Beyond the Surface: Investigating the Potential Mechanisms of Non‐Motor Symptoms in Myasthenia Gravis

ABSTRACT

Background

Myasthenia gravis (MG) is an autoimmune disorder affecting the neuromuscular junction (NMJ), driven by T cells, mediated by B cells, and dependent on autoantibodies. In addition to the typical motor symptoms of fluctuating weakness, the non‐motor symptoms are also prevalent among MG patients. This review aims to present the non‐motor symptoms of MG and their potential pathogenesis, hoping to contribute to personalized diagnosis and treatment.

Methods

This review elaborates the non‐motor symptoms of MG and systematically detail, for the first time, their potential pathogenic mechanisms, offering a new perspective for clinical evaluation.

Results

The non‐motor symptoms of MG include autonomic disorders (urinary, gastrointestinal, cardiovascular and ocular dysfunction), sensory disability (olfactory abnormalities, gustatory reduction and headaches), cognitive impairment, sleep disturbances, psychological problems (depression and anxiety), and TAMG‐associated specific syndromes. Due to their insidious onset and lack of awareness, these symptoms are often overlooked. We review the non‐motor symptoms of MG and first provide a systematic and detailed discussion on their potential mechanisms, including the influence of MG‐specific antibodies (cross‐reactivity of AChR‐Ab, expression of MuSK‐Ab, and striational antibodies at related functional sites), dysregulation of inflammatory factors and immune cells, collateral effects of motor symptoms, impacts of MG comorbidities, and paraneoplastic syndromes caused by thymoma.

Conclusion

Non‐motor symptoms are common in MG patients. Given a series of potential mechanisms probably involved exploring these non‐motor symptoms will not only enhance our understanding of MG but also aid in diagnosis and the development of precise, personalized treatments, ultimately improving the overall life quality of patients.

We review the non‐motor symptoms of MG and their potential pathogenesis, hoping to contribute to personalized diagnosis and treatment.

1. Introduction

Myasthenia gravis (MG) is an autoimmune disease that affects the neuromuscular junction (NMJ) and is primarily mediated by pathogenic antibodies against acetylcholine receptor (AChR), muscle‐specific kinase (MuSK), and low‐density lipoprotein receptor‐related protein 4 (LRP4) [1]. Patients with MG typically complain of fluctuating fatigue, where symptoms are exacerbated by exertion and alleviated by rest [2]. The weakness predominantly affects six muscle groups: ocular, bulbar, facial, limb, axial, and respiratory muscles [3]. In recent years, as our understanding of the pathogenesis of MG has advanced, there have been significant innovations in immunotherapy approaches. Treatment has evolved from the initial widespread use of steroids to the development of precise, personalized treatments based on the specific subtypes of the disease. Molecular therapies, such as inhibiting the activation of complement, blocking the immunoglobulin recycling pathway, and preventing the development of immune cells, have improved the efficacy and reduced the side effects [4]. Despite these advances, both diagnosis and treatment of MG tend to focus on motor symptoms resulting from muscle weakness, while non‐motor symptoms are often overlooked.

In fact, non‐motor symptoms are quite common in patients with MG. However, due to their insidious onset and overshadowing by motor symptoms, they receive little attention [5]. These non‐motor symptoms can significantly impact the quality of life of MG patients and even be life‐threatening. They affect a wide range of systems [6], manifesting as autonomic nervous system involvement that impacts urinary, digestive, and cardiovascular systems, as well as causing ocular symptoms, olfactory and taste abnormalities, headaches, cognitive impairment, sleep disorders, and psychological problems. Rare non‐motor symptoms can particularly be observed in patients with thymoma‐associated myasthenia gravis (TAMG). Mild non‐motor symptoms can bring inconvenience to patients' daily life, and severe non‐motor symptoms, such as those involving the cardiovascular system, can even be life‐threatening. In addition, sleep and psychological problems not only reduce the compliance of patients in treatment [7], but also cause a series of social problems, including suicide [8, 9, 10]. Therefore, we call for clinicians to pay as much attention to non‐motor symptoms in MG patients as to “weakness”.

To enhance the understanding of MG, we propose several mechanisms leading to non‐motor symptoms. First, MG‐specific antibodies can affect regions beyond the NMJ through various mechanisms, such as cross‐reactivity of anti‐AChR antibody (AChR‐Ab) and the expression of anti‐MuSK antibody (MuSK‐Ab) and striational antibodies at relevant functional regions. Second, the abnormal regulation of inflammatory factors and immune cells within the pathological environment of MG can impact multiple systems. Third, motor symptoms themselves can also contribute to non‐motor symptoms. Additionally, the role of comorbidities in MG cannot be overlooked. Finally, paraneoplastic syndromes resulting from thymomas in TAMG contribute to rare non‐motor symptoms (Figure 1, Figure 2).

FIGURE 1.

