pathologic features and treatment responses of these patients. Furthermore, they seek answers to the question of whether MG has a different prognosis in the elderly. Due to the nature of the disease, it is difficult to design prospective studies. Therefore, our knowledge can be improved by retrospectively evaluating monitored patients and by sharing the results of these evaluations.


  Subjects and Methods Top


Our patient population consisted of 93 retrospectively reviewed patients with MG who were monitored in the neuromuscular disorders outpatient clinic between 1998 and 2018 and whose records could be accessed properly.

Fifty-six (60.2%) of the patients were female and 37 (39.8%) were male. Their ages of onset ranged from 12 to 88 years, and the average age of onset was 46.49 ± 16.38 years. Of all the patients, 56 (60.2%) had an age of onset below 50 years and thus were included in the EOMG group, and 37 (39.8%) had an age of onset over 50 years, which placed them in the LOMG group. The LOMG group was also divided into two subgroups according to the age of onset, 50–64 years (AOO subgroup 50–64), and over 65 years (AOO subgroup >65). Some researchers name these two groups LOMG and very late-onset MG, respectively. Besides comparing the demographic features of the patients, the present study makes comparisons between the patient groups in terms of immunologic and pathologic features and treatment response and prognosis.

Given its retrospective nature, the study used the system proposed by the MG Foundation of America (MGFA) to assess the degree of weakness in patients before and after treatment using a 5-grade scale ([1] ocular muscle weakness only, [2] mild generalized weakness, [3] moderate generalized weakness, [4] severe generalized weakness, and [5] intubation required). The study evaluates the treatment response of each patient individually by comparing their initial and final MGFA values. Evaluation using MGFA-postintervention status could not be performed because the relationship between the retrospectively evaluated records of patients and the drug doses had not been fully specified for all patients. Records concerning the fluctuations in muscle strength were found to be more reliable.[13]

Statistical analyses

The Number Cruncher Statistical System 2007 (Kaysville, Utah, USA) software package was used for statistical analyses. For the evaluation of the study data, descriptive statistical methods (mean, standard deviation, median, frequency, ratio, minimum, and maximum) were used. Pearson's Chi-square test, the Fisher-Freeman-Halton test, and Fisher's exact test were used for the comparison of quantitative data. For intragroup comparisons of abnormally distributed data, Wilcoxon's signed-ranks test was used. Significance level was P < 0.05 minimum.


  Results Top


Of the 56 patients in the EOMG group, 46 (82.2%) were female and 10 (17.8%) were male. Their ages of onset ranged from 12 to 49.50 years. Most of the patients in this patient group had generalized MG (GMG) (89.2%) and 6 (10.7%) had ocular MG (OMG). Of the 37 patients in the LOMG group, 27 (75.6%) were male and 10 (27%) were female. Their ages of onset ranged from 50 to 88 years. Twenty-three (62.1%) of these patients had ages of onset from 50 to 64 years and 14 (37.8%) had ages of onset over 65 years. In the AOO subgroup 50–64 subgroup, 18 patients (78.2%) were male and five were female, and of all the patients in this group, three had OMG, whereas 20 had GMG. As for the AOO subgroup >65, 9 (64.2%) patients were male and five were female, and of all the patients in this group, 8 (57%) had OMG and 6 had GMG.

A comparison of sex between the groups revealed that the EOMG group had more female patients, whereas the LOMG group had more male patients (P = 0.001 and P < 0.01). GMG was more prevalent in the EOMG group and the LOMG group had more OMG cases (P = 0.020 and P < 0.05).

