Myasthenia Gravis






Abstract

Myasthenia gravis is an autoimmune neuromuscular disorder hallmarked by fatigability and weakness of all striated muscles. The clinical features arise from antibodies attacking receptors of the neuromuscular junction, causing impairment of communication between nerves and muscles leading to the generalized or localized weakness and fatigue. The clinical features of the disease, impacts and selection of medications, and modality of treatment are key factors with which clinicians should be thoroughly familiar. Muscles that are often involved in the disease are those that regulate facial expression, talking, eye and limb movement, chewing, and swallowing. The nature of the disease presents challenges to health practitioners and especially dentists in dental management of those diagnosed with myasthenia gravis. The manifestations of myasthenia gravis influence dental treatment, with patients requiring special management considerations to ensure safe and optimal dental treatment. Involvement of facial muscles and muscles of mastication requires careful treatment planning in order to prevent overactivity of the muscles, and exacerbation of the fatigability and weakness that hallmarks this disorder while the patient is undergoing a dental treatment.



Background of Myasthenia Gravis


Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction (NMJ) hallmarked by fatigability and weakness of all striated muscles. An oral health care provider is likely to encounter more than one patient with this disease throughout their career as approximately 1 in 10,000 people carry the condition.1 The manifestations of MG influence dental treatment, with patients requiring special management considerations to ensure safe and optimal dental treatment. The clinical features of the disease, impacts and selection of medications, and modality of treatment are key factors with which dentists should be thoroughly familiar. Recent research on MG and approaches to treatment and management of patients in the oral health setting are presented in this chapter.



Description of Myasthenia Gravis


Myasthenia gravis is an autoimmune neuromuscular disorder marked by fluctuating degrees of weakness of the voluntary (skeletal) muscles of the body, with deterioration during periods of action and improvement following periods of rest.2 MG was first clinically recognized by neuroanatomist, Thomas Willis, in 1672.3 The clinical features arise from antibodies attacking receptors of the NMJ, causing impairment of communication between nerves and muscles leading to the generalized or localized weakness and fatigue.3 Muscles that are often involved in the disease are those that regulate facial expression, talking, eye and limb movement, chewing, and swallowing.2 In some instances, the involvement of respiratory and bulbar muscles can be life-threatening.4 These manifestations adversely affect the quality of life, with the patients experiencing difficulty walking a long distance, rising from sitting position, loss of employment, and impairment of carrying out adequate oral hygiene and ability to wear dentures.1


The nature of the disease presents challenges to oral health workers in dental management of those diagnosed with MG. Involvement of masticatory and facial muscles requires careful treatment planning in order to prevent overactivity of the muscles.5 In addition, exacerbation of the fatigability and weakness that hallmarks this disorder can potentially be precipitated by certain medications used by a dentist, signifying that MG patients have specific requirements while undergoing dental treatment.3 Here we review the epidemiology, etiology, pathogenesis, clinical features, diagnosis, and medical management of MG, and discuss the role of a dentist, in coordination with a physician, in providing oral care and managing the dental complications that may arise from the disorder.



Epidemiology of Myasthenia Gravis


Epidemiology is the study of patterns, causes, and effects of the disease in a population. It helps identify risk factors for the disease, in this case, MG, and assists in providing preventive solutions. The main feature is the measurement of disease outcome in a population at risk. MG is quite an uncommon disease; however, prevalence has increased in recent times.6 The National Epidemiological study of MG in Australia (2012) reported an incidence rate of 24.9 per one million residents. Prevalence rates of 117.1 per million residents were found overall. The crude incidence in women was 21.9 per million and men was 27.9 per million. The incidence and prevalence rates were lower in men than women between the ages of 15 and 64 years. However, the prevalence and incidence rates were lower in women over the age of 65. Symptoms can occur from as young as 2 years of age, with the mean age of onset being 43.4 years for women and 53.4 years for men. It was also found that MG disproportionately affected younger females and older males.7 In a systematic review, it was found that the most accurate estimate of the incidence of MG was around 30 per million a year and the incidence in children and adolescents was between 1 and 5 per million per year.8 This is similar to the results discussed previously from the National Epidemiological study in Australia by Gattellari.7



