Research report: Neurological syndrome with CSF anti-Hu positivity during serplulimab therapy in extensive-stage small-cell lung cancer: a case report

A 52-year-old woman with extensive-stage small-cell lung cancer developed a severe neurological syndrome during treatment with the immune checkpoint inhibitor serplulimab, and cerebrospinal fluid testing revealed anti-Hu antibodies, according to a case report published in Frontiers in Oncology. The case highlights a difficult diagnostic gray zone: when neurological symptoms emerge during checkpoint inhibitor therapy in a cancer type already prone to paraneoplastic autoimmunity, clinicians must decide whether they are seeing drug-related neurotoxicity, tumor-driven autoimmunity, or an overlap of both. The patient had stage IV extensive-stage small-cell lung cancer, a disease in which immune checkpoint inhibitors have improved outcomes but which is also strongly associated with anti-Hu-associated paraneoplastic neurological syndromes.

She received four cycles of serplulimab combined with etoposide and carboplatin, followed by five cycles of serplulimab maintenance therapy. It was during this maintenance phase that the first warning signs appeared: anorexia, weight loss, and alternating constipation and diarrhea. The gastrointestinal symptoms were soon followed by progressive neurological deterioration.

The patient developed memory impairment, somnolence, cognitive dysfunction, and gait instability. Cerebrospinal fluid examination showed a mild increase in mononuclear cells, a sign of inflammation within the central nervous system, and a cell-based assay detected anti-Hu antibody in the cerebrospinal fluid at a titer of 1:100. Notably, the authors report that no residual specimen was available for independent confirmatory testing, a limitation that shaped how the findings could be interpreted.

Brain magnetic resonance imaging added a striking anatomical clue. The scans revealed newly developed bilateral paramedian thalamic abnormalities, while diffusion-weighted imaging and apparent diffusion coefficient mapping showed no evidence of acute cerebral infarction, ruling out stroke as the cause. To classify the syndrome, the team applied the 2021 PNS-Care criteria, a diagnostic framework for paraneoplastic neurological syndromes.

The clinical presentation was categorized as an intermediate-risk phenotype. If the reported cerebrospinal fluid anti-Hu result is accepted, the recalculated PNS-Care score would reach 9, corresponding to the definite paraneoplastic neurological syndrome category. The authors caution, however, that this interpretation is limited by the absence of orthogonal antibody confirmation, meaning the result was not verified by a second, methodologically independent test.

Treatment proceeded on two fronts. Serplulimab was permanently discontinued, and the patient received corticosteroids plus intravenous immunoglobulin, followed by an individualized intravenous immunoglobulin maintenance regimen. The response was substantial but incomplete.

On standardized assessments, the Montreal Cognitive Assessment improved from 11 out of 30 to 24, the Mini-Mental State Examination rose from 12 to 22, and the modified Rankin Scale, which measures disability, improved from 3 to 2. Residual cognitive impairment persisted despite the intervention. Meanwhile, the underlying cancer responded remarkably well to the therapy that was ultimately withdrawn.

A complete response was first documented on July 20, 2021, and radiological complete response remained confirmed through May 2023, with no subsequently documented clinical tumor progression before the patient's death in January 2025. A late complication added a further layer of complexity. In 2024, the patient developed intestinal pseudo-obstruction, a condition in which the bowel fails to propel its contents despite no mechanical blockage, and she required segmental colectomy.

Histopathological examination of the resected tissue demonstrated lymphocytic inflammation surrounding the myenteric plexus, the network of nerves that controls gut motility. The authors note that this gastrointestinal episode raised the possibility of enteric nervous system involvement, but its etiology remained uncertain. The report illustrates why anti-Hu antibodies complicate the interpretation of neurological events during checkpoint inhibitor therapy.

It also demonstrates the practical value of cerebrospinal fluid analysis, brain imaging, and structured diagnostic criteria in separating overlapping etiologies, while acknowledging that a single positive antibody assay, without confirmatory testing, cannot by itself settle whether a syndrome is paraneoplastic, treatment-induced, or both at once.

Subject of Research: Anti-Hu-positive neurological syndrome emerging during serplulimab therapy for extensive-stage small-cell lung cancer

Article Title: Neurological syndrome with CSF anti-Hu positivity during serplulimab therapy in extensive-stage small-cell lung cancer: a case report

Article References: Wang, L., Zhao, Y., Fan, B., Sang, S., Li, X., Yu, J., & Bai, Y. (2026). Neurological syndrome with CSF anti-Hu positivity during serplulimab therapy in extensive-stage small-cell lung cancer: a case report. Frontiers in Oncology, 16, Article 1974779. https://doi.org/10.3389/fonc.2026.1974779

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.1974779

Keywords: anti-Hu antibody, immune checkpoint inhibitor, serplulimab, small-cell lung cancer, paraneoplastic neurological syndrome, neurological toxicity, cerebrospinal fluid, intestinal pseudo-obstruction, intravenous immunoglobulin, case report, PNS-Care criteria, thalamic abnormalities