Associated conditions in myasthenia gravis: response to thymectomy

J. F. Te llez-Zenteno
a
, G. Cardenas
b
, B. Estan ol
a,c
, G. Garcia-Ramos
c
and N. Weder-Cisneros
a
Departments of
a
Neurology and
b
Internal Medicine, and
c
Neurophysiology Laboratory, Instituto Nacional de Ciencias Medicas y Nutricion,
Salvador Zubiran, Delegacion Tlalpan, Mexico
Keywords:
associated conditions,
immunological diseases,
myasthenia gravis, preg-
nancy, prognosis,
response, thymectomy
Received 30 December 2003
Accepted 28 March 2004
To compare the response of thymectomy in patients with associated conditions
(PWAC) and without associated conditions (PWOAC). Comparative, retrospective.
198 patients with the established diagnosis of myasthenia gravis who had a thymec-
tomy between 1987 and 2000, and who were folowed up for at least 3 years. We
formed two groups, one with associated conditions and the second without associated
conditions. The patients were divided into four groups: (i) patients in remission, (ii)
patients with improvement, (iii) patients without changes, and (iv) patients whose
condition worsened. Associated conditions (AC) were found in 49 patients (26%). The
main associated conditions were hyperthyroidism in 16 patients (33%) hypothyroid-
ism in seven (14%), rheumatoid arthritis in ve (10%) and hypothyroidism and Sjo -
gren syndrome in three (6%). Concerning the response of thymectomy, 13 patients
WAC showed remission (27%), vs. 54 patients WOAC (39%). Twenty patients WAC
showed improvement (41%) vs. 46 WOAC (33%). Thirteen patients WAC had no
changes (27%) vs. 37 WOAC (26%). Finally, in three patients WAC their condition
worsened (6%) vs. three WOAC (2%). The response to thymectomy was high (69%)
in both groups. We did not identify signicant dierences.
Introduction
Myasthenia gravis (MG) is an acquired, neuromuscu-
lar, autoimmune disorder characterized by weakness
and fatigue of the skeletal muscles. The disorder pro-
duces a decrease of the number of acetylcholine recep-
tors in the neuromuscular plates, because of an
autoimmune process mediated by antibodies directed
against the alpha-subunit of the nicotine receptor of
acetylcholine (Drachman, 1994). Blalock et al. (1939)
reported the remission of a case of MG in a 21-year-old
patient after the surgical removal of a thymic tumor.
Currently, thymectomy is indicated as a major treat-
ment in patients with MG. The removal of the thymus
induces remissions in a high percentage of cases; allows
a decrease in the needed doses of pyridostigmine and
immunosuppressants; and produces an improvement of
the weakness. The response to thymectomy may be
delayed for months and even years after the surgery.
Remissions of the disease are produced in 35% of the
patients, and there is an improvement in more than
60% of the cases (Lanska, 1990). Among the prognostic
factors (Frist et al., 1994; Busch et al., 1996; Marino
et al., 1997; Te llez-Zenteno et al., 2001a,b) it has been
shown that patients with the most advanced Osserman
stages of the disease have greater benets from the
thymectomy than patients with ocular myasthenia.
Another factor associated with a good prognosis is
being <50 years old (Romi et al., 2003). In some
studies, others factors have been described as markers
of poor prognosis. These include patients who have
been treated for more than 2 years after the diagnosis,
as well as those who took immunosuppressants before
the thymectomy. Patients with MG have a higher
incidence of autoimmune diseases (AD) than the nor-
mal population. There are several AD associated with
MG, including: thyroid diseases, polymyositis, systemic
lupus erythematosus, rheumatoid arthritis and auto-
immune hepatitis (Garlepp et al., 1981; Marino et al.,
1997; Han et al., 2000; Tsao et al., 2000). Patients with
MG often have circulating antibodies to a variety of
tissue constituents and several studies have shown an
increased occurrence of other AD in patients with MG.
The most frequent associated condition is autoimmune
thyroid disease, which is present in 510% of patients
with MG (Ratanakorn and Vejjajiva, 2002). However,
only 0.2% of patients with thyroid disease have MG.