Distribution of Myasthenia Gravis


The occurrence of MG is influenced by gender and age, with women being affected three times more often than men under the age of 40 years.6 Another study by Blum et al performed a community-based survey of 165 Australians with a general practitioner confirming the diagnosis of MG. It was found that early onset of ages less than 40 years of age was more frequently female whereas late onset of MG over the age of 40 years was more frequently male.10 It is important to question the reliability of the study due to the small sample population of the study. However, the results of this study had the same conclusion as the study by Gattellari.7 Both the studies indicate that prevalence of MG was higher in women between ages 15 and 64 and higher in men over the age of 65.7



Determinants of Myasthenia Gravis


The precise cause of MG is unknown; however, abnormalities relating to the thymus gland (hyperplasia and neoplasia) have been shown to play a part in patients with anti-acetylcholine receptor antibodies as well as genetic predisposition which is likely to have an impact on the development of the disease.6 Later onset after age 40 seems more likely to be a male patient and is usually reported to have normal thymic histology or thymic atrophy. More than 80% of those in early onset presented with positive anti-acetylcholine and thymic hyperplasia.6 In addition, a systematic review by Carr et al described the influence of environmental and hormonal problems contributing to disease onset.9


A study performed by Blum et al found that factors that triggered and worsened MG included physical and emotional stress, infections, surgery, trauma, and medications.10 They also found a cooccurrence of other immune-related diseases in 54% of the patients from the total of 165 Australian patients that they surveyed.10 Moreover, the quality of life is severely affected by MG. Around 30% of the patients experience very severe symptoms that require hospitalization. Blum et al concluded that the factor associated with poor quality of life was depression where close to 40% experience it. Further, they have found that 40.6% of the 165 patients were working and 50% had required sick leave due to MG in the past 12 months.10


Patients incur financial pressure due to impact on employment and need for assistance daily. This has also been due to the impact of comorbidities in patients with MG. Study by Diaz and colleagues11 concluded that out of the 253 patients, 73% were found to have comorbidities such as diabetes, hypertension, thymoma, and myasthenic crises. The study demonstrated that comorbidities are frequent in patients and may worsen the diagnosis of MG. It is recommended that patients with MG should be screened for diabetes, thyroid function, hypertension, and thymoma.11



Etiology and Pathogenesis of Myasthenia Gravis


The immune system is known for its role in defending the body against foreign organisms; however, occasionally it can counteract its normal function and turn against the host, resulting in an autoimmune disease.12 In these disorders, immune cells that would typically attack microbes and pathogenic organisms erroneously attack the cells and/or proteins that have crucial roles in the body.12 MG is a prototypical, autoimmune disease that is etiologically routed to the profile of the autoantibodies, the location of the affected muscles, the age of onset of symptoms, and thymic abnormalities.4 ,​ 13 ,​ 14


In the majority of reported MG cases, the immune system targets the nicotinic acetylcholine receptor (AChR), a membrane protein on muscle cells that is vital for muscle contraction (Fig. 8.1).4 ,​ 15 It is indicated that at a normal NMJ, an active nerve cell prompts contraction of a muscle cell by releasing acetylcholine (ACh) from the motor nerve terminal in discrete packages (quanta).13 ,​ 15 The ACh quanta attaches to the AChR, a voltage-gated channel on the presynaptic terminal, generating an inward flux of ACh into the synaptic cleft that leads to the end-plate potential and gets hydrolyzed by acetylcholinesterase inside the synaptic cleft.15 ,​ 16 These contractions enable the individual to move a hand or complete any other voluntary movement.15



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Fig. 8.1 Etiology of myasthenia gravis.


Commonly, 85% of the patients have antibodies against the nicotinic AChR present in their blood, and approximately 15% of individuals with MG are seronegative for antibodies to the AChR, implying that the antibodies are not identifiable in their serum.14 However, recent studies have indicated that a small fraction of these individuals have antibodies to muscle-specific receptor kinase (MuSK) or the lipoprotein-related protein 4 (LRP4), a protein that assists in the arrangement of AChRs on the surface of the muscle cell.6 ,​ 13 In both instances, the binding of the pathogenic antibodies leads to a reduction of available protein receptors and impairs the neuromuscular transmission by complement-mediated damage of the receptors on the postsynaptic membrane.17 ,​ 18 While the underlying cause of MG remains unknown, several factors involving the induction and preservation of specific autoantigen responses that are observed in most striated muscles are broadly explored.