In the EOMG group, 27 patients (48.2%) tested positive and 19 tested negative for AChR antibodies; test results for ten patients could not be accessed. Forty-five (80.4%) patients underwent thymectomy (thymectomized), and 11 patients (19.6%) did not undergo thymectomy (non-thymectomized). Of the non-thymectomized patients, four had OMG and six had GMG; one patient was initially ocular, but they were lost to follow-up. The distribution of thymic pathology in 45 thymectomized patients was as follows: 16 patients with thymomas, 19 with thymic hyperplasia, eight with thymic involution, and two with normal thymus (these last two groups were evaluated together). Two patients in the thymectomized group had OMG and 43 had GMG. In the LOMG group, 11 (29.7%) patients had OMG and 26 (70.3%) had GMG. Twenty-seven (72.9%) patients tested positive and six tested negative for AChR antibodies. In this group, 10 (27%) patients were thymectomized and 27 patients were nonthymectomized. All the thymectomized patients had GMG, and thymectomy revealed that four patients had thymoma, two had thymic hyperplasia, and four had thymic involution. Of the 27 nonthymectomized patients, 16 had GMG and 11 had OMG.

Nine of the 25 AChR-negative patients were tested for anti-MuSK antibodies and two tested positive. The number of patients does not allow for any comments about anti-MuSK antibody positivity.

In the EOMG group, 27 (48.2%) patients used corticosteroids, 24 (42.9%) used azathioprine (AZA), and 16 (28%) used a combination of corticosteroids and AZA. Twenty-one patients used only pyridostigmine. In the LOMG group, 15 (40.5%) patients used corticosteroids, 19 (51.4%) used AZA, and 7 (18.9%) used a combination of corticosteroids and AZA. Fourteen patients used only pyridostigmine. There was no significant difference in the amount of drug use and dose of medication between the EOMG and LOMG groups [Table 1].
Table 1: Demographic findings according to age of onset of disease

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Patients were followed up for 1–25 (average: 6.5) years after diagnosis and/or thymectomy. All patients with gMG were given immunosuppressive therapy in addition to symptomatic treatment. The dosage of corticosteroids was 1–1.5 mg/kg/day and the dosage of AZA was 2 mg/kg/day. Results of thymectomy were evaluated in the thymectomized patients with GMG who received immunosuppressive therapy with corticosteroids and immunosuppressants in the doses mentioned above. Mycophenolate mofetyl, cyclophosphamide, rituximab, and as necessary, intravenous immunoglobulin or plasma exchange were added to the treatment in some patients. The number of these patients did not reach statistical significance.

Thymomas were identified in 16 patients in the EOMG group and four patients in the LOMG group. Patients with thymomas were followed up in collaboration with the oncology department, and radiotherapy was given to those for whom it was deemed necessary (n = 7).

The LOMG group, on the other hand, required less intensive immunosuppressive therapy and fewer thymectomies.

Whereas 80.4% of the patients in the EOMG group underwent thymectomy, this percentage was 27% in the LOMG group. In the AOO subgroup 50–64 of the LOMG group, 39% of the patients underwent thymectomy, this percentage decreased to 7% in the AOO subgroup >65. The prevalence of thymectomy was significantly higher in the EOMG group than in the LOMG group (P = 0.001; P < 0.01). Patients with GMG in both groups responded to treatment very well (P = 0.001 and P < 0.01) [Table 1].

Patients with OMG, however, responded to treatment better in the LOMG group (P = 0.025 and P < 0.05). In the EOMG group, patients with OMG did not respond to treatment as well as those in the LOMG group (P = 0.157 and P > 0.05) [Table 2].
Table 2: Comparison of recovery of ocular myasthenia gravis patients according to age of onset

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The recovery ratio of the thymectomized patients in the EOMG group was significantly high (P = 0.001 and P < 0.01). By contrast, this ratio was not significant for nonthymectomized patients in the same group (P = 0.102; P > 0.05). In the LOMG group, the treatment responses of both thymectomized and nonthymectomized patients were similarly good (P = 0.026; P < 0.05, P = 0.041; P < 0.05). Thymectomy did not indicate any extra benefits in the LOMG group. It follows from these findings that thymic pathology was more prevalent in the EOMG group than in the LOMG group, which suggests that the earlier patients in the EOMG group undergo thymectomy, the better their prognoses. On the other hand, thymectomy does not have this remarkably striking effect on the treatment of patients with LOMG [Table 3].
Table 3: Recovery ratio of the thymectomized and nonthymectomized patients with generalized myasthenia gravis according to age of onset