Genkins et al. (1987) reported several associated con-
ditions in 2110 patients with MG. The most frequent
were rheumatoid arthritis in 37 patients, systemic lupus
erythematosus in nine and thyroid disease in 158.
Furthermore, the presence of other AD may suggest a
more generalized autoimmune disturbance, which could
Correspondence: Jose Francisco Te llez-Zenteno PhD, Department of
Neurology, Instituto Nacional de Ciencias Me dicas y Nutricio n
Salvador Zubira n, Vasco de Quiroga No. 15, Colonia Seccio n XVI,
Delegacio n Tlalpan, Me xico, D.F. (tel.: 52555731200x5059; fax:
525556430741; e-mail: jftellez@quetzal.innsz.mx, liztellez@correo.
unam.mx).
2004 EFNS 767
European Journal of Neurology 2004, 11: 767773
be associated with a less favorable prognosis. However,
it is not known whether the presence of an associated
disease could worsen the prognosis of MG (Christensen
et al. (1995) reported that remission rates were lower in
MG patients with AD than in patients without AD,
suggesting that the autoimmune response in MG
patients with AD is more severe).
In this study we analyzed the ocurrence of associated
AD in a cohort of MG patients who underwent thym-
ectomy. The main objective of this study was the eval-
uation of the clinical characteristics and the prognosis
after thymectomy in MG patients with associated
conditions (WAC). We compared these data with those
of the MG patients without associated conditions
(WOAC).
Patients, material and methods
Study design
Population-based study, comparative, retrospective.
Sample design
Acohort of 198 patients with an established diagnosis of
MG that has been followed since 1987 was studied. The
diagnosis was made on clinical grounds and conrmed
by positive edrophonium chloride, serum antibodies
against acetylcholine receptor and electrophysiological
tests (Te llez-Zenteno et al., 2001a,b).
Setting
The study was performed at the Neurology Department
of the National Institute of Medical Sciences and
Nutrition Salvador Zubiran (Me xico City).
Groups of associated conditions
We formed two groups, one with patients with MG and
associated conditions, including recent or history of
pregnancy and AD (PWAC); and patients with MG
without associated conditions (PWOAC).
Serum antibodies against acetylcholine receptor
We measured AchR-binding antibodies. The antigen
required for optimal assay sensitivity is human AchR,
prepared form a mixture of innervated and denervated
muscle. The assay involves precipitation of serum IgG
and IgM antibodies that bind to solubilized AchR,
complexed with a high-anity peptide antagonist,
125
I-
labeled -bungarotoxin (-BTx). The precipitates
c-emission reects the amount of AchR bound to
immunoglobulin. The antibodies were measured before
the surgery. The antibodies were assayed in 23 PWAC
and in 62 PWOAC.
Criteria to dene improvement or deterioration after
thymectomy
To evaluate the variable response to thymectomy, a
search for two important points was performed in the
records.
1) The rst criteria was the dosage of medications that
the patient took before and after the thymectomy. For
this purpose, a table was constructed, which was lled
with the doses of medicines that patients used (predni-
sone, pyridostigmine, azathioprine and cyclophospha-
mide). In order to determine that there was a favorable
response to the treatment, a decrease of 30% in the dose
of medication was considered signicant.
2) The second parameter was the stage of the Osserman
classication before and after the thymectomy.
Study groups to dene thymectomy response
Patients in remission: patients who underwent thym-
ectomy and experienced total disappearance of their
symptoms (Osserman stage 0) and who did not need to
take any medication. Patients with improvement:
patients who underwent thymectomy and experienced
improvement of their symptoms and a decrease in the
dosage of the medications that they previously received.
