2010 John Wiley & Sons A/S

Acta Neurol Scand 2010: 122 (Suppl. 190): 1217

ACTA NEUROLOGICA
SCANDINAVICA

Airway limitation and exercise intolerance in

well-regulated myasthenia gravis patients
Elsais A, Johansen B, Kerty E. Airway limitation and exercise
intolerance in well-regulated myasthenia gravis patients. Acta Neurol
Scand: 2010: 122 (Suppl. 190): 1217.  2010 John Wiley & Sons A/S.

Objectives Myasthenia gravis (MG) is an autoimmune disease of

neuromuscular synapses, characterized by muscular weakness and
reduced endurance. Remission can be obtained in many patients.
However, some of these patients complain of fatigue. The aim of this
study was to assess exercise capacity and lung function in wellregulated MG patients. Patients and methods Ten otherwise healthy
MG patients and 10 matched controls underwent dynamic spirometry,
and a ramped symptom-limited bicycle exercise test. Spirometric
variables included forced vital capacity (FVC), forced expiratory
volume in 1 s (FEV1), and maximum voluntary ventilation (MVV).
Exercise variables included maximal oxygen uptake (VO2 max),
anaerobic threshold (VO2 AT) maximum work load (W), maximum
ventilation (VE max), and limiting symptom. Results Myasthenia
gravis patients had signicantly lower FEV1 FVC ratio than
controls. This was more marked in patients on acetylcholine esterase
inhibitors. On the contrary, patients not using acetylcholine esterase
inhibitors had a signicantly lower exercise endurance
time. Conclusion Well-regulated MG patients, especially those using
pyridostigmine, tend to have an airway obstruction. The modest
airway limitation might be a contributing factor to their fatigue.
Patients who are not using acetylcholinesterase inhibitor seem to have
diminished exercise endurance in spite of their clinically complete
remission.

Background

Myasthenia gravis (MG) is an autoimmune disorder with specic autoantibodies directed against
the nicotinic acetylcholin receptor in the neuromuscular synapses. The disease is characterized by
fatigable and variable muscular weakness and
reduced endurance with remissions and exacerbations (1). Thymectomy could elicit a spontaneous
remission in some patients. In others, a pharmacological complete remission can be obtained with
corticosteroids and other immunosuppressive
treatments; i.e. no myasthenic symptoms or signs
can be found. However, a group of these wellregulated patients complain of fatigue.
Chronic fatigue is a known phenomenon in
many neurological and non-neurological diseases,
and is independent of muscle weakness (2, 3). The
12

A. Elsais1,2, B. Johansen2,3,
E. Kerty1,2
1

Department of Neurology, Oslo University Hospital,

Oslo, Norway; 2University of Oslo, Oslo, Norway;
3
Department of Respiratory Medicine, Division of
Cardiovascular and Respiratory Medicine, Oslo
University Hospital, Oslo, Norway

Conflicts of interest : none.

Key words: acetylcholine esterase inhibitors; exercise
test; fatigue; myasthenia gravis; pulmonary function
Ahmed Elsais, Department of Neurology, Oslo University
Hospital, Rikshospitalet Medical Center, 0027 Oslo,
Norway
Tel.: +47 23070000
Fax: +47 23070490
e-mail: ahmed.elsais@medisin.uio.no

perception of fatigue is subjective and no exact

denition exists (4). This fatigue can not be
predicted from their clinical status. In the absence
of objective measures of fatigue, both clinicians
and researchers must rely on measuring subjective
fatigue, what the patients complain of (5).
Physical exercise requires adequate supply of
oxygen and nutritional substances to the muscles.
In the muscles, these nutrients are metabolized to
produce the energy that is necessary to perform the
work. Dysfunction in any of these biochemical
processes may be responsible for fatigue. Ventilatory dysfunction was reported as a cause of
reduced exercise tolerance (6).
Lung function testing is an objective means to
verify ventilatory dysfunction (7, 8). A cardiopulmonary exercise test is usually used to differentiate
between cardiovascular and pulmonary causes of

Respiratory function in myasthenia gravis patients

exercise limitation (9), but should also be able to
detect diminished muscle function.
Several studies investigated the respiratory complications in severely aected patients as in myasthenic crisis, but only a few examined the
respiratory function and exercise tolerance in
well-regulated myasthenia patients.
The aim of this study was to asses exercise
capacity and respiratory function in well-regulated
and clinically stable patients with MG, but who
complain of fatigue, and whether limited lung
function could be responsible for their fatigue.

