SHORT COMMUNI CATI ON

Myasthenia gravis treatment of acute severe exacerbations in

the intensive care unit results in a favourable long-term prognosis
J. Spillane
a
, N. P. Hirsch
b
, D. M. Kullmann
a,b
, C. Taylor
b
and R. S. Howard
b
a
UCL, Institute of Neurology, London; and
b
ICU, National Hospital for Neurology and Neurosurgery, London, UK
Keywords:
intensive care,
myasthenic crisis,
myasthenia gravis
Received 26 November 2012
Accepted 3 January 2013
Background and purpose: Acute severe exacerbations of myasthenia gravis (MG)
are common in both early and late onset MG. We wished to examine the current
management in the intensive care unit (ICU) of severe exacerbations of MG and to
study the long-term prognosis of MG following discharge from the ICU.
Methods: We retrospectively reviewed the medical records of all patients admitted
to a specialist neuro-ICU with acute exacerbations of MG over a 12-year period.
Results: We identied 38 patients. Over 60% were over the age of 50 years, and
MG was newly diagnosed in over 40%. Intubation was required in 63%, and over
90% of patients were treated with prednisolone and/or intravenous immunoglobu-
lin. Four patients died in hospital. The remainder of patients were followed up for
a mean of 4 years, and the majority were either asymptomatic or had mild symp-
toms of MG at clinical review.
Conclusions: Despite the signicant morbidity and mortality associated with severe
exacerbations of MG, specialized neurointensive care can result in a good long-term
prognosis in both early- and late-onset MG.
Introduction
Myasthenic crisis (MC) is one of the most serious
complications of myasthenia gravis (MG), and occurs
in 1520% of patients during the course of their dis-
ease [1]. The denition of MC is acute respiratory fail-
ure due to worsening MG, requiring mechanical
ventilation [2]. Fifty years ago, estimates of mortality
of MC ranged from 50% to 80%, but mortality is
now reported to be <5% [24].
Not every patient with an exacerbation of MG will
require mechanical ventilation, but all need close
monitoring and immediate access to resuscitation
facilities. The present study consists of a cohort of
patients with severe exacerbations of MG admitted to
a neurological intensive care unit (ICU). Our objective
was to describe the current management and long-
term prognosis of severe exacerbations of MG in
patients with both early-onset and late-onset disease.
Methods
We retrospectively identied all patients admitted to
the Neuro-medical ICU at the National Hospital for
Neurology and Neurosurgery with severe exacerba-
tions of MG between January 1999 and January 2011
from the ICU admission logbook. The severity of
MG was classied according to the Myasthenia
Gravis Foundation of America (MGFA) grading sys-
tem. Patients were included in the study if they were
admitted to the ICU because of acutely developing
fatigable muscle weakness with severely impaired bul-
bar or respiratory function (MGFA Grade IVb or V).
Our study was approved as a retrospective audit.
SPSS (Chicago, IL, USA; version 20) was used for
statistical analysis. Categorical data (risk for intuba-
tion) were analysed by Fishers exact test. Continuous
data (ICU admission duration) were analysed using
Students t-test.
Results
Thirty-eight patients (23 female) were admitted during
the study period. The average age at admission was
57 years (range 1981 years), with an average age at
onset of MG of 53 years (1781 years). Thirty-one
patients (82%) were acetylcholine receptor antibody
positive, four (11%) were muscle specic tyrosine
kinase (MuSK) antibody positive, and three were
seronegative (8%).
Twenty-four (63%) were over the age of 50 years
on ICU admission, and 11 of these (46%) were new
presentations of MG. In those under 50 years, 3/14
Correspondence: J. Spillane, DCEE, UCL, Institute of Neurology,
Queen Square, London WC1 N3BG, UK (tel.: +44 (0) 2034484181;
fax: +44 (0) 2034483633; e-mail: jennifer.spillane.09@ucl.ac.uk).
2013 The Author(s)
European Journal of Neurology 2013 EFNS 171
European Journal of Neurology 2014, 21: 171173 doi:10.1111/ene.12115
patients (21%) were new presentations. The average
duration of MG prior to admission in those with an
established diagnosis was 3.8 years (0.511 years;
Table 1).
A factor that precipitated the acute exacerbation
was identied in 22 patients (58%). Sepsis, namely,
lower respiratory tract infection, was present in 20
patients (53%). One patient developed MC post-
thymectomy, while another patient deteriorated
during high-dose steroid treatment. No precipitant
was identied in the remainder (42%).
The mean ICU admission duration for the group
was 18.7 days (1111 days, SD 21.7, median 11.5), and
mean total hospital stay was 38.9 days (4157 days,
SD 31.1, median 30.5). Those with a new diagnosis of
MG had a trend towards a longer stay than those with
an established diagnosis, 25 days vs. 15 days, although
this did not reach statistical signicance (P = 0.1733;
Table 1).
Intubation and mechanical ventilation were
required in 24 patients (63%). Seventeen (71%) of
those requiring intubation had a preceding lower
respiratory tract infection, compared with 14% (2/14)
of those that were not intubated (P < 0.01). Four
additional patients (10.5%) required non-invasive ven-
tilation (Bilevel positive airway pressure).
Ninety-seven percent (37/38) of patients were trea-
ted with oral prednisolone, and 87% (33/38) received
intravenous immunoglobulin (IVIG). Seven patients
(18%) underwent plasma exchange. Additional oral
immunosuppression was initiated in 45% of patients
(17/38; Table 1).
Fourteen patients underwent thymectomy, eight
(21%) prior to admission and six (16%) after ICU
discharge. Eight (21%) had a thymoma.
