J Neurol (2012) 259:21672171

DOI 10.1007/s00415-012-6478-6

ORIGINAL COMMUNICATION

Characteristics of late-onset myasthenia gravis

ivkovic Paula R. Clemens
Sasa A. Z
David Lacomis

Received: 29 November 2011 / Revised: 4 March 2012 / Accepted: 5 March 2012 / Published online: 5 April 2012
Springer-Verlag (outside the USA) 2012

Abstract An increasing incidence of myasthenia gravis

(MG) has been reported in the elderly, but the full clinical
ramifications of late-onset myasthenia gravis (LOMG)
remain unclear. We describe the clinical features of our
cohort of patients with MG with an emphasis on an onset after
the age of 50. This was a retrospective analysis of medical
records of a cohort of patients followed in two tertiary neuromuscular clinics and comparison of early onset MG
(EOMG) versus LOMG. There were 174 patients with a mean
age of onset of 55.2 19.1 years, and 44 % were women.
Late onset of myasthenia gravis after age 50 was reported in
114 patients (66 %). Anti-AChR antibody titers were elevated
in 78 % of patients (65 % with EOMG vs. 85 % with LOMG;
p = 0.003), and frequency of elevated titers of anti-MuSK
antibodies was similar in both groups (present in 38 % of all
tested seronegative patients). Myasthenic crisis was equally
common in generalized EOMG and LOMG (13 %). Ocular
MG was more common in LOMG compared to EOMG (40
vs. 18 %, p = 0.021). Diabetes was more prevalent with
LOMG (27 vs. 5 %; p = 0.0002). Overlapping clinical features of EOMG and LOMG are consistent with a continuous
clinical spectrum of a single condition, with more frequent
S. A. Zivkovic
P. R. Clemens
Neurology Service, Department of Veterans Affairs,
University Drive C, Pittsburgh, PA 15240, USA
S. A. Zivkovic (&)
P. R. Clemens
D. Lacomis
Department of Neurology, University of Pittsburgh School
of Medicine, UPMC Presbyterian, 200 Lothrop St.,
Pittsburgh, PA 15213, USA
e-mail: zivkovics@upmc.edu
D. Lacomis
Department of Pathology (Neuropathology),
University of Pittsburgh School of Medicine,
200 Lothrop St., Pittsburgh, PA 15213, USA

occurrence of seropositive and ocular MG with a late onset. A

higher burden of comorbidities, such as diabetes mellitus,
may warrant a modified approach to treatment of myasthenia
in LOMG. However, overall disease severity may not be
higher with aging. These observations have implications for
design of MG clinical trials and outcomes studies.
Keywords Myasthenia gravis
Elderly
Ocular
myasthenia
Myasthenic crisis
Seropositive myasthenia
Abbreviations
AChR
Acetylcholine receptor
EOMG Early onset myasthenia gravis
LOMG Late-onset myasthenia gravis
MG
Myasthenia gravis
MuSK Muscle-specific tyrosine kinase

Introduction
Myasthenia gravis (MG) has been traditionally considered
a disease of predominantly younger women and older men
[1]. However, recent epidemiologic and clinical studies
suggest an increasing incidence of MG in the elderly of
both genders, at least in part due to improved diagnostic
methods and an aging population [25]. Multiple comorbidities may delay timely recognition of early symptoms of
MG and accurate diagnosis in the elderly (e.g., blurred
vision may be attributed to macular degeneration). Additionally, a relatively high prevalence of elevated anti-acetylcholine receptor (AChR) antibody titers was reported in
elderly patients ([75 years) not previously known to have
MG, suggesting that there are even more unrecognized
cases in this population [2]. Analogously, the onset of
symptoms as late as the seventh decade was also reported

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in MG associated with elevated titers of anti-muscle specific tyrosine kinase (MuSK) antibodies [6]. This evolving
epidemiology of MG, with an increasing prevalence in the
elderly, calls into question whether there is a difference in
phenotypes of early onset myasthenia gravis (EOMG) and
late-onset myasthenia gravis (LOMG), and whether a different approach is warranted. Furthermore, treatment
decisions may be especially complicated in the elderly,
given the more likely presence of multiple comorbidities
and subsequent iatrogenic complications.
Unfortunately, there is still no consensus on the definition of LOMG and the defining age of onset typically
ranges from 40 to 65 years [3, 4, 717]. It is still somewhat
controversial as to whether a later onset of symptoms is
associated with milder or more severe MG [7, 12], and
higher mortality is reported in elderly hospitalized patients
with MG [18].
In this study, we further characterize LOMG in our
patient population by comparing the key laboratory and
clinical features and comorbidities of patients with early
onset MG (before age 50) with those of late-onset MG
(after 50; also subdivided into two groups with onset
between 50 and 64 years and after age 65).

