Clinical Features, Diagnostic Implications, and Outcomes of Amyotrophic Lateral Sclerosis and Myasthenia Gravis Overlap Syndrome: A Systematic Review

Abstract

Objective

This review aimed to summarize the current evidence of reported myasthenia gravis (MG) and amyotrophic lateral sclerosis (ALS) overlap syndrome regarding clinical and laboratory features, diagnostic implications, management, outcomes, and comorbid conditions to raise awareness among healthcare providers and aid in proper care provision.

Methods

Recently, a few cases of an unusual association between both diseases have been reported. PubMed, Scopus, and Web of Science were searched from inception until May 2024 to identify eligible studies. After the screening and data extraction, 20 studies with 42 cases suffering from ALS and MG were included.

Results

Forty-two cases were categorized into four groups as follows: the first group had 26 cases with MG onset (age range 26–82 years) preceding ALS (age range 46–83 years). The second group had 9 cases with ALS onset (age range 34–89 years) preceding MG (age range 40–89 years). The third group comprised 5 cases of ALS with positive acetylcholine receptor antibodies but without clinical manifestations of MG. The fourth group involved 2 cases of ALS with initial ocular symptoms that were unresponsive to MG treatments.

Conclusion

The onset of new ptosis or diplopia in ALS patients should prompt clinicians to consider the possibility of a coexisting condition or alternative diagnosis. Additionally, positive acetylcholine receptor antibodies alone are insufficient to diagnose MG if ALS coexists. In patients with ALS, repetitive nerve stimulation tests may be less sensitive for detecting MG. Thus, diagnosing MG in ALS patients should rely on clinical presentation and response to empirical treatment.

Highlights of the Study

• Positive acetylcholine receptor antibodies alone are insufficient to diagnose myasthenia gravis (MG) if amyotrophic lateral sclerosis (ALS) coexists.

• Diagnosing MG in ALS patients should rely on clinical presentation and response to the empirical treatment.

• Muscle atrophy is rare in MG but common in ALS. Therefore, electromyography reevaluation is required when symptoms change.

Introduction

Myasthenia gravis (MG) is a chronic autoimmune disease characterized by the elevation of acetylcholine receptor antibodies (AChR-Ab) that attack post-synaptic nicotinic acetylcholine receptors at the motor end plate. This leads to the corruption of nerve-muscle transmission, resulting in fluctuating voluntary muscle weakness and fatigue [1]. The prevalence of MG is increasing, and it has been estimated to affect 37 per 100,000 persons in the USA [2]. Generalized MG is the most common type of MG, causing widespread muscle weakness. It is not specific to certain muscles unlike ocular MG [3]. Bulbar symptoms including dysarthria and dysphagia are usually reported with the generalized MG. Moreover, there is a rare, but severe form of MG known as muscle-specific tyrosine kinase MG [4]. MuSK is a plasma membrane receptor that plays a crucial role in AChR phosphorylation and clustering. It is activated by the binding of nerve-derived proteoglycan called agrin with lipoprotein receptor-related protein 4 (LRP4) [5]. Muscle-specific tyrosine kinase MG primarily affects the bulbar and respiratory muscles and can lead to a myasthenic crisis, which is a life-threatening condition [6]. Also, LRP4 antibodies were found in patients with MG [7]. Myasthenic patients can be diagnosed with several tests besides the clinical picture. Serum tests are the recommended tests to detect any positivity to specific antibodies. In addition, electrophysiological tests and chest CT or MRI can be performed to detect any abnormality. The main approaches for managing this condition involve anti-cholinesterase and immunosuppressive treatments [8].

