Autoimmune phenomena: extended abstract for thymoma and clinical neurology

Background

Although relatively rare, thymomas are associated with a variety of autoimmune and paraneoplastic phenomena, with the neuromuscular transmission disorder myasthenia gravis (MG) being the most common. However, a variety of other peripheral and central nervous system disorders have been described in the context of thymoma (1). It is believed that aberrant T cell activity mediated by thymic neoplasia generates dysfunctional autoreactive mechanisms that lead to this wide variety of neurologic disorders.

Methods

Case series literature was reviewed based on a PubMed search that merged autoimmune and paraneoplastic neurologic disorders with thymoma. Autoantibody associations and therapeutic approaches beyond thymoma resection and systemic tumor management were also reviewed for the various peripheral and central nervous system disorders.

Results

From the standpoint of neurologic disorders linked to thymoma, MG predominates, representing one-third to one-half of all associations. B2 thymomas are the most common histologic type, and autoantibodies to the acetylcholine receptor are present in nearly all these MG cases. The second most common association is most likely the central nervous system disorder of limbic encephalitis/encephalomyelitis, associated with autoantibodies to ANNA-1 and Ma2. Cognitive, neuropsychiatric, spinal cord and even peripheral nerve involvement can occur with this syndrome, with immunosuppressive therapy (IST), plasma exchange (PE), intravenous immunoglobulin (IVIg), and B-cell depletion representing the avenues of therapy. Other central nervous system disorders include brainstem encephalitis (ANNA-2 and Ma2 autoantibodies), opsoclonus-myoclonus (ANNA-1 or 2, Ma1 or 2, or Yo autoantibodies), cerebellar degeneration (Yo or ANNA-1 autoantibodies), and neuromyelitis optica (NMO; AQPR, MOG, or ANNA-1 autoantibodies). Management of these disorders is similar to the approach for limbic encephalitis with the exception that C5 complement inhibitors, and anti-IL6 receptor and anti-CD19 agents are approved for NMO (2).

The spectrum of peripheral nervous system disorders associated with thymoma is wide. In addition, to MG, Lambert Eaton myasthenic syndrome (LEMS) associated with the typical autoantibodies to the P/Q voltage-gated calcium channel has been reported with thymoma. Other conditions include cranial and polyneuropathies (GAD, amphiphysin, glycine receptor autoantibodies), autonomic neuropathy (neuronal acetylcholine receptor and CRMP5 autoantibodies), rippling muscle disease (neuronal acetylcholine receptor autoantibodies if thymomatous MG also present), neuromyotonia in the form of either Isaacs’ or Morvan’s syndrome (LGI1/CASPR2 autoantibodies), and inflammatory myopathies including granulomatous myositis (3). Of note, rippling muscle disease can also be inherited, with caveolin-3 gene mutations (4), and both stiff person and Morvan’s syndromes do cross over to involve the central nervous system. Beyond the specialized symptomatic and immunotherapy used for MG and LEMS, management of these other disorders typically involves IST, PE and IVIg. Stiff person syndrome can respond to benzodiazepines and anti-spasticity agents such as baclofen, while acetylcholinesterase inhibitors and agents used for orthostatic hypotension such as midodrine can help with autonomic neuropathies (5). Anti-epileptic agents such as phenytoin and carbamazepine have been used for many years to ameliorate symptoms of muscle stiffness in neuromyotonia.

Conclusions

Although thymomas are an uncommon form of neoplasia, they are frequently associated with a wide variety of autoimmune disorders and paraneoplastic syndromes, with the peripheral and central nervous systems often involved. Although the association with MG is well recognized, it is important for clinicians from a variety of specialty backgrounds to be aware of these disorders so that appropriate chest imaging can be ordered. For instance, some studies suggest that when autoimmune or paraneoplastic phenomena herald the presence of an underlying thymoma, the risk of tumor recurrence following therapy is lowered and clinical outcomes improve. Although the data on prognosis remains mixed, earlier diagnosis and management of thymoma in general can positively influence survival and minimize adverse events. Meanwhile, immunotherapy and other treatment modalities can favorably impact most autoimmune and paraneoplastic neurologic manifestations.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Malgorzata Szolkowska, Chul Kim, Mohammad Ashraghi, and Claudio Silva) for “The Series Dedicated to the 13th International Thymic Malignancy Interest Group Annual Meeting (ITMIG 2023)” published in Mediastinum. The article has undergone external peer review.

Peer Review File: Available at https://med.amegroups.com/article/view/10.21037/med-23-64/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-23-64/coif). “The Series Dedicated to the 13th International Thymic Malignancy Interest Group Annual Meeting (ITMIG 2023)” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

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4. Catteruccia M, Sanna T, Santorelli FM, et al. Rippling muscle disease and cardiomyopathy associated with a mutation in the CAV3 gene. Neuromuscul Disord 2009;19:779-83. [Crossref] [PubMed]
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