9th June 2023

Types of paraneoplastic neuromuscular syndromes

Lambert-Eaton Myasthenic Syndrome

Lambert-Eaton Myasthenic Syndrome (LEMS) is an immune disorder affecting the calcium channels on the presynaptic membrane of the neuromuscular junction, decreasing the levels of the neurotransmitter acetylcholine. The syndrome can be a primary autoimmune disorder or a paraneoplastic disorder, with no clinical differentiation between the two. It is characterised by proximal muscle weakness, oculo-bulbar weakness, areflexia and autonomic dysfunction. Rarely, it can progress to respiratory failure. Unlike myasthenia gravis, patients present initially with proximal limb weakness moving caudal-cranially, with progression to oculo-bulbar involvement at later stages.

The most common malignancy associated with LEMS is small cell lung cancer, which is found in ~50-60% of all patients with LEMS. Other lung malignancies, lymphoproliferative disorders, thymoma, gynaecological and prostate cancers have all been implicated. Its association with malignancy means that anybody presenting with LEMS should be screened for these cancers, starting with investigations targeted at the diagnosis of a lung malignancy. Treatment is directed at the syndrome itself, using acetylcholinesterase inhibitors or, in more severe cases, immunosuppression or immunoglobulin therapy.

Myasthenia Gravis

Myasthenia Gravis (MG) is distinct from LEMS in its pathophysiology and clinical profile, though there are common features to both that can make them difficult to distinguish. It is an immune disorder affecting the postsynaptic membrane of the neuromuscular junction, with the development of antibodies against acetylcholine receptor or muscle-specific tyrosine kinase. It is characterised by muscle weakness that displays fatiguability (worsening with activity), primarily involving the oculo-bulbar muscles and in late stages respiratory muscles. Limb weakness is rare in comparison to LEMS, and the progression of weakness moves cranio-caudally.

Thymoma is the predominant malignancy associated with MG, found in 15-30% of all MG diagnoses. The thymus is an endocrine organ involved in T cell maturation and proliferation, and as such, myasthenia gravis due to malignancy within this organ is not technically a paraneoplastic syndrome, as it occurs as a direct result of endocrine organ dysfunction. However, its synonymity with thymoma makes it worth a mention, as a diagnosis of MG will often lead to a diagnosis of thymoma. The management of the resultant MG is either through treatment of the thymoma (usually surgical resection) or with systemic treatment such as anticholinesterase inhibitors or immunosuppression.

Polymyositis

Polymyositis is a rare immune disorder affecting muscle fibres that express MHC class 1 antigens, with infiltration of the tissue by cytotoxic T cells. It is characterised by girdle muscle weakness (shoulders and hips), myalgia, fatigue and upper aerodigestive tract muscle weakness, though it can affect any muscle group. Patients can also present with systemic symptoms such as fever and weight loss. Biochemical abnormalities include elevated creatine kinase (CK) and myoglobinuria. For confirmation of the diagnosis a muscle biopsy is required.

Paraneoplastic polymyositis is associated most with non-Hodgkin lymphoma, bladder and lung malignancies; however, the association is not particularly strong, with <10% of patients with polymyositis subsequently being diagnosed with a malignancy. Management is directed both at the treatment of the underlying cancer, and the management of the syndrome with steroids or immunosuppressive therapy. Paraneoplastic polymyositis has a poorer prognosis than its non-paraneoplastic disorder, though whether that is to do with factors associated with the underlying cancer and its morbidity is unclear.