Isolated Respiratory Failure as the Presenting Symptom of Muscle-Specific Kinase Myasthenia Gravis: A Case Report and Literature Review

Although no epidemiological studies on myasthenia gravis (MG) have been done in Lebanon, it has been established that the prevalence of muscle-specific tyrosine kinase (MuSK) antibody-positive MG shows a distinct geographical pattern, with a higher occurrence in Mediterranean countries compared to northern regions [1, 2]. As such, we must become more familiar with this subtype of MG since it may differ from other more common subtypes. Pathophysiologically, anti-MuSK antibodies obstruct the binding sites on MuSK responsible for its interaction with essential binding proteins such as low density lipoprotein receptor-related protein 4 (LRP4) and collagen Q (ColQ) [3]. This obstruction results in the inactivation of MuSK, which subsequently leads to a decrease in the postsynaptic density of acetylcholine receptors (AChRs) and disrupts their proper alignment within the postsynaptic membrane [4]. The distinctive pathophysiology observed in MuSK MG patients could account for the distinct clinical presentation they exhibit. These patients tend to have a heightened incidence of bulbar involvement [5‒9] and respiratory crises [5, 7, 9, 10], setting them apart from other MG subtypes. A case series by Deymeer et al. [9] showed patients with MuSK MG also have a more unfavorable prognosis as they tend to have higher Myasthenia Gravis Foundation of America (MGFA) scales in comparison with anti-AChR-positive subtype, but there was no statistically significant difference from those with seronegative MG. As for treatment, the case-control by Deymeer et al. [9] showed that MuSK MG patients needed higher maintenance steroid doses, required treatment with azathioprine more often, and had poorer outcomes overall in comparison with the other subtypes [9]. In this paper, we present a patient that exhibited progressive dyspnea as his main and only symptom prior to presenting to the emergency department (ED).

The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000540916). A 51-year-old male with a history of gastroesophageal reflux disease and generalized anxiety disorder on paroxetine presented to the ED complaining of acute dyspnea that had been progressing over the past week. History goes back to 2 months prior when the patient started experiencing worsening dyspnea initially upon exertion which developed into dyspnea that limited his ability to speak to getting a few words in between breaths. To note, the patient had been complaining of a progressive weight decline of almost 20 kg over the past year; however, gastroenterology and endocrinology visits were negative. In the ED, the patient’s oxygen saturation reached 63% prompting administration of bilevel positive airway pressure (BiPAP). The patient continued to deteriorate, becoming minimally responsive to painful stimuli, and was thus intubated. Arterial blood gas showed severe respiratory acidosis. The patient was then transferred to the intensive care unit on the eve of day 1 pending further workup. CT brain ruled out hemorrhagic stroke, and CT abdomen was not significant. Infectious workup showed bilateral lower lobe pneumonia on CT scan; however, the infectious disease team remained unconvinced of this as the cause of his respiratory failure, since the patient was afebrile, had no history of cough, had no hypotension, and his laboratories and inflammatory markers were unimpressive. He was started on piperacillin-tazobactam 4.5 g for 7 days and was given 1 g vancomycin and amikacin. The neurology team was consulted and examined the patient thoroughly. On physical exam, patient showed normal muscle tone with 5/5 strength in upper and lower limbs bilaterally. Deep tendon reflexes were 3+ in both upper and lower extremities bilaterally. Babinski was negative. Ocular testing showed intact extraocular muscle movement, and bedside fatiguability testing failed to show fatiguability after 30 s. All other cranial nerve testing was insignificant. CT chest was reviewed, and no evidence of thymoma was detected. EMG was done and showed decremental response on repetitive accessory nerve stimulation with mild generalized myopathy (Fig. 1), which were suggestive of MG. MRI brain was negative. The patient was started on pyridostigmine (PYR) 60 mg three times daily and methylprednisolone 60 mg daily on day 2 in order to monitor for improvement, pending MG antibody workup. On day 4 of hospitalization, the patient received the first dose of intravenous immunoglobulins (IVIGs) 2 g/kg which was to be given for 5 days. Plasma exchange (PLEX) was declined by patient as they did not want a catheter to be placed. The patient was extubated on day 9 and switched to BiPAP. MuSK antibodies were positive (99.4), while AChR, CASPR-2, LGI 1, DPPX, and glutamate receptor antibodies were negative. The patient was discharged on day 20 after making a complete recovery. The patient was instructed to continue taking PYR 60 mg three times daily and was started on prednisone 70 mg daily to be tapered every 7 days by 5 mg. The patient was also started on mycophenolate mofetil and was scheduled to take IVIG 1 g/kg in 3 months; however, on follow-up 3 months later it was decided that due to the improvement of the patient’s condition we will not give another dose. Nighttime BiPAP was discontinued after 3 months of discharge.

In this case, we encountered a unique and rare clinical presentation of MG with isolated respiratory failure as the main and only symptom in a patient with MuSK MG. This distinct presentation stands in contrast to the more common manifestation of bulbar symptoms seen in the majority of MuSK MG cases reported in the literature [5‒11]. The geographical pattern of MuSK antibody-positive MG, with higher prevalence in Mediterranean countries like Lebanon, adds to the significance of recognizing and understanding this subtype of MG. It is interesting to note that only one paper was found in the literature on Lebanese MG patients, a cohort study of only 17 patients, none of which had MuSK MG [12]. This is not surprising as MuSK MG subtype patients only make up 5–8% of MG patients [13]. A systematic review published in 2015 on the epidemiology of MG in Arab countries concluded that the incidence rate of MG in Libya aligns with the worldwide average but is lower than most European estimates, while the prevalence rates in Egypt are inconsistent and significantly higher from the global average [14]. No other papers were published on MG in the region nor on MuSK MG specifically.