Three patients died in the ICU (8%). Two died of
sepsis and respiratory failure. The third died of severe
autonomic instability. A fourth patient died after dis-
charge from the ICU of a pulmonary embolism.
There were no signicant dierences between older
and younger patients in terms of ICU admission dura-
tion or treatment in ICU. The majority of the patients
(29/38; 76%) had mild to moderate symptoms of MG
(MGFA Grades I, II, III) at ICU discharge, although
one patient had a tracheostomy in situ (MGFA V).
There was a continued improvement in MGFA status
during follow-up in both age groups At the last clini-
cal review, a mean of 4 years after ICU discharge,
19% (6/31) of the patients for whom follow-up was
available were asymptomatic, and 48% (15/31) had
either purely ocular symptoms or mild generalized
Table 1 Clinical characteristics
Under 50 years 50 years or older
Number 14 24
Male 5 10
Female 9 14
New diagnosis 3 (21%) 11 (46%)
Established diagnosis 11 (29%) 13 (54%)
Average disease
duration
3.5 years
(0.514 years)
4 years
(0.59 years)
Treatment prior to ICU admission
Prednisolone 7 (64%) 8 (62%)
Azathioprine 4 (36%) 1 (8%)
IVIG 2 (18%) 1 (8%)
Plasma exchange 2 (18%)
Antibody status
AChR 11 (79%) 20 (83%)
MuSK 3 (21%) 1 (4%)
Seronegative 3 (13%)
Mean duration of
ICU admission
(days) (SD)
(median)
22.4 (19.8) (14.5) 16.7 (SD 22.9) (9)
Mean total stay
(days) (SD)
(median)
42.1 (28.7) (42.5) 37.1 (32.9) (26.5)
Intubation 9 (64%) 15 (63%)
Thymectomy
Before ICU
admission
4 (29%) 3 (13%)
After ICU admission 5 (36%) 1 (4%)
No thymectomy 5 (36%) 20 (83%)
Thymoma 4 (29%) 4 (17%)
Treatment in ICU
Intubation 9 (64%) 15 (63%)
Prednisolone 14 (100%) 23 (96%)
IVIG 13 (93%) 20 (83%)
Plasma exchange 3 (4%) 4 (17%)
Other immunosuppressant agent
Azathioprine 6 (43%) 8 (33%)
Mycophenolate 2 (14%) 2 (8%)
Rituximab 1
Cyclophosphamide 1 0
AChR, acetylcholine receptor; ICU, intensive care unit; IVIG, intra-
venous immunoglobulin; MuSK, muscle specic tyrosine kinase
Table 2 MG severity at ICU discharge and last clinical review
Clinical severity
(MGFA)
Number of patients
ICU discharge
Number of patients
Last clinical review
(mean time from
ICU discharge)
Age (years) <50
(n = 14)
>50
(n = 24)
<50 (n = 14)
6.3 years
>50 (n = 24)
2.7 years
Asymptomatic 2 4
I 1 2 1 1
II 2 14 5 8
III 6 4 1 4
IV 3 2
V 1
Died 2 1 4 1
Lost to follow-up 1 6
2013 The Author(s)
European Journal of Neurology 2013 EFNS
172 J. Spillane et al.
weakness (Table 2). Sixty-ve percent (20/31)
remained on oral prednisolone (average dose of
12.5 mg). Forty-eight per cent took additional oral
immunosuppression (8/31 on azathioprine, 6/31 on
mycophenolate and 1/31 on methotrexate). Three
patients (10%) required IVIG. There were no signi-
cant dierences in outcome between the older and
younger age groups. One patient, a 23-year-old female
with MuSK MG, had a sudden respiratory arrest and
died 2 years after discharge.
Discussion
Although our study is limited by its small size and ret-
rospective nature, we have demonstrated that acute
exacerbations of MG continue to carry a signicant
morbidity and mortality [1]. Our centre is a specialist
referral centre, and 60% of our admissions were trans-
ferred from other hospitals. It is possible that our
ICU is biased towards admission of more severe cases
of MG, which may explain the high mortality rate in
our group.
Our study has highlighted the need to be vigilant
for MG in the dierential diagnosis of acute respira-
tory failure particularly in older adults. MG is
increasingly recognized in the older population; 60%
of our cohort was over the age of 50 years, and over
40% of these patients were newly diagnosed with MG
in the ICU. Even in those with an established diagno-
sis of MG, predicting the occurrence of an acute exac-
erbation can be dicult; 42% of patients had no
obvious precipitant.
The management of acute exacerbations of MG has
changed in recent years. The vast majority (87%) of
our cohort received IVIG. Ten years ago, only 11.4%
of a similar cohort received IVIG, whereas 60%
underwent plasma exchange [5]. IVIG and plasma
exchange have recently been found to be equally
eective for exacerbations of MG, but the former is
better tolerated and is used increasingly [6].
Little is known about the long-term outcome of
patients with acute severe exacerbations of MG
following hospital discharge. We have follow-up data
for 82% of our patients for a mean of 4 years, and
found that the vast majority of patients were
asymptomatic or had mild manifestations of MG at
nal review. There was no signicant dierence in
long-term outcome between older and younger
patients.
We suggest that, despite the acute risk of mortality
associated with severe exacerbations of MG, the long-
term prognosis is favourable. The appropriate man-
agement of these patients requires the easy availability
of specialized neurointensive care facilities.
Disclosure of conicts of interest
The authors declare no nancial or other conicts of
interest.
Acknowledgement
J.S. is funded by a grant from the Myasthenia Gravis
Association UK.
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2013 The Author(s)
European Journal of Neurology 2013 EFNS
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