Chapter 33: Geoepidemiology of myasthenia gravis

doi:10.1016/j.autrev.2009.11.011

Autoimmunity Reviews

Volume 9, Issue 5, March 2010, Pages A383-A386

https://doi.org/10.1016/j.autrev.2009.11.011 Get rights and content

Abstract

Myasthenia gravis (MG) is an autoimmune disease that affects the post-synaptic area of the neuromuscular junction. Its hallmark is weakness that worsens with activity. MG incidence is rising in the recent decades, mostly the late onset subtype, which is considered to be due to the aging population or unknown environmental factors.

The disease has several subtypes which defer slightly in the clinical characteristics, immunological markers, population distribution and the suitable treatments. The autoimmune nature of the disease is manifested by a decrease in the number of acetylcholine receptors in the muscle receptors which makes the endplate potential to be lower than the threshold needed to activate muscle fiber action potential. In our review we try to find the environmental influence on the disease.

Introduction

Myasthenia gravis (MG) is an autoimmune disease affecting the post-synaptic side of the neuromuscular junction (NMJ). MG has been known for more than 300 years, but only in recent decades has there been a better understanding of the disease pathophysiology and its autoimmune nature which leads to better treatments and a lower mortality rate [1] making the disease name (Myathenia Gravis in Greek means severe muscle weakness) almost irrelevant.

Section snippets

Epidemiology

Most of the epidemiologic data about MG has been collected from Europe and North America [2]. The incidence and prevalence of MG is similar around the world (Table 1), except for childhood MG which is uncommon in the western world and is more common in Asian countries such as China [3], [4], [5]. The incidence of MG has increased in the last five decades, from 2–5 per million to 9–21 per million population [6], [7]. The prevalence of MG had been steadily growing as well, but mortality rate is

Clinical manifestations

MG is characterized by a painless weakness of striated muscles which is more prominent with activity and improves with rest. Ocular manifestations (diplopia and ptosis) are usually the first symptoms to appear, in approximately 85% of patients. Dysphagia, dysarthria, or chewing difficulties is an initial symptom in the minority of patients (Table 2). Respiratory muscle weakness is a rare presentation of the disease but can be life-threatening requiring prompt intubation to maintain airway,

Pathophysiology

The most prominent abnormality in MG is a decrease in the number of acetylcholine receptors. This decrease causes the endplate potential (EPP) to be lower than the threshold needed to activate the muscle fiber action potential [13]. Anti-AChR antibodies have been shown to have a causative role in the pathogenesis of MG. Transfusing plasma of MG patients to mice induced muscle weakness [14]. In addition, treatment with plasmapheresis and antibody removal can improve the weakness in an acute

Environmental aspects

A relationship between autoimmune disease and microbacterial pathogens has long been suggested [16]. There are a few reports about the link between MG appearance and active hepatitis C disease in two cases, during treatment with interferon-alfa [17], [18], [19]. AChR-specific serum antibody from MG patients, cross-reacts with herpes simplex virus (HSV). An epitope on the type I glycoprotein shares significant structural homology to the host receptor [20]. Epstein–Barr virus genome was found in

Diagnosis

The diagnosis of MG is a combined diagnosis. It includes bedside tests such as the edrophonium and icepack tests, electrophysiological tests and serum autoantibody levels.

The edrophonium test consists of administering edrophonium (a short acting acetylcholinesterase inhibitor) and observing the patient for improvement. It is an objective and reliable test with a 71.5–95% sensitivity in the diagnosis of MG. The ice pack test consists of putting an ice pack over the eyes of a patient with ptosis.

Treatment

Anticholinesterase drugs comprise the first line of therapy. They cause temporary improvement of weakness, which passes when the short effect of the drug subsides. When the autoimmune nature of the disease was discovered, immunomodulatory treatments were introduced, starting with high dose steroids, which can induce marked improvement and even remission. After the introduction of high dose steroids, there might be a temporary worsening of the weakness which might require cholinesterase

Take-home messages

•
The weakness in MG increases with activity.
•
The incidence of MG in older males is rising in recent years.
•
The disease can be exacerbated by a variety of factors such as infectious diseases.
•
Myasthenia crisis is an emergency necessitating an intensive care setting and maintaining of patient airway.
•
MG is diagnosed by a combination of clinical, electrophysiological and immunological tests.
•
The treatment of MG is treated with a combination of cholinesterase inhibitors and various immunomodulatory

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Cited by (53)