Subjects and methods

Subjects

In the context of another study (in preparation), all

125 myasthenia gravis patients treated at our
department during the last 15 years received a
mailed questionnaire. The questionnaire included
Fatique Questionnaire (FQ) (10) and disease-specic Myasthenia Gravis Questionnaire (MGQ)
(11). Seventeen patients who scored high in MGQ
(well-regulated) and high in FQ (fatigued) were
invited to participate in the present study. Two
patients declined, three were evaluated as not being
in complete pharmacological remission, while two
were excluded because of mild aortic stenosis and
symptomatic obstructive pulmonary disease.
The diagnosis of MG was based on the presence
of at least three of the following four inclusion
criteria: typical clinical features, the presence of
acetylcholine receptors antibodies in serum, positive edrophonium test and neurophysiologic ndings consistent with MG (decrement >10% at
3 Hz repetitive motor nerve stimulation, increased
jitter on single-ber electromyogram, or both).
The clinical graduation was in accordance to the
Medical Scientic Advisory Board of the Myasthenia Gravis Foundation of America (MGFA)
(12). All 10 patients, mean age 41(14) years, 9
women and 1 man, were in degree 01, only mild
ocular symptoms were accepted. Seven patients
were positive on testing for antibodies against
acetylcholine receptors. All patients had generalized MG and all but one (late onset myasthenia)
had undergone thymectomy. Four patients experienced complete spontaneous remission after thymectomy, while the rest had been in a
pharmacological remission 6 months or more
prior to the study start.
Five patients used small doses acetylcholine
esterase inhibitors (AChEi), namely pyridostigmine bromide maximum 120 mg day, four
patients received low dosage corticosteroid on

alternate days and one azathioprine in combination with prednisolone.

Ten carefully age- and height-matched controls
were included. None of the included patients or
controls had an additional chronic disease, in
particular no respiratory disease. All subjects
were declared cardiologically healthy after they
had undergone echocardiography in the context of
another study. Written informed consent from all
participating patients and controls, and approval
from the Regional Committee for Medical and
Health Research Ethics in Norway was obtained.
Methods

All subjects underwent tests of resting lung function (spirometry) and a cardiopulmonary exercise
test. The examinations were carried out between 14
and 15 pm in a single session and took place in the
Pulmonary Function Laboratory of the hospital.
Spirometry was performed with a Vmax Pulmonary Function Unit (Viasys, Santa Ana, CA,
USA). The equipment was calibrated daily. The
subject was asked to inhale as deep as possible, and
then exhale into the mouthpiece of the spirometer
as fast as he she could, and as long as possible. At
least three measurements were performed. Each
trial was assessed according to criteria adopted by
the European Respiratory Society (ERS). The
variables included forced vital capacity (FVC):
the volume of air that can forcibly be blown out
after a full inspiration; forced expiratory volume in
1 s (FEV1): the maximum volume of air that can
be exhaled in the rst second during the FVC
maneuver, measured in liters. The ratio of FEV1 to
FVC (FEV1 FVC) was also calculated. The maximum voluntary ventilation (MVV) is a measure of
the maximum amount of air that can be inhaled
and exhaled in 1 min. Reference values were taken
from those adopted by ERS (13).
The exercise test was performed on an electrically braked leg cycle ergometer. The exercise
protocol was selected with the goal of obtaining 8
12 min of data (symptom-limited incremental
exercise). The work rate increment for each subject
was individual and based on the reference value.
After a period of equilibration at rest, breathing
trough the mouthpiece, the subjects performed
unloaded pedaling for 2 min. The work rate then
increased until the subjects became exhausted.
Ventilation and gas exchange were continuously
measured using a bi-directional ow transducer.
Gas samples were analyzed breath-by-breath. The
subject was monitored for systemic arterial blood
pressure, taken every other minute, ECG and pulse
oxymetry. Variables like maximal ventilation (VE
13

