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Review

Neuroepidemiology 2010;34:171183
DOI: 10.1159/000279334

Received: August 4, 2009


Accepted: December 7, 2009
Published online: February 2, 2010

The Incidence of Myasthenia Gravis:


A Systematic Literature Review
Anita McGrogan a Samantha Sneddon b Corinne S. de Vries a
a

Department of Pharmacy and Pharmacology, University of Bath, Bath, and b Department of


Pharmacoepidemiology, Postgraduate Medical School, University of Surrey, Guildford, UK

Key Words
Myasthenia gravis, incidence Review literature
Epidemiology

Abstract
Background: A systematic review of literature published between 1980 and 2007, on the incidence of myasthenia gravis,
was undertaken. Methods: All relevant papers found through
searches of Medline, Embase and Science Direct were critically appraised and an assessment was made of the reliability of the reported incidence data. Results: Thirty-one studies were included in the review, the majority of which investigated populations in Europe. The incidence rates reported
were between 3.0 and 30.0/1,000,000/year. However, it is
thought that the rates at the upper end of this range, reported by the prospective studies, provided the most accurate
estimates. Overall, incidence rates have increased over time
owing to a greater awareness of the disease and improved
methods of diagnosis. Conclusions: The most accurate estimate of incidence of myasthenia gravis was around 30/
1,000,000/year. The incidence in children and adolescents
aged 019 years was found to be between 1.0 and 5.0/
1,000,000/year. The rates presented in this review are likely
to be an underestimate of the true incidence rates, as mild
cases will have been missed and cases in the elderly will have
been misdiagnosed.
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Introduction

Myasthenia gravis is an autoimmune disorder of the


neuromuscular junction characterised by abnormal muscle weakness and fatigue [1, 2]. The disease is caused by
the action of autoantibodies on the acetylcholine receptor
(AChRs) at the neuromuscular junction causing transmission difficulties. This deficiency in AChRs is the result of an antibody-mediated autoimmune attack [1, 3, 4].
Successive transmission failures desensitise any remaining available AChRs, which causes fatigability characteristics [5].
Classification of myasthenia gravis, originally undertaken by Osserman and Genkins [6] and recently updated [1] divides myasthenia gravis in adults into 5 groups:
ocular myasthenia, mild, moderate and severe weakness
other than ocular and very severe weakness defined by
intubation with or without mechanical ventilation [1]. It
has been recognised that many childhood cases of myasthenia gravis are congenital myasthenic syndromes and
therefore not autoimmune in origin [7]. However, a separate subtype of juvenile myasthenia gravis also exists that
can be diagnosed from the first year of life. There is a suggestion of differences in the presentation of juvenile myasthenia gravis with prepubertal patients being more
likely to have ocular symptoms, whereas postpubertal
patients present more with generalised disease [8]. Five
Dr. Anita McGrogan
Department of Pharmacy and Pharmacology
University of Bath
Bath BA2 7AY (UK)
Tel. +44 1225 384 142, Fax +44 1225 386 114, E-Mail a.mcgrogan @ bath.ac.uk

types of myasthenia gravis have been identified: acquired


autoimmune, juvenile, transient neonatal, drug-induced
disease and congenital myasthenic syndromes [1, 8].
Seropositive myasthenia gravis, where patients test
positive for anti-AChR antibodies, is detected in about
85% of the patients. In seronegative myasthenia gravis it
is thought that antibodies are present but are not detected
by anti-AChR radioimmunoassay. For example antibodies to muscle-specific tyrosine kinase have been found in
some patients with seronegative myasthenia gravis that
act against one or more components of the neuromuscular junction; these patients all have a similar pattern of
disease [1, 4].
In most patients a clinical history characteristic of myasthenia gravis and the presence of anti-AChR antibodies
confirms the diagnosis and no further investigation is
required [1, 6]. In borderline and seronegative patients
further evaluation such as the edrophonium test and
electrophysiological tests including electromyographic
measure of muscle action potential with repetitive nerve
stimulation and single-fibre electromyography may be
useful, with extensive use of the latter method in some
centres [2, 9]. Anti-muscle-specific tyrosine kinase antibody testing is also used in diagnosing seronegative myasthenia gravis [10]. Around 75% of the patients with myasthenia gravis exhibit thymic abnormalities, and it has
been suggested that the pathogenesis of the disease starts
in the thymus: 6070% have thymic hyperplasia and 10
15% have a thymoma [1, 3, 4, 11].
The epidemiology of myasthenia gravis has been investigated in conjunction with broader reviews of the disease; from the reviews available it appears that the incidence may have increased over time [12]. Following an
extensive search of the literature, no systematic review of
the incidence of myasthenia gravis has been found. Here
such a systematic literature review is presented: this has
been performed by identifying and critically appraising
published work on the incidence of myasthenia gravis
taking into account the methods used. An assessment has
been made of the likely accuracy of the rates given.

