Successful Recovery from Life-Threatening Ventilatory Failure with Efgartigimod in Seronegative Myasthenia Gravis: Two Case Reports

Abstract

Introduction

In Japan, efgartigimod is approved for treating generalized myasthenia gravis in patients who are anti-acetylcholine receptor antibody-positive, anti-muscle-specific kinase antibody-positive, or seronegative. Efgartigimod efficacy has been reported in seropositive patients with myasthenic crisis; however, evidence in seronegative patients with myasthenic crisis remains limited. We report 2 patients with seronegative generalized myasthenia gravis presenting with myasthenic crisis as the initial manifestation, successfully treated with efgartigimod.

Case Presentation

Case 1 involved an 83-year-old man admitted with acute dyspnea requiring mechanical ventilation for respiratory failure initially attributed to acute exacerbation of heart failure with pleural effusion. Due to poor respiratory recovery, he was referred to neurology on hospital day 14. Clinical features including ventilatory impairment and fatigable limb weakness, together with electrophysiological findings, supported myasthenia gravis diagnosis. Following oral immunosuppressants and intravenous efgartigimod, he was weaned from mechanical ventilation on hospital day 42. Case 2 involved a 75-year-old man with progressive dyspnea and signs of right heart failure requiring mechanical ventilation for respiratory failure. He was referred to neurology on hospital day 2. Electrophysiological testing under sedation suggested myasthenia gravis. After methylprednisolone pulse therapy, subcutaneous efgartigimod was initiated, achieving ventilator liberation on hospital day 40.

Conclusion

Efgartigimod was effective in treating myasthenic crisis requiring mechanical ventilation in seronegative generalized myasthenia gravis, regardless of autoantibody status. These cases suggest efgartigimod may serve as an alternative or adjunctive therapeutic option for severe myasthenia gravis exacerbations.

Introduction

Myasthenia gravis (MG) is an autoimmune neuromuscular disease characterized by fluctuating weakness of the ocular, bulbar, limb, and/or respiratory muscles. Patients with MG may develop myasthenic crisis (MC), a life-threatening exacerbation that requires tracheal intubation or noninvasive ventilation [1]. Historically, rapid treatment of MC has relied on therapeutic plasma exchange or intravenous immunoglobulin (IVIG) [2–4]. Efgartigimod is currently approved in the USA and European countries for the treatment of generalized MG (gMG) that is anti-acetylcholine receptor (AChR) antibody-positive. In Japan, efgartigimod is approved not only for anti-AChR antibody-positive gMG, but also for anti-muscle-specific kinase (MuSK) antibody-positive gMG and antibody-negative gMG. Multiple reports and reviews have demonstrated the effectiveness of efgartigimod in the treatment of MC [5]. However, no cases have been reported describing its efficacy in patients with double seronegative gMG who required intubation because of respiratory muscle weakness, corresponding to Myasthenia Gravis Foundation of America (MGFA) Class V. We report 2 cases of double seronegative gMG in which patients successfully discontinued mechanical ventilation after receiving efgartigimod as the initial treatment for MC.