Elsais et al.
max), maximal oxygen uptake (VO2 max), oxygen
uptake at anaerobic threshold (VO2 AT), work
load (Watts), and endurance time (mm:ss) were
recorded. The physiological indexes were displayed
graphically and printed in tabular form for analysis. After cessation of exercise the subjects specied the limiting symptom.
Statistical analysis was performed with SPSS
(version 17.0.2 for Microsoft Word; SPSS Inc.,
Chicago, IL, USA). Nonparametric, unpaired twotailed MannWhitney test for comparing two
groups was used. P-value less than 0.05 was
considered signicant. Results are presented as
median and corresponding approximately 95%
condence interval (CI).
Results

Table 1 shows that FEV1 FVC was signicantly

lower in patients compared with controls. Both
FEV1 and MVV tended to be lower in patients, but

the differences did not reach statistical signicance.

There was no difference between patients and
controls with regard to exercise data. All subjects
stated that leg discomfort was the reason for
exercise termination.
When patients (n = 5) treated with pyridostigmine were analyzed separately (Table 2), the
FEV1 FVC ratio was still signicantly lower. In
addition, the tendency to statistical difference for
FEV1 and MVV became stronger. There was still
no difference between patients and matched controls with regard to exercise data.
Separate analysis of patients not treated with
pyridostigmine (n = 5) shows lower FEV1 FVC
ratio in patients compared with controls, but the
dierence was not signicant. However, exercise
values tended to be lower in patients. The dierence in endurance time was statistically signicant.
Discussion

The main ndings of this study are:

Table 1 Lung function and exercise data of patients and controls

Variable
FVC
FEV1
FEV1 FVC
MVV
Work load
VO2 max
VO2 AT
VE
Endurancetime

Units
l
l
l min
W
l min
l min
l min
Min:sec

Controls
n = 10 median
(confidence interval)
4.27
3.48
83
129
155
1.75
1.10
66
10:16

(3.664.95)
(3.004.17)
(8087)
(118157)
(121231)
(1.452.65)
(0.841.69)
(5396)

Patients
n = 10 median
(confidence interval)
4.05
3.10
73
120
150
196
1.20
71
09:35

(3.455.22)
(2.683.71)
(6980)
(107148)
(114191)
(1.542.46)
(0.871.40)
(5685)

P-value
0.597
0.257
0.023
0.173
0.791
0.821
0.821
0.910
0.406

FVC, forced vital capacity; FEV1, forced expiratory volume in 1 s; MVV, maximal
voluntary ventilation; VO2 max, maximal oxygen uptake; VO2 AT, oxygen uptake at
anaerobic threshold; VE, maximal ventilation.

Table 2 Lung function and exercise data in patients on pyridostigmine and

matched controls

Variable

Units

FVC
l
FEV1
l
FEV1 FVC
MVV
l min
Work load
W
l min
VO2 max
l min
VO2 AT
VE
l min
Endurance time Min:sec

Controls
n = 5 median
(confidence interval)
4.64
3.66
80
134
143
1.73
1.00
63
09:26

(3.655.42)
(3.084.53)
(7890)
(120171)
(98214)
(1.262.49)
(0.681.34)
(35117)

Patients
n = 5 median
(confidence interval)
4.57
3.06
71
129
162
2.02
1.08
77(4891)
10:22

(3.455.06)
(2.393.79)
(6680)
(99142)
(115198)
(1.412.56)
(0.541.67)

P-value
0.602
0.117
0.047
0.059
0.675
0.465
0.754
0.917
0.116

FVC, forced vital capacity; FEV1, forced expiratory volume in 1 s; MVV, maximal
voluntary ventilation; VO2 max, maximal oxygen uptake; VO2 AT, oxygen uptake at
anaerobic threshold; VE, maximal ventilation.

14

(a) Patients with myasthenia gravis seem to have a

slight airway obstruction.
(b) The obstructive pattern is predominantly seen
in those treated with acetylcholine esterase
inhibitors (AChEi) such as pyridostigmine.
(c) Patients not treated with AChEi had no
signicant airway obstruction, but tend to
have a lower exercise capacity than matched
controls.
Assessment of the respiratory status of patients
with MG is important at all stages of the disease.
Most studies to date carried out pulmonary function examinations either in isolated ocular or
moderately to severely aected generalized MG
patients (7, 8, 1416). To our knowledge, this is the
rst study to focus on the pulmonary function in
previously generalized MG patients, who are
currently asymptomatic except for mild ocular
manifestations and fatigue.
Clinical assessment of general muscle strength
usually does not allow prediction of the occurrence
and, in particular, the degree of respiratory muscle
weakness. Spirometry with measurement of FVC
and FEV1 are the basic tests for the general lung
function. Reduced FEV1 FVC ratio is an indicator of airway obstruction. MVV is usually used to
assess airways capacity and to a lesser extent
endurance of respiratory muscles. However, exercise tests are often helpful to reveal subclinical
diminished muscle endurance and to dierentiate
between cardiovascular and pulmonary causes of
exercise limitation.