Method
Searches of the Medline (1980June 2007), Embase (1980
2007) and Science Direct (19802007) databases were conducted
using the keywords myasthenia gravis and incidence or epidemiology.
The inclusion criteria were that the studies reported original
work, that the estimates of population size and person time contributed were accurate and that no or very few incident cases were

172

Neuroepidemiology 2010;34:171183

missed. When assessing the inclusion of incident cases, papers


were evaluated as follows. (1) Did the authors ensure that all of the
subjects contributing to incidence denominator data would have
been eligible to have the disease diagnosed and did the authors
check all relevant medical records? (2) Were cases checked to ensure that they were incident and not prevalent? (3) Did the authors
ensure that the cause of myasthenia gravis was autoimmune, i.e.
not congenital and not secondary to another disease or drug?
Where possible we only included incidence rates for cases of myasthenia gravis caused by autoimmunity, the determination of
which relied on information given in the paper.
The titles and abstracts of all of the studies produced by the
searches were reviewed. For those meeting the criteria for the
study, full text papers were appraised. Studies published in English, French, German, Spanish or Dutch were included. Review
papers identified were searched for secondary references reporting on original research; secondary references found from any of
the other papers reviewed were also appraised.
A standard data abstraction form was used to record all details
of the papers appraised (appendix). Each study was classified as
being at low, medium or high risk for under- or overestimation of
reported incidence rates by considering the reliability of numerator and denominator data. For instance, inclusion of prevalent
cases or those thought not to be caused by autoimmunity will have
led to overestimated rates as will underestimated denominator
data. Conversely, missing cases or an overestimated denominator
(e.g. a catchment area from which not all inhabitants had access
to hospital services) would be considered to result in underestimated incidence rates. Explanations provided by the papers authors as to why the incidence rates were as expected or whether
they were considered to be an over- or underestimate of the true
incidence rate were taken into account in this process. If the extent of likely inaccuracy in rate was considered to be very great,
the study was excluded. To minimise subjectivity, this assessment
was agreed between the authors and random checks were performed to ensure consistency. The rates are presented as the number of cases/1,000,000/year and where sufficient data were given
in the paper, the rates were checked for accuracy.

Results

The results from the database searches are given in


figure 1; references for the papers rejected are available
from the authors on request. The summaries of the studies included and the overall incidence rates are given in
table 1; the incidence rates by age band are displayed in
table 2 and those by decade in figure 2.
Of the papers rejected, over half either did not report
on myasthenia gravis or incidence. Other key reasons
for rejecting papers were that the papers focused on
treatment of the disease, they only included patients already diagnosed as having myasthenia gravis or the patients had myasthenia gravis associated with another
disease.

McGrogan /Sneddon /de Vries

Incidence Rates
Geographical Variation
Most of the studies included in this review reported on
incidence rates for populations in Europe: the rates from
1970 to 2000 varied between 4.1 [13] and 30/1,000,000/
year [14]. Six studies reported on regions outside Europe:
Tanzania, Hong Kong, Japan, North America, Cuba and
Curaao and Aruba and the incidence rates found in
these areas ranged from 3.0 to 9.1/1,000,000/year.
Variation with Age and Sex
In most studies reporting incidence rates for males
and females separately, the incidence increased with increasing age. In studies of incidence rates in males, the
rates increased up to the 60- to 80-year age band in most
studies [13, 1525], with 2 showing an increase to the 40year age band [26, 27] and 2 reporting fluctuations in rate
with age but an overall increase [28, 29]. In females, there
was more fluctuation in incidence rates with age with
some studies showing a peak in incidence at 2040 years
and then a second one at 5070 years [15, 17, 1923, 26,
27, 29], others just had a peak in incidence in the latter age
band [13, 18, 24]. In some studies [13, 20, 22, 25, 29, 30]
the incidence in the elderly (65 or 70 years upwards) was
reported to be 0/1,000,000/year, which indicates possible
underdiagnosing or misdiagnosing of patients in this
group [20, 30].
In children (019 years) the incidence in males was
low (up to 3/1,000,000/year) and did not show an overall
association with age; in females it was higher (up to
11/1,000,000/year [24]) and increased with increasing
age.

849 papers identified in


database search

798 papers rejected after


abstract review

51 full papers appraised

12 secondary papers
appraised
32 papers rejected

31 full papers included


in review

Fig. 1. Results of the database searches and subsequent filtering.

Variation over Time


Between 1970 and 1990 the incidence rates reported
were mainly between 3.0 and 6.0/1,000,000/year [13, 16,
17, 25, 26, 3135]. From 1990 onwards they were higher
(6.030.0/1,000,000/year) [1315, 18, 19, 2124, 27, 28, 33,
3638]. Most of these studies were prospective or used
more comprehensive methods of case identification than
the earlier investigations.

conducted solely in hospital departments and did not


search for cases that were not diagnosed in hospital. The
fourth study, which produced the highest rate of 30/
1,000,000/year, had patients referred to a clinic run by the
study group but also used 6 other sources of data, from
primary and secondary care, to ensure all cases were included. This is thought to be the most accurate incidence
rate of myasthenia gravis.
Typical rates found by studies conducted retrospectively were between 4 and 10/1,000,000/year. Two exceptions to these were Casetta et al. [23], who included 1 year
of prospectively collected data in their 16-year study, and
Vincent et al. [15], who were likely to have overestimated
the incidence by potentially including cases not autoimmune in origin or secondary to other diseases. The majority of studies determined incidence using the date of
diagnosis of the disease. Two papers reported incidence
rates at onset and diagnosis for the same time periods
finding a slightly higher incidence rate at diagnosis compared to onset [16, 28].

