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PurposeParaneoplastic neurologic disease (PND) is an aberrant immune-mediated response against the nervous system triggered by malignancy. Given the rarity, a paucity of data describing breast cancer-related PND (BC-PND) exists; we sought to further examine this specific patient population.MethodsWe retrospectively identified patients at our institution from 1997 to 2016 with BC-PND. Retrospective review with a descriptive analysis determined factors associated with PND and BC, which were compared to national breast cancer median of age (61 years) and average stage at diagnosis (60% local disease).ResultsBC-PND was diagnosed in 56 female patients at a median age of 52.8 years. Only 20% of invasive cancer patients had local disease. The majority of patients were hormone receptor positive and Her2 negative. Neurological symptoms presented prior to BC diagnosis in 57.1% of patients. Of all patients, 30 (53.6%) had autoantibodies detected: Purkinje Cell Cytoplasmic Autoantibody Type-1 (PCA-1[anti-Yo]), n = 10; amphiphysin-IgG, n = 9; Anti-Neuronal Nuclear Autoantibody Type-2 (ANNA-2[anti-Ri]), n = 5; and others, n = 6. The most common neurologic findings were cerebellar ataxia, myelopathy, and myopathy. Immunotherapy benefit was found to be robust (21.6%), mild to moderate (52.9%), absent (17.6%), or indeterminate (7.8%).ConclusionsPND symptoms often presented prior to BC diagnosis, with the BC biologic subtype characteristics typical of the general BC population. BC diagnoses were often made at younger ages than that of the general BC population and with later-stage disease. Roughly 75% of patients benefited from immunotherapy. These data provide helpful information to providers treating this population of patients.

A paraneoplastic neurological syndrome (PNS) describes the neurological complications of a malignancy that are not due to local or metastatic effects. PNS are often associated with the presence of serum paraneoplastic neuronal antibodies (PNAb). However, the frequency of identification of PNAb in hospitals and laboratories is rarely reported. This information will help plan and deliver diagnostic and clinical services. To review the frequency, type and association with cancer of PNAb in a tertiary neurological centre over 9 years. Retrospective observational study in an adult and paediatric population. Walton Centre NHS Foundation Trust (WCFT), Liverpool, United Kingdom. Patients seen at the WCFT who tested positive for PNAb with a ‘high risk’ for cancer (HR PNAb) from April 2012 - April 2021. Antibodies detected, neurological diagnosis, presence of cancer. 1.6 % (107/6863) of the samples tested were positive for HR PNAb. We estimate the incidence of patients with HR PNAb seropositivity in the population to be 3.8/million/year. 20/33 patients for whom clinical details were available were found to have an associated malignancy. Crucially it was the initial detection of ‘high risk’ antibodies that led to the search and subsequent detection of cancer in 10 of the patients in this study. This is the first UK study to provide an estimated minimum incidence rate of HR PNAb from a defined geography and population. The inclusion of intermediate and low risk antibodies will make this number even higher. PNAb testing remains a vital investigation in neurology and for the early detection of cancer. •This is a UK based study investigating the incidence of high risk paraneoplastic antibodies in a defined population over nine years.•Our data suggests that the estimated incidence of patients with HR PNAb seropositivity in our population is 3.8/million/year.

Recently, the paraneoplastic neurologic syndrome (PNS) diagnostic criteria have received a major update with a new score system over the past 16 years. We aimed to evaluate the diagnostic performance and clinical utility in China. An eligible cohort of 113 Chinese patients diagnosed with PNSs from the Second Affiliated Hospital School of Medicine Zhejiang University and published data were enrolled retrospectively. Data including clinical phenotype, antibody type, the presence of cancer, and duration of follow-up were reviewed and re-evaluated to classify the diagnostic levels for the 2004 and 2021 PNS criteria. The performances of these 2 criteria were compared. The critical parameters of antibody and cancer for the updated criteria were further explored. The cohort consisted of 69 males and 44 females with a median age of 60 years. Limbic encephalitis (23, 20.4%), anti-Hu antibody (32, 28.3%), and small-cell lung cancer (32, 28.3%) were the most common clinical phenotype, detected antibody, and concomitant cancer, respectively. A total of 97 (85.8%) patients were diagnosed with definite PNS according to the 2004 criteria: only 42.3% (41/97) fulfilled the 2021 criteria, while the remaining 40, 14, and 2 re-diagnosed with probable PNS, possible PNS, and non-PNS. The requirement of cancers consistent with antibody and phenotype increased the specificity and thus greatly enhanced the accuracy of the 2021 criteria. The updated criteria for PNS emphasized the consistency between cancer phenotype and antibody and showed a better diagnostic value. A better diagnostic yield could benefit disease management.

