ORIGINAL COMMUNICATION

Characteristics of late-onset myasthenia gravis

Sasa A. Zivkovic Paula R. Clemens

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 neu-

romuscular 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 fea-

tures of EOMG and LOMG are consistent with a continuous

clinical spectrum of a single condition, with more frequent

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 Ocularmyasthenia 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 comor-

bidities 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). Addi-

tionally, a relatively high prevalence of elevated anti-ace-

tylcholine receptor (AChR) antibody titers was reported in

elderly patients ([75 years) not previously known to haveMG, 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

S. A. Zivkovic P. R. ClemensNeurology Service, Department of Veterans Affairs,

University Drive C, Pittsburgh, PA 15240, USA

S. A. Zivkovic (&) P. R. Clemens D. LacomisDepartment 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

123

J Neurol (2012) 259:21672171

DOI 10.1007/s00415-012-6478-6

in MG associated with elevated titers of anti-muscle spe-

cific 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 dif-

ferent 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 defini-

tion 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 (anti-

AChR 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

n 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 %)

Serology

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 %) 0 5 (7 %) 5 (4 %) 10 (6 %)

AChR-Pos elevated titers of anti-acetylcholine receptor antibodies, AChR-Neg normal titers of anti-acetylcholine receptor antibodies, MuSK-Poselevated titers of anti-MuSK antibodies, seroneg seronegative

* p \ 0.05 when compared to EOMG

2168 J Neurol (2012) 259:21672171

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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 statisti-

cally significant (p [ 0.05). AChR-seronegative general-ized 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). Seronega-

tive ocular EOMG was much more frequent than sero-

negative 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 symp-

toms 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 myas-

thenic 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 inci-

dence 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

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 con-

tinued 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 popula-

tion [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 prev-

alence 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 attribut-

able 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 underdi-

agnosis 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 sig-

nificance. 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

J Neurol (2012) 259:21672171 2169

123

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 popula-

tion, 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. Immuno-

suppression in the elderly patient is also fraught with other

risks including complex drugdrug interactions and phar-

macokinetic 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].

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 side-

effects 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 sug-

gestive of a continuous clinical spectrum influenced by

age-dependent comorbidities and senescence of the

immune system [4]. Increasing prevalence of LOMG par-

allels 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

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 immunosuppres-

sive 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 long-

term risk and benefits of different immunosuppressive

regimens and tailoring the treatment for subsets of patients

including juvenile and elderly MG patients with exclu-

sively ocular symptoms. Larger prospective longitudinal

studies should address outcomes and possible improve-

ments of diagnostic and treatment regimens in older

patients with MG.

Acknowledgments Preliminary results of this study were reportedin 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 The authors do not disclose any conflicts ofinterest.

References

1. Meriggioli MN, Sanders DB (2009) Autoimmune myasthenia

gravis: emerging clinical and biological heterogeneity. Lancet

Neurol 8:475490

2. Vincent A, Clover L, Buckley C, Grimley Evans J, Rothwell PM

(2003) Evidence of underdiagnosis of myasthenia gravis in older

people. J Neurol Neurosurg Psychiatry 74:11051108

3. Aragones JM, Bolibar I, Bonfill X, Bufill E, Mummany A,

Alonso F et al (2003) Myasthenia gravis: a higher than expected

incidence in the elderly. Neurology 60:10241026

4. Aarli JA (2008) Myasthenia gravis in the elderly: is it different?

Ann NY Acad Sci 1132:238243

5. Phillips LH 2nd, Torner JC (1996) Epidemiologic evidence for a

changing natural history of myasthenia gravis. Neurology

47:12331238

6. Guptill JT, Sanders DB, Evoli A (2011) Anti-MuSK antibody

myasthenia gravis: clinical findings and response to treatment in

two large cohorts. Muscle Nerve 44:3640

7. Donaldson DH, Ansher M, Horan S, Rutherford RB, Ringel SP

(1990) The relationship of age to outcome in myasthenia gravis.

