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An update on myasthenia gravis, challenging disease for the dental profession

Article in Journal of Oral Science · September 2015

DOI: 10.2334/josnusd.57.161

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Journal of Oral Science, Vol. 57, No. 3, 161-168, 2015

Review

An update on myasthenia gravis, challenging disease for the

dental profession
Alessandro Tamburrini1), Federico Tacconi1), Alberta Barlattani2),
and Tommaso C. Mineo1)
1)Thoracic Surgery Division, Multidisciplinary Myasthenia Gravis Unit, Tor Vergata University, Rome, Italy
2)Special Diseases in Odontostomatology, Tor Vergata University, Rome, Italy

(Received February 1, 2015; Accepted May 5, 2015)

Abstract: Myasthenia gravis is an autoimmune cations of MG have been described (1), but the dental
neuromuscular disorder characterized by fluctuating management of patients diagnosed as having MG still
weakness and skeletal muscle fatigue. Clinical signs presents a challenge to oral health care providers. The
and symptoms may vary considerably according to present communication covers current knowledge of
the age at presentation, patterns of autoantibodies MG, and details the clinical aspects of the disease that
and associated thymic abnormalities, so that thera- are relevant to the dental care of affected patients.
peutic options are highly individualized. Facial and
oropharyngeal muscle weakness is common at disease Epidemiology
onset, and therefore dentists are often the first health Although MG can occur at any age and in either gender,
professionals to encounter these patients. Myasthenic it is diagnosed most frequently in women in their second
patients require special consideration and advice in and third decades; men tend to be affected in their sixth
order to ensure optimal and safe dental treatment. and seventh decades. The incidence rate varies between
Oral manifestations, treatment timing and modality, 1.7 and 21.3 per million inhabitants, with a prevalence
the choice and effects of drugs and medications, and ranging between 15 and 179 per million inhabitants (2).
prevention of myasthenic crisis are all important
aspects with which dentists and oral health care Pathophysiology
providers should be thoroughly acquainted. In most cases the disease is caused by autoimmune
(J Oral Sci 57, 161-168, 2015) attack against components of the neuromuscular junction
(NMJ), on the postsynaptic membrane of striated skeletal
Keywords: myasthenia gravis; dental management; muscles (3). In most patients, the autoimmune response is
autoimmune disease. mediated by antibodies against the acetylcholine receptor
(AChR), which reduce the number of functional AChRs
through three possible mechanisms: direct destruction of
Introduction the receptors, blockade of the acetylcholine binding sites,
Myasthenia gravis (MG) is an autoimmune neuromus- or complement-mediated damage (4). Classically, AChR
cular disorder, clinically characterized by fluctuating antibodies have been found in 85% of MG patients, while
weakness of skeletal muscles and abnormal fatigue on the rest appear to be “seronegative” (5). However, in the
exertion. The clinical manifestations and dental impli- last decade, “seronegative” MG has become increasingly
rare with the discovery of antibodies against muscle-
Correspondence to Dr. Tommaso Claudio Mineo, Thoracic Sur- specific kinase (anti-MuSK) (6), antibodies against
gery Division, Tor Vergata University, Viale Oxford 81, Rome, clustered AChRs detected in a sensitive cell-based assay
Italy (7) and, most recently, antibodies against low-density
Fax: +39-0620902882 E-mail: [email protected] lipoprotein receptor-related protein 4 (Lrp4) (8). The role
doi.org/10.2334/josnusd.57.161 of the thymus in the pathogenesis of MG is highlighted
DN/JST.JSTAGE/josnusd/57.161
162