Design/methods
We performed an IRB-approved, retrospective analysis of
the medical records of 174 consecutive adult patients with
MG seen in the Neuromuscular Clinic at the University of
Pittsburgh Medical Center and in the Neurology Clinic at
the Department of Veterans Affairs Medical Center in
Pittsburgh, PA, between 2004 and 2006. Collected data
included demographics, comorbidities (including diabetes,

thyroid disease, other autoimmune conditions), type of MG

(ocular vs. generalized), results of antibody testing, and
history of myasthenic crisis. Patients with thymoma were
not included in the study. The diagnosis of MG was based
on the clinical history and either abnormal serology (antiAChR antibody titer or anti-MuSK antibody titer) or
electrodiagnostic testing (repetitive nerve stimulation or
single-fiber electromyography) [1, 19]. A late onset of MG
was defined as occurring after the age of 50. The late-onset
group was further subdivided into patients with symptom
onset between age 50 and 64 years, and after 65 years. The
study end-point for follow-up was December 31, 2009. The
study was exempt from obtaining informed consent and
was approved by VA Pittsburgh IRB and University of
Pittsburgh IRB. Statistical analysis was performed using
t test and Fishers exact test.

Results
In our cohort, there were 174 patients with a mean age of
onset of 55.6 19.7 years, and 44 % were women
(Table 1). Of the total, 18 % of patients were followed in the
Neurology Clinic at the Department of Veterans Affairs
Medical Center (mean age of onset 55.4 4.7 years; 13 %
women). Early age of onset of symptoms was reported by 60
patients (34 %), while there were 114 with LOMG (66 %; 38
with onset at 5064 years of age, 22 %; and 76 with onset
after the age of 65, 44 %) (Table 1). Juvenile onset of MG
before the age of 20 was reported by eight patients (5 %).
Anti-AChR antibody titers were elevated in 78 % of patients
(65 % with EOMG vs. 85 % with LOMG; p = 0.003). Titers
of anti-MuSK antibodies were examined in 16/39 patients
with AChR-seronegative MG and elevated titers were found

Table 1 Demographic characteristics of patients with myasthenia

Age of onset (years)

B49

5064

[65

Late (C50)

Total

60

38

76

114

174

Gender, % women (n)

56 % (33)

40 % (15)

37 % (28)

38 % (43)

44 % (76)

Ocular myasthenia (%)

11 (18 %)

11 (29 %)

35 (46 %)

46 (40 %)*

57 (33 %)

Crisis (%)

7 (12 %)

5 (13 %)

4 (5 %)

9 (8 %)

16 (9 %)

AChR-Pos

39 (65 %)

30 (79 %)

67 (88 %)

97 (85 %)*

136 (78 %)

AChR-Neg

21 (35 %)

8 (21 %)

9 (12 %)

17 (15 %)*

38 (22 %)

MuSK-Pos

4 (7 %)

1 (3 %)

1 (1 %)

2 (2 %)

6 (3 %; 15 % of seroneg)

Diabetes (%)

3 (5 %)

6 (16 %)

25 (33 %)

31 (27 %)*

34 (19 %)

Thyroid dysfunction (%)

8 (13 %)

8 (21 %)

20 (28 %)

28 (25 %)

36 (21 %)

Other autoimmune disorders

5 (8 %)

5 (7 %)

5 (4 %)

10 (6 %)

Serology

AChR-Pos elevated titers of anti-acetylcholine receptor antibodies, AChR-Neg normal titers of anti-acetylcholine receptor antibodies, MuSK-Pos
elevated titers of anti-MuSK antibodies, seroneg seronegative
* p \ 0.05 when compared to EOMG

