1 Introduction
Recent years have shown that immune checkpoint inhibitors (ICIs) increased survival and long-term remissions, even in patients with extensive metastatic cancer (, ). However, the resulting increase in T cell effector function often results in immune-related adverse events (irAEs), some affecting the nervous system (nirAEs) (, ), a subset of which constitute classical paraneoplastic neurological syndromes (PNSs) (). High-risk neurological phenotypes of PNSs include encephalomyelitis, limbic encephalitis, rapidly progressive cerebellar syndrome, opsoclonus myoclonus syndrome, subacute sensory neuronopathy, gastrointestinal pseudo-obstruction (GIPO, enteric neuropathy), and Lambert-Eaton myasthenic syndrome (). We have previously reported two cases of patients with small-cell lung cancer (SCLC) who developed PNSs induced by ICIs (), which prompted our focus on studies related to irAEs of ICIs, particularly nirAEs. In this context, we were greatly interested in the recent publication by Qian et al., titled “Immune-related intestinal pseudo-obstruction caused by immune checkpoint inhibitors: case report,” which describes a patient with hepatocellular carcinoma (HCC) developed intestinal pseudo-obstruction after treatment with pembrolizumab (). We appreciate the authors for sharing their valuable clinical insights and experiences. We would like to propose adding some considerations regarding their paper, which we hope to discuss with the authors.
2 Commentary and discussion
The authors regard this patient’s situation as immune therapy-related intestinal obstruction. However, we propose an alternative interpretation of this patient’s intestinal obstruction, which was a PNS induced by ICIs therapy.
Distinguishing between irAEs and PNSs presents significant challenges, and most clinical trial reports do not clearly define whether some of the observed nirAEs are in fact PNSs (). The 2021 expert panel recommends that the diagnosis of PNS be established using the PNS-Care Score, which considers the clinical phenotype, the presence or absence of neuronal antibodies, and the presence or absence of cancer, while systematically excluding other alternative etiologies (). In patients receiving ICIs when neurological symptoms occur, it is essential to assess both the presence of neuronal antibodies and the PNS-Care Score to ascertain whether the symptoms are attributable to an irAE or a PNS (). Based on the score, this case fulfilled the diagnostic criteria for probable PNS. There were no abnormalities in the intestinal tract prior to ICI administration, and the PNS manifested after six cycles of ICI therapy, with no other causes of intestinal obstruction identified. Notably, according to the 2004 diagnostic criteria for PNS, when a cancer patient exhibits symptoms of a nirAE after receiving ICIs, these symptoms fulfill the criteria for PNS if they are identical to classical PNS symptoms, regardless of the presence of neuronal autoantibodies (, ). The 2021 criteria refined diagnostic accuracy through a stringent scoring system, but at the cost of sensitivity. In this case, we inferred that the PNS was induced by the ICI. Regrettably, the patient was not tested for neuronal antibodies, which could have provided further clarity on the diagnosis.
Enteric neuropathy, also known as paraneoplastic gastrointestinal paresis or chronic intestinal pseudo-obstruction, is a high-risk neurological phenotype of PNSs, usually associated with anti-Hu antibody (Hu-Ab) and SCLC (). Reports have also indicated the presence of Hu-Ab in patients with HCC (). HCC with paraneoplastic GIPO is a rare presentation. However, nirAEs such as encephalitis () and Guillain-Barré syndrome () have been reported in HCC patients after treatment with ICIs. The pathology of GIPO is that Hu-Ab causes irreversible dysfunction of the enteric plexus along with lymphoplasmacytic infiltration (). There are limited accounts of GIPO potentially resulting from ICI-induced PNS along with positive anti-Hu antibodies. Kang et al. described a case of SCLC methylprednisolone for sintilimab-induced encephalitis that was started a few days before the onset of GIPO, cerebrospinal fluid Hu-Ab positive, and it is possible that GIPO improved because of early therapeutic intervention (). In another report by Saitou et al., a case of SCLC with GIPO elicited by durvalumab and serum Hu-Ab was positive. We have recently reported a similar case (). However, corticosteroid treatment did not improve the GIPO (). Post-immune checkpoint inhibitor PNSs are usually unresponsive to corticosteroids and lead to severe neurological disability and high mortality (). Anecdotal reports and small case series indicate that patients can have symptom improvements with intravenous immunoglobulin(IVIG) therapy (). Neuronal antibodies have important implications for the early diagnosis of PNSs. The potential benefits of conducting neural antibody screening in cancer patients likely to experience PNSs before initiating ICIs merit further investigation ().
In summary, it is important to recognize that GIPO is one of the high-risk phenotypes of PNS. From the viewpoint of neurologists, we propose an alternative diagnosis to enhance the understanding of ICI treatment-induced PNS. The PNS-Care Score may help differentiate irAEs from PNS. Furthermore, routine neuronal antibody testing is recommended to improve the diagnosis of PNSs occurring in the context of ICI therapy for all patients who develop neurologic irAEs that resemble high or intermediate risk PNS (). Patients experiencing such toxicities should be evaluated by neurologists with expertise in neuroimmunology.