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The comparison between thymectomized patients with GMG in terms of the presence of thymomas revealed that thymomatous patients in the EOMG group had poorer prognoses at entry (P = 0.012; P < 0.05). Both thymomatous and nonthymomatous patients responded to treatment well (P = 0.009, P = 0.001; P < 0.01). The presence of thymomas did not cause significant differences between the treatment responses of patients with LOMG. This result suggests that thymectomy in younger patients regardless of the presence of thymomas may be effective [Table 4].
Table 4: The comparison of the recovery between thymectomized patients with generalized myasthenia gravis in the presence of thymoma

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Of the 23 patients in the AOO subgroup 50–64, 19 (82.6%) tested positive and one tested negative for AChR antibodies; the results for three patients were unknown. Of the 14 patients in the AOO subgroup >65, eight (57%) patients tested positive and five tested negative for AChR antibodies; one patient had unknown results. AChR titers were high in both the LOMG and EOMG groups.

Nine (39%) patients in the AOO subgroup 50–64 underwent thymectomy, and only one (7%) patient underwent thymectomy in the AOO subgroup >65. Thymectomy in the first subgroup revealed thymomas in four patients, thymic hyperplasia in two, and thymic involution in three patients. In the AOO subgroup >65, thymectomy in one patient revealed thymic involution.

In the EOMG group, the frequency of myasthenic crisis was 35.7% (20/56). In the LOMG group, however, eight (34.8%) patients had a myasthenic crisis in AOO subgroup 50–64, and two patients (14.3%) had a myasthenic crisis in AOO subgroup >65. In the latter subgroup, one patient dies and the other had concurrent MG and LEMS.

In the EOMG group, thymectomy enhanced the treatment success in nonthymomatous patients receiving steroid therapy compared with non-thymectomized patients (P = 0.005; P < 0.01). In the LOMG group, however, thymectomy gave no such results. It follows that, regardless of the thymic pathology, thymectomy is more effective on treatment success in younger patients. This finding has paved the way for debate on the possible role of thymectomy in the LOMG group [Table 5].
Table 5: The effect of thymectomy on nonthymomatous patients with generalized myasthenia gravis receiving steroid therapy compared to nonthymectomized patients

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  Discussion Top


The present study is a retrospective evaluation comparing the clinical and immunologic features and treatment responses of patients with EOMG and LOMG. The most striking finding of this study is that patients in the LOMG group had better prognoses and did not benefit from thymectomy.

Although female patients constitute a larger part of the EOMG population, the LOMG group has more male patients, for whom the probability of developing OMG increases with age.

Various studies have reported different results concerning clinical severity and prognosis for patient with EOMG and LOMG. A Japanese study by Waka Sakai reported that patients with LOMG had poorer prognoses and a greater predisposition to having GMG, the risk of myasthenic crisis in thymectomized patients without thymomas was lower compared with nonthymectomized patients and patients with thymomas, and patients with LOMG needed aggressive immunomodulatory therapy.[14]

Contrary to Waka Sakai's study, however, the present study had patients with LOMG with better clinical prognoses. The majority of these patients did not need thymectomy. Furthermore, thymectomy did not have remarkably positive effects on the overall treatment response. In other words, the present study found no statistically significant difference between thymectomized and nonthymectomized patients in the LOMG group in terms of treatment success. Moreover, these patients rarely needed aggressive immunomodulatory therapy. This large disparity between the results of the present study and Waka Sakai's study may have been caused by the difference in races and antigenic features.

