Updated Diagnostic Criteria for Paraneoplastic Neurologic Syndromes

Abstract

ObjectiveThe contemporary diagnosis of paraneoplastic neurologic syndromes (PNSs) requires an increasing understanding of their clinical, immunologic, and oncologic heterogeneity. The 2004 PNS criteria are partially outdated due to advances in PNS research in the last 16 years leading to the identification of new phenotypes and antibodies that have transformed the diagnostic approach to PNS. Here, we propose updated diagnostic criteria for PNS.MethodsA panel of experts developed by consensus a modified set of diagnostic PNS criteria for clinical decision making and research purposes. The panel reappraised the 2004 criteria alongside new knowledge on PNS obtained from published and unpublished data generated by the different laboratories involved in the project.ResultsThe panel proposed to substitute “classical syndromes” with the term “high-risk phenotypes” for cancer and introduce the concept of “intermediate-risk phenotypes.” The term “onconeural antibody” was replaced by “high risk” (>70% associated with cancer) and “intermediate risk” (30%–70% associated with cancer) antibodies. The panel classified 3 levels of evidence for PNS: definite, probable, and possible. Each level can be reached by using the PNS-Care Score, which combines clinical phenotype, antibody type, the presence or absence of cancer, and time of follow-up. With the exception of opsoclonus-myoclonus, the diagnosis of definite PNS requires the presence of high- or intermediate-risk antibodies. Specific recommendations for similar syndromes triggered by immune checkpoint inhibitors are also provided.ConclusionsThe proposed criteria and recommendations should be used to enhance the clinical care of patients with PNS and to encourage standardization of research initiatives addressing PNS.

Case Report: A False Negative Case of Anti-Yo Paraneoplastic Myelopathy

“…Standard clinical autoantibody testing fails to identify a diagnostic antibody in up to one third of patients with PNDs, some of whom may harbor undetected classified autoantibodies (25). Few laboratories use multiple modalities upon initial screening for paraneoplastic autoantibodies, and single modality screening is known to risk false positive and negatives for some antibodies including anti-Yo (31). We previously showed that PhIP-Seq significantly enriched CDR2L and/or CDR2 peptides in all 36 screened cases of clinically diagnosed anti-Yo PCD (51 of 53 biospecimens) with no difference in sensitivity between serum and CSF (7).…”

Update on Paraneoplastic Cerebellar Degeneration

“…This landmark study demonstrated the autoimmune nature of PCD and paved the way for the discovery of further antibodies in patients with PCD such as Hu-, Ri-, and Ma2-antibodies and their association with specific malignancies [ 1 ]. Based on these findings, PCD was defined as a remote effect of cancer with an autoimmune pathogenesis [ 6 ]. The autoimmune response is thought to be elicited when proteins restricted to immune privileged neurons are presented by the underlying malignancy [ 7 , 8 ].…”

“…In the majority of patients with PCD, cytotoxic T-cell responses seem to play a crucial role [ 8 , 9 , 10 ]. Associated antibodies are directed against intracellular antigens and may not be directly pathogenic but rather biomarkers for the condition [ 6 ]. In some patients with PCD, however, antibodies against neural cell surface or synaptic proteins, e.g., P/Q-type voltage-gated calcium channels-(VGCC) and metabotropic glutamate receptor 1-(mGluR1) antibodies, can be detected [ 11 , 12 , 13 ].…”

“…Malignancies typically associated with PCD are small cell lung cancer (SCLC), gynecologic and breast cancer, as well as Hodgkin lymphoma [ 18 ]. By definition, diagnosis of PCD requires the exclusion of a direct (e.g., metastasis) or indirect (e.g., coagulopathy) cancer involvement as well as the exclusion of other metabolic, iatrogenic, or infectious causes [ 3 , 6 ]. Diagnostic criteria and screening recommendations have been published, which should guide clinical decision making when a patient presents with a rapidly progressive cerebellar syndrome [ 6 ].…”

“…By definition, diagnosis of PCD requires the exclusion of a direct (e.g., metastasis) or indirect (e.g., coagulopathy) cancer involvement as well as the exclusion of other metabolic, iatrogenic, or infectious causes [ 3 , 6 ]. Diagnostic criteria and screening recommendations have been published, which should guide clinical decision making when a patient presents with a rapidly progressive cerebellar syndrome [ 6 ]. When PCD is suspected, treatment should be initiated as soon as possible and includes acute immunotherapy, oncologic treatment, and maintenance immunotherapy.…”