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The Journal of Emergency Medicine, Vol. -, No. -, pp.

1–5, 2015
Copyright Ó 2015 Elsevier Inc.
Printed in the USA. All rights reserved
0736-4679/$ - see front matter

http://dx.doi.org/10.1016/j.jemermed.2015.04.019

Selected Topics:
Neurological Emergencies

EMERGENCY DEPARTMENT MANAGEMENT OF A MYASTHENIA GRAVIS PATIENT


WITH COMMUNITY-ACQUIRED PNEUMONIA: DOES INITIAL ANTIBIOTIC CHOICE
LEAD TO CURE OR CRISIS?

Megan A. Van Berkel, PHARMD, BCPS,* Jennifer D. Twilla, PHARMD, BCPS,* and Bryan S. England, MD†
*Department of Pharmacy, Methodist Healthcare University Hospital, University of Tennessee Health Sciences Center, Memphis, Tennessee
and †Department of Emergency Medicine, Methodist Healthcare University Hospital, University of Tennessee Health Sciences Center,
Memphis, Tennessee
Reprint Address: Megan A. Van Berkel, PharmD, BCPS, Department of Pharmacy, Methodist Healthcare University Hospital, University of
Tennessee Health Sciences Center, 1265 Union Avenue, Memphis, TN 38104

, Abstract—Background: Myasthenic crisis is a rare, yet of tigecycline to the armamentarium of therapies available
serious condition that carries a 3% 8% mortality rate. to treat myasthenia gravis patients presenting to the emer-
Although infection is a common cause of decompensation gency department with CAP. Ó 2015 Elsevier Inc.
in myasthenia gravis, several antibiotics classes have also
been associated with an exacerbation. Selecting antibiotics , Keywords—myasthenia gravis; community-acquired
can be a daunting clinical task and, if chosen inappropri- pneumonia; tigecycline; myasthenic crisis; infection
ately, can carry significant deleterious consequences. Not
only do clinicians have to focus on treating the underlying
infection appropriately, but avoiding antibiotics that may INTRODUCTION
potentiate a myasthenic crisis is also vital. Case Report:
An 85-year-old female with a history of myasthenia Myasthenia gravis is an autoimmune disorder affecting
gravis presented to the emergency department (ED) with
5 15 people per 100,000 (1). A myasthenic crisis occurs
increasing generalized weakness and shortness of breath.
when antibodies are formed against nicotinic acetylcho-
Clinical work-up was consistent with a community-
acquired pneumonia (CAP) diagnosis. Her medical history line receptors, causing the inability to sustain a neuro-
included a myasthenia gravis exacerbation shortly after muscular contraction, and is often defined as acute
receiving moxifloxacin for CAP. After reviewing the respiratory failure prompting intubation. Although
patient’s allergies, as well as potential antibiotic triggers, many patients with myasthenia are controlled with
the decision was made to treat with tigecycline. The patient acetylcholinesterase inhibitor medications, acute myas-
responded well to tigecycline therapy and was deemed stable thenic crisis affects 15% 20% of patients with myas-
for discharge on day 4 of hospitalization. Why Should an thenia and carries a 3% 8% mortality rate (1). A
Emergency Physician Be Aware of This?: Evaluation of myasthenic crisis can be precipitated by a number of fac-
the myasthenia gravis patient frequently originates in the tors; however, infection is responsible for 40% 70% of
ED. It is important for clinicians to be able to distinguish be-
crisis episodes (1,2). Additionally, several medications,
tween an underlying illness and a myasthenic crisis. In the
including antibiotics, have been implicated in causing a
event of an infectious process causing clinical deterioration
in a myasthenia patient, optimal antibiotic selection be- myasthenic crisis. The unique situation of treating an
comes paramount. This patient case highlights the addition underlying infection without precipitating or worsening

RECEIVED: 20 November 2014; FINAL SUBMISSION RECEIVED: 30 March 2015;


ACCEPTED: 7 April 2015

1
2 M. A. Van Berkel et al.