Respiratory function in myasthenia gravis patients

In myasthenia gravis, respiratory dysfunction is
mainly a feature of weakness of respiratory muscles as part of severe generalized myasthenic
muscle weakness, as in myasthenic crisis (1719).
However, isolated weakness of respiratory muscles
was also reported in MG patients (20, 21). This was
manifested as a restrictive impairment of pulmonary function, that is, reduced total lung capacity.
On the contrary, airway obstruction in MG is an
infrequently reported respiratory impairment. Previous studies have reported airway obstruction in
moderate or severe generalized MG patients (14,
15). Putman and Wise (15) studied owvolume
loops of 12 MG patients and found that seven of
them (58%) were obstructive. They concluded that
upper airway obstruction is a more frequent
complication than previously realized. Shale et al.
(14) have studied the effect of pyridostigmine on
airways, and explained obstruction by the use of
pyridostigmine. Two patients, who were also
obstructive, but not treated with pyridostigmine,
therefore, were excluded. However, the authors did
not explain why those patients had a signicant
airway obstruction. They showed that generalized
MG patients tended to be obstructive after pyridostigmine intake.
Pyridostigmine is known to increase the endurance in respiratory muscles, in spite of inducing an
adverse eect in the form of airway obstruction
(22, 23).
There are several possible explanations for the
airow limitation that we observed in our patients.
In our study, patients using pyridostigmine were
more obstructive than non-pyridostigmine-treated
patients and controls. This raises the question of
whether pyridostigmine is the cause of obstruction,
or whether there is a subclinical myasthenic weakness in these patients behind this obstruction, and
that pyridostigmine worsens it. The cholinergic
eect of pyridostigmine includes spasm and excessive mucous production in airways. The cholinergic
eect is the most likely explanation for the
narrowing of the airways. The fact that patients
without pyridostigmine and matched controls did
not dier signicantly with respect to airway
function, is in agreement with this. However, four
of the ve patients in this group have a lower,
FEV1 FVC than matched controls. The ow
volume loop of a 30 year old military ocer, in a
total clinical remission after thymectomy and in
very good physical form, demonstrates the
obstructive pattern (Fig. 1).
One might speculate that these well-regulated
MG patients have some kind of subclinical weakness in bulbar or upper airways muscles, which
could explain the airow limitation. The latter was

16

16

12

12

Figure 1. Flowvolume loop showing: (A) obstructive pattern

in MG patient without any medication (B) normal loop in
matched control.

independent of muscle force and endurance in

extremities, as the most obstructive patients
showed more endurance than their matched
controls. It, therefore, seems that weakness in
bulbar or upper airways muscles is less likely in
these, clinically asymptomatic patients. However,
isolated weakness in these muscles is a frequent
nding in both humans (2427) and animals (28).
Putman and Wise (15) explained air way obstruction as weakness in the upper airway muscles.
Vincken et al. (29) found that ow-volume loops
were in accordance with, and indicated bulbar
muscular involvement with a sensitivity of 90%
and a specicity of 85%.
Both airway hyper-reactivity and myasthenia
gravis could be explained as coexistence of two
autoimmune disorders. The role of T helper cell 2
(Th2) in the pathophysiology of airway hyperreactivity is well-known (3032). The same pertains
for Th1 and Th2 lymphocytes and cytokines that
probably participate in the development of myasthenia gravis (3335).
Recently, there has been mounting evidence
indicating that obstructive pulmonary disorder is
a disease with a strong autoimmune feature (36,
37). It is possible that repetitive infections trigger
the immune system to react with hyper-reactivity
and hence airway limitation.
Airway limitation was independent of muscle
force and endurance, as these patients showed
more endurance than their matched controls with
respect to work load. However, the clinical examination of general muscle strength does not usually
allow prediction of subclinical weakness of the
respiratory muscles. The results of Mier-Jedrzejowski et al. (38) were similar to ours: they could
nd no relation between the degree of myasthenia
and or the severity of dyspnea and respiratory
muscle strength. The absence of a clear correlation
between extremity muscle power and lung function
underlines the important clinical nding that
abnormalities can be found in patients with rela15

