Population-Based Epidemiology Study of Paraneoplastic Neurologic Syndromes

ObjectivesPopulation-based epidemiologic data for paraneoplastic neurologic syndromes (PNSs) in the United States are lacking. Our objective was to evaluate the incidence, prevalence, and associated morbidity of PNS.MethodsWe performed a population-based epidemiology study in Olmsted County, Minnesota, with patients identified between January 1, 1987, and December 31, 2018, using the medical records linkage system of the Rochester Epidemiology Project (REP) who met the definite/probable 2021 PNS criteria and 2004 PNS criteria. Patients with dermatomyositis and myasthenia gravis with underlying tumors were included. Age- and sex-specific population counts were obtained from REP resources for January 1, 2014 (prevalence denominator) and annually for 1987–2018 (incidence denominator). Morbidity was estimated using disability-adjusted life years (DALYs; years lived with disability [YLD] plus years of life lost [YLL]).ResultsThere were 28 patients with PNS identified (50% female) residing in Olmsted County, Minnesota, with median age at diagnosis of 54.5 (IQR 46.5–69.0) years. All patients had a cancer diagnosis, and 18 (64%) patients were neural autoantibody positive including antineuronal nuclear autoantibody type 1 (ANNA-1/anti-Hu; n = 1), ANNA-2/anti-Ri (n = 1), muscle-type acetylcholine receptor (AChR; n = 6), Purkinje cell cytoplasmic antibody type 1 (PCA-1/anti-Yo; n = 1), kelch-like protein 11 (KLH11; n = 3), collapsin response mediator protein 5 (CRMP-5/anti-CV2; n = 2), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (n = 1), neurofilament light chain (n = 1), leucine zipper 4 (LUZP4; n = 1), and unclassified neural antibodies (n = 1). PNS incidence was 0.6/100,000 person-years and increased over time from 0.4/100,000 person-years (1987–2002) to 0.8/100,000 person-years (2003–2018) (p = 0.06). Prevalence was 5.4/100,000 people. The median follow-up period after PNS diagnosis was 3.1 years (IQR, 1.1–9.9 years). Total disability-adjusted life years (DALYs) for 28 patients with PNS were 472.7 years, based on total years of life lost (YLL) for patients dying between 1987 and 2018 (n = 15) of 445.3 years plus years lived with disability (YLD) 27.4 years.DiscussionPNSs are rare neurologic disorders but are associated with severe morbidity and mortality. The estimated number of prevalent PNS cases in the United States is 17,099, and predicted DALY for all US PNS cases is 292,393 years. Their apparent increasing rate of detection is attributable to increasing physician awareness and availability of serologic testing.

Anti-Ma2 Antibody-Associated Paraneoplastic Neurological Syndromes: A Pilot Study

Paraneoplastic neurologic syndromes (PNSs) are a heterogeneous group of disorders caused by the remote effects of cancer with immune-mediated pathogenesis. Anti-Ma2 antibody was defined as one of the well-characterized onconeural antibodies that could help establish a definite PNS diagnosis. We aimed to report and explore patients with anti-Ma2 antibody-associated paraneoplastic neurologic syndrome (Ma2-PNS) who frequently exhibit sensorimotor neuropathy (SMN) using a new method of factor analysis of mixed data (FAMD). Clinical data from a case series of eight patients with definite diagnoses were retrospectively reviewed. FAMD conducted further analyses with a comprehensive visualization in R software. Our cohort, with a predominance of females (5/8), presented more frequently with SMN (4/8), followed by limbic encephalitis (LE) (3/8). Two patients with LE were found to have a testicular germ-cell tumor and a thymoma, respectively. In addition, a patient who developed chronic SMN was diagnosed with multiple myeloma (MM) involving multiple organs. FAMD exhibited the overall features into a two-dimensional coordinate and located each individual into their corresponding position with high relevance. It provided a clue for determining their potential relationships and predictors. Our findings indicated that Ma2-PNS could frequently involve the peripheral nervous system, MM might be one of its associated cancers with a presentation of chronic SMN, and FAMD might be a clinically valuable tool.

Paraneoplastic myelitis associated with durvalumab treatment for extensive-stage small cell lung cancer

SummaryParaneoplastic neurologic syndromes(PNSs) caused by immune checkpoint inhibitors(ICIs) is rare and requires clinicians to differentiate between disease progression and immune-related adverse effects(irAEs). We hereby report the case of immune-related myelitis accompanied by positive paraneoplastic autoantibodies following durvalumab treatment for extensive-stage small cell lung cancer (ES-SCLC). A 70-year-old Chinese woman with ES-SCLC was administered durvalumab with etoposid-platinum(EP) as first-line treatment. Four cycles after treatment with EP plus ICI, she developed immune-related myelitis with positive paraneoplastic autoantibodies (CV2, SOX1, ZIC4). Spinal MRI showed diffuse abnormal signal shadow in the cervicothoracic spinal cord. She was discontinued for chemotherapy, and treated with high-dose steroids, intravenous immunoglobulin and plasmapheresis, maintenance therapy with steroids resulted in a favorable neurologic outcome. This is the first report of durvalumab-related PNSs. We supposed that the development of paraneoplastic myelitis was causally related to immune activation by durvalumab. Prompt diagnosis and therapeutic intervention are essential for the effective treatment of paraneoplastic myelitis.