by the presence of frequent histologic abnormalities such 3:1). Both bulbar and limb/trunk muscles can be quite
as thymoma and follicular hyperplasia, as well as by the variably affected, with no evident correlation between
clinical benefits of thymectomy (9). Fifteen to twenty symptoms severity and antibody titres. Thymic hyper-
percent of patients, usually those older than 40, have plasia is frequently evident, and thymectomy is often an
a thymoma caused by proliferation of epithelial cells effective therapeutic option (3,5,9). The late-onset form,
(10). In 50% of patients younger than 45 years, typically on the other hand, appears to show a male predominance
females with the AChR antibody, the thymus is the site (18), most patients presenting with severe symptoms
of follicular hyperplasia characterized by the presence of and bulbar involvement (3). The associated presence of
germinal centers (11). thymoma is well known (10) and other autoantibodies
directed against ryanodine, titin and striated muscle
Signs and symptoms are frequently found (3). Among “seronegative” MG
In over 50% of the cases, the initial presentation of MG patients, those with anti-MuSK antibodies (5% of the
entails weakness of the extraocular muscles, resulting MG population) have key clinical features, being almost
in ptosis and diplopia. However, the disease remains exclusively young women (19), often presenting with a
restricted to the extraocular muscles in only 15-20% of severe form of the disease and showing a clear correla-
patients (pure ocular form). In the remaining 80-85%, tion between symptom severity and antibody titers (3,5).
widespread weakness of other muscle groups occurs Facial, bulbar and respiratory muscles are frequently
(generalized form), most commonly within the first involved, while ocular involvement and thymic disease
two years after onset (3,12). As the disease progresses, are rare (3). In these patients also, myasthenic crisis and
facial and masticatory muscle weakness may appear, respiratory failure are common (20). Approximately 50%
leading to dysphagia, dysarthria and the appearance of of “seronegative” MG patients have antibodies against
an expressionless face (13). Changes to phonation with clustered AChRs detected by a cell-based assay and their
a nasal quality may occur due to soft palate muscle clinical pattern is similar to the classic form of AChR MG
weakness and impaired lip movement (14). The proximal (7). Lastly, the majority of myasthenic patients with Lrp4
limb muscles, the diaphragm and the neck extensors are antibodies (20-50% of “seronegative” MG) are female,
also often affected. The severity of muscular weakness ranging in age from 17 to 79 years and with clinical
tends to fluctuate during the day, being less severe in the characteristics mostly resembling MuSK MG (5).
morning, and gradually worsening as the day progresses,
especially after prolonged use of the affected muscles. Diagnosis
Myasthenic symptoms can be worsened by emotional From a clinical viewpoint, demonstration of weakness
stress, systemic illness (especially viral respiratory infec- and fatigability of skeletal muscles, with improve-
tions), hypothyroidism and hyperthyroidism, pregnancy, ment following rest is by itself diagnostic of MG (21).
the menstrual cycle, increased body temperature, drugs However, detection of serum AChR antibodies is
and medications affecting neuromuscular transmission considered to be the diagnostic gold standard. These
(15). Severe involvement of the respiratory muscles may antibodies are found in 80-85% of patients with gener-
lead to myasthenic crisis, a life-threatening respiratory alized MG and in 50-60% of those with ocular MG
collapse requiring immediate treatment with mechanical (22). The diagnosis can also be confirmed by systemic
ventilation. Myasthenic crisis occurs in about 15-20% administration of acetylcholinesterase inhibitors, such as
of MG patients, among which 4-8% of cases are fatal neostigmine or edrophonium (“Tensilon test”), followed
(15,16). Infections, surgical procedures, drugs and by an unequivocal improvement in an objectively weak
emotional stress may predispose to myasthenic crisis muscle (23). Among electromyography studies, repeti-
(16). The most widely accepted classification for the tive nerve stimulation is a commonly used technique
clinical severity of MG is the Myasthenia Gravis Foun- for investigation of neuromuscular transmission. Albeit
dation of America Clinical Classification (17). employed for diagnostic purposes in MG, its sensitivity
can be quite low, especially for patients with mild
Clinical characteristics symptoms (24) and in those with anti-MuSK+ MG (25).
Approximately 85% of MG patients have detect- Single-fiber electromyography has instead demonstrated
able serum AChR antibodies and can be categorized excellent sensitivity (over 90% of positive results) and
according to clinical features and pathogenesis into two should always be employed in the diagnostic pathway for
sub-groups: early-onset MG and late-onset MG. Early- MG (26).
onset MG shows a clear female predominance (sex ratio
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Table 1 Current therapeutic options for myasthenia gravis

