Diagnostic Criteria for Paraneoplastic Neurologic Syndromes

By Ulrike W. Kaunzner, MD

Synopsis: This study evaluates the effectiveness of the updated 2021 Paraneoplastic Neurologic Syndromes (PNS)-CARE score in diagnosing PNS, highlighting significant improvements in sensitivity and specificity compared to the 2004 criteria, while also addressing limitations related to study design, diagnostic criteria comparison, and the need for further research in diverse patient populations.

Source: Zhao-Fleming H, Rezk M, Shah S, et al. Comprehensive analysis of paraneoplastic neurologic syndrome and PNS-CARE diagnostic criteria in clinical practice. Neurol Neuroimmunol Neuroinflamm. 2024;11(6):e200316.

Paraneoplastic neurologic syndromes (PNS) are a group of rare, immune-mediated disorders associated with different cancer types. These syndromes can involve any part of the nervous system, including the brain, spinal cord, peripheral nerves, and muscles. What makes PNS distinct is that the neurological symptoms often precede the detection of cancer, making early diagnosis and intervention crucial not only for managing neurological symptoms but also for potentially identifying an underlying malignancy.

In many cases, patients with PNS produce specific autoantibodies that can target different types of antigens, often neuronal in origin, which can assist in both diagnosis and prognosis. However, the clinical presentations of PNS can vary widely, and many patients may go undiagnosed or misdiagnosed for years because of a lack of awareness or understanding of these conditions among healthcare providers.

In recent years, advances in the understanding of autoantibodies and their role in PNS have led to the development of new diagnostic criteria, notably the updated 2021 PNS-CARE criteria. These criteria represent a significant step forward in the consistent and accurate diagnosis of PNS, incorporating new information on autoantibodies and clinical syndromes, and addressing some of the limitations of earlier diagnostic systems.

At the Mayo Clinic, 484 patients were identified as suspected cases of PNS. Of these, 212 patients were confirmed to have PNS, with demographics consistent across the group. The study highlights significant improvements in sensitivity from the 2004 criteria (67%) to the 2021 criteria (93%), while specificity remained high (100% for the 2021 criteria).

The 2021 criteria for diagnosing PNS introduced significant advancements over the previous 2004 criteria by incorporating newly identified autoantibodies and syndromes, thus enhancing sensitivity and diagnostic precision. The most common presenting syndromes were rapidly progressive cerebellar syndrome (29%), brainstem encephalitis (14%), and limbic encephalitis (8%). The most common antibodies in the PNS+ cohort were PCA1 (Yo)-immunoglobulin G (IgG) (17%), KLHL11-IgG (16%), and CRMP5-IgG (14%).

Magnetic resonance imaging (MRI) features included fluid-attenuated inversion recovery (FLAIR) hyperintensities in the medial temporal lobes, brainstem, and diencephalon, as well as cerebellar atrophy. The most associated malignancies were small-cell lung carcinoma (17%), breast adenocarcinoma (14%), and seminoma (13%), followed by ovarian adenocarcinoma (10%), non-small-cell lung carcinoma (6%), lymphoma (5%), thymoma (2%), and gastrointestinal cancers (2%).

Notably, the inclusion of newly identified autoantibodies, such as SOX1-IgG and NMDAR-IgG, was a key advancement in the updated criteria. The authors emphasize that the 2021 criteria use a more objective scoring system, reducing reliance on clinician judgment, which can vary based on experience.

The authors elegantly discuss some difficulties of their study design: The retrospective nature of the study introduces biases in patient selection and data interpretation, limiting the generalizability of its findings. The cohort composition reflects a referral bias typical of a tertiary care center specializing in these diseases, such as the Mayo Clinic, potentially skewing the prevalence of certain autoantibodies and syndromes.

Additionally, the lack of a gold standard for diagnosing PNS creates variability and subjectivity, especially when diagnoses rely on neurologist expertise. Although the PNS-CARE score standardizes diagnosis, certainty in classification still can vary depending on the physician’s, and particularly the neurologist’s, experience, affecting sensitivity and specificity.

The authors emphasize the need for further multicenter research to validate and refine the 2021 PNS-CARE criteria, particularly for newly identified antibodies. Comparing the 2004 and 2021 criteria is difficult because of different diagnostic levels (two-tier vs. three-tier systems: possible, probable, and definite) and converting them introduces limitations. Although patients with immune checkpoint inhibitor-related syndromes were excluded from the study, this could be a missed opportunity to explore the effect of cancer immunotherapy on PNS diagnosis.

Commentary

Overall, this study validates the effectiveness of the 2021 PNS-CARE score and provides a more structured approach to diagnosing PNS. However, it also highlights several limitations that need to be addressed in future research. Specifically, the retrospective design, lack of gold standard, and referral bias all limit the generalizability of the findings.

Further multicenter, prospective studies are necessary to refine the criteria and improve the accuracy of PNS diagnosis, especially for patients with atypical presentations. Future studies should incorporate these patients to provide a more comprehensive overview of PNS presentations and the associated diagnostic challenges in the era of immunotherapy. Continuous updates to the diagnostic criteria are essential to ensure that the PNS-CARE score remains applicable across diverse healthcare settings and patient populations.

Ulrike W. Kaunzner, MD, is Assistant Professor of Clinical Neurology, Weill Cornell Medical College.