Syncope as a Presenting Symptom of MuSK-Associated Myasthenia Gravis: A Case Report

Myasthenia gravis is best characterized by antibodies against different targets at the neuromuscular junction that cause transmission failure. It leads to a host of symptoms, most commonly including muscle fatigability and fluctuating weakness. ¹ Although 75% to 85% of myasthenia gravis cases are associated with acetylcholine receptor auto-antibodies (AChR), about half of the seronegative cases eventually test positive for antibodies against muscle-specific tyrosine kinase (MuSK),^1,2 which plays a unique role in both the development and maintenance of the neuromuscular junction. ³ Clinical presentation can prominently involve the neck and respiratory muscles and also carry association with muscle atrophy. ²

In MuSK-related myasthenia gravis, clinical autonomic signs, such as orthostatic intolerance have been reported in up to 88% of patients in one review. ¹ Generally, dysautonomia in neuromuscular junction disorders is rarely reported. Autonomic instability has been linked to thymoma and autoimmune autonomic ganglionopathy, or in the case of cardiac dysfunction, KV1.4. ⁴ Yet, autonomic instability can be found even when these secondary findings are not present, such as in MuSK myasthenia gravis. Additionally, it is generally unclear how severity and timing of autonomic symptoms relate to the neuromuscular disease course. Here we present a case of MuSK-related myasthenia gravis in a teen who presented at least up to a year prior with dysautonomic symptoms, primarily orthostatic intolerance.

Case Report

An adolescent with a background of hypertension had been presenting for at least a year with recurrent transient loss of consciousness or prodromal symptoms including intermittent tachycardia at rest and constipation. Scattered care across several emergency departments, urgent care, and primary care visits did not yield any definitive answers. Several obtained electrocardiographs (ECGs) were significant only for unexplained tachycardia at rest, and recorded vitals for borderline hypoxia. Referrals were made to pediatric specialty services, including cardiology and neurology, for further investigation of syncope, but were never followed up. However, shortly after onset of those symptoms, the patient also began to experience intermittent double vision, occasional ptosis, and difficulty lifting heavy objects. A first evaluation by ophthalmology yielded no abnormalities because of fluctuating symptomatology. A referral was once again directed toward neurology. Thereafter, a neurologic history and examination led to initial workup for neuromuscular and motor disease because of increasing weakness and reported atrophy, as well as workup for multiple sclerosis and related diseases in the setting of ocular complaints. Another referral to cardiology was made for continuing syncope, tachycardia, and fatigue. Testing, including electrodiagnostic studies with repetitive nerve stimulation to the right abductor pollicis brevis muscle, was unremarkable. Prior to completion of imaging studies, cardiology visit, and neurology clinic follow up, the patient presented to the emergency department with dysphagia, recurring prodromal syncopal events, and increasing difficulty with breathing in the setting of an ongoing respiratory illness. As the patient was being examined in the emergency department, rapid progression to respiratory failure with loss of consciousness occurred, requiring intubation and hospitalization. Because of clinical history and knowledge of the interrupted neurologic investigations, an autoimmune workup including autoimmune neuromuscular-related and ganglionic antibody testing was conducted in addition to stabilization and treatment of intercurrent respiratory illness. Additionally, empirical treatment for myasthenia gravis with intravenous immunoglobulin was given over 2 days. Further testing was sent for myopathy and mitochondrial disease due to exhibited pain, limited range of motion, and baseline weakness of upper extremities. The patient was extubated shortly after intravenous immunoglobulin and subsequent improvement of extremity weakness. However, there were persistent signs of respiratory weakness requiring overnight biphasic positive airway pressure, hypertension, and unprovoked tachycardia with orthostatic changes requiring pharmacologic treatment. Telemetry and echocardiogram, reviewed by cardiology, was not significant, but follow-up on an outpatient basis was arranged. With symptomatic management involving pulmonology and neurology, the patient was stabilized enough for discharge home. Mayo Clinic antibody testing confirmed positive MuSK myasthenia gravis titers (161 nmol/L). Myopathic and mitochondrial testing were unremarkable. No thymoma, autonomic ganglionic ,or Kv1.4 antibodies were found. The patient continued to have autonomic relapses (syncopal prodrome, resting tachycardia with reproducible orthostatic changes) and neuromuscular symptoms (respiratory muscle weakness requiring nightly biphasic positive airway pressure, upper extremity fatigue, intermittent ptosis, and diplopia) requiring repeat infusions of intravenous immunoglobulin. The family has remained reluctant to go on alternative immunotherapy such as rituximab. The potential for better outcomes on rituximab for patients with MuSK-related myasthenia gravis was overshadowed by concern of potential side effects. ⁵ Residual tachycardia and weakness also remain, but the patient has been able to return to good function.