Epidemiology of myasthenia gravis in France: Incidence, prevalence, and comorbidities based on national healthcare insurance claims data
2024, Revue Neurologique
The European literature has reported high variability in the incidence and prevalence rates of myasthenia gravis (MG), but no specific epidemiological data for France have been published. This study aimed to assess the incidence and prevalence rates of myasthenia gravis in France based on data extracted from the French National Health Insurance Claims Database (the SNIIRAM database).
We conducted a retrospective repeated cross-sectional population study from 2008 to 2018 using a representative sample of the French population (Échantillon généraliste des bénéficiaires) covered by health insurance. We calculated the incidence, prevalence, and sex ratio of MG and screened for comorbidities associated with MG (standardized to the general population).
In total, 331 MG patients were identified between 2008 and 2018. The average incidence of MG in France was 50 per million person-years, while the mean prevalence was 465 per million people. The female-to-male ratio was 1.33. The Incidence of MG gradually increased from 40 years of age for women and 60 for men. Thymoma was present for 5.1% of MG patients and a thymectomy was performed for 4.7%. Thyroid disease was the most prevalent autoimmune comorbidity, affecting approximately 8.5% of cases. MG patients had an increased cancer risk, with a standardized rate ratio of 2.38 (95% CI: 1.64–3.46).
The incidence and prevalence rates of MG are significantly higher than those previously reported in the literature and the incidence increases with age. The excess risk of cancer raises concerns for MG patients, in particular, concerning the management of immunosuppressive drugs.
Targeting HIF-1α alleviates the inflammatory responses and rebuilds the CD4<sup>+</sup> T cell subsets balance in the experimental autoimmune myasthenia gravis inflammation model via regulating cellular and humoral immunity
2024, Life Sciences
Cells and tissues in an inflammatory state are usually hypoxic. The hypoxic environment can affect the differentiation of immune cells and produce Hypoxia-inducible Factor-1α (HIF-1α). Inflammation is also a major contributor to the development and deterioration of Myasthenia Gravis (MG). There are limited studies on the immunopathological mechanism and targeted therapy associated with MG exacerbated with inflammation. This research aimed to explore whether BAY 87–2243 (HIF-1α inhibitor) ameliorates the symptoms of the Experimental Autoimmune Myasthenia Gravis (EAMG) inflammation model and study its regulatory mechanism on cellular immunity and humoral immunity.
We first establish the EAMG inflammation model using Lipopolysaccharide (LPS), BAY 87-2243 was applied to the EAMG inflammation model and its therapeutic effects were evaluated in vivo and in vitro experiments.
The proportion of Treg cells was increased whereas Th1, Th17, and Th1/17 cells were decreased in BAY 87-2243-treated EAMG inflammation model. BAY 87-2243 ameliorated the acetylcholine receptors (AChRs) loss and the complement deposited at the neuromuscular junction of the EAMG inflammation model, declined the levels of IFN-γ, IL-17, and IL-6 in serum, and further attenuated responses in the germinal center and reduced the antibody levels by inhibiting the IL-6-dependent STAT3 axis.
BAY 87-2243 restored the balance of CD4⁺T cell subsets and reduced the production of the pro-inflammatory cytokines, thus acting as both an immune imbalance regulator and anti-inflammatory. The current study suggests that HIF-1α might be a potential target for the treatment of MG exacerbated with inflammation.
Neurologic dysphagia
2018, Dysphagia Evaluation and Management in Otolaryngology
The neurologic basis of swallowing is supremely important, which includes neuromuscular control, sensory feedback, and brainstem coordination and influence. Thus, the many potential defects often seen in neurodegenerative disease, stroke, and dementia can have a profound impact on safe swallowing. Since neurologic dysphagia is most commonly seen in the elderly, other comorbid conditions can have a synergistic effect on aspiration risk, including deconditioning, oropharyngeal muscular atrophy, impaired cognition, and medication-related sicca. We review features of these diseases, and advise on approaches to screening, evaluation, intervention, and recognizing sentinel indicators of decline which increase aspiration risk.
Sensory aspects in myasthenia gravis: A translational approach
2016, Journal of the Neurological Sciences
Citation Excerpt :
Since the presynaptic, synaptic and postsynaptic clefts mechanisms of Ach formation, actions and termination are found in practically all cells [29], widespread sensory dysfunctions either immune or congenital mediated in myasthenia make sense. The incidence of classical autoimmune muscle-related MG ranges from 2 to 21 per million of the population, and its prevalence oscillates between 5 and 25 per million of the population [30,31]. Early and late-onset autoimmune MG are the main clinical types defined for the disease.
Myasthenia gravis is a paradigmatic muscle disorder characterized by abnormal fatigue and muscle weakness that worsens with activities and improves with rest. Clinical and research studies done on nicotinic acetylcholine receptors have advanced our knowledge of the muscle involvement in myasthenia. Current views still state that sensory deficits are not “features of myasthenia gravis”. This article discusses the gap that exists on sensory neural transmission in myasthenia that has remained after > 300 years of research in this neurological disorder. We outline the neurobiological characteristics of sensory and motor synapses, reinterpret the nanocholinergic commonalities that exist in both sensory and motor pathways, discuss the clinical findings on altered sensory pathways in myasthenia, and propose a novel way to score anomalies resulting from multineuronal inability associated sensory troubles due to eugenic nanocholinergic instability and autoimmunity. This medicine-based evidence could serve as a template to further identify novel targets for studying new medications that may offer a better therapeutic benefit in both sensory and motor dysfunction for patients. Importantly, this review may help to re-orient current practices in myasthenia.
Sex bias in paediatric autoimmune disease - Not just about sex hormones?
2016, Journal of Autoimmunity
Autoimmune diseases affect up to 10% of the world's population, and approximately 80% of those affected are female. The majority of autoimmune diseases occur more commonly in females, although some are more frequent in males, while others show no bias by sex. The mechanisms leading to sex biased disease prevalence are not well understood. However, for adult-onset autoimmune disease, at least some of the cause is usually ascribed to sex hormones. This is because levels of sex hormones are one of the most obvious physiological differences between adult males and females, and their impact on immune system function is well recognised. While for paediatric-onset autoimmune diseases a sex bias is not as common, there are several such diseases for which one sex predominates. For example, the oligoarticular subtype of juvenile idiopathic arthritis (JIA) occurs in approximately three times more girls than boys, with a peak age of onset well before the onset of puberty, and at a time when levels of androgen and oestrogen are low and not strikingly different between the sexes. Here, we review potential explanations for autoimmune disease sex bias with a particular focus on paediatric autoimmune disease, and biological mechanisms outside of sex hormone differences.
Myasthenia gravis: Predictive factors associated with the synchronized elevation of anti-acetylcholine receptor antibody titer in Kanazawa, Japan
2014, Journal of Neuroimmunology
Citation Excerpt :
In 2012, at Kanazawa University Hospital, a valuable opportunity to investigate the phenomena associated with MG was identified when an elevation of the anti-acetylcholine receptor (anti-AChR) antibody titer was observed in approximately 60% of outpatients with MG. This phenomenon was considered important because it facilitated investigation of factors associated with immune-exacerbation in MG (Somnier, 2005; Le Panse et al., 2008; Meyer and Levy, 2010). Therefore, the purpose of this case–control study was to determine the factors predictive of an elevation in the anti-AChR antibody titer in patients with MG and to determine if these factors indicate different pathogenic backgrounds in MG.
For a brief period, an increased incidence of elevated anti-acetylcholine receptor antibody titer was observed in patients with myasthenia gravis (MG) in Kanazawa, Japan. The purpose of this study was to examine the predictive factors associated with this antibody titer elevation. Decreased odds of titer elevation were seen in patients with early-onset MG than in those with late-onset MG. In patients with non-thymoma-related MG, thymectomy prevented the antibody titer elevation. Our data suggest that late-onset MG may have a different immunogenic response and the thymus might play an immunoregulatory role against extrinsic factors in some types of MG.