Variation by Study Method


The main difference between the incidence rates can
be explained by the method used: of the 5 prospective
studies, 4 produced the highest rates, between 11.1 and
30/1,000,000/year [14, 24, 28, 36]; the fifth from Tanzania
reported a lower rate that may be due either to using inaccurate denominator estimates or a true lower incidence in
Africa compared to Europe [39]. Of these 4 studies 3 were

Accuracy of Rates
The main causes of missing cases in the studies were
mild symptoms or cases being diagnosed and managed in
primary care but the case finding strategy of the incidence
study only including secondary care records [1618, 20
25, 27, 30, 37, 40, 41], death before a diagnosis was made
[17, 21, 22, 27, 42] and misdiagnosis [36, 42]. Most studies
used similar methods and criteria for diagnosing cases

Incidence of Myasthenia Gravis

Neuroepidemiology 2010;34:171183

173

174

Neuroepidemiology 2010;34:171183

McGrogan /Sneddon /de Vries

As above

Retrospective: databases reviewed and some neurologists


19751989
contacted; MW, RF in 1/more muscle groups or significant
response to AChE drugs; used Osserman/Osserman and
Genkins classification

Retrospective: database records and neurologists contacted; 19901999


antibodies against AChR, abnormal EMG or response to
acetylcholinesterase inhibitors in addition to variable
ocular, bulbar or MW; diagnosis of thymoma made
histologically; diagnosis checked against checklist
Retrospective: hospital and database and prescription
records; clinical features and positive Desmedt test during
RNS; anti-AChR antibody titre also measured

Nagano Prefecture,
Honshu Island, Japan

Norway

East Denmark
(East of the Great Belt)

Eastern Denmark

Peninsula of Jutland
and several islands,
Western Denmark
Viborg County,
Denmark

Amsterdam,
The Netherlands

Northern Region of
South Holland,
The Netherlands

Trento
(Northern Italy)

Matsuda et al. [33]


Risk of underestimationa
Risk of overestimationa
Cases: 213

Storm-Mathisen [16]
Risk of underestimationb
Risk of overestimationa
Cases: 557

Somnier et al. [30]


Risk of underestimationb
Risk of overestimationa
Cases: 182

Somnier and Engel [13]


Risk of underestimationb
Risk of overestimationa
Cases: 397

Christensen et al. [17]


Risk of underestimationa
Risk of overestimationb
Cases: 22

Sorenson and Holm [41]


Risk of underestimationb
Risk of overestimationb
Cases: 36

Oosterhuis [31]
Risk of underestimationb
Risk of overestimationa
Cases: 17

Wirtz et al. [18]


Risk of underestimationb
Risk of overestimationa
Cases: 110

Ferrari and Lovaste [29]


Risk of underestimationa
Risk of overestimationb
Cases: 33

19511981
incidence:
diagnosis
onset

19821986
19871991
19921996
19972001

19751987

Retrospective: hospital records and archives reviewed;


FMW which improved with rest, positive response to
AChE drugs; classified according to Osserman; anti-AChR
tests performed once available

Retrospective: hospital records of cases diagnosed by


neurologists; MW with recovery after rest and positive
response to AChE test

19811990

19611965

19731987

19701979
19801989
19901999

Retrospective: lab results, hospital records, databases;


19701987
typical history, clinical findings, pharmacological tests,
neurophysiological examination, laboratory tests; incidence
at onset7

Retrospective: hospital records reviewed;


according to accepted criteria: few details given

Retrospective: hospital records and information from GPs;


records reviewed by doctor; FMW, positive response to
ECT; Anti-AChR tests available from mid 1980s and RNS
tests at low frequency; disease severity according to MGFA;
incidence at onset7

Retrospective: letters sent to hospital and GPs; records


reviewed; clinical features, either positive intravenous
ECT or decremental response to RNS; classified according
to Osserman and Genkins/Bundey/Engel

Hong Kong
(Chinese only)

Yu et al. [32]
Risk of underestimationb
Risk of overestimationa
Cases: 202

19881998

Prospective study; clinical diagnosis based on positive


fatigue test or ECT test; Ossermans classification used

Dar es Salaam,
Tanzania (African)

Matuja et al. [39]


Risk of underestimationb
Risk of overestimationb
Cases: 47

Period

Study details and diagnostic test/criteria

Location

Study

Table 1. Summaries and incidence rates for studies included in the systematic review

7.4 (4.9, 9.9)1, 8


5.6 (3.4, 7.8)1, 8

3.1 (1.8, 5.0)1

10.41

5.0 (4.4, 5.7)1

4.1
5.8
7.9

4.4

4.5 (2.4, 8.5)1


3.6 (1.8, 7.2)1
4.5 (2.4, 8.3)1
6.9 (4.2, 11.4)1

4.01

3.0 (2.0, 3.6)

both

All
4.61
All (excl. 3.21
thymoma
cases)

101
7.81

4.7 (2.5, 8.0)1

5.9 (4.9, 7.0)1

5.0

5.3 (4.9, 6.1)1, 8


4.8 (4.3, 5.5)1, 8

5.5 (2.5, 12.0)1


4.2 (1.7, 10.0)1
6.1 (2.9, 12.7)1
9.0 (4.9, 16.5)1

female

6.5 (5.4, 7.8)