Mechanism of autonomic involvement. Both the preganglionic fibers of the sympathetic and parasympathetic nervous systems are cholinergic neurons, and their ganglia contain α3‐nAChR, a pentameric structure composed of two α3 and three β subunits. In MG, the AChR‐Ab primarily targets the α1‐nAChR at the NMJ, which consists of two α1 subunits, one β, one ε, and one δ subunit. Due to structural similarities between α3‐nAChR and α1‐nAChR, the AChR‐Ab produced in MG might potentially affect autonomic ganglia through cross‐reaction. This can subsequently impact neurotransmitters (NE, ACh) release from the postganglionic nerve fibers, leading to dysfunction in the cardiovascular, gastrointestinal, and urinary systems, as well as causing ocular symptoms. MG, myasthenia gravis; nAChR, nicotinic acetylcholine receptor; NMJ, neuromuscular junction; AChR‐Ab, antiacetylcholine receptor antibody; NE, norepinephrine; ACh, acetylcholine.

FIGURE 2.

Pathogenesis of non‐motor symptoms in TAMG. The expression of AIRE is deficient in the mTEC in thymomas of TAMG, which leads to a lack of MHC II and affects the negative selection of CD4⁺ T cells, failing to establish the effective central immune tolerance and allowing immature CD4⁺ T cells to enter the periphery. These immature CD4⁺ T cells can promote the proliferation and activation of B cells, which in turn produce autoantibodies against the VGKC complex. The production of anti‐CASPR2 antibodies is related to limbic encephalitis, acquired neuromyotonia, and Morvan's syndrome. And anti‐Kv1.4 antibodies are involved in myocarditis. Additionally, the lack of MHC II leads to Treg dysfunction of inhibition. The neoplastic proliferation of CD8⁺ T cells may cause PRCA. Activated CD8⁺ NKG2D⁺ T cells can produce IFN‐γ, which destabilizes immune privilege in hair follicles, resulting in alopecia areata. AIRE, autoimmune regulator; mTEC, medullary thymic epithelial cell; TAMG, thymoma‐associated myasthenia gravis; MHC, major histocompatibility complex; Treg, T regulatory cell; PRCA, pure red cell aplasia.

This review summarizes the non‐motor symptoms of MG (Table 1) and firstly reveals their potential mechanisms in detail to provide a comprehensive understanding of MG, aiding in diagnosis and precision treatment, and ultimately aims to enhance the overall quality of life for MG patients.

TABLE 1.

Summary of the non‐motor symptoms in MG patients.