a myasthenia crisis can be difficult to accomplish, were noted to be fully intact. Admission laboratory values
especially in a patient with medication allergies. We included a basic metabolic panel within normal limits,
present a case of success using tigecycline for treatment pro brain natriuretic peptide of 1394 pg/mL (normal
of community-acquired pneumonia (CAP) in a patient range 0 125 pg/mL), and a white blood cell count of
with myasthenia gravis and to provide a brief overview 10.7 thousand cells/mL with 9% bands. Blood cultures
of other antibiotics associated with the development of obtained on admission were negative for growth, and a
myasthenic crises. urinalysis was not performed.
A chest x-ray study was initially obtained and was in-
CASE REPORT terpreted by radiology as cardiomegaly with central
vascular congestion, an elevated left hemi-diaphragm
An 85-year-old female presented to the emergency and trace pleural effusion in the left lung base. Given
department (ED) with a 1-week history of shortness of these findings and an overall lack of clarity for a clinical
breath, cough, increasing generalized weakness, and diagnosis, a chest computed tomography was obtained
decreased appetite. The family of the patient reported showing ‘‘bibasilar airspace disease and consolidation,
seeing increased work for breathing and inability to pneumonia and atelectasis are primary differential
expectorate. She was still able to complete activities of considerations,’’ and the decision was made to initiate
daily living and did not complain of any arthralgias, my- antibiotics for CAP. Tigecycline 100 mg i.v. bolus was
algias, or chills. Her medical history included myasthenia administered, followed by 50 mg every 12 h until the
gravis for 18 years; controlled, treated hypertension; patient was discharged on doxycycline. The patient
atrial fibrillation with a rapid ventricular response, responded well to antibiotics and was stable for discharge
controlled and in normal sinus rhythm throughout hospi- after 3.5 days.
talization; congestive heart failure with an estimated ejec- It is notable that 6 months before this hospitalization,
tion fraction of 35% 40% 6 months prior; pacemaker the patient was admitted for a similar shortness of breath
placement; right breast cancer diagnosed 7 months prior, episode due to myasthenia gravis and CAP. She presented
undergoing treatment; colon cancer status post resection in a similar fashion with progressive worsening of short-
14 years prior; and chronic hearing loss. The patient re- ness of breath and wheezing. The diagnostic differential
ported an allergy to penicillin, but was unable to recall included both myasthenia gravis and CAP, and the patient
the previous reaction to the medication. Per the patient’s had initial doses of aztreonam, azithromycin, and moxi-
report, there was a family history of severe anaphylactic floxacin (two doses). Approximately 16 h after the second
reactions to penicillins. Our medical records did not administration of moxifoxacin, the patient required intu-
reveal a previous administration of a penicillin or cepha- bation and was placed on mechanical ventilation. Addi-
losporin. Her home medications included pyridostigmine tionally, the patient had a diffuse, morbilliform rash
180 mg orally (p.o.) daily, azathioprine 50 mg p.o. daily, involving the chest and abdomen, as well as some of
prednisone 7.5 mg p.o. every other day, rivaroxaban the upper extremities, and an erythematous face. At the
15 mg p.o. daily, digoxin 0.25 mg p.o. daily, aspirin advisement of neurology, the patient underwent plasma-
81 mg p.o. daily, omeprazole 40 mg p.o. daily, lisinopril pheresis and antibiotics were changed to tigecycline. It
2.5 mg p.o. daily, carvedilol 3.125 mg twice daily, furose- was not possible to fully determine during chart review
mide 20 mg p.o. daily, exemestine 25 mg p.o. daily, and whether the intubation was required secondary to wors-
calcium carbonate 200 mg p.o. daily. ening myasthenic crisis (due to either infection or medi-
Upon physical examination, the patient was noted to cation administration), acute pneumonia, or both. The
be mildly tachypnic at a respiratory rate of 22 breaths/ patient was extubated 7 days later and discharged to a
min with some use of accessory muscles, but was able rehabilitation facility on hospital day 16.
to speak in full sentences. Heart rate and blood pressure
were stable at 80 beats/min and 132/55 mm Hg, and the DISCUSSION
patient had an oral temperature of 39.3 C. Her initial ox-
ygen saturation was 96% on room air, which increased to We report a case of successful use of tigecycline for
100% on 2 L oxygen delivered via nasal cannula. On presumed CAP in a patient with myasthenia gravis and
auscultation, breath sounds were clear bilaterally without an antibiotic allergy. Given her history of potential
wheezes, rales or rhonchi appreciated. A negative inspira- antibiotic-induced myasthenic crisis, antibiotic selection
tory force was obtained and felt to be adequate for the in the ED for treatment of CAP (in accordance with cur-
patient to proceed without ventilator support (value not rent Infectious Disease Society of America recommenda-
documented). She had a 4 out of 5 strength in bilateral tions) and avoidance of trigger medications were of
upper and lower extremities and was able to do repetitive crucial importance. Choice of antibiotic therapy in a
motion without tiring. Her cranial nerves and sensation patient with myasthenia can be challenging, as many
Myasthenia Gravis and Community-Acquired Pneumonia 3