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in six patients (15 % of all AChR-seronegative MG: 38 % of

tested seronegative patients).
Generalized MG was diagnosed in 67 % of patients, and
the remaining 33 % had exclusively ocular symptoms.
There was a trend of an increase of AChR-seronegative
EOMG in men (41 vs. 30 %), and AChR-seronegative
LOMG in women (11 vs. 21 %), but this was not statistically significant (p [ 0.05). AChR-seronegative generalized EOMG was more frequent than seronegative
generalized LOMG, but this was not statistically significant
(29 vs. 13 %; p = 0.058).
Ocular MG was significantly more common in LOMG
compared to EOMG (40 vs. 18 %, p = 0.021). Seronegative ocular EOMG was much more frequent than seronegative ocular LOMG (63 vs. 17 %; p = 0.004).
Sixteen patients (10 %) had a history of myasthenic crisis
requiring mechanical ventilatory support (19 episodes), with
the same frequency in generalized EOMG and LOMG (13
%), and a non-significant decrease after age of 65 (3 %;
p = 0.19). Myasthenic crisis occurred within 2 years from
reported onset of MG in 69 % of patients (11/16). Delayed
myasthenic crisis at 2 years or later after the onset of symptoms was reported at an average of 7.3 years after the initial
diagnosis of MG (range 317 years) in 31 % of patients (5/16)
for a total of eight episodes. The prevalence of delayed onset
of myasthenic crisis was the same in both generalized EOMG
and LOMG (4.3 and 4.4 %). Two patients (13 % of subjects
with myasthenic crisis) had at least two episodes of myasthenic crises (both with onset after age 60).
Abnormal thyroid function was found in 21 % of
patients (n = 36; 13 % EOMG vs. 27 % LOMG,
p = 0.11). Diabetes was diagnosed in 19 % of patients, and
it was more prevalent in LOMG than in EOMG (27 vs. 5
%; p = 0.0002). Diabetes was also twice as common in
LOMG when compared to the appropriate age brackets of
the general population (n = 27; 18 vs. 9 %), including
patients with onset of MG after 65 years (33 vs. 17 %)
[20]. The prevalence of diabetes was no different with
generalized and ocular MG, and apparently independent of
AChR antibody status.

Discussion
Epidemiology and MG subtypes
Recent epidemiologic studies demonstrated a rising incidence of MG in the elderly. Nonetheless, it is likely that the
prevalence of MG in older people remains underestimated
due to diagnostic difficulties [2]. Continued aging of the
population and increasing life expectancy will further
increase the relevance of MG in the elderly. Since there is no
consensus on the age of onset that defines LOMG, it is

2169

difficult to compare the studies previously reported in the

literature [3, 4, 717]. Most studies that report an increased
prevalence of LOMG originate from developed countries
with aging populations. New onset of MG has been described
in individuals as old as 98 years of age, illustrating a continued risk [21]. This observation contrasts with younger
populations in developing countries with different ethnic,
racial, and genetic backgrounds. A high prevalence of
childhood MG has been reported in the East Asian population [16, 22, 23], and EOMG also predominates in Brazil
[14]. In contrast, a higher prevalence of LOMG is reported in
India [20]. In our patient population, we found a high prevalence of LOMG (64 %) with more common occurrence of
ocular LOMG (40 %) and seropositive LOMG (85 %),
especially after the age of 65 years. An increased rate of
seropositive MG has been reported in LOMG and parallels
an increased prevalence of elevated anti-AChR antibody
titers in an elderly general population, including some
without a prior diagnosis of MG [2]. Interestingly, the higher
rate of AChR-seropositivity in LOMG was largely attributable to an increase of seropositivity in ocular LOMG and
overall in men with generalized or ocular LOMG. This
phenomenon resembles the common occurrence of other
autoimmune disorders in the elderly including Sjogrens
syndrome and rheumatoid arthritis, and may be explained
partly by aging-related declines in immunocompetence [24,
25]. Another consideration is the possibility of an underdiagnosis of seronegative ocular myasthenia in the elderly as
blurriness of vision and ptosis may be attributed to other
causes. In generalized myasthenia, there was a trend of
higher prevalence of seronegative generalized EOMG when
compared to LOMG, but this did not reach a statistical significance. Interestingly, our study showed a trend of a higher
proportion of seronegative LOMG in women, which is a
reversal from a higher prevalence of seronegative EOMG in
men. We did not find any statistically significant differences
between LOMG with onset between 50 and 64 years when
compared to LOMG with onset at 65 years or older.
Our study is tertiary clinic-based and might not fully
reflect the local population due to a referral bias. The
demographic composition of our cohort was also somewhat
skewed by a relatively older local catchment population in
western Pennsylvania (19.9 % above age of 65 in 2009,
compared to the national average of 12.9 %) [26], and a
typically higher proportion of men in a group of patients
followed in our clinic at the Department of Veteran Affairs
Medical Center (18 % of the total study population, with
only 13 % of women in this subgroup).
Comorbidities
Frequent comorbidities increase the risk of complications
in the elderly. In our cohort, there was also a trend toward a