The required dosage decrease in order to classify the
patient as having had an improvement had to be at
least 30% of the dose that he or she took before the
thymectomy. Patients without changes: patients who
underwent thymectomy and neither presented
improvement in the intensity of their symptoms (same
Osserman stage as before the surgery), nor showed a
decrease in the dosage of their medication. Patients
with deterioration: patients who underwent thymecto-
my and experienced a deterioration of the disease
(worsening of the Osserman stage), and an increase in
the dosage of medications that was used before the
thymectomy, or required immunosuppressive drugs like
azathioprine and prednisone. The Osserman Classi-
cation used in this study was established according to
the Myasthenia Gravis Foundation of America; grade
I: any ocular muscle weakness; grade II: mild weakness
aecting muscles other than ocular muscles; III: mod-
erate weakness aecting muscles other than ocular
muscles; IV: severe weakness aecting muscles other
than ocular muscles; and V: dened by intubation, with
or without mechanical ventilation, except when em-
ployed in routine postoperative management (Jaretzki
et al., 2000).
768 J. F. Te llez-Zenteno et al.
2004 EFNS European Journal of Neurology 11, 767773
Patients follow-up and data recollection
After thymectomy, patients were followed-up every 2 or
3 months. In each visit we reviewed the dosage of
medications, the Osserman stage and also performed a
clinical evaluation. All patients were evaluated for at
least 3 years and the nal assessment was used to dene
the response.
Compared variables in respect to thymectomy
The factors that were compared between the groups
with and without associated conditions were the fol-
lowing: age, sex, period of total duration of the disease,
time between the diagnosis and the performance of the
thymectomy, medications prior to the surgery, stage of
the disease and histological results of the thymectomy.
Statistical analysis
Descriptive statistics were used according to the type of
measurement of the variables. The odds ratio and its
condence interval were estimated at 95%. The statisti-
cal signicance of the associations was evaluated by the
chi square test, and in those cases in which the conditions
for its performance were not fullled; the exact test of
Fisher was used. The level of statistical signicance was
xed <0.05 for the bimarginal null hypothesis. Para-
metric tests (t-test) and nonparametric tests (Wilcoxon,
chi-square) were used to compare numerical variables.
Results
General characteristics
We found associated conditions (AC) in 49 patients
(26%) including pregnancy, and in 40 (21%), excluding
pregnancy. The remaining 140 patients did not have
associated conditions (74%). In the group of PWAC, 42
were female (86%) compared with 104 in the group of
PWOAC (74%). The duration between the beginning of
the symptoms and the thymectomy in PWAC had a
median time of 21.31 months (1180) vs. 18.48 (1168)
in the group of PWOAC. Finally, ve PWAC had a
history of myasthenic crises (10%), vs. 14 in PWOAC
(10%). The Osserman stages before surgery are shown
in Table 1.
Associated conditions
49 patients had associated conditions including the
following: hypothyroidism in 16 patients (33%), preg-
nancy in nine (18%), hypothyroidism in seven (14%),
rheumatoid arthritis in ve (10%) and hypothyroidism
and Sjo gren syndrome in three (6%). The remainder
conditions are shown in Table 2.
Serum antibodies against acetylcholine receptor
See description in Table 1.
Medications
Before surgery 45 PWAC (92%) were taking pyrido-
stigmine vs. 137 (98%) PWOAC. The mean dose of
pyridostigmine was 307.5 mg (60560) in PWAC vs.
319.12 mg (90720) in PWOAC. Twenty-one PWAC
were taking steroids (43%) vs. 51 (36%) PWOAC. The
mean doses in PWAC were 38.33 mg (10100) vs.
40.92 mg (5100) in PWOAC. After surgery, 39 PWAC
were taking pyridostigmine (80%) vs. 97 of PWOAC
(69%). The mean dose was 254.49 mg (15560) vs.