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is a fatal progressive neurodegenerative disorder that impacts both upper and lower motor neurons, resulting in the gradual deterioration of the patient’s health [9]. The prevalence of ALS in the USA ranges from 2 to 11.8 cases per 100,000 people [10]. Most patients with ALS get paralyzed and develop respiratory failure. The mean survival time of ALS is between 1 and 5 years after diagnosis [11, 12]. The etiology of ALS is not fully understood yet. Indeed, about 90% of cases with ALS are sporadic. This means that they have no family history or any associated risk factors with the disease [9]. Generalized weakness, dysarthria, spasticity, and fasciculations are common in ALS patients. Currently, there are no standard methods for diagnosing ALS due to overlapping with other neurological diseases, so, it depends on the electrophysiological and clinical screening [13]. There is no current curable approved treatment for ALS. Riluzole and edaravone can be used to reduce symptoms and improve the survival time of ALS but not prevent the progression of the disease [14].

There have been a few reported cases of an unusual association between both MG and ALS. In some instances, one disease presents itself with its characteristics as the inaugural disease then, after a certain interval, the special symptoms of the second disease appear. However, this is not the rule, both can present with similar symptoms, particularly ocular or bulbar symptoms, at the same time which may lead to misdiagnosis [15]. This correlation seems to be more than a mere coincidence [16]. The precise cause of this association is not yet clear. However, it is thought that the correlation between MG and ALS may be due to immunological dysfunction or sharing of autoantibodies to MuSK, LRP4, or AChR. Herein, in this review, we aimed to summarize the current evidence of reported ALS/MG overlap syndrome in terms of clinical and laboratory features, diagnostic implications, management, outcomes, and comorbid conditions to raise awareness among healthcare providers and aid in proper care provision.

Methods

This review was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines to investigate cases with overlapping features of ALS and MG. This review is registered in the PROSPERO database (ID: CRD42024572524).

Search Strategy, Inclusion Criteria, and Outcomes

A comprehensive search was performed on PubMed, Scopus, and Web of Science databases from their inception until May 2024. The search terms used were as follows: (“Myasthenia Gravis” OR Myasthenia OR “Neuromuscular junction disorder”) AND (“Motor Neuron Disease” OR “Motor System Disease” OR “Gehrig Disease” OR “Lou Gehrig’s Disease” OR “Lou Gehrig” OR “Charcot Disease” OR “Amyotrophic Lateral Sclerosis” OR “Lateral Sclerosis” OR “Guam Disease” OR ALS). No limitations or filters were applied. Case reports or case series written in English that described cases of ALS overlapping with MG were included in this review. The primary outcome focused on studying the rare overlap of ALS and MG and describing the characteristics of individuals diagnosed with both diseases during their lifetime, regardless of the inaugural disease.

Screening and Data Extraction

Two authors independently screened the titles and abstracts. Irrelevant studies were excluded, and conflicts were resolved through a third author. The third author retrieved the full texts of the included papers for final discussion. Data extraction was performed, and the following information was recorded: (a) study ID, country, sex, and inaugural disease; (b) MG features, including the age of onset, reported symptoms, MG classification and localization, level of AChR-Ab, and chest CT (online suppl. Table 1; for all online suppl. material, see https://doi.org/10.1159/000545806); (c) ALS features, including the age of onset, site of onset, symptoms of onset, ALS classification, treatment with riluzole, immunomodulating therapy, time from diagnosis to respiratory failure, and survival time (online suppl. Table 2), and (d) items related to the quality assessment of the study (Table 1). Extracted data were summarized using median and range for continuous variables or frequency and percentage for categorical variables (Table 2).

Table 1.