antibiotic medications are temporally associated with a most reports suggest a timeframe of 24 48 h for develop-
myasthenic crisis. However, evidence consists almost ment of symptoms, with dyspnea being the most
exclusively of case report experiences, as randomized commonly reported event, followed by muscle weakness
controlled trials would largely be considered unethical. and fatigue (7). In cases that reported a recovery time after
Antibiotics commonly associated with precipitating a withdrawal of the medication, a rapid improvement was
myasthenic crisis include fluoroquinolones, aminoglyco- typically seen. This recovery period ranged from immedi-
sides, macrolides, and b-lactams (2–4). Although rare, ate or within 8 h to days (7). Similarly, our patient devel-
clindamycin and tetracyclines have also been oped respiratory symptoms that necessitated intubation
implicated, however, there is a paucity of data approximately 38 h after the first two doses of moxifloxa-
regarding these medications, and they will not be cin were administered, with a recovery period that lasted 1
further discussed in this report (3,5). As mentioned week.
previously, initial antibiotic therapy is often chosen in Antibiotics from the macrolide class have also been re-
the ED, which may occur before a consultation with a ported to be associated with inducing a myasthenic crisis.
neurology or infectious disease specialist. For this Erythromycin has been classified previously as having a
reason, it is increasingly important for the emergency ‘‘possible association’’ with inducing a crisis after two
medicine physician to be aware of the potential reaction case reports were reviewed implicating it as a potential
between antibiotic medication administration and cause (10,11). The first report described an unmasking of
precipitating a myasthenic crisis. the disease in a pediatric patient; and the second report,
Antibiotics can have a presynaptic effect, by blocking in an adult patient, identified an exacerbation that
the release of acetylcholine, impairing the acetylcholine resolved 3 h after administration. In the second case, the
receptor post synapse, or a combination of the two. Un- patient experienced recurrent symptoms after a lower
fortunately, the mechanism of effect for many of the anti- dose was given in a rechallenge. Clarithromycin was also
biotic classes that elicit a myasthenic response is largely described as unmasking the disease in a patient infected
unknown. In reviewing the literature, myasthenia symp- with human immunodeficiency virus, also concomitantly
toms unfold within the first 24 48 h after initiation of receiving fluconazole. Weakness resembling myasthenia
new therapy and resolve shortly after drug cessation. occurred after 2 days of therapy, but an electromyogram
Our patient received moxifloxacin during a previous was negative. The symptoms resolved 6 h after
admission, which was thought to be a possible culprit in discontinuing the drug and a rechallenge was not
inducing a myasthenic crisis. The ubiquitous use of fluoro- performed (12). The timelines reported here are consistent
quinolones sheds light on adverse effects that may be asso- with those of the fluoroquinolones, with symptom onset
ciated with these agents. Although common adverse within 24 48 h and resolution shortly after cessation of
reactions include gastrointestinal disturbances, headache, therapy.
and dizziness, less frequent reactions have now been eluci- Telithromycin is a ketolide antibiotic derived from the
dated with increased medication exposure, including erythromycin compound and the only medication with a
myasthenic crisis. In 1988, Moore et al. described a manufacturer and US Food and Drug Administration
possible case of myasthenia gravis exacerbation which (FDA) warning against use in patients with myasthenia
was thought to be due to ciprofloxacin (6). Since this gravis (13–16). However, a review article closely
time, numerous post-marketing and case reports have examining 8 patient cases of myasthenia exacerbations
been published regarding this adverse effect. Jones et al. postulated that most of these events could be explained
reviewed not only post-marketing reports, but case reports by a concomitant respiratory illness and not solely the
published in the literature identifying 37 unique cases of drug (17). The authors theorized that the mechanism for
fluoroquinolone-induced myasthenia gravis exacerbations causing an exacerbation is most likely peripherally,
(7). It was concluded from this review that myasthenia because the drug does not readily cross the blood brain
gravis exacerbation with systemic fluoroquinolone use is barrier. Recent experiences have not been described, as
a class effect. Although not fully understood, it has been this medication is heavily avoided in the myasthenia
theorized that fluoroquinolones attenuate neuromuscular gravis population and the drug is no longer commonly
transmission through chelation of ionized calcium, thereby used due to the black box warning against severe hepato-
inhibiting acetylcholine release presynaptically (8). toxicity (16,18).
Conversely, it has also been surmised that fluoroquino- The b-lactam class of antibiotics may also have a
lones exhibit a direct toxic effect on the acetylcholine possible association with causing a myasthenic reaction.
ion channel (9). As with the mechanism of injury associ- Ampicillin has been implicated in two case reports
ated with these medications, the exact incidence and risk describing reactions in adult females in which pre-
of myasthenic crisis after exposure to a fluoroquinolone existing symptoms of myasthenia gravis worsened
is not known. Despite lack of information in these areas, shortly after administration (19). One of the cases was
4 M. A. Van Berkel et al.