The detection of antibodies targeting neuronal antigens is a keystone for the diagnosis of autoimmune encephalitis (AE) and paraneoplastic neurological syndromes (PNS). This study aimed to compare the performance of a commercial tissue-based immunofluorescence assay (cIFA) to that of an inhouse IFA (hIFA) for the screening of autoantibodies targeting neuronal surface proteins in the cerebrospinal fluid (CSF) and to compare the performance of commercial cell-based assays (cCBA) to that of in-house CBA (hCBA) in serum samples. Between March and June 2021, 2135 CSF samples and 524 serum samples from 2283 patients referred to the French Reference Center on PNS and AE were prospectively included. CSF samples were all tested using 3 different assays: cIFA, hIFA, and cCBA. Serum samples were all tested using at least 1 cCBA and 1 hCBA for the detection of the following autoantibodies: CASPR2, GABABR, and LGI1. Among the 2135 CSF tested, 93 (4.4%) were positive using both cIFA and hIFA, 1 (0.05%) was positive using only cIFA, and 6 (0.3%) were positive using only hIFA. Among the double-positive samples, 37 (39.8%) were positive using cCBA for the following autoantibodies: anti-NMDAR (n=16), -LGI1 (n=8), -CASPR2 (n=7), -GABABR (n=5), and -DPPX (n=1) autoantibodies. The remaining 56 (60.2%) double-positive samples were negative using cCBA and additional tests were performed to identify the autoantibodies according to the pattern observed on the IFA. The only sample positive using cIFA but negative using hIFA was positive for anti-LGI1 autoantibodies using cCBA. Among the 6 samples negative using cIFA but positive using hIFA, only one sample was positive with cCBA for anti-NMDAR autoantibodies. These data indicate that, in CSF, cIFA and hIFA performed similarly for the detection of autoantibodies targeting neuronal surface proteins.Regarding serum samples, cCBA and hCBA were both positive in 3 patients for CASPR2, 4 patients for LGI1, and 1 patient for GABABR. A positive cCBA and negative hCBA was observed in 2 patients for LGI1 and 4 patients for GABABR. A lack of specificity of GABABR cCBA is suspected as CSF explorations were negative in 3 of these patients and none presented clinical features highly suggestive of AE.

Background and purpose Paraneoplastic neurological autoimmunity is well described with small‐cell lung cancer, but information is limited for other neuroendocrine neoplasms (NENs). Methods Adult patients with histopathologically confirmed non‐pulmonary NENs, neurological autoimmunity within 5 years of NEN diagnosis, and neural antibody testing performed at the Mayo Clinic Neuroimmunology Laboratory (January 2008 to March 2023) were retrospectively identified. Control sera were available from patients with NENs without neurological autoimmunity (116). Results Thirty‐four patients were identified (median age 68 years, range 31–87). The most common primary tumor sites were pancreas (nine), skin (Merkel cell, eight), small bowel/duodenum (seven), and unknown (seven). Five patients received immune checkpoint inhibitor (ICI) therapy before symptom onset; symptoms preceded cancer diagnosis in 62.1% of non‐ICI‐treated patients. The most frequent neurological phenotypes (non‐ICI‐treated) were movement disorders (12; cerebellar ataxia in 10), dysautonomia (six), peripheral neuropathy (eight), encephalitis (four), and neuromuscular junction disorders (four). Neural antibodies were detected in 55.9% of patients studied (most common specificities: P/Q‐type voltage‐gated calcium channel [seven], muscle‐type acetylcholine receptor [three], anti‐neuronal nuclear antibody type 1 [three], and neuronal intermediate filaments [two]), but in only 6.9% of controls. Amongst patients receiving cancer or immunosuppressive therapy, 51.6% had partial or complete recovery. Outcomes were unfavorable in 48.3% (non‐ICI‐treated) and neural autoantibody positivity was associated with poor neurological outcome. Discussion Neurological autoimmunity associated with non‐pulmonary NENs is often multifocal and can be treatment responsive, underscoring the importance of rapid recognition and early treatment.