Statements
Author contributions
J-QX: Writing – original draft, Writing – review & editing. JF: Writing – original draft, Writing – review & editing. G-QS: Conceptualization, Investigation, Writing – review & editing. HS: Conceptualization, Supervision, Writing – review & editing.
Funding
The author(s) declare that no financial support was received for the research and/or publication of this article.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declare that no Generative AI was used in the creation of this manuscript.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1
GrausFVogrigAMuniz-CastrilloSAntoineJGDesestretVDubeyDet al. Updated diagnostic criteria for paraneoplastic neurologic syndromes. Neurol Neuroimmunol Neuroinflamm. (2021) 8:e1014. doi: 10.1212/NXI.0000000000001014
2
DuongSLPrussH. Paraneoplastic autoimmune neurological syndromes and the role of immune checkpoint inhibitors. Neurotherapeutics. (2022) 19:848–63. doi: 10.1007/s13311-022-01184-0
3
GrausFDalmauJ. Paraneoplastic neurological syndromes in the era of immune-checkpoint inhibitors. Nat Rev Clin Oncol. (2019) 16:535–48. doi: 10.1038/s41571-019-0194-4
4
FarinaAVillagran-GarciaMVogrigAZekeridouAMuniz-CastrilloSVelascoRet al. Neurological adverse events of immune checkpoint inhibitors and the development of paraneoplastic neurological syndromes. Lancet Neurol. (2024) 23:81–94. doi: 10.1016/S1474-4422(23)00369-1
5
ShiGQLianHNWangHXiaJQMaLJZhouJ. Case report: immune checkpoint inhibitor-induced paraneoplastic neurological syndrome in two patients: A case series. Front Oncol. (2024) 14:1404829. doi: 10.3389/fonc.2024.1404829
6
QianYZhiZAiJKangLQiuGHuangXet al. Immune-related intestinal pseudo-obstruction caused by immune checkpoint inhibitors: case report. Front Oncol. (2024) 14:1415117. doi: 10.3389/fonc.2024.1415117
7
GrausFDelattreJYAntoineJCDalmauJGiomettoBGrisoldWet al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry. (2004) 75:1135–40. doi: 10.1136/jnnp.2003.034447
8
MatsuiTHoriYNaganoHEguchiHMArubashiSWadaHet al. Poorly differentiated hepatocellular carcinoma accompanied by anti-hu antibody-positive paraneoplastic peripheral neuropathy. Pathol Int. (2015) 65:388–92. doi: 10.1111/pin.12304
9
SagongMKimKTJangBK. Atezolizumab- and bevacizumab -induced encephalitis in a patient with advanced hepatocellular carcinoma: A case report and literature review. J Cancer Res Clin Oncol. (2024) 150:397. doi: 10.1007/s00432-024-05918-9
10
YeLYueWRShiHLiJRQunYY. Case report: successful immune checkpoint inhibitor rechallenge after sintilimab-induced guillain-barre syndrome. Front Immunol. (2025) 16:1546886. doi: 10.3389/fimmu.2025.1546886
11
SaitouAShioyaMNagahisaYHaseyamaANiwaRTsuchimotoJet al. Small-cell lung carcinoma with gastrointestinal pseudo-obstruction as a paraneoplastic neurological syndrome elicited by an immune checkpoint inhibitor. Intern Med. (2024) 63:2059–62. doi: 10.2169/internalmedicine.2648-23
12
KangKZhengKZhangY. Paraneoplastic encephalitis and enteric neuropathy associated with anti-hu antibody in a patient following immune-checkpoint inhibitor therapy. J Immunother. (2020) 43:165–8. doi: 10.1097/CJI.0000000000000314
13
ShiGQLianHNWangXXiaJQWangHMaLJet al. Immune checkpoint inhibitor-induced anti-hu antibody-associated gastrointestinal pseudo-obstruction: A case report and literature review. Front Immunol. (2025) 16:1555790. doi: 10.3389/fimmu.2025.1555790
Summary
Keywords
immune checkpoint inhibitor, paraneoplastic neurologic syndromes, gastrointestinal pseudo-obstruction, PNSs, PNS-Care Score
Citation
Xia J-Q, Fan J, Shi G-Q and Sun H (2025) Commentary: Immune-related intestinal pseudo-obstruction caused by immune checkpoint inhibitors: case report. Front. Oncol. 15:1543608. doi: 10.3389/fonc.2025.1543608
Received
11 December 2024
Accepted
08 May 2025
Published
23 May 2025
Volume
15 - 2025
Edited by
Judith Raimbourg, Institut de Cancérologie de l’Ouest (ICO), France
Reviewed by
Lila Autier, Institut de Cancérologie de l’Ouest (ICO), France
Updates
Copyright
© 2025 Xia, Fan, Shi and Sun.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Guang-Qing Shi, 576396342@qq.com; Hao Sun, sunhao223@163.com
†These authors have contributed equally to this work
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.