1.5 (0.4, 3.8)1

4.2 (3.4, 5.5)1

3.7

2.6 (2.3, 3.1)1, 8


2.2 (1.9, 2.7)1, 8

3.5 (1.3, 9.5)1


3.1 (1.1, 8.7)1
2.8 (1.0, 8.3)1
4.8 (2.1, 11.1)1

male

Rate/1,000,000 /year

All

All

All

All

All
All
All

All

All

All

All

All

Age

Incidence of Myasthenia Gravis

Neuroepidemiology 2010;34:171183

175

Province of Ferrara,
Emilia-Romagna
Region, Italy

Emilia-Romagna
(7 provinces), Italy

North-West Sardinia,
Italy

Casetta et al. [23]


Risk of underestimationa
Risk of overestimationa
Cases: 119

Emilia-Romagna
Study Group [28]
Risk of underestimationa
Risk of overestimationa
Cases: 86

Aiello et al. [27]


Risk of underestimationb
Risk of overestimationa
Cases: 27

All

19801994

Greece

UK (9 centres
carrying out most
tests in the UK)
Cambridgeshire, UK

Poulas et al. [40]


Risk of underestimationc
Risk of overestimationb
Cases: 733

Vincent et al. [15]


Risk of underestimationb
Risk of overestimationb
Cases: 2,795

Robertson et al. [36]


Risk of underestimationb
Risk of overestimationa
Cases: 38

Prospective study; 3 or more of the following: typical


history, evidence of fatigability with recovery, response
to AChE drugs, detection of anti-AChR antibodies,
decrement of electrical activity on RNS, exclusion of
other diagnoses; used Ossermans classification

Retrospective: lab test archives; positive anti-AChR test

19921997

19971999

19831997

Prospective study; clinical features, neurologic examination 19932000


and response to the edrophonium test with RNS, abnormal
EMG or anti-AChR test

County of Osona,
Barcelona, Spain

Aragones et al. [24]


Risk of underestimationb
Risk of overestimationa
Cases: 26

Retrospective study: lab test archives and interview; only


seropositive cases based on anti-AChR tests; incidence at
onset7

Retrospective study: hospital records reviewed; abnormal


fatigue, MW, response to administration of AChE and
decremental EMG response; incidence at onset7

Sardinia, Italy

19581986
19581967
19681977
19781986

19821994

19931994

Giagheddu et al. [26]


Risk of underestimationb
Risk of overestimationa
Cases: 110

Retrospective: hospital records and GPs contacted;


surviving patients examined; clinical, neurophysiological
and conventional pharmacological findings; response to
AChE, RNS, EMT; Osserman and Genkins classification;
incidence at onset7

Prospective study; FMW or response to AChE drugs and


electrophysiologic findings; positive anti-AChR antibody
tests considered confirmatory, but absence of anti-AChR
did not preclude inclusion

24 (19, 30)1

17 (13, 23)1

All

All

All

All

All

All

11.11

18

4.8 (4.1, 5.5)1

5.0 (4.3, 5.7)1

4.6 (3.9, 5.2)1

2.7
1.7
2.3
3.0

8 (5, 12)1

21.3 (13.9, 31.2)1

3.9

9 (5, 15)1

14.7 (11.8, 18.2)


10.8 (8.3, 13.8)

21 (17, 25)1

7.8 (5.8, 10.3)1

3.1

16.7 (4.8, 18.4)1 25.7 (9.1, 26.0)1

1.4

6 (3, 11)1

15.6 (11.4, 20.1)


12.6 (8.9, 17.3)

9.3 (6.3, 13.5)1

6.6 (3.8, 9.7)1

All
Diagnosis 13.8 (9.8, 21.3)
onset
8.3 (5.7, 13.1)

All

All

19691989

Retrospective: hospital records and GPs contacted(1993


19852000
1994 used prospective data [28]); FMW, response to AChE
drugs, electrophysiologic findings; positive anti-AChR tests
considered confirmatory but absence did not preclude inclusion; response to immunosuppressive therapy considered confirmatory of AI aetiology; incidence at onset7

Reggio Emilia Province, Retrospective: hospital department records,


GPs contacted; typical history and clinical findings
Emilia-Romagna
Region, Northern Italy aggravated weakness by repeated muscle contraction with
recovery at rest, improvement in MW after administration
of AChE drugs, reduction in electrical amplitude on RNS,
detection of anti-AChR antibodies; Ossermans
classification scheme

Guidetti et al. [19]


Risk of underestimationa
Risk of overestimationa
Cases: 49

Retrospective: hospital records reviewed; received AChE


medication; records from department of neurology,
ophthalmology, chest surgery and intensive care checked

North-East Italy

Angelini et al. [34]


Risk of underestimationc
Risk of overestimationb
Cases: not given

176

Neuroepidemiology 2010;34:171183

McGrogan /Sneddon /de Vries

19761996
Retrospective: database records; typical history,
clinical findings including weakness by repeated muscle
contraction with recovery at rest, improvement with AChE
drugs, reduction in electrical amplitude on RNS, detection
of anti-AChR antibodies
Retrospective: hospital and GP records; FMW and positive
response to AChE drugs; other tests also carried out;
Ossermans classification used; incidence at onset7
Retrospective: hospital records; FMW, involvement of
voluntary muscles, fatigue, improvement with AChE

County of the
Coast and Gorskikotar,
Croatia

Belgrade, Yugoslavia

Benghazi, Libya

Zivadinov et al. [22]


Risk of underestimationb
Risk of overestimationa
Cases: 43

Lavrnic et al. [21]