Case Presentation

Case 1

An 83-year-old man with a history of chronic heart failure, type 2 diabetes mellitus, and chronic kidney disease presented to the emergency department with an acute onset of dyspnea. On arrival, oxygen saturation was 87% on room air. Physical examination revealed generalized edema, and chest computed tomography (CT) demonstrated massive bilateral pleural effusions, leading to a presumptive diagnosis of acute exacerbation of chronic heart failure. Oxygen therapy was initiated; however, his level of consciousness gradually deteriorated. Arterial blood gas analysis revealed a pH of 7.250, PaCO₂ of 63.1 Torr, PaO₂ of 56.1 Torr, and HCO₃^– of 27.1 mmol/L, consistent with respiratory acidosis accompanied by hypoxemia and hypercapnia. He was diagnosed with carbon dioxide narcosis, and noninvasive positive-pressure ventilation was initiated. Despite this intervention, respiratory status failed to improve, necessitating admission to the high-care unit, followed by endotracheal intubation and mechanical ventilation. Aggressive pharmacological management of heart failure resulted in a rapid reduction of pleural effusions and improvement in pulmonary congestion. Muscle relaxants, sedatives, and analgesics were subsequently tapered and discontinued. After a successful cuff leak test, extubation was performed. Shortly thereafter, the patient developed recurrent respiratory distress with a decline in oxygen saturation, requiring reintubation and resumption of mechanical ventilation. A tracheostomy was subsequently performed. Chest CT ruled out primary pulmonary pathology. Given the unexplained respiratory failure, a neuromuscular disorder was suspected, and a neurology consultation was requested on hospital day 14. Neurological examination at the bedside revealed no obvious limb paralysis; however, the patient reported marked fatigability when lifting his arms. Sensory and autonomic examinations were unremarkable. Nerve conduction studies showed no evidence of peripheral neuropathy. Repetitive nerve stimulation (RNS) of the ulnar nerve at the wrist before treatment, recorded over the abductor digiti minimi muscle, demonstrated a 35.6% decrement at the fourth compound muscle action potential during 3-Hz stimulation (Fig. 1a). An edrophonium test did not produce any observable clinical improvement. Plain chest CT confirmed the absence of thymoma. Based on these findings, he was diagnosed with MC secondary to gMG, corresponding to MGFA Class V. The initial MG composite (MGC) score was 40, and the MG-activities of daily living (MG-ADL) score was 17. Treatment was initiated with oral prednisolone at 5 mg/day and cyclosporine at 100 mg/day. Efgartigimod at a dose of 10 mg/kg was then administered intravenously once weekly for four consecutive weeks. Two weeks after initiation of efgartigimod, spontaneous tidal volume began to increase, and by 3 weeks, ventilatory support was no longer required. The patient was successfully weaned from mechanical ventilation on hospital day 42, with sustained respiratory stability thereafter. No adverse events were observed during the course of treatment. Posttreatment, the MGC score improved to 13, and the MG-ADL score improved to 8. Follow-up RNS after weaning from mechanical ventilation demonstrated resolution of the decremental response (Fig. 1b). Serological testing confirmed negativity for both anti-AChR and anti-MuSK antibodies, establishing a diagnosis of double seronegative gMG. Efgartigimod was not readministered. The patient was transferred to a rehabilitation hospital on hospital day 65. Subsequent follow-up confirmed closure of the tracheostomy site and successful discharge home.

Fig. 1.

a Pretreatment RNS of the ulnar nerve at the wrist, recorded over the abductor digiti minimi muscle on hospital day 16, demonstrated a significant decremental response, with a 35.6% reduction at the fourth compound muscle action potential during 3-Hz stimulation. b Follow-up RNS of the ulnar nerve performed after successful weaning from mechanical ventilation showed complete resolution of the decremental response.