Joanna Brigg’s Institute critical appraisal checklist for case reports

Study ID	Q1	Q2	Q3	Q4	Q5	Q6	G7	G8	Total
Liu et al. [17] (2024)	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes	7
	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes	7
	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes	7
	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes	7
	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes	7
Narayan et al. [18] (2023)	Yes	UC	UC	Yes	No	No	No	Yes	3
Sun et al. [19] (2023)	Yes	Yes	Yes	Yes	Yes	UC	UC	Yes	6
Greenblatt et al. [20] 2022	Yes	Yes	Yes	Yes	Yes	Yes	UC	Yes	7
Hodzic et al. [21] (2021)	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes	6
Santos-lasosa et al. [22] (2020)	Yes	UC	Yes	Yes	No	No	No	Yes	4
	Yes	UC	Yes	Yes	UC	UC	No	Yes	4
	Yes	UC	Yes	Yes	UC	No	No	Yes	4
Cho et al. [23] (2019)	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes	7
Ohnari et al. [24] (2018)	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes	7
Yamashita et al. [25] (2017)	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes	7
Tai et al. [26] (2017)	UC	Yes	Yes	Yes	Yes	Yes	No	Yes	6
	UC	Yes	Yes	Yes	Yes	Yes	No	Yes	6
Takahashi et al. [27] (2016)	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes	7
	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes	7
Gotass et al. [28] (2016)	Yes	No	Yes	Yes	UC	UC	No	Yes	4
	Yes	Yes	Yes	Yes	UC	UC	No	Yes	5
	Yes	No	UC	No	UC	UC	No	Yes	2
	Yes	No	UC	Yes	UC	UC	No	Yes	3
de Pasqua et al. [16] (2016)	Yes	No	Yes	Yes	UC	UC	No	No	3
	Yes	No	Yes	Yes	UC	UC	No	No	3
	Yes	No	Yes	Yes	UC	UC	No	No	3
	Yes	No	Yes	Yes	UC	UC	No	No	3
	Yes	No	Yes	Yes	UC	UC	No	No	3
del Mar Amador et al. [29] (2016)	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes	7
	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes	7
	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes	7
	Yes	Yes	Yes	Yes	Yes	UC	No	Yes	6
	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes	7
	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes	7
	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes	7
Petrou et al. [30] (2014)	Yes	Yes	Yes	Yes	Yes	Yes	Yes	No	7
Mehanna et al. [31] (2012)	Yes	Yes	Yes	Yes	UC	UC	UC	Yes	5
Naik et al. [32] (2012)	Yes	Yes	Yes	Yes	Yes	Yes	Yes	No	7
Pinto et al. [33] (2008)	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	8
	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	8
Restivo et al. [34] (2000)	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes	7
Okuyama et al. [35] (1997)	Yes	Yes	Yes	Yes	No	No	No	Yes	5

Table 2.

Summary of patients in the first and second groups

	Myasthenia gravis (MG) as inaugural disease	Amyotrophic lateral sclerosis (ALS) as inaugural disease	Total
Total, N	26	9	35
Males:females	15:9	7:2	22:11
Median age of onset of MG (range)	62 (26–82)	53 (40–89)	67 (26–89)
Median age of onset of ALS (range)	72 (46–83)	57.5 (34–89)	68 (34–89)
Interval between two conditions	3 months to 41 years	3 months to 71 months	3 months to 41 years
ALS site of onset, n (%)
Limb	21/26 (80.1)	7/9 (77.7)	28/35 (80)
Bulbar	18/26 (69)	3/9 (33.3)	21/35 (60)
Localization of MG symptoms, n (%)
Ocular	17/26 (65.4)	9/9 (100)	25/35 (71.4)
Bulbar	17/26 (65.4)	3/9 (33.3)	20/35 (57.2)
Limbs	3/26 (11.5)	3/9 (33.3)	6/35 (17.2)

Risk-of-Bias Assessment

Two authors independently assessed the quality of the included studies using the revised Joanna Briggs Institute (JBI) checklist for case reports and case series. The JBI risk of bias tool comprised eight domains, including demographic characteristics, history, diagnosis, investigations, interventions, post-intervention clinical condition, adverse events, and provided takeaway lessons.

Results

Of the 2,032 items identified from the comprehensive search of the databases, 1,998 irrelevant studies were excluded. Of the 34 studies assessed for eligibility, 3 studies reported cases with no coexistence of the 2 diseases and 11 studies exhibited no definite diagnosis of either disease. In the end, 20 studies with 42 cases presented with ALS and MG coexistence were included in this review (Fig. 1). The risk of bias for each included study is shown in Table 1. The reported cases were categorized into four groups, as derived from a literature review published in 2017 [26].

Fig. 1.