Risk of underestimationb
Risk of overestimationa
Cases: 124

Radhakrishnan et al. [25]


Risk of underestimationc
Risk of overestimationa
Cases: 9

Retrospective: hospital records, some cases interviewed;


unequivocal clinical features: positive reaction to AChE
and/or positive anti-AChR test and/or decrement of
compound muscle action potential

Curaao and Aruba


(near Venezuela)

Holtsema et al. [42]


Risk of underestimationb
Risk of overestimationb
Cases: 15

19801995

Retrospective: hospital records; diagnosis made on clinical 19771981


and electromyographic material using Engels classification 19871991

Cuba

Cisneros et al. [35]


Risk of underestimationb
Risk of overestimationc
Cases: 131

19701984

Central and Western


Virginia, USA

Phillips et al. [43]


Risk of underestimationb
Risk of overestimationb
Cases: 73

Retrospective: hospital records, discharge diagnoses and


patient group records; diagnosis on basis of muscle
weakness and fatigability and by neurologist; in most
patients an edrophonium test and electromyographic
studies undertaken and in later years AChR antibody tests

19831986

All

All
All

All

All

All

All

19701996

Estonia

Oopik et al. [20]


Risk of underestimationa
Risk of overestimationb
Cases: 162

19901997

All

Retrospective: lab test database and medical records;


19942001
only seropostive MG; acetylcholine receptor antibody assay

Tayside, Scotland

Farrugia [38]
Risk of underestimationa
Risk of overestimationc
Cases: 44
Retrospective: hospital records reviewed; FMW, positive
response to AChE drugs; doubtful diagnoses discussed;
all suspected cases seen by a neurologist

All

Prospective study; diagnoses checked by neurologist

13 GP practices in
the London area, UK

All

All

Age

MacDonald et al. [14]


Risk of underestimationa
Risk of overestimationa
Cases: not given
19951996

Retrospective: patients referred to 1 consultant neurologist; 19871994


no diagnostic criteria given

Croydon, UK

Schon et al. [37]


Risk of underestimationb
Risk of overestimationa
Cases: 22

Period

Study details and diagnostic test/criteria

Location

Study

Table 1 (continued)

6.8 (4.9, 9.1) 1, 5

8.36

6.81, 2

5.3 (3.8, 7.1)1, 5

5.86

2.11, 2

4 provinces
4 different
provinces

4.9 (4.0, 5.9)1, 4

female

2.5 (1.8, 3.3)1, 4

male

Rate/1,000,000/year

4.7 (2.3, 7.0)1, 8

5.6 (4.5, 6.7)1, 8


2.9 (1.9, 3.9)1, 8

9.1

4.41, 2

7.16

6.2 (4.5, 8.4)1, 5

3.7 (3.2, 4.3)1, 4

10.51

30 (8, 70)3

9.1 (5.7, 13.8)1

both

including detection of anti-AChR antibodies and identification of clinical features such as abnormal fatigue and
patient response to treatment. Three studies [21, 38, 40]
only included patients who were seropositive for antiAChR antibodies, which will have underestimated the incidence rates by about 15% [1, 4, 40]. Ten investigations
used census or other national statistics data for their denominator [21, 22, 24, 27, 29, 31, 36, 39, 40, 43], one did not
give any denominator data [13] and the others provided
denominator estimates but did not give their source.
Overestimation of incidence rates was thought to be
unlikely where specialists diagnosed or reviewed the cases included [14, 16, 18, 19, 2427, 29, 32, 36, 37]; other
studies reported reliable case identification [40], using a
3-year follow-up period to ensure correct diagnosis [23]
and a regular clinical follow-up to exclude questionable
cases [13]. Another important factor in reducing the possibility of overestimating cases is owing to the changes
that have taken place in diagnosing myasthenia gravis
[22, 28, 33, 36]: Oosterhuis [31] reported that he retested
patients with a diagnosis established before 1985 who
were still alive and traceable and found that 26 of 29 patients were positive for anti-AChR antibodies; the remaining patients were thought to have had seronegative
myasthenia gravis.

Discussion

Myasthenia gravis was first described in 1672 [7], but


the majority of research into its diagnosis and treatment
took place between 1950 and 1980 [5]. To a certain extent
this is reflected by the incidence rates found: the earliest
studies gave the lowest rates. It is likely that earlier figures
underestimate the true incidence rate owing to incom-

Table footnote
Figures in parentheses are 95% confidence limits. Incidence rates given/1,000,000/year; risk of under- or overestimation: low (a), medium (b), high
(c). ECT = Edrophinium chloride test; MGFA = Myasthenia Gravis Foundation of America; FMW = fluctuating muscle weakness; MW = muscle weakness; AChE = anticholinesterase; RNS = repetitive nerve stimulation; EMT =
eye movement tests; RF = rapid fatigue; AI = autoimmune. 1 Incidence rate
confirmed using data given in paper; 2 age-adjusted to the Libyan population;
3
age- and sex-adjusted to the UK population; 4 age- and sex-adjusted to the
world standard population; 5 age-adjusted to 1991 Croatian population;
6
standardised to Dolls world population; 7 no details given about criteria
used for diagnosis at onset; Somnier et al. [30] note that onset can be up to
2 years before diagnosis; incidence at diagnosis unless otherwise specified;
8 95% confidence limits calculated from data given in paper.