Cholinsterase Immunosuppressive Drugs under evaluation Interventional Thymectomy
drugs agents
Pyridostigmine Prednisone Tacrolimus Plasmapheresis Transsternal
Neostigmine Azathioprine Cyclophosphamide IVIG VATS
Cyclosporine Rituximab Robot-assisted
Mycophenolate Transcervical
IVIG: intravenous immunoglobulin

Therapeutic options mized by complete removal of the thymus gland and any
Treatment for MG primarily consists of five options, ectopic thymic tissue that may be scattered throughout
three of which are pharmacological interventions that the mediastinal and cervical fat (35). However, the role
may have an impact on dental care (Table 1). Therapy, of thymectomy in older myasthenic patients, including
however, is highly individualized, and a number of those with the purely ocular form of MG, or all those
factors such as the rate of disease progression, degree who are seronegative, particularly anti-MuSK+ patients,
of functional impairment, patient age and distribution of is much less clear (30).
muscle weakness, all influence treatment choices (27-29).
Cholinesterase inhibitors are the first therapy of choice. Dental management considerations
These drugs inhibit breakdown of acetylcholine so it Myasthenia gravis may represent a challenging issue for
can accumulate at the NMJ. The drug most commonly dentists, oral health care providers, and also the patients
prescribed, pyridostigmine bromide (Mestinon), is themselves. Indeed, several important features of MG
administered orally every 4-6 h at a dosage of 30-60 mg may significantly impact on the dental management of
(4). Oral corticosteroids are also widely used in the treat- affected patients.
ment of MG and achieve significant improvement in up
to 80% of patients; prednisone and prednisolone are those Relevant clinical aspects
most commonly used. The adverse effects of high steroid The clinical manifestations of MG frequently include
doses can be minimized by the use of immunosuppressive facial and oropharyngeal muscle weakness, especially
agents such as azathioprine, cyclosporine, methotrexate at the time of onset. In this regard, dentists are in a
and cyclophosphamide. Among the newer immunosup- unique position, as they may be the first health profes-
pressive agents, tacrolimus or mycophenolate mofetil, in sionals to encounter patients with a potential diagnosis
conjunction with steroids or even as monotherapy, can of MG. This is particularly true for anti-MuSK+ MG,
also be effective. where bulbar symptoms (weakness of the muscles inner-
Recently, a significant benefit in AChR+ patients and a vated by the lower brainstem) are often predominant,
dramatic benefit in seronegative anti-MuSK+ disease have although they can be variably present in every form of
been reported with the use of Rituximab, a monoclonal MG (3). Therefore, being familiar with the disease and
antibody directed against the CD20 epitope on B cells having a thorough knowledge of its pathophysiology
(30). Short-term immunotherapy using plasmapheresis is of paramount importance. As reported and evaluated
or intravenous immunoglobulin is also a valid therapeutic by Weijnen et al. (36), patients with bulbar MG may
option for rapid and temporary treatment of acute MG complain of poor masticatory performance. As a result of
exacerbation (myasthenic crisis) (4). Since its introduc- masseter weakness, chewing can become progressively
tion over 70 years ago by Blalock et al. (31), thymectomy difficult with increasing discomfort (“jaw claudication”)
has gained widespread acceptance in the management of so that patients are forced to stop and rest during meals
MG, and is integrated with pharmacological treatment. (34). In severe cases, they may need to support their
Benefits from this operation have been reported, espe- lower jaw while eating in order to allow mastication
cially in patients with seropositive non-thymomatous and between meals to prevent spontaneous dropping
disease, associated with thymic hyperplasia (32,33). Even of the jaw and opening of the mouth (37,38). Chewing
in the absence of any thymus abnormality, the available difficulty, fatigable reduction in biting force, inability to
evidence suggests that up to 85% of myasthenic patients close the jaw and weak jaw closure are thus typical of
experience significant improvement of symptoms and MG patients (34,39), occurring in at least 4% of cases
that 35% achieve drug-free remission (34). Beneficial (40). Therefore, dentists should be particularly aware of
effects of thymectomy have been reported to be maxi- these clinical presentations, as they may be able to pick
164