Moreover, the pathogenesis of MG depends upon the target and isotype of the antibodies. Most AChR antibodies belong to immunoglobulin (Ig) G1 and IgG3 (human) subclasses, which respond with various epitopes on the surfaces of AChRs.4 Some antibodies stimulate, complement, and cause enzymatic lysis of the AChR on muscle cells; however, those that are exclusive to the key immunogenic region are more liable to crosslink the AChRs in the membrane and elevate their degradation rate, both mechanisms lead to the loss of AChR from the postsynaptic membrane.4 The subsequent loss of AChRs at the NMJ impairs neuromuscular transmission, translating clinically to fatigue and muscle weakness.4 ,​ 16


In the minority of patients, however, the autoantibodies bind to MuSK.19 MuSK is a postsynaptic transmembrane tyrosine receptor kinase that is critical for the development and preservation of AChR at the NMJ.20 MuSK forms the receptor configuration for agrin, a protein extant on synaptic basal lamina.16 Interactions of Agrin/MuSK stimulate and preserve RAPSN-dependent clustering of AChR and other proteins present on the postsynaptic membrane.21 RAPSN, present on the postsynaptic membrane, is a peripheral membrane protein essential for the clustering of AChR. Mice deficient in agrin or MuSK are unable to form NMJs and die at natal due to extreme muscle fatigue and weakness.16 ,​ 22 These antibodies are evidently pathogenic, but the mechanisms are only beginning to be understood.15


Furthermore, there is evidence that an immune regulator gland, thymus, is commonly associated with MG.14 The thymus plays a critical part in the development of the immune system as it is responsible for producing a specific type of leukocytes, namely T-lymphocytes and T-cells, to defend the body from pathogenic organisms.14 ,​ 23 However, its role in the pathogenesis is highlighted by the assistance of thymectomy and the presence of recurrent histologic aberrations such as thymoma (benign or malignant) and follicular hyperplasia in the germinal center of the thymus.23 ,​ 24 This abnormality of the thymus gland leads to T-cells losing their capacity to distinguish between self and non-self, making them more probable to attack the body’s normal cells.25



Genetic Component of Myasthenia Gravis


MG is a multifactorial disorder, significantly predisposed by genetic factors, even though it displays narrow scope for heritability.26 MG predisposition has been investigated via family27 ,​ 28 and twin studies,29 introspective of the disease’s hereditary clustering and then of genetic inheritance. Bogdonas et al observed higher concordance values of MG among monozygotic twins than among dizygotic twins, strongly suggesting genetic interference in the pathogenesis of MG.29 In addition, another study has reported that patients diagnosed with MG may be worsened with the presence of another autoimmune disease, most commonly, thyroid disorders and/or rheumatoid arthritis, indicating to the objective that a more generalized disturbance in the individual’s immune system has occurred.26


Furthermore, in the onset of MG, the human leukocyte antigen (HLA) complex is implicated as a prominent involved genomic region. HLA-A1 and B8 alleles for the class I and DR3 for the class II encompass an inherited multigene haplotype termed “8.1” that has been reproducibly correlated with early onset MG and thymic hyperplasia.30 ,​ 31 In contrast to HLA, several HLA-unlinked genetic loci have also been explored with regards to their link to MG susceptibility.26 In addition, other regulatory factors, genes, and cytokines, such as interferon regulatory factor 5, TNFα-induced protein 3, SNP rs13207033, and interleukin-10, all play a critical yet undefined role in immune system function.19 The advancement of the human genome, genotyping, sequencing instruments, and the accessibility of statistical methods currently construct new possibilities in understanding the complex genome for variants influencing disease predisposition.19



Diagnostic Evaluation of Myasthenia Gravis


The defining characteristic of MG is fluctuating weakness and fatigue of skeletal muscles.1 Signs and symptoms vary depending on the age of presentation and severity of the disease, including patterns of autoantibodies and associated thymic abnormalities (Fig. 8.2). In more than 50% of cases, the initial presentation of MG involves ptosis and diplopia, resulting from weakness of the extraocular and levator palpebrae muscles.32



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Fig. 8.2 Symptoms of myasthenia gravis.