Author	Year	Involved non‐motor symptoms	Main findings in the studies
Nikolić A et al. [11]	2014	urinary dysfunction, diarrhea, constipation, bradycardia, dry eye	This study reported a series of autonomic dysfunctions in MG patients, including urinary dysfunction, diarrhea, constipation, bradycardia, and dry eye.
Zawadka‐Kunikowska M et al. [12]	2024	autonomic nervous system abnormalities, cardiovascular disorders, dysuria, gastrointestinal problems	This study reported that MG patients had autonomic dysfunction, affecting the cardiovascular, urinary, and gastrointestinal system.
Donskov AO et al. [13]	2021	overactive bladder symptoms, characterized by polyuria, nocturia, urgency, and stress incontinence	This cross‐sectional population‐based study reported overactive bladder symptoms in MG patients.
Meeusen JW et al. [14]	2013	gastrointestinal dysmotility	This study demonstrated that α3*‐nAChR‐IgG positive mice can develop autoimmune gastrointestinal dysmotility.
Kocabas ZU et al. [15]	2018	arrhythmia, autonomic nervous system abnormalities	This case–control matched study supported the presence of cardiac autonomic involvement with a prominence of parasympathetic insufficiency in MG patients.
Peric S et al. [16]	2011	arrhythmia, autonomic nervous system abnormalities	This case–control matched study showed a parasympathetic cardiac impairment in MG patients.
Puneeth CS et al. [17]	2013	arrhythmia, autonomic nervous system abnormalities	This cross‐sectional case–control study suggested parasympathetic deficiency and a shift in sympathovagal balance toward increased sympathetic tone.
Shukla G et al. [18]	2013	arrhythmia, autonomic nervous system abnormalities	MG patients were sympathetic hyper‐reactivity, which could be responsible for serious hemodynamic instability in patients in crisis.
Kim S et al. [19]	2023	myocarditis	The presence of anti‐titin antibody was associated with myocarditis in patients with MG.
Cheng W et al. [20]	2021	myocarditis	The prognosis of patients with MG complicated with myocarditis is poor, and dyspnea was the most common cardiac symptom.
Leon‐Sarmiento FE et al. [21]	2012	olfactory dysfunction	The case–control matched olfactory‐related assessments showed an olfactory dysfunction of MG patients.
Tekeli H et al. [22]	2015	olfactory and gustatory dysfunction	The case–control matched study presented olfactory and gustatory dysfunction in MG patients.
Kabasawa C et al. [23]	2013	taste disorders	Taste disorders were more common in MG patients than that in the general population. For taste disorders in MG, sweet taste loss was more common than salty, bitter, and sour taste loss.
Takamori S et al. [24]	1999	dysgeusia	This case report indicated the improvement of dysgeusia after thymectomy in MG with thymoma.
Chabwine JN et al. [25]	2014	sweet dysgeusia	This case report showed that the improvement of sweet taste paralleled reduction of the MG composite score with immunosuppressive and surgical treatments. Sweet dysgeusia may be related to gustducin‐positive G‐protein‐coupled taste receptor cells.
Cull RE et al. [26]	2003	headache	This case report pointed out that MG patient can experience unilateral headache.
Nishimoto Y et al. [27]	2011	tension‐type headache, migraine	Tension‐type headache and migraine were observed in MG patients. Mild ocular symptoms was one of the independent predictive factors of headache.
Dhand UK et al. [28]	2021	headache	This case report pointed out that the headache in MG patient was cervicogenic with head drop.
Paul RH et al. [29]	2000	cognitive deficit	Compared to control groups, MG patients exhibit poorer abilities in response fluency, information processing, and verbal and visual learning.
Iacono S et al. [30]	2023	mild cognitive impairment	The presence of mild cognitive impairment is rather frequent in MG and is characterized by multidomain amnestic impairment.
Zhou X et al. [31]	2023	cognitive disorders	MG patients may have cognitive disorders, including those associated with the domains of language, visuospatial function, information processing, verbal immediate and delayed recall memory, visual immediate recall memory and response fluency.
Tucker DM et al. [32]	1988	memory dysfunction	This case report supposed that MG has central cholinergic effects manifested by cognitive dysfunction.
Zhou X et al. [33]	2021	memory dysfunction	MG patients showed lower memory performance, such as immediate and delayed recall ability.
Kumar R et al. [34]	2024	sleep disorders	This questionnaire‐based study showed sleep disorders in MG patients.
Dewilde S et al. [35]	2024	sleep disorders, mental problems	MG patients experienced the burden in terms of breathing, fatigue, sleep, mental health, discomfort and usual activities compared to the general population.
Bogdan A et al. [36]	2020	chronic stress, depression	This study found a significant association of MG severity with depression and chronic stress.
Nadali J et al. [37]	2023	depression, anxiety	MG patients experienced anxiety and depression, which were higher than that of other autoimmune diseases.
Gastaldi M et al. [38]	2019	acquired neuromyotonia	Acquired neuromyotonia can be found in TAMG patients.
Suzuki S et al. [39]	2003	pure red cell aplasia	Pure red cell aplasia can be found in TAMG patients.
Mizobuchi S et al. [40]	1998	pure red cell aplasia	This case report showed a TAMG patient with pure red cell aplasia.
Fujiu K et al. [41]	2004	pure red cell aplasia	This case report indicated a TAMG patient with pure red cell aplasia.
Suzuki S et al. [42]	2005	alopecia areata	This retrospective study found the coexistence of alopecia areata and MG. Moreover, DRB1*0901 and DQB1*0303 tended to be more frequently detected in MG patients with alopecia areata.
Kubota A et al. [43]	1997	alopecia areata	This study found that in 202 MG patients, all the patients who developed alopecia areata had thymoma, and patients with alopecia areata accounted for 35% of TAMG patients.
Nes MS et al. [44]	2023	limbic encephalitis	This case report pointed out that a TAMG patient had limbic encephalitis with antibodies to AMPAR and Lgi1.
Sindhu T et al. [45]	2022	limbic encephalitis	This case report showed a TAMG patient with limbic encephalitis.
Lee CH et al. [46]	2014	limbic encephalitis	This case report indicated that TAMG patient can accompany by limbic encephalitis. TAMG patients with Caspr2 antibodies may have poor prognosis.

2. Autonomic Disorder and Underlying Causes

In MG, the involvement of the autonomic nervous system can lead to a range of non‐motor symptoms (Figure 1). When the urinary system is affected, patients may experience dysuria or an overactive bladder. Dyspepsia, constipation, and diarrhea are manifestations of gastrointestinal dysfunction. When the cardiovascular system is involved, disrupting the balance between the sympathetic and parasympathetic nerves, the risk of malignant arrhythmias will increase. Additionally, non‐motor symptoms in the cardiovascular system arise not only from autonomic nervous system involvement but also from myocarditis, which is another important aspect that we will elaborate on here together. Autonomic involvement can also cause dry eyes. Overall, non‐motor symptoms of the autonomic nervous system are relatively common, yet they are often overlooked due to unclear causes and a lack of awareness.