Incidence of Myasthenia Gravis

plete knowledge of the disease and limited methods of


diagnosis.
In this systematic review of the incidence of myasthenia gravis, the most reliable estimates found were
30/1,000,000/year with the majority of studies originating in Europe. Most of the studies were conducted in a
similar way using a retrospective review of medical records, which enhanced the comparability although the
prospective studies are thought to provide more reliable
estimates of incidence rates owing to their comprehensive case finding methods. No papers were found that
covered populations in South America, Australia or New
Zealand. This triggers questions about the incidence in
these areas and whether it is similar to that in Europe.
Only 1 study each was included from Africa and the Middle East, with 2 included from Asia and the Caribbean.
This is in line with other work that suggests fewer studies
of autoimmune disease incidence have been conducted in
these areas of the world compared with Europe, North
America and Australasia [44, 45]. Matuja et al. [39] commented there was a lower awareness of the disease among
health care professionals and patients in sub-Saharan Africa. In addition the health care systems here are less
comprehensive compared to more developed countries,
which can make this type of study more difficult.
Patterns of incidence with age and sex were reported
and overall it was found that the incidence increased with
increasing age in males and females with a bimodal trend
in incidence in females [1]. In the elderly, the cases of myasthenia gravis are thought to be underreported because
they are mistaken for other conditions such as stroke or
motor neurone disease; the management of other chronic diseases in this age group may take precedence [15].
Most studies reported their highest incidence rates in the
60- to 80-year age band; however, this is likely to still underestimate the true rate in this age group. It is unlikely
there has been a selective increase in myasthenia gravis
in older people [37], rather that more cases in the elderly
are detected and diagnosed.
One of the main reasons for missing incident cases of
myasthenia gravis in the studies included was that mild
or GP-diagnosed cases are not always referred to tertiary
care and therefore will have been missed when only tertiary care records were used for case identification; mild
forms of myasthenia gravis are also difficult to diagnose.
In contrast, very severe cases of myasthenia gravis may
die before a diagnosis has been made, which should also
be taken into account when considering the incidence
rates presented. Records of deaths were checked in 3 of
the studies [16, 19, 22]. The incidence of myasthenia graNeuroepidemiology 2010;34:171183

177

Table 2. Incidence rates of myasthenia gravis by age band


Study

Sex

Age bands and incidence rates/1,000,000/year

M
F

04
2.51, 2
0.11, 2

59
01, 2
0.91, 2

1014
0.11, 2
4.31, 2

1519
0.21, 2
6.31, 2

2024
3.31, 2
9.71, 2

2529
3.71, 2
2.61, 2

3034
3.71, 2
5.91, 2

3539
1.31, 2
7.01, 2

4044
2.21, 2
3.91, 2

4549
2.41, 2
4.21, 2

M
F

04
0
1

59
1
0

1014
1
1

1519
3
6

2024
3
17

2529
6
17

3034
3
15

3539
8
18

4044
8
11

4549
14
14

M
F

09
0.1 (0, 0.3)4
0.42 (0, 0.9)4

1019
0.98 (0.4, 1.7)4
4.6 (3.3, 6.2)

2029
2.09 (1.1, 3.2)4
8.6 (6.7, 11.0)4

3039
2.74 (1.6, 4.1)4
8.2 (6.3, 10.7)4

4049
3.7 (2.4, 5.3)4
6.1 (4.5, 8.2)4

M
F

09
1.01
0.21

1019
0.51
5.01

2029
3.01
6.51

3039
2.51
6.01

4049
2.41
5.01

M
F
B

09
0.7 (0.1, 2.6)
1.5 (0.4, 3.8)
1.1 (0.4, 2.4)

1019
1.2 (0.3, 3)
4 (2.1, 6.8)
2.6 (1.5, 4.1)

2029
2.2 (0.9, 4.6)
7 (4.4, 10.6)
4.6 (3.1, 6.7)

3039
2.1 (0.9, 4.4)
6.1 (3.7, 9.5)
4.1 (2.6, 6.1)

4049
2.1 (0.7, 4.8)
5.1 (2.6, 8.8)
3.6 (2.1, 5.7)

M
F

09
0
2.2

1019
2.2
5.4

2029
0.8
4.5

3039
1.6
4.0

4049
1.8
5.0

M
F
B

09
7 (0, 17)4
0
4 (0, 9) 4

1019
2 (0, 7)4
5 (0, 13)4
4 (0, 8)4

2029
2 (0, 7)4
11 (1, 21)4
7 (1, 12)4

3039
7 (1, 15)4
14 (3, 25)4
10 (4, 17)4

4049
5 (2, 11)4
5 (0, 12)4
5 (0, 9)4

M
F
B

09
4.1
0.0
2.1

1019
0.0
3.1
1.5

2029
0.0
14.8
7.2

3039
9.2
13.1
11.1

4049
6.9
10.2
8.6

Giagheddu et al.
[26]
M
F
B

010
0.0
0.5
0.2

1120
1.0
4.7
2.8

2130
0.9
4.4
2.7

3140
1.1
5.7
3.4

4150
4.0
5.2
4.6

Oopik et al.
[20]

M
F
B

09
1.3 (0.3, 3.3)
0.7 (0.1, 2.49)
1 (0.4, 2.2)

1019
2.7 (1.2, 5.4)
5.9 (3.4, 9.5)
4.2 (2.7, 6.3)