PRISMA 2020 flow diagram for new systematic reviews which included searches of databases and registers only.

The first group represents patients diagnosed with MG as the initial disease, followed by ALS. The group consisted of 26 cases (males = 15), with MG age of onset ranging between 26 and 82 years (median = 62). MG is located predominantly in the bulbar and ocular regions; only 3 patients exhibited limb involvement besides the ocular and bulbar symptoms. The AChR-Ab test was negative in 7 cases. However, these cases showed clear clinical findings for MG and improved after conventional MG treatment. Repetitive nerve stimulation (RNS) showed no decrement in 4 cases. Most of the MG symptoms were resolved with conventional treatment such as pyridostigmine, IVIG, or corticosteroids, and some resolved spontaneously. The time interval to develop ALS symptoms ranged from 3 months to 41 years. It was presented at ages 46–83 years (median = 72). It has been observed that the earlier the MG onset, the longer the interval before ALS development. ALS symptoms involve mainly the bulbar and limb regions. All ALS symptoms deteriorated even after using the immune-modulating therapy except for one case who received autologous enhanced mesenchymal stem cells (MSCs) and showed significant improvements. In addition to the included cases, there were two abstracts, not included in the study, reported 2 cases in their 80s diagnosed with MG and who then developed the ALS symptoms [36].

The second group included patients who inaugurally developed ALS followed by MG. This group included 9 patients (males = 7). The age of ALS onset varied widely, ranging between 34 and 89 years (median = 57.5). MG symptoms appeared between 40 and 89 years (median = 53), with an interval of 3–71 months following ALS onset. All patients with ALS were followed by ocular MG symptoms. Three patients have bulbar or limb symptoms associated with these ocular symptoms. One patient came with a myasthenic crisis after nearly 2 years of developing the ALS symptoms. AChR-Ab tested negatively in 1 patient with MG. The RNS test showed decrement in all patients. All of the MG symptoms improved with time, while ALS symptoms worsened. A Summary of the first and second group is shown in Table 2.

Regarding the third group, 5 patients (males = 2) had ALS onset at 37–88 years of age (median = 70). They showed a positive AChR-Ab test with no clinical symptoms or signs of MG. These cases may be classified as examples of false-positive AChR-Ab test [26].

The fourth group consisted of 2 patients diagnosed with definite ALS. It has been reported that extraocular muscles remain remarkably unaffected, even in the advanced stages of ALS [20]. The patients in fourth group presented initially with ocular symptoms, including lid fatigue and fluctuating ptosis, then dysphagia, dysarthria, and progressive weakness in the lower limbs. Investigations found negative AChR-Ab, negative neostigmine, and negative RNS tests. There was no response to either the cholinesterase inhibitors or immunosuppressive therapy. However, the lack of sufficient evidence weakened the diagnosis of MG.

Discussion

The overlap syndrome of MG and ALS presents a rare and complex clinical phenomenon, characterized by the coexistence of two distinct neurologic conditions with overlapping symptoms. This review consolidates existing knowledge and explores various aspects of this intriguing association, aiming to elucidate its clinical implications, diagnostic challenges, and potential underlying mechanisms. Patients with MG typically exhibit fluctuating muscle weakness due to autoantibodies targeting AChR at the neuromuscular junction (NMJ), leading to impaired neuromuscular transmission [37]. In contrast, ALS is a neurodegenerative disorder affecting primarily the motor system. The loss of upper and lower motor neurons in the motor cortex, the brain stem nuclei, and the anterior horn of the spinal cord gives rise to progressive muscle weakness and wasting [38]. The overlap between these conditions manifests primarily in the bulbar region, commonly presenting with dysarthria and dysphagia, which can complicate the diagnosis and management [26].

Pathophysiological Insights

Although the precise causes of MG and ALS co-occurring are unknown, common autoimmune pathways and intricate immunological abnormalities are believed to be involved. Autoantibodies directed against shared antigens, such as AChR, LRP4, or MuSK, may be a key factor in the development of this overlap syndrome [17]. These autoantibodies against the mentioned receptors lead to selective degeneration of the upper and lower motor neurons, resulting in diffuse muscle weakness, atrophy, and fasciculation [24].