2.1. Urinary Dysfunction

Urinary dysfunction may be one of the most common autonomic symptoms in patients with MG. A study on dysautonomia in MG found urinary dysfunction in 26 patients, accounting for 39% of the cohort [11]. Zawadka‐Kunikowska et al. [12] reported dysuria in 27 out of 53 MG patients. Additionally, compared to healthy controls, 83 MG patients experienced overactive bladder symptoms, characterized by polyuria, nocturia, urgency, and stress incontinence [13]. Unfortunately, although this manifestation was noted in the current study, substantial studies on the underlying mechanisms are still lacking. The prevalence of urinary dysfunction predominantly in patients with AChR‐Ab positive MG (AChR‐MG) may help elucidate the underlying mechanisms. Micturition is regulated by both the sympathetic and parasympathetic nervous systems [47], suggesting that urinary dysfunction in MG could result from neuromodulation disorders. The α3‐nicotinic acetylcholine receptors (nAChRs) are regarded as the primary nAChRs facilitating transmission through both sympathetic and parasympathetic autonomic ganglia [48]. Moreover, the α1‐nAChR contains the main immunogenic region (MIR), which is the principal target for pathogenic antibodies in MG [49, 50]. Interestingly, the monoclonal antibody mAb35 was found to bind to both the α1 and α3 subunits of the nAChR, indicating the potential for MG antibodies targeting the MIR to cross‐react with receptors on the autonomic ganglia of the urinary system [51, 52]. Furthermore, urinary dysfunction was also observed in some MuSK‐MG patients who lack AChR‐Abs [11]. We speculate that antibodies against agrin or LRP4 in certain MuSK‐MG patients [53] may significantly disrupt the urinary system due to their potential impact on synapses within sympathetic neurons and the central nervous system [54, 55]. In the future, experimental studies are still needed for further verification.

2.2. Gastrointestinal Dysregulation

Gastrointestinal issues such as dyspepsia, constipation, and diarrhea are prevalent among patients with MG. In a study involving 53 MG patients, gastrointestinal problems were identified in 43 individuals [12]. Another study found that 9% of 67 MG patients experienced constipation [11]. The enteric nervous system plays a crucial role in regulating the gastrointestinal tract, with extensive synaptic connections involving neurons and neurotransmitters such as acetylcholine (ACh) [56]. ACh released by secretomotor neurons facilitates moistening of the intestinal lumen by stimulating the secretion of chloride and bicarbonate ions [57]. Additionally, ACh's role in the ascending excitatory reflex triggers the contraction of intestinal smooth muscles [58]. The presence of α3‐nAChRs in the enteric nervous system has been confirmed [56], and these receptors are recognized as critical targets for antibodies responsible for autoimmune gastrointestinal dysmotility [14]. Moreover, Meeusen et al. also consider that the loss of α3‐nAChRs in gastrointestinal dysmotility results from receptor internalization and degradation due to binding with autoantibodies [14], which mirrors the pathogenesis seen in MG [4]. Therefore, it is plausible to speculate that MG‐related antibodies targeting nAChRs may cross‐react with gastrointestinal α3‐nAChRs, leading to dysmotility. If nAChR‐Abs in MG affect sympathetic neurons, reducing inhibitory control over the gastrointestinal system, this could lead to increased gut activity and diarrhea [59]. Furthermore, MG patients show an increased abundance of Bacteroidetes and a decreased abundance of Firmicutes in their gut microbiota compared to healthy individuals [60]. This change in the intestinal microbial composition can also be observed in irritable bowel syndrome [61], which may be another answer to explain the constipation and diarrhea. Of course, some drugs for the treatment of MG can also lead to gastrointestinal dysregulation such as diarrhea, which needs to be identified in clinical practice based on the adjustment of treatment regimens and professional experience.

2.3. Cardiovascular Issues

As previously discussed regarding the urinary and digestive systems, specific AChR‐Abs in MG may impact nAChRs in both sympathetic and parasympathetic ganglia through cross‐reactivity. Consequently, the cardiovascular system may also be affected by reactions triggered by these AChR‐Abs. Numerous studies have demonstrated that in patients with MG, the balance between the sympathetic and parasympathetic nervous systems is disrupted, with a tendency toward dominance of sympathetic regulation. This is primarily characterized by reduced heart rate variability (HRV), decreased baroreflex sensitivity (BRS), and increased low‐frequency/high‐frequency (LF/HF) ratio [11, 15, 16, 17, 18]. Among MG patients with relatively stable conditions, this imbalance is mainly due to a deficiency in parasympathetic activity [11, 15, 16, 17]. Conversely, in patients who have undergone thymectomy, experienced disease exacerbation, or even crisis, heightened sympathetic activity is the primary cause of this imbalance [18]. This sympathetic/parasympathetic imbalance predisposes patients to arrhythmias, increasing the risk of atrial fibrillation, ventricular arrhythmias, and even sudden cardiac death [11]. These findings further indicate that MG patients presenting with arrhythmias warrant prompt systematic evaluation. When cardiology specialists reveal no organic abnormalities, non‐motor symptoms should be actively investigated. Moreover, immune disorders in MG can also result in arrhythmias. A study based on UK Biobank reported that the increased systemic inflammation in the autoimmune diseases may lead to new‐onset atrial fibrillation, and a prominent relationship was found between MG and the new‐onset atrial fibrillation [62].