Objectives To investigate the association between human leukocyte antigen (HLA) and paraneoplastic neurological syndromes (PNS) with Hu antibodies, and potential specificities according to clinical presentation and cancer status. Methods HLA genotypes at four-digit resolution were imputed from available genome-wide association data. Allele carrier frequencies were compared between patients (whole cohort, n  = 100, and according to clinical presentation and cancer status) and matched healthy controls ( n  = 508) using logistic regression controlled by the three main principal components. Results The clinical presentation of 100 anti-Hu patients involved the central nervous system (28, 28%), the peripheral nervous system (36, 36%) or both combined (36, 36%). Cancer diagnosis was certain in 75 (75%). HLA association analyses revealed that anti-Hu PNS patients were more frequently carriers of DQA1*05:01 (39% vs. 19%, OR = 2.8 [1.74–4.49]), DQB1*02:01 (39% vs. 18%, OR = 2.88 [1.79–4.64]) and DRB1*03:01 (41% vs. 19%, OR = 2.92 [1.80–4.73]) than healthy controls. Remarkably, such DR3  ~  DQ2 association was absent in patients with pure central involvement, but more specific to those manifesting with peripheral involvement: DQA1*05:01 (OR = 3.12 [1.48–6.60]), DQB1*02:01 (OR = 3.35 [1.57–7.15]) and DRB1*03:01 (OR = 3.62 [1.64–7.97]); being even stronger in cases with sensory neuropathy, DQA1*05:01 (OR = 4.41 [1.89–10.33]), DQB1*02:01 (OR = 4.85 [2.04–11.53]) and DRB1*03:01 (OR = 5.79 [2.28–14.74]). Similarly, DR3  ~  DQ2 association was only observed in patients with cancer. Discussion Patients with anti-Hu PNS show different HLA profiles according to clinical presentation and, probably, cancer status, suggesting pathophysiological differences.

Encephalitis is parenchymal brain inflammation due to infectious or immune-mediated processes. However, in 15-60% the cause remains unknown. This study aimed to determine if the cytokine/chemokine-mediated host response can distinguish infectious from immune-mediated cases, and whether this may give a clue to aetiology in those of unknown cause. We measured 38 mediators in serum and cerebrospinal fluid (CSF) of patients from the Health Protection Agency Encephalitis Study. Of serum from 78 patients, 38 had infectious, 20 immune-mediated, and 20 unknown aetiology. Of CSF from 37 patients, 20 had infectious, nine immune-mediated and eight unknown aetiology. Heat-map analysis of CSF mediator interactions was different for infectious and immune-mediated cases, and that of the unknown aetiology group was similar to the infectious pattern. Higher myeloperoxidase (MPO) concentrations were found in infectious than immune-mediated cases, in serum and CSF (p = 0.01 and p = 0.006). Serum MPO was also higher in unknown than immune-mediated cases (p = 0.03). Multivariate analysis selected serum MPO; classifying 31 (91%) as infectious (p = 0.008) and 17 (85%) as unknown (p = 0.009) as opposed to immune-mediated. CSF data also selected MPO classifying 11 (85%) as infectious as opposed to immune-mediated (p = 0.036). CSF neutrophils were detected in eight (62%) infective and one (14%) immune-mediated cases (p = 0.004); CSF MPO correlated with neutrophils (p<0.0001). Mediator profiles of infectious aetiology differed from immune-mediated encephalitis; and those of unknown cause were similar to infectious cases, raising the hypothesis of a possible undiagnosed infectious cause. Particularly, neutrophils and MPO merit further investigation.