There are multiple genetics involved in ALS pathogenesis. One of these genes is survival motor neuron gene (SMN) [39]. SMN controls NMJ integrity [40]. However, there is no established link between genetics and MG occurrence as it is primarily an autoimmune process [41]. Thus, further research is necessary to clarify the immunological foundation and genetic susceptibility influencing the concomitant onset of various neurological conditions.

Overlapping in the Clinical Presentation

Overlapping in clinical presentation of both MG and ALS is rare but can occur [26]. MG manifests with easy fatigue. Also, fatigue is common among ALS, which leads to a marked clinical impact on patients’ quality of life. Bulbar muscle affection could be affected in both disorders. A summary of the main clinical overlapping of both has been shown in Figure 2.

Fig. 2.

Diagram of amyotrophic lateral sclerosis and myasthenia gravis overlap syndrome.

Main Clinical Findings of the Study

Our study results reported 4 groups of patients. In the first group, patients were diagnosed with MG as an initial disease, followed by ALS. ALS symptoms involved mainly the bulbar and limb regions, and the symptom localization was the same in MG and ALS in 13 patients (50%). Other neurophysiological parameters for diagnosis were not always positive at the initial presentation. The AChR-Ab test was negative in only 7 cases. Despite the possibility of seronegative myasthenia gravis, the seronegativity could be attributed to low-affinity antibodies or low antibody levels, necessitating the use of more sensitive assays for detection [42]. RNS provided a good screening tool to prove the MG diagnosis for most cases except for only 4 cases in the first group. Notably, in ocular MG, RNS was only 10–30% sensitive [43].

However, in the second group, which included the patients in whom ALS was the inaugural disease and was followed by MG, all patients showed a decrement in the RNS test. This could be explained by an important hypothesis for ALS called “distal axonopathy,” which describes degenerative changes at the NMJ very early in the disease before motor neurons degenerate and even before clinical symptoms appear. Even though we now know the genetic causes of this illness, a significant question about the initial pathological site remains unanswered. The theories of dying forward and dying back have both been explored [44]. The first suggests that glutamate excitotoxicity from the cortex causes anterograde motor neuron degeneration, whereas the latter suggests that ALS may begin distally at the nerve terminal or the NMJ and move toward the cell body. It is best to treat the back and forward dying processes in this complex scenario as two separate mechanisms that operate concurrently [45]. These theories could have an impact on the suspicion of the sensitivity and specificity of the RNS test to be included in the diagnostic criteria for MG.

In this review, the time interval between the two entities varies in the included studies from 3 months to 41 years in the first group. It has been observed that the earlier the MG onset, the longer the interval before ALS development with no clear explanation. Nevertheless, we recommend repetition of electromyography (EMG) examination especially with disease progression as the diagnosis of ALS should be considered particularly when there is muscle atrophy that is more common with ALS. For the second group, an interval of 3–71 months following ALS onset suggested a faster involvement of NMJ. This shorter time interval might be related to the faster pathophysiological process of ALS.

The overlapping symptoms between the two entities were further observed in the third and fourth groups; the third group contained 5 patients who had ALS and showed only a positive AChR-Ab test and had no other symptoms or signs of MG. It has been postulated that NMJ functional properties can be influenced by immunoglobulin from ALS patients, and AChR activity appears to be involved in the innervation and re-innervation of muscle fibers [46]. Also, it may be due to the cross-reactivity between antibodies produced in ALS and the AChR antibodies [47]. Immune system dysregulation in both diseases may be the cause of the association between them. ALS is associated with both general and tissue-specific immune activity, T-regulatory cell deficiency or reduction (Treg cells) [48, 49], upregulated atrophy-related atrogenes, and neuronal nitric oxide synthase abnormalities [50] that could be found in both MG and ALS.