up early signs of the disease. Examining a patient who thenic patients have stable and well controlled disease
has difficulty in opening the mouth or keeping the jaw with limited or mild neuromuscular involvement, so that
open may be aided by the use of a mouth prop, as this routine dental treatments and minor procedures (root
helps to reduce stress on the masticatory muscles (38). canals, fillings etc.) can be performed safely within the
When using a mouth prop, ensuring efficient suction is setting of a private dental office. A hospital-based dental
mandatory to avoid aspiration of oral debris (38). The clinic, with emergency intubation and respiratory support
mouth prop can also be removed periodically to allow facilities, would otherwise be chosen when treating
the patient a rest break, and overstretching should be patients with severe MG symptoms, those with serious
avoided. Possible differential diagnosis between MG and anxiety, and also when more significant oral surgery
temporomandibular joint dysfunction in patients with (multiple extractions, wisdom tooth extractions etc.) is
limited mouth opening should also be taken into consid- planned (38). If the patient’s recent medical history is
eration. Application of an occlusal splint in a myasthenic consistent with frequent exacerbations, severe bulbar
patient may in fact induce masticatory muscle fatigue and respiratory symptoms and generalized weakness,
and exasperate symptoms. Additional concerns should the dentist should consult the patient’s physician and a
also be addressed in elderly patients. It is well known that neurologist, as additional therapy may be recommended
severe limitations of masticatory performance, together prior to treatment, especially for significant oral surgery
with chewing and swallowing difficulties, may lead to (37,38) (Fig. 1). In all cases, multiple and short early
malnutrition and weight loss in MG patients (37,38). morning appointments are preferable, in order to avoid
However, feeding and swallowing difficulties as well cumulative muscle weakness, and also to take advan-
as malnutrition can be common findings in the geriatric tage of the greater muscular strength typically noted
population, mostly due by poor appetite (41), stroke (42), during morning hours (1). Oral anticholinesterase drugs
neurological disorders (43) or dentition status (44,45). should be preferably administered 1.5 h before dental
Despite its increased incidence in older adults (18), it treatment to achieve maximum effectiveness during
is important not to overestimate MG. Lastly, in myas- the dental session (37,38). Emotional stress is a known
thenic patients, dentists may notice a typical, furrowed risk factor for myasthenic crisis. In order to avoid it, the
and flaccid clinical appearance of the tongue, resulting patient should be allowed to arrive and rest for a while
from lipomatous atrophy, triple longitudinal furrowing prior to dental appointment, possibly in a peaceful and
(myasthenic tongue) being observed only in severe cases relaxing environment (37,38). Establishing an open
(37,38). and friendly relationship between the patient and the
dental staff would also help to reduce emotional stress
Dental care for myasthenic patients (37,38). It is also important for all necessary equipment
The provision of dental treatment for patients with MG and supplies to be set up and prepared before starting
requires special management considerations, as well as the dental session, to assure efficiency and optimization
advice and precautions with which all oral health care (38). Positioning on the dental chair during treatments
specialists should be sufficiently acquainted. A complete should be carefully taken into consideration as well,
review of the patient’s symptoms and an assessment of especially in MG patients with bulbar symptoms. A
phonation and swallowing should be done prior to any comfortable, semi-upright position rather than a deep
treatment (46). Simple methods for assessing the degree recline is preferred, in order to reduce the risk of closing
of disease control and the severity of symptoms include the throat or regurgitating saliva and other fluids. Indeed,
evaluating the length of time the patient is able to look up failure of the supraglottic constrictors to properly seal the
before ptosis develops and the period of time the patient laryngeal inlet, in conjunction with increased salivation
can maintain outstretched arms (46). These assess- often caused by anticholinesterase drugs, creates a higher
ment should be conducted regularly, and any changes risk of aspiration of saliva and oral debris (38). Isolation
in symptom severity should be reported to the treating of the working field with a rubber dam is recommended,
physician (46). If concern arises about a patient’s ability and good oral evacuation suction is imperative to rapidly
to breathe adequately, spirometry is a useful examination remove all dental debris and avoid aspiration (37,38).
for assessment of respiratory muscle function (47). In Resting periods should be allowed during the dental
recent years, several patient-oriented questionnaires have session, and it is of great importance that the patient
also been proposed for evaluation of MG patients in daily remains seated until all oral debris and fluids have been
clinical practice (48-50). removed and muscular strength is well controlled (37).
It is important to stress that in most instances, myas-
 165