263.52 mg (0720) in PWOAC. Nineteen PWAC were
taking steroids (39%) vs. 28 PWOAC (20%). The mean
Table 1 General description of patients (n 189)
WAC [n 49 (26%)] WOAC [n 140 (74%)] P-value
Male 42 (86%) 104 (74%) 0.11
Age 32.54 13.38 32.19 14.44 0.87
Osserman (before surgery)
I 1 (2%) 9 (6%) 0.45
II 18 (37%) 59 (42%) 0.50
III 26 (53%) 63 (45%) 0.40
IV 3 (6%) 7 (5%) 0.72
V 1 (2%) 2 (1%) 1.0
Duration of disease in months (from the onset of symptoms to diagnosis) 29.20 (1180) 23.17 (1204) 0.28
Duration of disease in months (from the onset to the thymectomy) 21.31 (1180) 18.48 (1168) 0.57
Myasthenic crises before surgery 5 (10%) 14 (10%) 1.00
Serum antibodies against acetylcholine receptor
a
Positive 16 (70%) 54 (87%) 0.06
Negative 7 (30%) 8 (13%)
a
The antibodies were measured in 23 PWAC and in 62 PWOAC.
Associated conditions in myasthenia gravis 769
2004 EFNS European Journal of Neurology 11, 767773
dose was 24.11 mg (550) in PWAC vs. 27.93 mg
(0100) in PWOAC. Both groups had the same rate of
plasmapheresis before the surgery. In our institution we
usually use the plasmapheresis before thymectomy in
patients with Osserman IV and V, or in patients with a
lot of weackness in Osserman III. The remaining
medications are shown in Table 3.
Events related to thymectomy
Three PWAC (6%) had complications after surgery vs.
21 PWOAC (15%). The most frequent complications
after surgery were pneumonia, myasthenic crises, wound
infections, hemorrhages, diaphragmatic paralysis and
pneumothorax. Two WAC required plasmapheresis
after surgery (4%) vs. eight PWOAC (6%). There were
no deaths during and after surgery in any of the groups.
Response to thymectomy
Concerning the response to thymectomy, 13 PWAC
showed remission (27%) vs. 54 PWOAC (39%).
Twenty PWAC had an improvement (41%) vs. 46
PWOAC (33%). Thirteen patients WAC showed no
changes (27%) vs. 37 patients WOAC (26%). Finally,
three patients WAC showed deterioration (6%) vs.
three patients WOAC (2%). See results in Table 4.
Histology
One patient WAC (2%) had normal thymus histology
vs. three patients WOAC (2%). Thirty-ve PWAC had
hyperplasia (71%) vs. 90 PWOAC (64%). Thymus
atrophy was present in nine PWAC (19%) vs. 39
PWOAC (28%). Thymoma was present in three PWAC
(6%) vs. eight PWOAC (6%). The absence of thymus
was found in one patient WAC (2%).
Analysis
We compared all the characteristics in both groups and
we did not identify any dierences. We did the same
analysis excluding pregnancy cases and did not nd any
dierences either.
Discussion
Myasthenia gravis is frequently associated with other
AD (Ratanakorn and Vejjajiva, 2002). Patients with
MG often have circulating antibodies to a variety of
tissue constituents and several studies have shown an
increased occurrence of other AD. In previous studies,
the frequency of this association varied from 8 to 26%
(Drachman, 1994). The most frequently associated
conditions found were thyroid diseases (Kiessling et al.,
1981), but other conditions could be present, such as
Table 2 Associated conditions (n 49)
Associated conditions n (%)
Hyperthyroidism 16(33)
Pregnancy 9(18)
Hypothyroidism 7(14)
Rheumatoid arthritis 5(10)
Sjo gren syndrome and hypothyroidism 3(6)
Cyclic neutropenia 2(4)
Systemic lupus erythematosus 1(2)
Others (HAA, vitiligo) 6(12)
Table 3 Treatment of patients before and after thymectomy (n 189)
WAC [n 49
(26%)]
WOAC [n 140
(74%)] P-value
Pyridostigmine
Before surgery
No. of patients 45 (92%) 137 (98%) 0.61
Mean dose (mg) 307.56 (60560) 319.12 (90720)