Diagnostic Considerations

Diagnosing MG and ALS concurrently poses significant challenges due to overlapping symptoms and the absence of specific biomarkers for either condition. Diagnostic criteria rely heavily on clinical manifestations, neurophysiological studies, and serological tests for autoantibodies such as AChR antibodies in MG and the exclusion of other neurological disorders in ALS [8].

As observed in group 1, progressive muscle weakness with UMN signs unresponsive to MG treatment suggests ALS as a possible differential diagnosis. Muscle atrophy is rare in MG but common in ALS. Therefore, EMG reevaluation is required when symptoms change. Furthermore, bulbar-onset MG can mimic ALS. This makes immune-modulating therapy trials necessary in ambiguous cases.

As observed in group 2, MG mainly affects the ocular and bulbar regions in ALS cases. Also, ophthalmoplegia is rare in ALS, making it a potential clue for MG. If ALS patients show fluctuating muscle weakness, MG should be considered.

It was noted that over 10% of MG patients were seronegative, making it more challenging, and the diagnosis in such cases depends mainly on the clinical manifestation, neurophysiological studies, and empirical therapy [51]. In addition, ALS as in the third group, may show a positive AChR-Ab. AChR-Ab are specific to MG; however, they were found in 5% of ALS with no clinical manifestations of MG [52]. Also, AChR-Ab was found to fluctuate with ALS severity. It is recommended that the clinicians should consider all the probabilities, interpret test results carefully, consider the overall clinical picture, and try an empirical treatment. The review underscores the importance of a comprehensive diagnostic workup, including EMG, nerve conduction studies, and imaging modalities to differentiate between the 2 diseases and identify the potential overlap.

Management Strategies

In our review, most patients within the first group in whom MG was the inaugural disease showed complete or even partial remission of symptoms. The results showed a discrepancy in the second group, in whom ALS was the inaugural disease. A study by del Mar Amador et al. [29] showed improvement and even complete resolution for those presented later by ocular and generalized myasthenia as well. A study by Takahashi et al. [27] showed partial improvement in ocular MG symptoms and a modest improvement in generalized MG symptoms in another study [53]. If there is a suspicion that MG symptoms and ALS symptoms coincide, these observations recommend a therapeutic trial using standard MG treatment procedures.

Treatment strategies for MG and ALS aim to alleviate symptoms and improve quality of life but differ fundamentally due to their distinct pathophysiological mechanisms. MG management typically involves acetylcholinesterase inhibitors, immunosuppressive therapies, and in severe cases, thymectomy [54]. Conversely, ALS has no established cure yet; however, treatment options are limited to symptom management with medications like riluzole, alongside supportive care to prolong survival and enhance the quality of life [55]. Autologous enhanced MSCs showed significant improvement in ALS patients [30, 56]. The anti-inflammatory, immunoregulatory, and differentiation ability of MSCs make them a suitable treatment for ALS [57].

Although immune therapy trials for ALS have been unsuccessful, timing is crucial since diagnosis often occurs at a late stage when motor neuron damage is irreversible. Detecting ALS early and initiating immune-modulating therapy before the symptoms appear could be beneficial, as molecular changes at NMJs emerge long before onset. Targeting the motor neuron, muscle fiber, and terminal Schwann cells may help preserve neuromuscular function, potentially delaying disease progression. However, this remains speculative and requires further scientific validation [58, 59].

The current cases and the hypotheses regarding the overlapping between ALS and MG encourage future studies to focus on the role of the peripheral targets in ALS development and progression and to look beyond the nerves in understanding MG and ALS. This review highlights the necessity for tailored therapeutic approaches in patients presenting both conditions, considering concurrent treatments’ potential interactions and adverse effects.

Prognosis and Outcomes

Prognosis in patients with ALS/MG overlap syndrome varies depending on the timing and sequence of disease onset, as well as the extent of neurological involvement. Additionally, muscle degeneration may play a role in disease progression. The non-cell-autonomous degeneration includes defects in glial cells, particularly astrocytes, and muscles. ALS is linked to disruptions in energy balance caused by mitochondrial muscle dysfunction in addition to the changes in trophic factors produced by the skeletal muscles like the glial cell-derived neurotrophic factor and the insulin growth factor-1, which are essential for maintaining the NMJ and promoting motoneuron survival. So, besides glial cells, skeletal muscles have the potential to accelerate ALS progression through energy depletion and diminished trophic factor release [60].