2029
1.6 (0.5, 3.6)
5.8 (3.4, 9.2)
3.7 (2.3, 5.5)

3039
2.2 (0.8, 4.7)
7.4 (4.6, 11.3)
4.8 (3.2, 7)

4049
1.9 (0.6, 4.4)
4.5 (2.4, 7.7)
3.3 (1.9, 5.2)

M
F
B

09
0.01, 3
0.01, 3
0.01, 3

1019
0.01, 3
8.01, 3
4.51, 3

2029
4.01, 3
13.61, 3
8.21, 3

3039
3.41, 3
12.91, 3
7.21, 3

4049
5.81, 3
5.81, 3
5.81, 3

M
F
B

09
0.0
0.0
0.0

1019
3.1 (0, 13.6)
9.4 (0, 28.3)
6.2 (0, 13.8)

2029
4.0 (0, 19.7)
19.1 (0, 51.9)
11.5 (0, 24.3)

3039
0.0
8.5 (0, 33.0)
4.3 (0, 13.2)

4049
20.3 (0, 65.3)
0.0
9.8 (0, 24.9)

2029
4.0
8.3
6.2

3039
3.4
9.2
6.4

4049
4.1
9.9
7.0

Somnier et al.
[30]
Vincent et al.
[15]
StormMathisen
[16]
Somnier and
Engel [13]
Christensen
[17]

Wirtz et al.
[18]
Guidetti et al.
[19]

Ferrari and
Lovaste [29]

Lavrnic et al.
[21]

Aiello et al.
[27]

Zivadinov et al.
[22]
M
F
B

019
2.6
0.0
1.4

Casetta et al.
[23]

014
01
41
21

178

M
F
B

Neuroepidemiology 2010;34:171183

1524
31
111
71

2534
141
291
211

3544
151
261
211

McGrogan /Sneddon /de Vries

4554
231
241
241

Age bands and incidence rates/1,000,000/year


5054
01, 2
3.21,2

5559
8.81, 2
5.81, 2

6064
3.81, 2
6.51, 2

6569
12.21, 2
6.31, 2

7074
18.91, 2
9.41,2

7579
111, 2
6.61, 2

8084
16.11, 2
4.11, 2

8589
0.01, 2
4.31, 2

9094
0.01
0.01

5054
19
21

5559
25
21

6064
36
21

6569
67
39

7074
86
38

7579
94
47

8084
89
43

8589
72
29

9094
39
17

5059
3.7 (2.4, 5.3)4
5.3 (3.8, 7.3)4

6069
7.0 (4.9, 9.6)4
5.0 (3.3, 7.1)4

7079
3.5 (1.4, 5.8)4
6.7 (4.2, 9.6)4

80+
5.0 (0.6, 9.7)4
2.7 (0.1, 5.5) 4

5059
5.51
7.01

6069
13.01
8.01

7079
23.01
12.51

8089
20.01
14.01

5059
5.2 (2.6, 9.2)
7.3 (4.1, 9.2)
6.2 (4.1, 9)

6069
15.1 (10.3, 21.1)
9.7 (5.9, 15)
12.4 (9.2, 16.3)

7079
14.1 (8.3, 22.3)
11.7 (7, 18.3)
12.9 (9, 17.1)

80+
8.6 (2.3, 22.1)
1.3 (0, 7.2)
5 (1.6, 11.6)

5059
6.0
8.0

6069
26.5
18.5

7079
28.5
22.4

80+
24.0
17.0

5059
7 (1, 16)4
10 (0, 19)4
8 (2, 15)4

6069
11 (0, 23)4
17 (5, 30)4
15 (6, 23)4

>70
10 (0, 21)4
9 (0, 17)4
9 (2, 16)

5059
7.7
3.6
5.6

6069
10.1
20.1
15.7

70+
0.0
14.1
8.9

5160
3.3
3.6
3.4

6170
2.9
5.9
4.5

70+
0.9
2.2
1.6

5059
3.6 (1.6, 7.1)
5.9 (3.4, 9.4)
4.9 (3.2, 7.2)

6069
4.5 (1.5, 10.5)
9.7 (5.8, 15.1)
7.8 (5, 11.6)

7079
10.5 (4.5, 20.6)
4.1 (1.6, 8.4)
6.0 (3.4, 9.9)

8089
0.0 (0, 14.2)
0.0 (0, 4.1)
0.0 (0, 3.2)

5059
11.51, 3
7.51, 3
9.81, 3

6069
27.01, 3
9.01, 3
16.51, 3

7079
29.31,3
20.81, 3
23.41, 3

80+
0.01, 3
12.61, 3
7.01, 3

5059
11.7 (0, 50.6)
16.0 (0, 57.9)
13.9 (0, 34.3)

60+
13.6 (0, 46.2)
11.0 (0, 34.7)
12.1 (0, 25.9)

5059
11.4
9.6
10.6

6069
15.3
4.6
9.1
5564
381
321
351

Incidence of Myasthenia Gravis

9099
01
41

70+
0.0
15.9
10.6
6574
281
261
271

75+
121
281
221

Neuroepidemiology 2010;34:171183

179

Table 2 (continued)
Study

Sex

Age bands and incidence rates/1,000,000/year

EmiliaRomagna
Study Group
[28]

M
F
B

014
0.01
3.31
1.61

Matuja et al.
[39]

019
2.2 (1.4, 3.4)

Aragones et al.
[24]
M
F
B

014
0.0
10.8
5.0

Radhakrishnan et al.
[25]

020
0.0
6.7
3.3

M
F
B

1524
0.01
11.31
5.51

2534
4.31
13.71
8.91

3544
2.51
7.61
5.01

4554
15.11
12.21
13.61

2039
3.2 (2, 4.9)

4059
3.3 (1.4, 6.8)

2039
0.0
13.3
6.5

4059
7.5
0.0
4.0

1564
12.0
17.0
14.7

Figures in parentheses are 95% confidence limits. 1 Incidence rate read from graph; 2 age- and sex-standardised; 3 age- and sex-standardised to the
world population according to Doll; 4 95% confidence intervals calculated from data given in paper.