Elsais et al.
tively well-preserved general muscle strength (7).
The same ndings were described in other groups
of stable chronic myopathy patients (29).
Is the airway obstruction of clinical importance?
Global Initiative for Chronic Obstructive Lung
Disease (GOLD) guidelines considers the
FEV1 FVC ratio of <70% as indicative of airow
limitation (39). The same guidelines considered
FEV1 below 80% of the predicted value as a mild
obstruction. We could not consider these patients
as chronic obstructive as they have not met criteria
for chronic obstructive lung disease (COPD),
despite that their FEV1 FVC being so close to
70%. All patients, included the ones on pyridostigmine, have FEV1 over 80% and have no
respiratory complaints. However, in objective
terms, these patients have a mild narrowing of
their airways. Therefore, relatively minor respiratory disturbances, like an upper airway infection or
inuenza, can cause an unexpected severe respiratory disturbance in MG patients.
Thus, no patient with MG, even with absence of
respiratory complaints, should be considered as
having normal respiratory muscle function on the
basis of a relatively normal clinical examination of
general muscle strength.
The next issue is whether this subclinical
obstruction is the cause of fatigue in these patients.
Fatigue is common in MG patients (A. Elsais
et al., unpublished data) and exists also in patients
who have no clinically demonstrable weakness. A
generalized fatigue could be related to an underlying dysautonomia. Earlier studies showed
decreased lung function (40) and bronchial hyperresponsiveness (41) in chronic fatigue patients. We
found that, well-controlled MG patients have an
obstructive airway limitation compared with
healthy controls. Obstructive breathing pattern
can make the patients more vulnerable the development of sleep apnea that previously detected in
well-regulated MG patients (42, 43). In a previous
study, 89% of MG patients reported experiencing
fatigue at the night (44). Well-regulated MG
patients may exhibit sleep apnea, and a common
consequence of sleep apnea is daytime fatigue (45).
Physical exercise requires adequate supply of
oxygen and nutritional substances to the muscles.
In the muscles, these nutrients are metabolized to
produce the energy that is necessary to perform the
work. Dysfunction in any of these biochemical
processes may be responsible for fatigue. It is
unlikely that reduced respiratory function alone
can explain fatigue. This is in agreement with the
fact that leg discomfort and not dyspnea was the
limiting factor in exercise test. Previous studies of
exercise test and patients with COPD showed that
16

patients who were severely affected complained of

breathlessness, while mildly affected patients
terminate the exercise test because of leg discomfort as was the case in our study (4649).
There are more females than males in this study
and it is well known that fatigue is more frequent in
females than in men (10).
The small number of patients limits the conclusion that can be drawn from this study. Further
investigations assessing fatigue in a large cohort of
MG patients are needed. However, despite the
small number of subjects, dierences were clearly
present.
Conclusion

Our study demonstrates that well-regulated MG

patients have an airway limitation. This obstruction is more pronounced in those treated with
acetylcholine esterase inhibitors. Obstruction can
not be predicted from clinical examination and
general muscle strength. Specic testing of the
respiratory muscles should be an integral part of
clinical examination. Airway obstruction is not
likely to be a causal factor of fatigue, but it might
be a perpetuating factor in some of the patients.
Patients who are not using acetylcholine esterase
inhibitors seem to have diminished exercise endurance in spite of their clinically complete remission.
Acknowledgement
The authors are grateful to Professor Lars Walle, Department
of Physiology, Institute of Basic Medical Sciences, University
of Oslo, for his critical review of the statistical data.