After surgery
No. of patients 39 (80%) 97 (69%) 0.75
Mean doses (mg) 254.49 (15560) 263.52 (0720)
Steroids
Before surgery
No. of patients 21 (43%) 51 (36%) 0.65
Mean dose (mg) 38.33 (10100) 40.92 (5100)
After surgery
No. of patients 19 (39%) 28 (20%) 0.004
Mean dose (mg) 24.11 (550) 27.93 (0100)
Azathioprine
Before surgery
No. of patients 1 (2%) 6 (4%) 0.60
Mean dose (mg) 100 mg 75 (50100)
After surgery
No. of patients 5 (10%) 21 (15%) 0.08
Mean dose (mg) 70 (50100) 50 (25100)
Plasmapheresis
before surgery
6 (12%) 11 (8%) 0.38
Table 4 Osserman stage and response after surgery (n 189)
WAC [n 49
(26%)]
WOAC [n 140
(74%)] P-value
Osserman after surgery
0 (Asymptomatic) 22 (45%) 73 (52%) 0.41
I 7 (14%) 18 (13%) 0.80
II 8 (16%) 24 (17%) 1.00
III 11 (22%) 24 (17%) 0.40
IV 0 0 0
V 1 (2%) 1 (1%) 0.45
Response to surgery
Remission 13 (27%) 54 (39%) 0.16
Improvement 20 (41%) 46 (33%) 0.38
No changes 13 (27%) 37 (26%) 1.00
Deterioration 3 (6%) 3 (2%) 0.18
770 J. F. Te llez-Zenteno et al.
2004 EFNS European Journal of Neurology 11, 767773
connective tissue disorders like as lupus and rheuma-
toid arthritis, autoimmune diabetes, autoimmune
hepatitis and pemphigus (Kim et al., 1995; Meguro
et al., 2002; Te llez-Zenteno et al., 2003). In our study
the frequency of autoimmune disorders was 21% and
the main associated conditions (AC) were thyroid dis-
orders, followed by rheumatic diseases (Table 2). We
analyzed some characteristics of PWAC and PWOAC.
We could not identify signicant dierences with
respect to the general condition (Table 1). The patients
had the same age, gender, the same frequency of
myasthenic crises before thymectomy and the same
disease duration. Regarding treatment, we found some
dierences in the use of prednisone after thymectomy:
39% of PWAC took steroids vs. 20% of PWOAC. This
could be explained by the more frequent use of steroids
in patients with MG associated with autoimmune dis-
orders, such as rheumatic diseases, for example. In
Table 5 we showed the characteristics related to thym-
ectomy. The types of surgery were similar; in both
groups the percentages of transsternal and transcervical
thymectomy were the same. The complications of
thymectomy were similar too, as well as the use of
plasmapheresis and gamaglobulin after surgery.
Christensen et al. (1995) reported an epidemiological
study of MG in western Denmark. They analyzed the
occurrence, clinical characteristics and prognosis of
associated AD in MG patients. Autoimmune diseases
were found in 20 of 212 incident cases (9%) and in 30 of
220 prevalent cases (14%). The most common diseases
found were thyroid disorders and rheumatic arthritis.
Thorlacius (Thorlacius et al., 1989) reported a group of
48 patients with MG. Autoimmune disorders were
found in 11 of 48 patients (23%). The occurrence of
autoimmune disorders was the following; thyroiditis in
ve patients (10.4%), systemic lupus erythematosus in
four patients (8.3%), and rheumatoid arthritis in two
patients (4.2%). Tola (Tola et al., 1994) studied the
prevalence of immunological disorders in 47 patients
with MG; 12 of 47 (25.5%) had concurrent immuno-
logical disorders. Hypothyroidism was diagnosed in ve
patients, Graves disease in three, rheumatoid arthritis
in two, one patient had rheumatoid arthritis and Sjo -
gren syndrome and one patient had inclusion body
myosytis. In general, our study showed that the fre-
quency of autoimmune disorders is within the range of
other reported studies.