Weakness can remain localized in closely related muscle groups for long periods of time. For example, ocular myasthenia frequently affects the eye muscles, which occurs in roughly 15 to 20% of patients.33 But it can also spread to other muscles, which is a condition termed generalized MG. The symptoms of generalized MG progress in a craniocaudal direction, the order being: from the ocular muscles, to the facial muscles to the lower bulbar muscles, to the truncal muscles, and finally to the limb muscles.29 This occurs mostly within 2 years of the onset of the disease.32


Muscular weaknesses can lead to a plethora of related conditions. Dysphagia, dysarthria, and reduced facial expression (which often manifests as a snarling appearance when attempting to smile) can result from facial and masticatory muscular weakness.33 Weakness in the soft palate and impaired lip movement may cause changes in phonation, usually with a nasal quality.33 Weakness in the neck can cause problems such as head droop, and when the neck extensors are affected, the diaphragm is often affected. Severe cases may affect respiratory muscles to the point of myasthenic crisis, which is a respiratory collapse that can be fatal. It requires urgent treatment with mechanical ventilation.33


Much of muscular weaknesses are detectable on examination, but mild cases would necessitate tests of fatigue to be sure. Classic tests involve asking the patient to look up for several minutes (diagnosing ptosis or extraocular muscle weakness), repeatedly testing the strength of proximal muscles as well as counting aloud to 100 (listening for slurring or any exaggerated nasal quality in the voice).33 These tests allow the physician to determine the severity and extent of the disease, in addition to providing feedback for implemented treatment plans. Diagnosis of MG in those patients presented with generalized muscle weakness that lacks ocular involvement, and with both normal sensory examination and deep tendon reflexes is always doubtful.33


Clinically a presentation of weakness and fatigability of skeletal muscles, with improvement after rest, is a rudimentary diagnostic test of MG.33 The most touted diagnosis stems from detecting serum anti-acetylcholine receptor antibodies (AChK-ab).34 These are found in 50 to 60% of patients with ocular MG and in 80 to 85% of patients with generalized MG.34 An exception is an anti-AChR antibody, the concentrations of which are unreliable indicators of the severity of MG. If anti-AChR antibodies are negative, the next step is to test anti-MuSK antibodies.34 The seroconversion rate is 15% after 1 year for seronegative patients.34 Immunosuppression can sometimes cause the disappearance of antibodies. Although some of these anti-striational antibodies can potentially indicate the disease prognosis and phenotype, the exact association has not yet fully elucidated.


In addition, diagnosis can also be aided by systemic administration of acetylcholinesterase inhibitors, known as the Tensilon test, which often uses neostigmine or edrophonium.35 It aims to ascertain any reversibility of muscular weakness and can only be performed once that weakness has been confirmed. The sensitivity of the test peaks at 88% for generalized MG and 92% for ocular MG, with specificities of 97% for both disease forms.35 However, it should be noted that false-positive edrophonium tests have been reported in various diseases, including non-neuromuscular diseases.35 Hence, the diagnosis of MG has been a function of both clinical features and edrophonium responsiveness and other laboratory findings.


Electromyography studies have shown that repetitive nerve stimulation (RNS) is an effective technique for investigating neuromuscular transmission. However, its sensitivity can be relatively low, particularly for patients with mild symptoms and in those with anti-MuSK and MG.36 Patients on chronically high doses of acetylcholinesterase inhibitors can also have misleading results.


Single-fiber electromyography (SFEMG), however, has shown impressive sensitivity, peaking at 99% for generalized MG and 80% for ocular MG and is always recommended in the diagnostic pathway for MG.37 The specificity of SFEMG can be inconsistent; however, an atypical test can be demonstrated in other conditions such as mitochondrial cytopathy, motor neurone disease, or radiculopathy.38

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Dec 13, 2021 | Posted by in NEUROLOGY | Comments Off on Myasthenia Gravis
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