Incidence rate (/1,000,000/year)


Ref.
No.
30
30
13
20
16
26
30
30
13
20
16
26
30
30
13
20
16
26
30
30
13
20
16
26
30
30
13
20
16
26
30
30
13
20
16
26
30
30
13
20
16
26
26
30
30
13
20
16
16
30
30
13
20
30
a 13

180

Age
0
(years)
04
59
09
09
09
010
1014
1519
1019
1019
1019
1120
2024
2529
2029
2029
2029
2130
3034
3539
3039
3039
3039
3140
4044
4549
4049
4049
4049
4150
5054
5559
5059
5059
5059
5160
6064
6569
6069
6069
6069
6170
70+
7074
7579
7079
7079
7079
80+
8084
8589
8089
8089
9094
9099

20

40

60

80

100
Males
Females

Neuroepidemiology 2010;34:171183

Ref.
No.
17
19
29
27
22
25
17
19
29
27
17
19
29
27
22
17
19
29
27
22
25
17
19
29
27
22
25
17
19
29
27
22
17
19
29
22
27
25
17
19
29
22
b 17

Age
(years) 0
09
09
09
09
019
020
1019
1019
1019
1019
2029
2029
2029
2029
2029
3039
3039
3039
3039
3039
2039
4049
4049
4049
4049
4049
4059
5059
5059
5059
5059
5059
6069
6069
6069
6069
60+
60+
7079
70+
70+
70+
80+

Incidence (/1,000,000/year)
20

40

60

80

100
Males
Females

McGrogan /Sneddon /de Vries

Age bands and incidence rates/1,000,000/year


5564
10.51
9.81
10.21

6574
32.31
28.41
30.11

75+
10.91
12.31
11.81

60+
3.4 (0.6, 11.3)
65+
55.9
65.8
62.4
60+
13.9
0.0
7.2

Ref.
No.
15
15
18
21
40
23
28
24
15
15
18
21
23
28
15
15
18
21
23
28
15
15
18
21
40
23
28
15
15
18
21
23
28
15
15
18
21
40
23
28
15
24
15
18
21
40
23
28
24
15
15
23
28
18
21
18
21
15
15
c 15

Age
(years) 0
04
59
09
09
019
014
014
014
1014
1519
1019
1019
1524
1524
2024
2529
2029
2029
2534
2534
3034
3539
3039
3039
2039
3544
3544
4044
4549
4049
4049
4554
4554
5054
5559
5059
5059
4059
5564
5564
6064
1564
6569
6069
6069
60+
6574
6574
65+
7074
7579
75+
75+
7079
7079
80+
80+
8084
8589
9094

Incidence (/1,000,000/year)
20

Incidence of Myasthenia Gravis

40

60

80

100
Males
Females

Fig. 2. Incidence rates of myasthenia gravis by age band and sex for the 1970s (a),
1980s (b) and 1990s (c).

Neuroepidemiology 2010;34:171183

181

vis was not reported on with reference to disease subtype


but in the papers that reported the numbers of cases by
subtype, the most frequently diagnosed were the mildgeneralised, moderate-severe generalised and ocular subtypes [3033, 36].

Conclusion

The most accurate estimate of incidence of myasthenia gravis was found to be around 30.0/1,000,000/year
(95% CI 870), with the incidence in children and
adolescents aged 019 years being between 1.0 and 5.0/
1,000,000/year. Few studies of incidence rates in popula-

Appendix

Ref Manager ID
Year published

tions from outside Europe have been published. Therefore, it is not possible to comment on the geographical
variation of rates. Improvements in the diagnosis of myasthenia gravis and a greater knowledge of the disease
have led to an apparent increase in incidence over time.
Although case identification in older people has improved with time, it is likely that the incidence in this
group of people is still underestimated.
Acknowledgements
This work was supported by a grant from GSK Biologicals. The
authors are grateful to Dr. Nicola Giffin, consultant neurologist,
for helpful comments on an earlier draft of the manuscript.

Case definition

Risk of missing cases

Reasons

Low
Medium

Reviewer

High
Original in English?

Number of cases
Translation

Base population:
person years

Risk of overestimating cases

Base population:
number of people

Excluded?

Reason for exclusion


Secondary references

Source of case identification

Notes

Country
Study dates
Region
Run in period

Ref Manager ID

Race
Other ethnic origin

Ethnic distribution

Type of rate
Incidence

Units
Lower CI

Upper CI

Gender
Multiple locations?

Time period

Figures checked?
Figures correct?

Other descriptor
Notes
Age range

182

Neuroepidemiology 2010;34:171183

McGrogan /Sneddon /de Vries

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