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Chapter 33: Geoepidemiology of myasthenia gravis

Abstract

Introduction

Section snippets

Epidemiology

Clinical manifestations

Pathophysiology

Environmental aspects

Diagnosis

Treatment

Take-home messages

Curr Opin Immunol

Lancet Neurol

J Neurol Sci

Ann Thorac Surg

J Neurol Sci

Lifetime course of myasthenia gravis

Muscle Nerve

The epidemiology of myasthenia gravis

Semin Neurol

The epidemiology of myasthenia gravis

Ann N Y Acad Sci

Clinical and serological study of myasthenia gravis in HuBei Province, China

J Neurol Neurosurg Psychiatry

Myasthenia gravis: population differences in disease expression and acetylcholine receptor antibody titers between Chinese and Caucasians

Neurology

Epidemiology of neuroimmunological diseases

J Neurol

Epidemiologic evidence for a changing natural history of myasthenia gravis

Neurology

Increasing incidence of late-onset anti-AChR antibody-seropositive myasthenia gravis

Neurology

Myasthenia gravis: a higher than expected incidence in the elderly

Neurology

Immunogenetic heterogeneity and associated autoimmune disorders in myasthenia gravis: a population based survey in the province of Ferrara, northern Italy

Acta Neurol Scand

Associated autoimmune disease in myasthenia gravis. A population-based study

Acta Neurol Scand

Striational antibodies in myasthenia gravis

Arch Neurol

Myasthenia gravis

N Engl J Med