An important question that has arisen is whether
MG patients with associated AD have a poorer prog-
nosis than those without them. In this study the re-
sponse in both groups was similar after 3 years of
follow-up; we did not identify signicant dierences in
the response of the groups established in this study (see
Table 6). The benet was quite similar in both groups,
including subgroups. We performed the analysis
excluding and including pregnancy cases and the
observation was also the same. Our nding is important
because we have shown that thymectomy has the same
ecacy in patients with MG and is not related with the
presence of associated conditions. As mentioned before,
Christensen et al. (1995) (16) previously reported that
the remission rate was lower in MG patients with AD
than in patients without AD, suggesting that the
autoimmune response in MG patients with AD is more
severe. This was not reproduced in our study. In an-
other study (Ratanakorn and Vejjajiva, 2002) assessed
the response of thymectomy in patients with myasthe-
nia and hyperthyroidism. Seventy percent of patients
showed remission and signicant improvement. The
study concluded that the response of thymectomy is
comparable with the response of the majority of
patients with MG, but the thymectomy has no inuence
on hyperthyroidism. There are few studies evaluating
the response in PWAC; therefore this problem needs
further studies to clarify the issue.
The disease is twice as common in women than in
men and frequently aects young women in the second
and third decades of life, overlapping with the child-
Table 6 Histology (n 189)
WAC [n 49
(26%)]
WOAC [n 140
(74%)] P-value
Normal 1 (2%) 3 (2%) 1.00
Hyperplasia 35 (71%) 90 (64%) 0.38
Atrophy 9 (18%) 39 (28%) 0.25
Thymoma 3 (6%) 8 (6%) 1.00
Absence of thymus 1 (2%) 0 0.25
Table 5 Events related to thymectomy (n 189)
WAC [n 49
(26%)]
WOAC [n 140
(74%)] P-value
Thymectomy
Transsternal 33 (67%) 106 (76%) 0.26
Transcervical 16 (33%) 34 (24%)
Hospital stay (days) 14 5.9 15.33 8.3 0.25
Postoperatory complications
Pneumonia 1 (2%) 7 (5%) 0.68
Myasthenic crisis 1 (2%) 4 (3%) 1.00
Wound infection 0 4 (3%) 0.56
Mediastinitis 0 1 (1%) 1.00
Haemorrhage 0 1 (1%) 1.00
Diaphragmatic
paralysis
1 (2%) 0 0.26
Pneumothorax 0 4 (3%) 0.57
Plasmapheresis 2 (4%) 8 (6%) 1.00
Death 0 0 0
Associated conditions in myasthenia gravis 771
2004 EFNS European Journal of Neurology 11, 767773
bearing years. It is well known that during pregnancy
immunological changes occur that could change their
outcome (Djelmis et al., 2002). Batocchi studied 47
women who became pregnant after the onset of MG.
During pregnancy, MG relapsed in four of 23 (17%)
asymptomatic patients who were not on therapy before
conception; in patients taking therapy, MG symptoms
improved in 12 of 31 pregnancies (39%); remained
unchanged in 13 (42%); and worsened in six (19%).
They concluded that the course of the disease is highly
variable and unpredictable during gestation and may
change in subsequent pregnancies, but pregnancy does
not worse the long-term outcome of MG (Batocchi
et al., 1999). In our study, pregnancy did not inuence
the results of thymectomy. It is possible that pregnancy
only causes the immunological disturbances during its
duration, but does not aect the long-term prognosis.
In relation to histology, we could not identify dif-
ferences in both groups. The association between
thymoma, MG and immunological disorders is well
known. Jacques et al. (1974) reported a study of asso-
ciated conditions in 598 patients with thymoma. A total
of 422 patients had an associated condition (71%). A
44% of patients had MG, 21% cytopenias, 17% cancer,
6% hypogamaglobulinemia, 5% polymyositis and 2%
systemic lupus erythematosus. They found a low per-
centage of patients with thyroid disease. In our study
we did not have a large number of patients with
thymoma to analyze the problem, but the frequency of
thymoma was similar in both groups. Concerning other
histological categories, the frequencies were similar in
both groups.
In contrast to other studies, we did not nd dier-
ences between patients with and without associated
conditions including clinical data, complications, and
response to thymectomy in patients with MG.
Acknowledgements
FUNSALUD and CONACYT (SNI) funded Dr Te llez-
Zentenos postdoctoral fellowship.
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