References
1. Romi F, Gilhus NE, Aarli JA. Myasthenia gravis: clinical,
immunological, and therapeutic advances. Acta Neurol
Scand 2005;111:13441.
2. Havlikova E, van Dijk JP, Rosenberger J et al. Fatigue in
Parkinsons disease is not related to excessive sleepiness or
quality of sleep. J Neurol Sci 2008;270:10713.
3. Stephen SA. Fatigue in older adults with stable heart failure. Heart Lung 2008;37:12231.
4. Chaudhuri A, Behan PO. Fatigue in neurological disorders.
Lancet 2004;363:97888.
5. Wessely S. The measurement of fatigue and chronic fatigue
syndrome. J R Soc Med 1992;85:18990.
6. Mioxham J, Jolley C. Breathlessness, fatigue and the
respiratory muscles. Clin Med 2009;9:44852.
7. Fernandez CM, Tejedor ED, Frank A, Pino JM, Conde CP,
Barreiro P. Maximal respiratory pressures in myasthenia
gravis. Relation to single ber electromyography. Acta
Neurol Scand 2001;103:3925.
8. Thieben MJ, Blacker DJ, Liu PY, Harper CM Jr, Wijdicks
EF. Pulmonary function tests and blood gases in worsening myasthenia gravis. Muscle Nerve 2005;32:6647.

Respiratory function in myasthenia gravis patients

9. Ferrazza AM, Martolini D, Valli G, Palange P. Cardiopulmonary exercise testing in the functional and prognostic
evaluation of patients with pulmonary diseases. Respiration 2009;77:317.
10. Loge JH, Ekeberg O, Kaasa S. Fatigue in the general
Norwegian population: normative data and associations. J
Psychosom Res 1998;45:5365.
11. Rostedt A, Padua L, Stalberg EV. Validation of the
Swedish version of the disease-specic Myasthenia Gravis
Questionnaire. Neurol Sci 2006;27:916.
12. Jaretzki A III, Barohn RJ, Ernstoff RM et al. Myasthenia
gravis: recommendations for clinical research standards.
Task Force of the Medical Scientic Advisory Board of the
Myasthenia Gravis Foundation of America. Ann Thorac
Surg 2000;70:32734.
13. Laszlo G. European standards for lung function testing:
1993 update. Thorax 1993;48:8736.
14. Shale DJ, Lane DJ, Davis CJ. Air-ow limitation in
myasthenia gravis. The eect of acetylcholinesterase
inhibitor therapy on air-ow limitation. Am Rev Respir
Dis 1983;128:61821.
15. Putman MT, Wise RA. Myasthenia gravis and upper airway obstruction. Chest 1996;109:4004.
16. Keenan SP, Alexander D, Road JD, Ryan CF, Oger J,
Wilcox PG. Ventilatory muscle strength and endurance in
myasthenia gravis. Eur Respir J 1995;8:11305.
17. Wu JY, Kuo PH, Fan PC, Wu HD, Shih FY, Yang PC. The
role of non-invasive ventilation and factors predicting extubation outcome in myasthenic crisis. Neurocrit Care
2009;10:3542.
18. Seneviratne J, Mandrekar J, Wijdicks EF, Rabinstein AA.
Predictors of extubation failure in myasthenic crisis. Arch
Neurol 2008;65:92933.
19. Seneviratne J, Mandrekar J, Wijdicks EF, Rabinstein AA.
Noninvasive ventilation in myasthenic crisis. Arch Neurol
2008;65:548.
20. Zulueta JJ, Fanburg BL. Respiratory dysfunction in
myasthenia gravis. Clin Chest Med 1994;15:68391.
21. Dushay KM, Zibrak JD, Jensen WA. Myasthenia gravis
presenting as isolated respiratory failure. Chest
1990;97:2324.
22. Radwan L, Strugalska M, Koziorowski A. Changes in
respiratory muscle function after neostigmine injection in
patients with myasthenia gravis. Eur Respir J 1988;1:119
21.
23. Liggett SB, Daughaday CC, Senior RM. Ipratropium in
patients with COPD receiving cholinesterase inhibitors.
Chest 1988;94:2102.
24. Fairley JW, Hughes M. Acute stridor due to bilateral vocal
fold paralysis as a presenting sign of myasthenia gravis. J
Laryngol Otol 1992;106:7378.
25. Kanemaru S, Fukushima H, Kojima H, Kaneko K,
Yamashita M, Ito J. A case report of myasthenia
gravis localized to the larynx. Auris Nasus Larynx 2007;34:
4013.
26. Schmidt-Nowara WW, Marder EJ, Feil PA. Respiratory
failure in myasthenia gravis due to vocal cord paresis. Arch
Neurol 1984;41:5678.
27. Teramoto K, Kuwabara M, Matsubara Y. Respiratory
failure due to vocal cord paresis in myasthenia gravis.
Respiration 2002;69:2802.
28. Jeffery ND, Talbot CE, Smith PM, Bacon NJ. Acquired
idiopathic laryngeal paralysis as a prominent feature of
generalised neuromuscular disease in 39 dogs. Vet Rec
2006;158:17.