Case 2

A 75-year-old man with a heavy smoking history and no prior hospital admissions developed dyspnea approximately 1 month before presentation, which progressively worsened. He was brought to our emergency department after visiting a nearby clinic, where severe hypoxemia was noted, with an oxygen saturation of 77% on room air. On arrival, oxygen saturation improved to 93% with 2 L/min of supplemental oxygen; however, respiratory distress worsened with minimal exertion. Chest auscultation was unremarkable, but bilateral lower limb edema was present. Chest CT revealed cardiomegaly, bilateral pleural effusions, and subcutaneous edema of the trunk. Transthoracic echocardiography showed a preserved left ventricular ejection fraction of 60% but marked enlargement of the right-sided cardiac chambers. No thymoma was identified, although imaging findings were suggestive of descending colon cancer. Given his smoking history, pulmonary disease was considered; however, chronic obstructive pulmonary disease and other primary lung pathologies were excluded. Arterial blood gas analysis demonstrated a pH of 7.260, PaCO₂ of 87.3 Torr, PaO₂ of 88.6 Torr, and HCO₃^– of 30.3 mmol/L, consistent with respiratory acidosis secondary to hypercapnia. Initial management targeted a presumed acute exacerbation of heart failure with diuretics and antihypertensive therapy. Despite the initiation of noninvasive positive-pressure ventilation, his level of consciousness deteriorated because of carbon dioxide narcosis, necessitating sedation, endotracheal intubation, and mechanical ventilation. Based on the clinical course and experience with case 1, a neurology consultation was requested on hospital day 2 to evaluate for a possible neuromuscular disorder. Because the patient was sedated, objective assessment of muscle strength and sensation was not feasible. Gross inspection revealed no evidence of generalized muscle atrophy, including the tongue, and no fasciculations were observed. Deep tendon reflexes were decreased in the limbs, and Babinski sign was negative bilaterally. RNS of the ulnar nerve at the wrist, recorded over the abductor digiti minimi muscle, demonstrated a 31.6% decrement prior to treatment during 3-Hz stimulation (Fig. 2a). An edrophonium test was not performed. These findings strongly suggested the possibility of MC secondary to gMG, corresponding to MGFA Class V. Given the anticipated surgical resection of the descending colon cancer and concerns regarding perioperative management, oral immunosuppressive agents were withheld. Treatment was initiated on hospital day 6 with oral ubretid at 2.5 mg/day and steroid pulse therapy consisting of intravenous methylprednisolone at 1 g/day for three consecutive days. Efgartigimod at a dose of 1,008 mg was subsequently administered subcutaneously once weekly for four doses, beginning on hospital day 9. A tracheostomy was performed on hospital day 13, and sedatives and analgesics were discontinued. At that time, the MGC score was 37, and the MG-ADL score was 17. Approximately 2 weeks after initiating efgartigimod, spontaneous tidal volume increased, and by 3 weeks, ventilatory support was transitioned to continuous positive airway pressure. Mechanical ventilation was fully discontinued on hospital day 40, with no recurrence of respiratory deterioration. The treatment was well tolerated, with no adverse events observed. By hospital day 48, the MGC score had improved to 12, and the MG-ADL score to 7. Posttreatment RNS, performed after completion of the efgartigimod course, demonstrated resolution of the decremental response (Fig. 2b). Serological testing confirmed negativity for both anti-AChR and anti-MuSK antibodies. The patient remained clinically stable while awaiting transfer to the surgical department for management of the descending colon cancer. No re-exacerbation of MG symptoms occurred, despite the absence of efgartigimod readministration.

Fig. 2.

a Initial RNS of the ulnar nerve at the wrist, recorded over the abductor digiti minimi muscle on hospital day 2, revealed a marked decremental response, with a 31.6% reduction at the fourth potential during 3-Hz stimulation, while the patient was under sedation. b Follow-up RNS of the ulnar nerve performed after completion of the efgartigimod course and successful discontinuation of mechanical ventilation demonstrated normalization of the previously observed decremental pattern.

Discussion

Both cases presented with type II respiratory failure at admission, initially attributed to acute exacerbation of heart failure. In cardiogenic pulmonary edema, hypoxemia typically occurs first due to decreased lung compliance and alveolar flooding, followed by carbon dioxide retention secondary to respiratory muscle fatigue [6]. However, carbon dioxide retention has been reported in only approximately 13% of patients with acute heart failure [7]. Given that type II respiratory failure has a broad differential diagnosis, with neuromuscular disorders representing a major cause [8], it should be actively considered when patients present with pronounced hypercapnic respiratory failure.

Because both cases were negative for anti-AChR and anti-MuSK antibodies, the diagnosis of MG was based on electrophysiological findings, particularly RNS. In RNS testing, a decrement greater than 10% is considered abnormal. This test identifies abnormalities in approximately 75–80% of patients with gMG [9, 10], with detection rates exceeding 90% among patients presenting with MC [11, 12]. However, this finding is not specific to MG and may also be observed in other disorders of neuromuscular transmission, such as Lambert-Eaton myasthenic syndrome (LEMS) or motor neuron disease. Measurement of antibodies against voltage-gated calcium channels is useful for the definitive diagnosis of LEMS. Although antibody testing was not performed in our cases, their clinical features were not consistent with the typical manifestations of LEMS. In addition, high-frequency repetitive stimulation at 50-Hz performed before treatment produced a decremental response rather than the incremental amplitude typically seen in LEMS. Moreover, the decremental responses improved reversibly following efgartigimod therapy, and no clear progressive neurological deterioration was observed during follow-up. Taken together, these alternative diagnoses were considered unlikely.