Discussion

Literature suggests that autonomic dysfunction in myasthenia gravis is likely underestimated, especially in patients without evidence of thymoma or who are negative for previously implicated antibodies. ⁶ In Japanese studies, ECG abnormalities were associated with anti-Kv1.4 antibodies, but the association with MuSK and the time course for appearance of symptoms in a myasthenia gravis patient is not known. ⁴ The criteria for autoimmune autonomic ganglionopathy include fainting and constipation. However, in addition to being without ganglionic antibodies, there was hypertension rather than hypotension, and tachycardia at rest in addition to postural tachycardia in this patient. The pupillary and urinary symptoms of autoimmune autonomic ganglionopathy were not seen. ⁶ Nikolic et al ¹ found 88% of their MuSK-related myasthenia gravis cohort to have a significant number of clinical signs for autonomic dysfunction, though varied and heterogeneous. One report highlights cardiac dysfunction within 1 month of MuSK diagnosis. ⁴ Another noted simultaneous onset of severe MuSK-related myasthenia gravis and autonomic dysfunction, with transient loss of consciousness as a leading symptom. ⁷ The patient in our case exhibited autonomic and syncopal burden prior to myasthenia gravis symptom onset. Evidence suggests there may be an early role for autonomic symptomatology in MuSK-related myasthenia gravis as well as a severity of clinical course.

There is lack of literature for dysautonomia as presenting symptomatology in myasthenia gravis alone. Autonomic symptoms are often found well into the disease course of studied patients. Abnormal autonomic features have been best characterized in myasthenia gravis with thymoma as a possible effect of paraneoplastic inflammation. In the case of patients with AChR antibodies, it is explained by involvement and cross-reactivity with ganglionic AChR. ¹ However, it has been difficult to explain autonomic dysfunction in MuSK. ¹ During development, MuSK is intimately involved in each step of the formation and differentiation of the neuromuscular junction. ³ Its maintenance role at the mature junction is through the MuSK-LRP4 tetramer, which activates differentiation and clustering of ACh receptors on the postsynaptic membrane. It also contributes to membrane stabilization. ⁸ Although more areas have been recently clarified concerning the junctional role of MuSK, it is unknown if MuSK has activity in other areas. If acetylcholine receptors cluster similarly at other non-neuromuscular junction acetylcholine synapses, then perhaps there is a yet unknown role for MuSK during development for those synapses as well. ⁹ Further, MuSK has been found to be involved in both the formation and maintenance of excitatory neuronal synapses in the central nervous system. ⁹ Our presented case could suggest that possible effects of the MuSK protein may include a broader range of systemic involvement and a broader role for its unique IgG-4 class autoantibody. ⁸

Conclusion

This case underscores the diagnostic complexity of MuSK antibody–positive neuromuscular disease and the role of autonomic dysfunction, primarily orthostatic intolerance. It challenges the conventional diagnostic framework for neuromuscular disease and emphasizes consideration for MuSK in cases of unexplained orthostatic intolerance followed by atypical symptoms of neuromuscular disease.

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