Lambert-Eaton Myasthenic Syndrome, Botulism, and Immune Checkpoint Inhibitor–Related Myasthenia Gravis

Abstract

PURPOSE OF REVIEW This article reviews the pathophysiology, epidemiology, clinical presentation, diagnosis, and treatment of Lambert-Eaton myasthenic syndrome (LEMS) and of botulism, and immune-related myasthenia gravis (MG) occurring in the context of immune checkpoint inhibitor therapy for cancer. RECENT FINDINGS The suspicion that LEMS is rare but also likely underdiagnosed is supported by recent epidemiologic data. A validated, LEMS-specific scale now exists to assess and monitor disease, and symptomatic and immunomodulatory treatments are available. As presynaptic disorders of neuromuscular transmission, LEMS and botulism share electrodiagnostic abnormalities but have important distinguishing features. Knowledge of the clinical features of botulism is needed, particularly with continued cases of infant botulism, the opioid epidemic increasing the incidence of wound botulism, and medical use of botulinum toxin, which may cause iatrogenic botulism. Foodborne botulism remains rare. Prompt recognition of botulism and administration of antitoxin can improve outcomes. MG may be exacerbated or may present de novo in the context of immune activation from immune checkpoint inhibitor therapies for cancer. Immune-related MG commonly overlaps with myositis and myocarditis. Corticosteroids typically result in improvement. However, immune-related MG can be more fulminant than its idiopathic counterpart and may cause permanent disability or death. SUMMARY The diagnosis of LEMS, botulism, or immune-related MG can generally be made from the patient’s history, supplemented with directed questions, a physical examination designed to demonstrate abnormalities, and laboratory and electrodiagnostic testing. Early diagnosis and carefully selected treatment not only improve outcomes of the neuromuscular disease but can affect the prognosis of underlying malignancy, when present.

Case Report of Lambert Eaton Myasthenic Syndrome in a Patient with Small Cell Lung Cancer on Immune Checkpoint Inhibitor Therapy

“…The next steps in the work up depends on the specific irAE (muscle biopsy, EMG etc. ), and consultation with a neuromuscular or irAE expert neurologist is suggested [20]. Counter to classic LEMS, the first line treatment for most neuromuscular irAEs is high dose corticosteroids [21].…”

“…Results for re-challenges with ICI therapies after neuromuscular irAE are mixed. Some experts recommend retrial with a different class of ICI [2,3,20,[24][25][26].…”

Immunoglobulins to mitigate paraneoplastic Lambert Eaton Myasthenic Syndrome under checkpoint inhibition in Merkel cell carcinoma

“…Antagonists against this or other ligands and receptors, however, can lead to the collateral offense of other targets including the pre-synaptic calcium channel VGCC that structurally resembles certain tumor antigens [3,4]. A paraneoplastic LEMS can precede the tumor diagnosis by several years [1]. There are no trial-based data on using ICI drugs in cases of pre-existing paraneoplastic syndromes [5], especially if the tumor stage prevents other alternatives.…”

“…We began a symptomatic treatment of the Lambert-Eaton myasthenic syndrome (LEMS) with 3,4-diaminopyridine and pyridostigmine. As 50% of LEMS cases arise in a paraneoplastic context [1], a PET-CT revealed inguinal lymph nodes suspicious for malignancy. A biopsy disclosed lymphogenic metastases of Merkel cell carcinoma, the primary origin of which remained unknown.…”

Pathomechanisms and Clinical Implications of Myasthenic Syndromes Exacerbated and Induced by Medical Treatments

“…Other conditions affecting neuromuscular transmission include Lambert-Eaton myasthenic syndrome (LEMS) ( Titulaer et al, 2011 ), a range of congenital myasthenic syndromes (CMS) due to variants in > 30 different genes (e.g., CHRNE , RAPSN , DOK7 , etc.) ( Vanhaesebrouck and Beeson, 2019 ) and botulism ( Guidon, 2019 ), all of which may be caused by various presynaptic, postsynaptic or combined mechanisms at the NMJ. In addition, drugs or medical treatments may also compromise neuromuscular transmission, the physiology of which will be introduced before outlining the mechanisms underlying the exacerbation of myasthenic syndromes by medical treatments.…”