In the present study, the ratio of thymectomy in the EOMG group was considerably higher than in the LOMG group, and the recovery ratio was significantly higher in thymectomized patients with EOMG. Thymectomized and nonthymectomized patients in the LOMG group showed comparable treatment responses. Patients with EOMG should be thymectomized as early as possible, and thymectomy in LOMG group produced no additional benefits for the treatment. In other words, patients with LOMG need thymectomy less. Our results comply with the results of some studies suggesting that thymectomy provides no significant benefit for patients with LOMG.[15],[16]

The incidence of MG without thymoma is higher in older patients. The average age of onset in this patient group ranges from 50 to 60 years. It has been argued that, during normal aging, thymic tissue becomes atrophied and turns into fatty tissue, and thus the antibody titer is expected to be low. Accordingly, some studies have reported lower AChR concentrations in older patients with MG.[17]

Of these studies, the study by Limburg et al. and Mantegazza et al. suggested that thymic pathology and age of onset were not correlated, and patients with LOMG without thymomas had the lowest AChR antibody titers.[17],[18] A later study by Ishii and many others, on the other hand, showed that patients with LOMG with atrophic thymuses had higher AChR antibody concentrations in germinal centers.[16],[19],[20] Compatible with the results of Ishii's study, 72.9% of our patients with LOMG tested positive for AChR antibodies. This ratio increased up to 82.6% in the 50–64 age group.

Suzuki's study had similar results to the present study in that it showed that the ocular form was more prevalent in the LOMG group, especially in patients with AChR seropositivity, than in the EOMG group. Treatment success was also higher in patients with OMG in the LOMG group.[21] In addition, immunologic features of patients with LOMG are not fully known. It is thought that immunologic profiles of patients with EOMG and LOMG are different.[7]

Kawaguchi et al. reported that, among the nonthymomatous patients in the LOMG group, thymectomized patients were more severely disabled than nonthymectomized patients at entry, but there was no significant difference in the outcomes of the two groups. They concluded that thymectomy was an effective treatment for nonthymomatous patients with LOMG with mild GMG.[1] In the present study, patients with LOMG had had better prognoses since entry. Furthermore, the benefit of thymectomy was negligible.

The present study has findings in parallel with the results of earlier studies showing that, during normal aging, patients with LOMG have thymic abnormalities less frequently and have better clinical prognoses compared with patients with EOMG.[19],[22],[23]

In the present study, the presence of thymoma did not change the treatment response in the LOMG group, nor did thymectomy produce any additional benefits in the treatment. In the EOMG group, thymomatous patients had more severe symptoms at entry, but their treatment responses were good. In parallel with this finding, myasthenic crisis occurs more in young patients. The incidence of myasthenic crisis decreases with age. Even though LOMG has more treatment-related comorbidities because of aging, treatment success does not differ between the EOMG and LOMG groups. The outcome in both subgroups is similar. The LOMG group does not require aggressive therapy.[7] Older patients have better results with low doses of immunosuppressive treatment.[24]

The present study has shown that thymectomy significantly increases the treatment success in nonthymomatous patients with EOMG receiving steroid therapy, and it has no such effect in patients with LOMG. This finding indicates that, regardless of thymic pathology, thymectomy is more effective on treatment success in younger patients. It also has opened the way for discussion on the benefits of thymectomy in patients with LOMG.

Patients with LOMG had better prognoses than those with EOMG, patients with LOMG did not benefit from thymectomy, and heavy use of immunosuppressants is not necessary.


  Conclusion Top


Patients with EOMG and LOMG have different clinical prognoses, immunologic features, and treatment responses. The EOMG group has more female patients and GMG cases, and male patients and OMG are more prevalent in LOMG. In the EOMG group, MG symptoms are more severe and the incidence of myasthenic crisis and thymic abnormalities is higher. In the LOMG group, however, patients have better prognoses and less myasthenic crises. Although thymectomy significantly increases the treatment success in patients with EOMG, no such effect on treatment success has been observed in patients with LOMG. Patients with LOMG should be considered and evaluated as a separate group. If these patients are nonthymomatous, thymectomy may not be necessary because no positive effects or benefits of this procedure could be observed in such cases. Patients with LOMG need less intensive immunosuppressive treatment than those with EOMG.

Acknowledgment

We thank Gizem Gürsoy MD for documentation, and Tamer Okay MD, Bulent Aydemir MD, and Oya İmamoğlu Uncu MD for performing the surgeries. We also thank Ayşe Akpınar MD for follow-up of some of the patients. We would like to thank Abdullah Karaakın of Beykent University for proofreading.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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