For the purpose of comparing our case report with other similar cases in the literature (MuSK MG patients presenting with respiratory insufficiency), we compiled a table of case reports/case series with age of onset, gender, clinical presentation, treatment, and outcomes of MuSK MG patients, all of which included patients with respiratory insufficiency (refer to Table 1). All cases of MuSK MG patients reported having bulbar symptoms as the most common and predominant symptoms on presentation except for Tsai et al. [15] who reported a presentation similar to our case (isolated respiratory dyspnea upon presentation). A study that included MuSK MG patients from both Catholic University in Rome and Duke University showed that only 2% of patients presented with respiratory failure at disease onset, while the majority presented either with pure ocular (36%), oculobulbar (26%), pure bulbar (19%), and generalized weakness (11%) [16].

The patient in this case report was treated with PYR, steroids (methylprednisolone), and IVIG. The combination of the 3 was enough to wean the patient off ventilation and treat the acute presentation of the disease. The patient was discharged on maintenance PYR, steroids, and an immunosuppressant (mycophenolate mofetil). Comparing that to the case reports/series in the literature, all patients received steroids and immunosuppressive therapy. Excluding the 32 MuSK MG patients in Deymeer et al. [9] (due to treatments being unspecified), 1/13 patients received IVIG therapy and 2/13 received PLEX therapy. This is to be expected as MuSK MG patients have been previously shown to show clinical improvement more often when using PLEX with the advantage of having a faster response [16]. The most reported on therapy was thymectomy, where 9/13 patients underwent the procedure. One of the latter, mentioned by Lau et al. [19], did not receive any noticeable benefit from thymectomy, and it was not until the patient received rituximab after a failure of PYR and 3 courses of IVIG and 1 trial of cyclophosphamide that the patient showed improvement. The remaining 8 patients (all part of the same case series) benefited from the procedure. It is worth noting that 2 of the 8 patients had respiratory failure and no longer suffered from respiratory insufficiency after the procedure [17]. Other sources in the literature did report such benefits post-thymectomy, as patients rarely became symptom free on immunosuppression alone [7, 16, 18, 20], but it is still too early to establish superiority of this procedure as the long-term post-intervention scale outcomes can be similar between thymectomized and non-thymectomized patients (refer to Table 1 for definitions) [16]. Our patient was discharged on maintenance immunosuppressive therapy without the need for thymectomy and is currently being monitored for any further symptoms.

The outcomes observed in the reported cases of MuSK MG patients with respiratory insufficiency showed substantial heterogeneity, making it challenging to draw definitive conclusions from the available data. The wide variation in clinical presentations, treatment approaches, and treatment outcomes among the different case reports and case series precludes the establishment of a unified pattern or standardized management strategy for this rare subgroup of MG. All the patients managed were able to regain independent function after their hospital courses; however, follow-up differed and most case reports did not report on a long enough follow-up period. Nevertheless, Deymeer et al. [9] showed that MuSK MG subtype had the poorest outcome when compared to both SN MG and AChR MG (although the difference between AChR MG and MuSK MG was marginal). These findings are supported by Guptill et al. [16] who concluded that long-term outcomes of MuSK MG patients are generally favorable and comparable to those of patients with AChR-Ab⁺ MG, although patients often require long-term management with multiple immunosuppressive agents. Due to the heterogeneity of reported outcomes, no definitive conclusions can be drawn, but overall, long-term prognosis appears favorable, requiring ongoing immunosuppressive management.

This case report underscores the importance of recognizing the potential enigmatic presentations of MuSK MG patients, especially when MuSK MG patients have the poorest outcomes among other MG subtypes. While the majority of MuSK MG cases in the literature exhibit bulbar symptoms, this unique presentation highlights the diverse potential clinical spectrum of the disease. The geographical pattern of MuSK antibody-positive MG, with higher prevalence in Mediterranean countries like Lebanon, further emphasizes the need for heightened awareness and consideration of this subtype in specific regions. Despite the challenges associated with the variable clinical presentations, our case suggests that early recognition and prompt initiation of appropriate treatment can lead to a successful resolution of the acute respiratory failure associated with MuSK MG. This report serves as a valuable contribution to the understanding of atypical presentations of MuSK MG, urging clinicians to maintain a high index of suspicion for MG in cases of isolated respiratory distress, as timely intervention can significantly impact outcomes in these patients. Furthermore, it adds to the literature on MuSK MG patients in the region highlighting the need for more extensive epidemiological studies.

We like to extend our appreciation to the American University of Beirut Medical Center, where the research was conducted. Their support and provision of resources were instrumental in the successful completion of this study.

Ethical approval is not required for this study in accordance with guidelines at the American University of Beirut. We would like to thank the patient who gave us permission to publish this case report. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images.

The authors have no conflicts of interest to declare.

We would like to express our sincere gratitude to the Neurology Department at the American University of Beirut for providing the funding support that covered the publication fees for this article. Their financial assistance made it possible for us to disseminate the results of our research to the scientific community.

Dr. Hassan Doumiati and Dr. Ali Ezzeddine contributed equally to the production of this manuscript. Manuscript writing, literature review, and manuscript editing were divided equally.

The data that support the findings of this study are not publicly available due to privacy reasons but are available from the corresponding author upon reasonable request.