MC is a severe, life-threatening complication that occurs in approximately 20–30% of patients with MG [13, 14]. It often develops early in the disease course, frequently within the first year after symptom onset [15, 16]. In up to 20% of patients, MC may represent the initial manifestation of MG [16, 17]. According to Berrouschot et al. [18], among 63 episodes of MC in 44 patients, generalized weakness, bulbar symptoms, and respiratory muscle weakness were observed in 76%, 19%, and 5% of cases, respectively. These findings indicate that patients with MG who present initially with respiratory failure, as observed in our 2 cases, are exceedingly rare. Based on the age at onset, both cases were classified as belonging to the subgroup of very late-onset gMG (onset ≥65 years). This subgroup is typically characterized by a higher proportion of males, a higher rate of anti-AChR antibody positivity, and a greater frequency of ocular symptoms, bulbar involvement, and life-threatening events at presentation [19]. In our 2 cases, the absence of detectable antibodies and the lack of ocular and bulbar symptoms at onset were atypical; however, several other clinical features were consistent with this subgroup.

In the present study, we treated 2 patients with seronegative MG who required mechanical ventilation because of MC using efgartigimod. In both of our cases, heart failure was identified on admission, raising concerns about cardiovascular risks associated with IVIG and plasma exchange. For this reason, efgartigimod was selected as the therapeutic option. A growing body of case reports has demonstrated the effectiveness of efgartigimod in the treatment of MC [5]. Furthermore, an observational study comparing IVIG and efgartigimod in anti-AChR antibody-positive patients with MC (MGFA Class IIIb or IVb) reported that the efgartigimod group achieved significantly faster and greater improvement in MG-ADL scores than the IVIG group [20]. These findings support the rationale for our treatment choice in the present cases. In case 2, a course of intravenous methylprednisolone pulse therapy was administered immediately prior to the initiation of efgartigimod. Although corticosteroid therapy may have contributed to clinical improvement, previous reports have indicated that repeated courses of steroid pulse therapy are often required to achieve stabilization in MC [21]. In case 2, clinical stabilization was achieved after a single course of steroid pulse therapy followed by one cycle of efgartigimod, without the need for additional steroid administration. This clinical course suggests that efgartigimod played a central role in the patient’s recovery, although the relative contribution of each therapy cannot be fully separated. For seronegative disease, a single case report has described the effectiveness of efgartigimod in a patient with recurrent MC during long-term follow-up [22]. However, no prior reports have described the use of efgartigimod in seronegative MC requiring mechanical ventilation, as observed in the present cases. This report provides novel evidence suggesting that efgartigimod may be effective even in critically ill seronegative patients.

Several limitations should be acknowledged. This report is based on only 2 cases; therefore, while efgartigimod demonstrated remarkable efficacy in our patients, these findings may not be generalizable to the broader population of patients with seronegative gMG. Furthermore, the follow-up period was relatively short. Although the patients remained stable without efgartigimod readministration during hospitalization, the long-term prognosis and optimal timing for potential re-treatment remain unclear. In summary, efgartigimod appears to be effective in the treatment of MC regardless of autoantibody status, suggesting that it may serve as an alternative or adjunctive therapeutic option for disease exacerbations.

Acknowledgment

The authors thank Editage (http://www.editage.jp) for assistance with English language editing.

Statement of Ethics

Written informed consent was obtained from the patients for publication of case details and accompanying images. This research complies with ethical guidelines and adheres to Japan’s local legal requirements. Ethical review was not required for this type of article. 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/10.1159/000552505).

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This research did not receive any funding.

Author Contributions

S.T.: conceptualization, investigation, resources, data curation, and writing – original draft. H.Y.: conceptualization, investigation, resources, supervision, and writing – review and editing. All the authors contributed to the article and approved the submitted version.

Funding Statement

This research did not receive any funding.

Data Availability Statement

All relevant data are included in the article. Further inquiries may be directed to the corresponding author.