In addition to arrhythmias, myocarditis is closely associated with MG. Studies indicate that 10% of MG patients have myocarditis, and among those with myocarditis, 64% experience a crisis [19]. Myocarditis can manifest at any point during the MG disease course, with dyspnea being its most common symptom [20]. Given the insidious onset of myocarditis and the fact that dyspnea is a common symptom of MG [35], this non‐motor symptom is often easily overlooked. However, given myocarditis's potentially fatal nature, early screening is crucial. Although there have been reports of immune checkpoint inhibitor (ICI)‐induced myocarditis in recent years, not all cases of myocarditis can be explained by ICIs [63]. Current theories suggest that striational antibodies, such as anti‐titin and anti‐Kv1.4 antibodies, are potential biomarkers for cardiac involvement in MG patients [64, 65, 66, 67]. Titin is a giant protein that forms the elastic scaffolding of cardiac fibers, participating in the contraction and relaxation process of the myocardium [68]. The Kv1.4 channel is involved in regulating the repolarization of cardiac action potentials, impacting heart rate and cardiac contractile function [69]. Therefore, we have reason to believe that these striational antibodies play a role in the development of myocarditis in MG patients.

2.4. Eye Symptoms

Ocular symptoms are widespread in MG due to physiological characteristics such as a low density of AChRs and a smaller number of ACh‐containing vesicles in the extraocular muscles [70]. Among them, dry eye was found in some MG patients [11]. Firstly, the dysclosure of eyelid due to the involvement of extraocular muscles can cause dryness of the patient's eyes. Secondly, as an autoimmune disorder, MG exhibits a disrupted immune microenvironment. In MG, there is a deficiency in regulatory T cell (Treg) function and elevated expression of inflammatory factors such as IL‐1 and TNF‐α [71]. This may lead to T cell infiltration of the lacrimal glands, subsequently reducing tear production [72]. The formation of chronic inflammation in MG is associated with Treg dysfunction and Th17 cell activation [73], which aligns with the pathogenesis of dry eye [74]. Tirdly, tear secretion is regulated by sensory, sympathetic, and parasympathetic autonomic nerves [75], so the immune dysregulation in MG, characterized by the production of AChR‐Abs, may also contribute to dry eye. Finally, the impact of MG comorbidities also plays a role. The most common comorbidities in MG include autoimmune thyroid disease, systemic lupus erythematosus (SLE), and rheumatoid arthritis [76], all of which can lead to dry eye [72].

3. Sensory Impairments and Potential Mechanisms

3.1. Disability of Olfactory and Gustatory

Olfactory and gustatory abnormalities can also be considered non‐motor symptoms of MG. Leon‐Sarmiento et al. [21] conducted olfactory‐related assessments on MG patients and controls, finding that MG patients experienced significant olfactory dysfunction. Another independent study also confirmed that anosmia and taste abnormalities occurred in MG patients, and the extent of these chemosensory dysfunctions is correlated with the severity of the disease [22]. Kabasawa et al. [23] reported taste loss in MG patients, primarily characterized by the loss of sweetness perception, which correlated with disease severity, occurred in TAMG patients, and improved following immunotherapy. ACh‐mediated cholinergic signaling appears to affect olfaction and taste in multiple ways. M3 muscarinic acetylcholine receptors (mAChRs) are found on olfactory sensory neurons and enhance the response of odorant receptors to smells. Selective inhibition of M3 mAChRs diminishes the activity of odorant receptors [77]. A study by Mandairon et al. [78] in mice suggests that age‐related declines in olfactory sensitivity are associated with reduced mAChR density in the olfactory bulb. Additionally, α7‐nAChRs might play a crucial role in olfactory signal transduction. α‐Bungarotoxin (α‐BGT)‐sensitive nAChRs, a subtype of α7‐nAChRs, are present on both presynaptic and postsynaptic membranes of olfactory bulb neurons, indicating a complex ACh‐mediated influence on olfactory signaling [79]. Moreover, Hakan et al. [22] proposed that interactions between α‐BGT‐sensitive nAChRs and glutamatergic synapses may amplify signals transmitted in the olfactory bulb. An experiment in mice indicated that the expression levels of α‐BGT‐sensitive nAChRs affect the detection and discrimination of odors [80]. Overall, blocking mAChRs and α7 nAChRs results in varying degrees of olfactory dysfunction. Research demonstrates that blocking mAChRs can reduce olfactory perception, while blocking α7‐nAChRs leads to a complete loss of olfactory discrimination in rats [81], suggesting that α7‐nAChRs may be involved in an upstream and broader olfactory signaling pathway. Takamori et al. [24] reported that improvements in dysgeusia following thymectomy were parallel to a decrease in AChR‐Ab titers, suggesting that ACh may play a role in taste regulation. ACh can bind to the M1 mAChRs on taste receptors and regulate taste response through the activation of the PLC/IP3 pathway [82]. Furthermore, upon taste stimulation, the type II receptor of taste bud cells can synthesize and release ACh in an autocrine manner, which then acts on their M3 mAChRs to enhance taste signal transmission [83]. Thus, we hypothesize that AChR‐Abs in MG patients might not only target the NMJ but could also cause olfactory and gustatory dysfunction through cross‐reactivity or more complex mechanisms. Additionally, there is a hypothesis that MG patients may produce specific antibodies acting on α‐gustducin positive receptor cells, thereby interfering with taste signal transduction and leading to taste loss [25].