Neurology 40:786790

8. Phillips LH 2nd, Torner JC, Anderson MS, Cox GM (1992) The

epidemiology of myasthenia gravis in central and western Vir-

ginia. Neurology 42:18881893

9. Schon F, Drayson M, Thompson RA (1996) Myasthenia gravis

and elderly people. Age Ageing 25:5658

2170 J Neurol (2012) 259:21672171

123

10. Slesak G, Melms A, Gerneth F, Sommer N, Weissert R, Dichgans

J (1998) Late-onset myasthenia gravis. Follow-up of 113 patients

diagnosed after age 60. Ann NY Acad Sci 841:777780

11. Aarli JA (1999) Late-onset myasthenia gravis: a changing scene.

Arch Neurol 56:2527

12. Somnier FE (2005) Increasing incidence of late-onset anti-AChR

antibody-seropositive myasthenia gravis. Neurology 65:928930

13. Grob D, Brunner N, Namba T, Pagala M (2008) Lifetime course

of myasthenia gravis. Muscle Nerve 37:141149

14. Aguiar Ade A, Carvalho AF, Costa CM, Fernandes JM,

DAlmeida JA, Furtado LE et al (2010) Myasthenia gravis in

Ceara, Brazil: clinical and epidemiological aspects. Arq Neuro-

psiquiatr 68:843848

15. Mantegazza R, Baggi F, Antozzi C, Confalonieri P, Morandi L,

Bernasconi P et al (2003) Myasthenia gravis (MG): epidemio-

logical data and prognostic factors. Ann NY Acad Sci

998:413423

16. Murai H, Yamashita N, Watanabe M, Nomura Y, Motomura M,

Yoshikawa H et al (2011) Characteristics of myasthenia gravis

according to onset-age: Japanese nationwide survey. J Neurol Sci

305:97102

17. Singhal BS, Bhatia NS, Umesh T, Menon S (2008) Myasthenia

gravis: a study from India. Neurol India 56:352355

18. Alshekhlee A, Miles JD, Katirji B, Preston DC, Kaminski HJ

(2009) Incidence and mortality rates of myasthenia gravis and

myasthenic crisis in US hospitals. Neurology 72:15481554

19. AAEM Quality Assurance Committee (2001) Practice parameter

for repetitive nerve stimulation and single fiber EMG evaluation

of adults with suspected myasthenia gravis or LambertEaton

myasthenic syndrome: summary statement. Muscle Nerve

24:12361238

20. Cowie CC, Rust KF, Byrd-Holt DD, Eberhardt MS, Flegal KM,

Engelgau MM et al (2006) Prevalence of diabetes and impaired

fasting glucose in adults in the US population: National Health

and Nutrition Examination Survey 19992002. Diabetes Care

29:12631268

21. Phillips LH 2nd, Juel VC (1999) Myasthenia gravis in the tenth

decade. Muscle Nerve 22:12971298

22. Zhang X, Yang M, Xu J, Zhang M, Lang B, Wang W et al (2007)

Clinical and serological study of myasthenia gravis in HuBei

Province, China. J Neurol Neurosurg Psychiatry 78:386390

23. Shinomiya N, Nomura Y, Segawa M (2004) A variant of child-

hood-onset myasthenia gravis: HLA typing and clinical charac-

teristics in Japan. Clin Immunol 110:154158

24. Stacy S, Williams EL, Standifer NE, Pasquali A, Krolick KA,

Infante AJ et al (2010) Maintenance of immune tolerance to a

neo-self acetylcholine receptor antigen with aging: implications

for late-onset autoimmunity. J Immunol 184:60676075

25. Symmons DP (2002) Epidemiology of rheumatoid arthritis:

determinants of onset, persistence and outcome. Best Pract Res

Clin Rheumatol 16:707722

26. US Census Bureau (2011) Census 2009: Quickfacts.

http://quickfacts.census.gov/qfd/states/42000.html. Accessed on

29 Sept 2011

27. Kuypers DR (2009) Immunotherapy in elderly transplant recipi-

ents: a guide to clinically significant drug interactions. Drugs

Aging 26:715737

28. Basic-Jukic N, Brunetta B, Kes P (2010) Plasma exchange in

elderly patients. Ther Apher Dial 14:161165

29. Caress JB, Kennedy BL, Eickman KD (2010) Safety of intrave-

nous immunoglobulin treatment. Expert Opin Drug Saf

9:971979

30. Thomas CE, Mayer SA, Gungor Y, Swarup R, Webster EA,

Chang I et al (1997) Myasthenic crisis: clinical features, mor-

tality, complications, and risk factors for prolonged intubation.

Neurology 48:12531260

J Neurol (2012) 259:21672171 2171

123

Characteristics of late-onset myasthenia gravisAbstractIntroductionDesign/methodsResultsDiscussionEpidemiology and MG subtypesComorbiditiesMyasthenic crisis

ConclusionsAcknowledgmentsReferences