able to reproduce symptoms during a patient-consented weakness, this class of medications should be highly
rechallenge. The same authors performed an animal avoided in a myasthenia gravis patient unless clinically
study, which did not produce any disease-related symp- necessary.
toms (19). The carbapenem combination imipenem- Limited options are available for antibiotic therapy in
cilastatin is also considered to have a possible association patients with myasthenia gravis that have not been asso-
with causing a worsening of outcomes after one case ciated with precipitating an exacerbation. Tigecycline, a
report described a myasthenia gravis exacerbation occur- glycylcycline derivative of minocycline, is a bacteriostatic
ring 48 h after administration, along with symptom antibiotic approved for use by the FDA in 2005 for compli-
improvement to edrophonium (4). The patient’s symp- cated skin and skin structure infections and for complicated
toms resolved fully 48 h later. Penicillins do not have a intra-abdominal infections (26). In 2009, tigecycline was
prominent neuromuscular blocking property, so the approved for use in CAP. Although not considered a mem-
mechanism of action is largely unknown (19). To our ber of the tetracycline antibiotic class, tigecycline may
knowledge, cephalosporins have not yet been associated share some of the tetracycline class-associated adverse
with causing an exacerbation. effects. Although tetracyclines have been loosely asso-
Finally, the class that is perhaps the most heavily asso- ciated with causing a myasthenia crisis, to date there is
ciated with precipitating a myasthenia reaction is amino- no report of tigecycline precipitating a myasthenic crisis
glycosides. Aminoglycoside antibiotics affect both (Pfizer, personal communication. April 2014).
impairment of acetylcholine release in the presynapse Current guidelines for the treatment of CAP, as well as
and post-synaptic blockage of the acetylcholine receptor the Centers for Medicare and Medicaid Services require-
(4,10,20). A letter to the British Medical Journal in 1964 ments, recommend a respiratory fluoroquinolone or a
first described symptom appearance in a patient with a b-lactam plus a macrolide as initial inpatient therapy
history of myasthenia gravis that was temporally (27,28). Given our patient’s comorbid condition and
associated with the administration of streptomycin and allergy history, we concluded that this agent was the
penicillin for appendicitis (21). Weeks after resolution most appropriate, despite the FDA warning regarding
of the infection, streptomycin and penicillin were given tigecycline use and the risk for increased mortality in
independently. Streptomycin elicited the same symptom- patients treated for CAP (29). Although the increased
atic response, and penicillin administration had no effect. risk of mortality has been much debated, it is noted that
Another report the same year described five cases of particularly high mortality rates were observed in patients
myasthenia symptoms after receiving 1 g streptomycin treated with tigecycline for ventilator-associated pneu-
(22). Upon review, only 1 patient had a concomitant monia and bacteremia at baseline (30,31). A recent
infection. McQuillen et al. described a case report of res- analysis of tigecycline use in the critically ill
piratory weakness after administration of kanamycin, population showed success rates of infection resolution
colistin, and sulfadiazine without response to edropho- in patients receiving tigecycline were comparable to
nium (23). In the same report, the authors further evalu- patients receiving alternative therapy without significant
ated 120 previously published cases of post-surgical safety concerns (32). It is notable, however, that only
neuromuscular blockade in patients given neomycin, approximately 40% of the study patients were receiving
streptomycin, kanamycin, polymyxin, and colistin. Clin- tigecycline as monotherapy.
ically relevant information was available for only 25 pa-
tients. The routes of administration of these medications WHY SHOULD AN EMERGENCY MEDICINE
ranged from intramuscular, intrapleural, intravenous, PHYSICIAN BE AWARE OF THIS?
retroperitoneal, and others. The authors found that
many patients had concomitant administration of intrao- Many patients present with a complicated clinical picture,
perative paralytics (such as tubocurarine), and other vari- where it is difficult to delineate if acute shortness of breath
ables that could have contributed to neuromuscular is caused by either a myasthenic crisis or underlying
weakness. A review article of medication administration illness. In addition, clinical deterioration of the patient sta-
and myasthenia exacerbations stated that aminoglyco- tus can be attributed to progression of the underlying acute
sides have definitely been associated with symptoms illness, myasthenia, or medications administered during
and should be avoided (3). Muscle weakness due to ami- the hospital stay. When initiating new antibiotic medica-
noglycoside administration is not unique to myasthenia tions in a patient with a history of myasthenia gravis, it
patients, and aminoglycosides have been implicated in may be wise to observe the patient for the first 1 2 days
causing intensive care unit (ICU) related weakness, of therapy to determine the safety. If any symptoms of
more recently referred to as critical illness polyneurop- myasthenia gravis exacerbation are noted in a patient
athy (24,25). Because of the high association of receiving any antibiotics, it is recommended to stop the
aminoglycosides with both myasthenia and ICU-related agent and use an alternative antibiotic if feasible. We
Myasthenia Gravis and Community-Acquired Pneumonia 5

report a case where tigecycline was successfully used to 17. Nieman RB, Edelberg H, Caffe SE. Telithromycin and myasthenia
gravis [letter]. Clin Infect Dis 2003;37:1579.
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19. Argov Z, Brenner T, Abramsky O. Ampicillin may aggravate clin-
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