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higher prevalence of thyroid dysfunction with LOMG, as

previously reported by Donaldson [7], but this occurrence
was not statistically significant. Management of LOMG is
also complicated by the common occurrence of diabetes,
cataracts, and osteoporosis in the geriatric patient population, which limits the use of corticosteroid treatment. We
have observed a higher prevalence of diabetes in LOMG
when compared to age-matched controls or EOMG, further
illustrating the increased risks of corticosteroid use in this
population. A higher incidence of corticosteroid-related
adverse events was previously reported with LOMG [7].
These observations highlight the importance of tailoring
treatment regimens to individual patients needs. Immunosuppression in the elderly patient is also fraught with other
risks including complex drugdrug interactions and pharmacokinetic changes [27]. Importantly, the risk of adverse
effects of plasmapheresis and IVIG, which are the standard
treatments of myasthenic crisis, is also higher in the elderly
[28, 29].

J Neurol (2012) 259:21672171

and genetic backgrounds, which may influence clinical

manifestations of the disease. Our cohort has also included
very few patients with juvenile MG (onset before age 20),
and long-term consequences of chronic immunosuppressive therapy in this population are still not well understood.
Overall, the clinical features of autoimmune MG appear
very similar in patients with either early or late-onset
symptoms. Late-onset MG is associated with an increased
rate of AChR-seropositivity and of MG with exclusively
ocular symptoms. Clinical significance of an increased
burden of comorbidities in elderly patients with MG may
warrant a different treatment approach. Available clinical
data do not answer the important questions regarding longterm risk and benefits of different immunosuppressive
regimens and tailoring the treatment for subsets of patients
including juvenile and elderly MG patients with exclusively ocular symptoms. Larger prospective longitudinal
studies should address outcomes and possible improvements of diagnostic and treatment regimens in older
patients with MG.

Myasthenic crisis
Morbidity and mortality in patients with MG are closely
related to the occurrence of myasthenic crisis. While ocular
MG may be more common in the elderly, the risk of
myasthenic crisis is similar across the age groups in
patients with generalized MG. Larger studies also suggest
that age is not a risk factor for myasthenic crisis [30]; and,
in our study, the prevalence of myasthenic crises was
almost identical to generalized EOMG and LOMG. We
found that myasthenic crisis occurred within 2 years of
onset of MG in the majority (69 %) of our patients, which
is similar to the 74 % reported by Thomas et al. [30].
Timing of myasthenic crisis was also not dependent on the
age of onset of MG. However, increased risk of mortality
was reported in hospitalized elderly patients with MG [18].
Additionally, a higher incidence of treatment-induced sideeffects in the elderly also mandates a cautious approach
tailored to individual patient needs [7, 28, 29].

Conclusions
Most studies (including ours) show very similar features of
EOMG and LOMG. Overall, such findings may be suggestive of a continuous clinical spectrum influenced by
age-dependent comorbidities and senescence of the
immune system [4]. Increasing prevalence of LOMG parallels diagnostic advances and demographic changes with
aging of the population in developed countries with a
greater burden of chronic diseases. However, caution is
needed if these observations are to be extrapolated to MG
populations in developing countries with different ethnic

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Acknowledgments Preliminary results of this study were reported

in a poster format at the 61st Annual Meeting of the American
Academy of Neurology, Seattle, WA, April 916, 2009. The authors
take full responsibility for the contents of this paper, which do not
represent the views of the Department of Veterans Affairs or the
United States Government.
Conflicts of interest
interest.

The authors do not disclose any conflicts of

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