Fig. 1   A suggested decision-making flowchart for planning of dental treatment in myasthenic patients.

Table 2 Drugs used in dentistry that may impact on myasthenia gravis

Medication Relatively contraindicated Use with caution Relatively safe
Acetaminophen X
Amide-type anesthetics X
Aminoglicosides X
Aspirin X
Barbiturates X
Benzodiazepines X
Carbopenems X
Cephalosporines X
Corticosteroids X
Ester-type anesthetics X
Fluoroquinolones X
Hypnotics X
Macrolides X
Morphine and Opioids X
N2O/O2 sedation X
NSAIDS X
Penicillines X
Sulfonamides X
Tetracyclines X
Vancomycine X

Drugs and medications in the dental care of aminophen, aspirin, and non-steroidal anti-inflammatory
myasthenic patients agents do not affect neuromuscular transmission, metab-
Many common drugs used in dentistry may lead to olism and acetylcholine release, and can be administered
possible complications in MG patients by exacerbating safely to MG patients (1). On the other hand, morphine
muscle weakness or interfering with breathing (1,37). and other opioids may cause respiratory depression, and
Dental procedures may require sedation to reduce their use should be avoided (37).
anxiety and avoid emotional stress. In this setting, the Local anesthetics decrease the postsynaptic memb-
use of benzodiazepines, hypnotics and barbiturates rane’s sensitivity to acetylcholine and may worsen
should be avoided since these drugs may lead to respira- weakness in MG patients (51), so that careful attention
tory depression, worsening of myasthenic symptoms should be paid to their usage. Ester-type local anesthetics
and myasthenic crisis (1,34,38). Nitrous oxide-oxygen like procaine are to be avoided. In fact, ester anesthetics
sedation has instead been reported to be safe (1,37,38). are inactivated by plasma cholinesterase and, in myas-
Pain control is also of prominent importance. Acet- thenic patients receiving anticholinesterase drugs, their
166