3.2. Headache

Headache in MG patients is an area lacking extensive research, possibly due to the complex etiology of headaches and the fact that some MG treatments can also induce headaches as a side effect [84, 85, 86]. Nevertheless, we should pay attention to this symptom, as it does occur in some patients. It might be surprising, but there are cases where OMG patients present with headache as their primary complaint [26]. Headaches could be a collateral effect triggered by MG's motor symptoms. In a study by Nishimoto et al. [27], about 39% of 184 MG patients followed up were found to have tension‐type headaches, and 5% experienced migraines. In this study, the prevalence of tension‐type headache was 13% higher than that in the general population, whereas the prevalence of migraine was approximately 9% lower [87]. Although these results show that the prevalence of headache in MG is not always higher than that in the general population, it has its own clinical significance. It points out that approximately 14% of patients reported headache onset or worsening following MG diagnosis, and mild ocular symptoms are the most important independent risk factor related to headache in MG patients. Additionally, as a motor symptom of MG, head drop is also considered a trigger of headache. Dhand [28] reported a case of an MG patient with “head drop” who suffered from headaches. Interestingly, in all of these cases, initial treatment with sumatriptan did not alleviate the headaches, but treatment with pyridostigmine did provide relief. As well, it is suggested that restricted neck motion can trigger cervicogenic headache [88]. However, we cannot entirely dismiss the role of AChR‐Abs in the headaches experienced by MG patients. As early as 1997, a rat‐based study suggested that mAChRs released by the parasympathetic nervous system could induce neurogenic inflammation in the dura mater, potentially leading to migraines [89]. Trigeminovascular activation is a well‐accepted mechanism underlying migraine pathogenesis [90], in which mast cell degranulation and plasma protein extravasation play significant roles [91]. Shelukhina et al. [92] found that ACh released by the parasympathetic nervous system could act on both mAChRs and nAChRs on trigeminal neurons to stimulate trigeminovascular nociceptive traffic. Additionally, ACh can potentially promote mast cell degranulation via mAChRs or directly affect meningeal microvessels to cause plasma protein extravasation.

4. Cognitive Deficit and Possible Contributors

A meta‐analysis showed that patients with immune‐mediated inflammatory diseases had troubles in overall cognition, complex attention/executive function, memory, and language/verbal fluency compared to controls [93]. In addition, cognitive processing speed, learning, and memory are often affected in patients with multiple sclerosis (MS) [94]. Such cognitive impairments can also be observed in MG patients. Previous studies have indicated that compared with age‐ and education‐matched controls, MG patients often experience cognitive impairment, which is generally mild in severity [29, 30]. Research by Paul et al. [29] found that compared to control groups, MG patients exhibit poorer abilities in response fluency, information processing, and verbal and visual learning. Beyond these cognitive areas, a recent meta‐analysis indicated that MG patients also have difficulties in verbal immediate and delayed recall memory, as well as visual immediate recall memory [31]. We note that the average age of patients in most of these included studies is about 40–55 years old, while the onset age of traditional cognitive disorders such as Alzheimer's disease is basically over 65 years old [95]. Therefore, we should not ignore the cognitive deficit in MG. Structural and functional brain changes have been observed in MG patients, providing potential organic evidence for cognitive impairment [96]. Changes in gray matter volume in the cingulate gyrus and inferior parietal lobe may lead to declines in memory and executive function, while reductions in the volume of the inferior parietal lobe may impact somatosensory‐related spatial orientation. There are several hypotheses regarding cognitive impairment in MG patients. First, impairment of the central cholinergic system and the effects of peripheral AChR‐Abs on subcortical and cortical central nicotinic receptors may contribute to cognitive dysfunction [32, 33]. While this hypothesis is debated [97]. According to previous studies, AChR‐Abs could not be synthesized intrathecally [98]. However, Barbara et al. found that AChR‐Abs in MG can bind to the α3‐ and α7‐nAChRs in the brain tissue, suggesting that these antibodies can cause dysfunction in the central nervous system. This makes the potential cross‐reactivity between analogs of peripheral AChR‐Abs and central receptors remain a worthwhile subject of investigation [99]. Second, the possible involvement of respiratory muscles leading to hypoxia or hypercapnia could further impact cognitive function [29]. Third, persistent physical and mental fatigue may also play a role [33]. MG patients experience long‐term chronic fatigue and have certain psychological health problems; some patients are also accompanied by headaches, which greatly increases the risk of functional cognitive disorder [100]. Additionally, changes in neurometabolites such as γ‐aminobutyric acid (GABA), N‐acetylaspartate (NAA), and choline (Cho) in the medial prefrontal cortex and left thalamus have been shown to be associated with cognitive impairment in MG patients [101]. Lastly, MuSK antibodies may affect the perirhinal cortex, leading to a decline in object recognition memory [102].