29. Vincken W, Elleker G, Cosio MG. Detection of upper

airway muscle involvement in neuromuscular disorders
using the ow-volume loop. Chest 1986;90:527.
30. Lloyd CM, Hawrylowicz CM. Regulatory T cells in asthma. Immunity 2009;31:43849.
31. Barrett NA, Austen KF. Innate cells and T helper 2 cell
immunity in airway inammation. Immunity 2009;31:425
37.
32. Desai D, Brightling C. Cytokine and anti-cytokine therapy
in asthma: ready for the clinic? Clin Exp Immunol
2009;158:109.
33. Aarli JA. Role of cytokines in neurological disorders. Curr
Med Chem 2003;10:19317.
34. Ragheb S, Lisak RP. Immune regulation and myasthenia
gravis. Ann N Y Acad Sci 1998;841:21024.
35. Kakoulidou M, Pirskanen-Matell R, Lefvert AK. Treatment of a patient with myasthenia gravis using antibodies
against CD25. Acta Neurol Scand 2008;117:2116.
36. Stefanska AM, Walsh PT. Chronic obstructive pulmonary
disease: evidence for an autoimmune component. Cell Mol
Immunol 2009;6:816.
37. Leidinger P, Keller A, Heisel S et al. Novel autoantigens
immunogenic in COPD patients. Respir Res 2009;10:20.
38. Mier-Jedrzejowicz AK, Brophy C, Green M. Respiratory
muscle function in myasthenia gravis. Am Rev Respir Dis
1988;138:86773.
39. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd
SS. Global strategy for the diagnosis, management, and
prevention of chronic obstructive pulmonary disease.
NHLBI WHO Global Initiative for Chronic Obstructive
Lung Disease (GOLD) Workshop summary. Am J Respir
Crit Care Med 2001;163:125676.
40. De LF, Hargreaves J, Kakkar VV. Lung function test
ndings in patients with chronic fatigue syndrome (CFS).
Aust N Z J Med 1996;26:5634.
41. Nijs J, De BP, De MK et al. Associations between bronchial hyperresponsiveness and immune cell parameters in
patients with chronic fatigue syndrome. Chest
2003;123:9981007.
42. Amino A, Shiozawa Z, Nagasaka T et al. Sleep apnoea in
well-controlled myasthenia gravis and the eect of thymectomy. J Neurol 1998;245:7780.
43. Quera-Salva MA, Guilleminault C, Chevret S et al.
Breathing disorders during sleep in myasthenia gravis. Ann
Neurol 1992;31:8692.
44. Ochs CW, Bradley RJ, Katholi CR et al. Symptoms of
patients with myasthenia gravis receiving treatment. J Med
1998;29:112.
45. Guilleminault C, Philip P, Robinson A. Sleep and neuromuscular disease: bilevel positive airway pressure by nasal
mask as a treatment for sleep disordered breathing in patients with neuromuscular disease. J Neurol Neurosurg
Psychiatry 1998;65:22532.
46. Hamilton AL, Killian KJ, Summers E, Jones NL. Muscle
strength, symptom intensity, and exercise capacity in patients with cardiorespiratory disorders. Am J Respir Crit
Care Med 1995;1:202131.
47. Man WD, Soliman MG, Gearing J et al. Symptoms and
quadriceps fatigability after walking and cycling in chronic
obstructive pulmonary disease. Am J Respir Crit Care Med
2003;168:5627.
48. Calverley PM. Dynamic hyperination: is it worth measuring? Proc Am Thorac Soc 2006;3:23944.
49. Gibson GJ. Clinical tests of respiratory function. London:
Hodder, 2009;14992.

17

Copyright of Acta Neurologica Scandinavica is the property of Wiley-Blackwell and its content may not be
copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written
permission. However, users may print, download, or email articles for individual use.