effects may be particularly long-lasting, leading to an Prednisone and other immunosuppressive agents such
increased risk of systemic toxicity (1,51). Amide-type as azathioprine are widely employed in the treatment of
anesthetics (lidocaine, mepivacaine) are instead metabo- MG, often with good results (61). However, corticoste-
lized by the liver (52) and should be considered the roids and immunosuppressants may have an unfavorable
option of choice in view of their shorter duration and the effect on the immune system’s efficiency (61). Further-
rarity of their side effects; intravascular injection should more, both thymic follicular hyperplasia and thymomas
be avoided (1,38). Combination of a vasoconstrictor such are associated with complex dysregulation of the immune
as 1:100,000 epinephrine with the anesthetic agent is system due to dysfunctional T cells and a cytokine-
advantageous for both maximizing the efficacy of anes- related pro-inflammatory environment (62,63). As a
thesia and minimizing the anesthetic dose (1,38). The result of these intricate immune networks, MG patients
dosage can also be reduced using local infiltration and (especially those with thymic abnormalities and those
the intraligamentary or intrapulpal injection technique, receiving high-dose steroids) have an increased risk of
rather than nerve blocks (1,38). Due to swallowing opportunistic infections such as chronic mucocutaneous
problems, bilateral mandibular blocks should be avoided candidiasis, oral infections and delayed wound healing
(38). (38). Prophylactic antibiotic therapy should always be
Certain antibiotics may cause muscle weakness due to considered for dental procedures. Lastly, as mentioned
their ability to produce partial neuromuscular blockade previously, plasmapheresis may be recommended prior
by inhibiting the release of acetylcholine from the to significant oral surgery in patients with severe myas-
presynaptic membrane (38). Aminoglycosides (genta- thenic symptoms (37,38). Since the plasma exchange
micin, streptomycin, amicacin, neomycin, kanamycin) protocol entails the use of anticoagulants (heparin or
must be avoided as they are known to cause clinically acid-citrate-dextrose solutions), the dental procedure
significant muscle weakness by blocking presynaptic should be scheduled on a non-exchange day (38).
voltage-activated calcium channels (53). Myasthenic
crises have been documented after administration of Prevention
fluoroquinolones (54), and they should not be used. The Patients should be properly instructed in good preven-
hypothesized mechanisms responsible are either blockade tive oral care and dental hygiene at home, underlining
of the acetylcholine receptor or direct toxicity, and these the importance of this aspect at every dental appointment
effects are known to be dose-dependent (55). Sporadic (38). Oral musculature dysfunction, and weakness of the
worsening of myasthenic symptoms have been reported upper extremities and hand muscles (weakened grasp,
for macrolides and tetracyclines (38), while the ketolide wrist and finger extensors) are common findings that may
antibiotic telithromycin (reports of fatal myasthenic all create challenges to oral self-care (38). Consequently,
crisis) is absolutely contraindicated (55-57). Penicillins, personal dental hygiene may be impaired, increasing the
cephalosporins, sulfonamides and carbopenems have risk for oral infections. Patients should be encouraged to
instead been widely used in MG patients and can be perform regular brushing using an electric toothbrush or
administered safely (34,37,38), with only occasional and a manual toothbrush with a modified handle to reduce
uncertain side-effects reported (58,59). muscle fatigue (38). Use of a tartar control toothpaste
might be recommended to facilitate control of excess
Dental implications of anti-myasthenic treatments calculus deposition. Chlorhexidine or a fluoride mouth
Cyclosporine can cause dose-dependent gingival over- rinse to prevent decay and periodontal disease can also
growth, especially if dental plaque or other local irritants be used safely by MG patients.
are present, and this may lead to gingival and periodontal
disease. A number of medications, such as vancomicine, Myasthenic crisis
ketoconazole, and fluconazole, are also contraindicated If exacerbation of myasthenic symptoms occurs, the
because of their synergistic toxic effects (1,38). Anticho- oral health care provider and the dental staff should be
linesterase agents are the mainstay of treatment for MG, able to promptly evaluate the severity of neuromuscular
and hypersalivation is one of their main drawbacks (60). involvement and eventually treat the crisis. An open
This is of importance since, in addition to the previously airway and adequate respiratory exchange must be estab-
mentioned increased risk of aspiration of saliva and oral lished in cases of respiratory collapse (38). High-speed
fluids during dental sessions (38), excess salivation and suction should be used to rapidly remove oral fluids
drooling may also result in supragingival calculus forma- from the oropharynx, in order to prevent aspiration and
tion. mechanical blockage of the airway. Steps to prevent a
 167

401-412.
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