5. Sleep Disorders and Psychological Problems

Previous studies have reported other non‐motor symptoms such as sleep disturbances, depression, and anxiety. A prospective cross‐sectional study demonstrated that patients with MG experience sleep disturbances, including snoring, early morning headaches, difficulty falling asleep, and challenges in maintaining sleep, with consistency of the severity between these disturbances and MG [34]. A recent observational study indicated that MG patients have higher PROMIS‐Sleep Disturbance scores compared to the general population [35]. Moreover, about 69.6% and 18.5% of MG patients suffered from moderate to severe anxiety and depression, respectively. Furthermore, studies have shown a significant association between the severity of MG and depression [36]. A meta‐analysis conducted by Nadali et al. reported a prevalence rate of 36% for depression and 33% for anxiety among MG patients [37]. According to their results, depression and anxiety in MG patients are more severe than those in other autoimmune diseases such as MS and SLE, and depression is more prevalent than in other common neurological diseases like dementia, amyotrophic lateral sclerosis, MS, and mild cognitive impairment dementia. Moreover, patients with these psychological comorbidities also exhibit suboptimal treatment adherence, indirectly contributing to the exacerbation of disease severity [7]. Furthermore, sleep disorders and psychological diseases precipitate societal burdens and even constitute a risk factor for suicide [8, 9, 10]. Therefore, greater emphasis should be placed on sleep disturbances and psychological disorders in MG patients. These conditions sustain complex pathogenesis, and no studies to date have elucidated the distinct pathophysiological mechanisms of them in MG patients. Based solely on the characteristics of MG itself, it may be explained through the following reasons: As a chronic disease, recurrent or incurable conditions can arouse anxiety and depression of the patients [103]. Chronic stress, such as the financial burden from long‐term treatment and social pressure due to inability to work normally, is also one of the causes [104, 105]. Other non‐motor symptoms like headaches also exhibit a complex bidirectional relationship with them [106, 107]. Moreover, sleep disorders and psychological problems may also interact with each other [108].

6. Specific Non‐Motor Symptoms in TAMG

TAMG is an important and special subtype of MG. Compared with other subtypes, TAMG is more severe and has a poor prognosis [109]. In order to conduct well comprehensive management of TAMG patients, we should also pay attention to their possible non‐motor symptoms. Its non‐motor symptoms mainly have two sources: Firstly, like other subtypes of MG, they may have autonomic dysfunction, sensory disability, cognitive impairment, sleep, and psychological problems. Additionally, the distinguishing particularity, with thymoma, is also one of the causes. The distinctiveness of TAMG is readily apparent merely from its pathogenesis [110]. The pathogenesis of EOMG involves thymic hyperplasia and overactivation of CD4⁺ T cells. The thymic pathology of LOMG shows atrophy. However, the pathogenesis of TAMG is relatively more complex. The characteristics of thymoma, such as deficiencies in autoimmune regulator (AIRE) expression, a reduction of myoid cells in the thymus, and a lack of major histocompatibility complex (MHC) II, can result in the dysfunction of Tregs and the proliferation of non‐tolerant T cells. Meanwhile, from the two different aspects of diagnosis, TAMG can be described as a specific type of MG, or alternatively, it can be considered as the most common and representative paraneoplastic syndromes of thymoma [111]. Thus, a series of paraneoplastic syndromes of thymoma, such as acquired neuromyotonia, Morvan's syndrome, pure red cell aplasia (PRCA), alopecia areata, and limbic encephalitis, can also affect TAMG patients. A retrospective study of 268 cases of TAMG reported 5 cases of neuromyotonia [38]. In a study based on 135 TAMG patients, 4 cases of PRCA were found [39]. Previous cases also reported PRCA in TAMG patients [40, 41]. In a study by Suzuki et al. [42], 3.7% of the 159 MG patients developed alopecia areata, and all but one of these patients had TAMG. Additionally, a study involving 202 TAMG also described six cases of alopecia areata [43]. There are also case reports of TAMG patients developing limbic encephalitis [44, 45, 46]. Arising from the unique immune response of thymoma, an inherent connection between the symptoms mentioned above and TAMG may have been established (Figure 2). Antibodies against contactin‐associated protein 2 (CASPR2), a protein related to the voltage‐gated potassium channel (VGKC) complex [112], are often found in malignant thymic tumors [113]. VGKC plays a significant role in the release of ACh at the presynaptic membrane, and its related antibodies can also be detected in MG [114]. Several studies have indicated that neuromyotonia, limbic encephalitis, and Morvan's syndrome in TAMG are closely associated with CASPR2 [38, 115, 116, 117]. In the previous discussion, we mentioned that anti‐Kv1.4 antibodies might be involved in the pathogenesis of myocarditis, and MG patients who develop myocarditis often have thymomas. Moreover, Kv1.4 is one of the α subunits of VGKC and is primarily present in the brain, peripheral nerves, and skeletal and heart muscles [118]. Thymomas in TAMG are generally predominantly of types AB and B [53], which can generate polyclonal CD4⁺ and CD8⁺ thymocytes [119]. The abnormally activated CD4⁺ T cells in TAMG will promote the production of antibodies against the VGKC‐complex, which probably leads to the aforementioned symptoms [5]. Furthermore, others like PRCA and alopecia areata are related to the increase in polyclonal CD8⁺ T cells. Research indicates that thymoma‐associated PRCA is relevant to the neoplastic proliferation of CD8⁺ T cells in the peripheral blood and thymus [120, 121]. The immune pathogenesis of alopecia areata involves the activation of CD8⁺ NKG2D⁺ T cells, resulting in the production of large amounts of IFN‐γ and the disruption of the immune privilege of hair follicles [122].