Paraneoplastic neurological autoimmunity is often associated with small‐cell lung cancer (SCLC), a highly malignant neuroendocrine tumor. Paraneoplastic autoimmunity often correlates with longer survival. We describe the paraneoplastic neurological manifestations of patients with SCLC with and without SCLC‐predictive autoantibodies and the correlation between autoimmunity and survival. We reviewed the records of 116 patients (51% male) from the Mayo Clinic with histopathologically confirmed SCLC for whom stored serum was available for neural autoantibody testing. Cancer was limited stage in 41%; the median age at diagnosis was 64 years. Paraneoplastic neurological manifestations were recorded in 61% (decreasing frequency: peripheral neuropathy, dysautonomia, cognitive decline, cerebellar ataxia, neuromuscular junction disorder, seizures, cranial neuropathy, movement disorder, brainstem disorder, or myelopathy). Neural autoantibodies, some with pathogenic potential, were detected in the sera of SCLC patients with and without neurological autoimmunity. The most frequent among patients with neurological manifestations were: anti‐neuronal nuclear antibody‐type 1, voltage‐gated calcium channel (VGCC)‐N‐type, VGCC‐P/Q‐type, glutamic acid decarboxylase 65 (GAD65), SOX1, and muscle acetylcholine receptor (AChR); while the most common in patients without neurological manifestations were: GAD65, muscle‐AChR, and VGCC‐P/Q‐type. Neither cancer stage at diagnosis nor survival correlated with neurological manifestations or autoantibody‐positivity, except for shorter survival in patients with myelopathy. The only predictor of longer survival was limited‐stage disease at diagnosis.

Favourable small cell lung carcinoma (SCLC) survival outcomes have been reported in patients with paraneoplastic neurological disorders (PNDs) associated with neuronal antibodies (Neur-Abs), but the presence of a PND might have expedited diagnosis. Our aim was to establish whether neuronal antibodies, independent of clinical neurological features, correlate with SCLC survival. 262 consecutive SCLC patients were examined: of these, 24 with neurological disease were excluded from this study. The remaining 238 were tested for a broad array of Neur-Abs at the time of cancer diagnosis; survival time was established from follow-up clinical data. Median survival of the non-PND cohort (n = 238) was 9.5 months. 103 patients (43%) had one or more antigen-defined Neur-Abs. We found significantly longer median survival in 23 patients (10%) with HuD/anti-neuronal nuclear antibody type 1 (ANNA-1, 13.0 months P = 0.037), but not with any of the other antigen-defined antibodies, including the PND-related SOX2 (n = 56, 24%). An additional 28 patients (12%) had uncharacterised anti-neuronal nuclear antibodies (ANNA-U); their median survival time was longer still (15.0 months, P = 0.0048), contrasting with the survival time in patients with non-neuronal anti-nuclear antibodies (detected using HEp-2 cells, n = 23 (10%), 9.25 months). In multivariate analyses, both ANNA-1 and ANNA-U independently reduced the mortality hazard by a ratio of 0.532 (P = 0.01) and 0.430 (P<0.001) respectively. ANNAs, including the newly described ANNA-U, may be key components of the SCLC immunome and have a potential role in predicting SCLC survival; screening for them could add prognostic value that is similar in magnitude to that of limited staging at diagnosis.

Background Paraneoplastic syndromes are serious immune caused diseases of the peripheral and/or central nervous system associated with malignant neoplasm. Symptoms develop when antibodies against antigens expressed by tumor cells cross-react with neuronal proteins. Antineuronal antibodies are usually examined in patient’s sera while examination of the cerebrospinal fluid (CSF) often fails. Furthermore, the few previous reports describing CSF data summarized different antineuronal antibodies and/or regarded patients with different neurological symptoms as one group. Methods We retrospectively evaluated data of 18 patients with paraneoplastic syndromes due to anti-Hu antibodies. The study aimed to differentiate patients with peripheral neuropathy and encephalitis by cerebrospinal fluid (CSF) parameters including anti-Hu antibody titers. Results Our results confirm previous observations that serum titers of anti-Hu antibodies and standard CSF values do not differ between patients with neuropathy and encephalitis. However, analysis of CSF anti-Hu titers and calculating the intrathecal synthesis helped to discriminate between both groups. Conclusion In conclusion, our results indicate that patients even with one defined antineuronal antibody need to be regarded separately depending on the involved location of the nervous system. We recommend incorporation of anti-Hu analyses in the CSF and calculating the intrathecal synthesis in patients with anti-Hu syndrome.