Immunomodulatory treatment offer transient improvement in MG-related symptoms but did not significantly alter the ALS progression. A case with ALS in group 1 became symptom free for 4 years after riluzole, corticosteroids, and azathioprine [53]. Also, another case with ALS showed significant improvements after MSC treatment [30]. Early recognition and intervention are crucial in mitigating disease progression and optimizing clinical outcomes. Longitudinal studies focusing on disease progression, survival rates, and response to therapy are essential to refine prognostic predictions and inform therapeutic decisions.

Limitations and Future Directions

This research deals with the different possible types of overlapping syndrome between ALS and MG. We investigated the differences between the possible four groups of overlapping syndromes. We discussed the disease interval, the clinical presentation, treatment, possible causes of overlapping, and the prognosis. The small sample size of the past literature is due to the rarity of this condition. Also, there is a lack of research about the common definite causes of occurrence of this overlapping syndrome including genetic, immune processes, and histopathological studies. The included studies did not clarify whether respiratory failure is attributed to ALS or it was due to MG. However, the role of MG cannot be ruled out, potentially in accelerating and exacerbating the progression of respiratory failure in ALS. Overlapping respiratory muscle involvement can potentially accelerate the progression to respiratory failure. A recent study found a genetic overlap between ALS and neuromuscular disorders [61].

Future research should be directed to explore the exact cause of these overlapping symptoms. Also, more research is needed on various diagnostic tests to diagnose this problem such as electrophysiological tests, specific antibodies, and neuro-histopathological examination. Moreover, it is recommended that the future studies should give attention to the role of the peripheral targets in ALS development and progression and look beyond the nerves in understanding MG and ALS.

Conclusion

The overlap syndrome of MG and ALS represents a unique clinical entity characterized by overlapping symptoms, diagnostic challenges, and management complexities. This review synthesizes current evidence and underscores the need for heightened awareness among healthcare providers to facilitate early recognition, accurate diagnosis, and individualized management strategies. Extraocular muscles are known to remain remarkably unaffected, even in the advanced stages of ALS. Therefore, the onset of new ptosis or diplopia in these patients should prompt clinicians to consider the possibility of a coexisting condition or alternative diagnosis. Additionally, positive acetylcholine receptor antibodies alone are insufficient to diagnose MG if ALS coexists. In patients with ALS, repetitive nerve stimulation tests may be less sensitive for detecting MG. Thus, diagnosing MG in ALS patients should rely on clinical presentation and response to empirical treatment. Future research efforts should focus on unraveling the underlying mechanisms driving this intriguing association to improve clinical outcomes and enhance patient care.

Statement of Ethics

The protocol is reviewed and registered in the PROSPERO database (ID: CRD42024572524).

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

Conceptualization and methodology: Yousef Hawas and Abdullah Ashraf Hamad; screening: Abdullah Ashraf Hamad, Ahmed Elshahat, and Manar Alaa Mabrouk; data extraction: Yousef Hawas, Rashad G. Mohamed, Ahmed Elshahat, and Manar Alaa Mabrouk; quality assessment: Yousef Hawas and Rashad G. Mohamed; formal analysis and interpretation: Mohamed Elbehary and Yousef Hawas; drafting the manuscript: Yousef Hawas, Basem Hamdy Fouda, Mostafa Meshref, and Mohamed Elbehary; critical revision: Yousef Hawas, Abdulqadir J. Nashwan, Mostafa Meshref, and Abdullah Ashraf Hamad; and administration: Yousef Hawas. All authors have read and agreed to the published version of this paper.

Funding Statement

This study was not supported by any sponsor or funder.

Data Availability Statement

Not applicable.