7. Outlook

In most cases, patients with MG present with motor symptoms as their primary complaint, and current diagnostic criteria as well as disease classifications are based on these motor symptoms, with attention largely focused on “weakness.” [52] However, non‐motor symptoms of MG are widespread and significantly impact patients' daily lives and psychological health [6]. Some non‐motor symptoms can even be life‐threatening, such as malignant arrhythmias, myocarditis, and suicidality due to psychological problems. To enhance the understanding of MG, we propose several mechanisms leading to non‐motor symptoms. Specific antibodies can play a role. The cross‐reactivity of AChR‐Abs and the expression of MuSK‐Ab and striational antibodies may contribute to some disorders. Moreover, dysregulated inflammatory factors and immune cells can impact multiple systems. Critically, the effects of motor symptoms on non‐motor symptoms also require attention. Additionally, the influence of comorbidities cannot be overlooked. Finally, some rare non‐motor symptoms may originate from thymoma. Given the universality of non‐motor symptoms in MG, multidisciplinary engagement is imperative—extending beyond neurologists to include psychological specialists, rehabilitation experts, and nursing staff—to implement scientific and systematic care coordination. We have now entered a new era of targeted therapy for MG, greatly improving the motor symptoms of patients [123]. Neonatal Fc receptor (FcRn) inhibitors, complement inhibitors, and B‐cell targeted therapies offer various treatment options, providing highly effective, personalized treatments of motor symptoms. Research on cutting‐edge treatment strategies like stem cell therapy and the reconstruction of immune tolerance has also made some progress [123, 124]. However, to date, there has not been any treatment protocol specifically targeting the non‐motor symptoms. Furthermore, research in this domain remains limited, predominantly comprising observational studies with a paucity of experimental investigations. In the future, it is important to prioritize these non‐motor symptoms and conduct extensive and in‐depth studies to reveal their causes, ultimately providing the patients with personalized and comprehensive management and improving their overall health.

Admittedly, there are some limitations of this review, primarily stemming from the paucity of studies, which constrains our understanding of the non‐motor symptoms in MG. They manifest in four key aspects: First, non‐motor symptoms are complex and may be affected by a variety of confounding factors, including side effects of drugs and a high underlying morbidity in the population of certain symptoms. Future studies should employ multivariate modeling and stratified analyses to elucidate the pathogenetic links between MG and non‐motor manifestations. Second, the current study was mainly observational without experimental validation. Thus, the mechanisms underlying certain non‐motor symptoms remain speculative, but they provide valuable directions for future experimental studies. In addition, with the advent of novel immunosuppressants, mechanistic understanding will guide the selection of targeted agents, facilitating more effective control of multiple motor and non‐motor symptoms while minimizing the risks of polypharmacy. Third, the inclusion of rare symptoms, while necessary for comprehensiveness, warrants cautious interpretation of them due to insufficient primary data. Finally, this review relied exclusively on the existing publications, possibly omitting relevant non‐motor symptoms in some studies with small sample sizes. Consequently, multicenter large‐scale cohort studies and mechanistic investigations represent critical research priorities to provide comprehensive evidence for non‐motor symptoms.

8. Conclusion

In this review, we overview the non‐motor symptoms of MG and systematically detail, for the first time, their potential pathogenic mechanisms, offering a new perspective for clinical evaluation. This contributes to a deeper understanding of MG, provides novel auxiliary ideas for diagnosing the disease, and aids in precise, personalized treatment strategies. However, current research on the non‐motor symptoms of MG is relatively limited. While we have listed a series of non‐motor symptoms, there could be potential symptoms yet to be discovered, necessitating further investigation through large‐scale cross‐sectional studies.

Author Contributions

Benqiao Wang: conceptualization, methodology, writing – review and editing, writing – original draft, supervision. Dan Liu: writing – review and editing, supervision. Yingying Yang: supervision, writing – review and editing. Ruixia Zhu: conceptualization, writing – review and editing, supervision.

Conflicts of Interest

The authors declare no conflicts of interest.

Wang B., Liu D., Yang Y., and Zhu R., “Beyond the Surface: Investigating the Potential Mechanisms of Non‐Motor Symptoms in Myasthenia Gravis,” European Journal of Neurology 32, no. 8 (2025): e70309, 10.1111/ene.70309.

Data Availability Statement

The authors have nothing to report.