Updated Diagnostic Criteria for Paraneoplastic Neurologic Syndromes

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.

Paraneoplastic Cerebellar Degeneration

ObjectiveInvestigate the value of including cerebellar degeneration-related protein 2-like (CDR2L) as a marker in commercial diagnostic tests for anti-Yo–associated paraneoplastic cerebellar degeneration (PCD).MethodsWe included sera and CSF samples from 24 patients with suspected PCD (6 of whom had PCD with underlying gynecologic or breast cancer), who were positive for Yo antibodies using the commercially available, paraneoplastic neurologic syndromes (PNS) 14 Line Assay from Ravo Diagnostika. The samples were further evaluated using the EUROLINE PNS 12 Ag Line Assay and a cell-based assay (CBA) from Euroimmun. For confirmation of positive lineblot results, we used indirect immunofluorescence of rat cerebellar sections. We also tested all samples in 2 assays developed in-house: a CBA for CDR2L and a Western blot analysis using recombinant cerebellar degeneration-related protein 2 (CDR2) and CDR2L proteins.ResultsIn PNS 14 and PNS 12 Ag Line Assays, anti-CDR2 reactivity was observed for 24 (100%) and 20 (83%) of the 24 samples, respectively. Thirteen of 24 subjects (54%) were also positive using the Euroimmun CBA. Rat cerebellar immunofluorescence was the best confirmatory test. In our in-house CBA for CDR2L and Western blot for CDR2 and CDR2L, only the 6 patients with confirmed PCD reacted with CDR2L.ConclusionsCommercially available tests for Yo antibody detection have low specificity for PCD because these assays use CDR2 as antigen. By adding a test for CDR2L, which is the major Yo antigen, the accuracy of PCD diagnosis greatly improved.Classification of EvidenceThis study provides Class III evidence that a CBA for CDR2L accurately identifies patients with PCD.

Serum Tumor Markers in Paraneoplastic Neurologic Syndromes: A Systematic Review of Guidelines

Purpose: Algorithms for the detection of a malignancy in patients with unclear neurologic symptoms of suspicious paraneoplastic origins are not universally applied. Frequently, circulating tumor markers (TMs) are considered a valuable tool for cancer diagnosis in patients with paraneoplastic neurologic syndromes (PNS). Our aim was to extract the recommendations on the use of TMs and onconeural antibodies (Abs) for the diagnosis of malignancies in PNS from clinical practice guidelines and put them forward as evidence in a common framework to facilitate diffusion, dissemination, and implementation.Methods: Systematic literature searches were performed for guidelines on both oncology and PNS published since 2007. Guidelines containing information and recommendations for clinical practice pertaining to the screening and diagnosis of PNS were selected. Information on circulating TMs and onconeural Abs was extracted and synthesized in consecutive steps of increasing simplification.Results: We retrieved 799 eligible guidelines on oncology for the potential presence of information on PNS but only six covered treated diagnosis or the screening of cancer in PNS, which were then selected. Seventy-nine potentially relevant guidelines on PNS were identified as eligible and 15 were selected. Synoptic tables were prepared showing that classical TMs are not recommended for the screening or the diagnosis of a malignancy in patients with a suspected PNS. Neither should onconeural Abs be considered to screen for the presence of a malignancy, although they could be helpful to define the probability of the paraneoplastic origin of a neurologic disorder.Conclusion: The present work of synthesis may be a useful tool in the diffusion, dissemination, and implementation of guideline recommendations, potentially facilitating the decrease of the inappropriate use of circulating biomarkers for cancer screening in the presence of PNS.

Myelitis Presenting Anti-Yo Antibody in a Patient with Prostatic Adenocarcinoma

Antineuronal antibody-associated paraneoplastic neurologic syndromes result from tumor-stimulated autoimmune attacks against components of the nervous system. Paraneoplastic myelopathy associated with Purkinje-cell cytoplasmic autoantibody type 1 (anti-Yo) is extremely rare disorder. It is almost exclusively reported in women with gynecological tumors. Even though few cases of anti-Yo-associated paraneoplastic neurologic syndrome related to other cancers are reported, it is a very uncommon condition, especially in males. The author report here the first case of anti-Yo myelopathy with prostatic adenocarcinoma.