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Background and Objectives: Autoimmune encephalitis (AIE) and paraneoplastic neurologic syndromes (PNSs) encompass a heterogeneous group of antibody-associated disorders. Both the number of syndromes and commercially available antibody tests have increased considerably over the past decade. High-quality population-based data on epidemiology of these disorders and real-world performance of antibody tests are needed., Methods: In this nationwide retrospective cohort study, we identified all serum and CSF samples tested for antibodies against intracellular antigens (IAs: Hu [ANNA1], Yo [PCA1], CV2 [CRMP5], Ri [ANNA2], Ma1, Ma2 [Ta], amphiphysin, GAD65, GFAP, KLHL11, CARP VIII) or extracellular antigens (EAs: NMDAR, LGI1, Caspr2, GABA-B-R, GABA-A-R, AMPAR, DPPX, GlyR, mGluR1, VGCC, IgLON5, Tr [DNER]) between January 2016 and December 2021 in the Netherlands. Nationwide coverage was guaranteed for all antibodies except anti-GAD65 and anti-VGCC. We calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV); obtained clinical information about patients who tested positive; assigned diagnosis of AIE/PNS according to diagnostic criteria; and calculated incidence rates for IA, EA, and individual antibody-associated syndromes., Results: In the study period, 2,877 (9.5%) of 30,246 samples, belonging to 1,228 patients, tested positive. Sensitivity and specificity were high (>95%) to very high (>99%) for most tests in both serum and CSF. PPVs for several tests were moderate to poor, especially for serum testing of IA antibodies (25%-80%). Clinical data were available for 940 (76.5%) of 1,228 patients. A total of 578 AIE/PNS diagnoses were made. The incidence rate for AIE/PNS (per million person-years) increased from 4.70 (95% CI 3.72-5.85) in 2016 to 5.76 (4.69-7.00) in 2021. Overall, the incidence rate was 5.57 (5.13-6.05), 2.96 (2.64-3.31) for the EA and 2.61 (2.31-2.94) for the IA subgroup. The 4 most common AIE/PNS types were anti-NMDAR, anti-LGI1, anti-Hu, and anti-GAD65, together comprising almost two-thirds of all diagnoses (364/578, 63.0%)., Discussion: Most commercial antibody tests perform well overall, but important pitfalls remain. Although almost all tests had high specificity, PPV was only modest in the setting of these rare diseases and mass testing. We observe trends toward increasing incidence of antibody-associated AIE/PNS.

Paraneoplastic neurologic syndromes (PNS), initially depicted as seemingly cryptic remote manifestations of malignancy, were first described clinically in the early 20th century, with pathophysiologic correlates becoming better elucidated in the latter half of the century. There remain many questions not only about the pathophysiology but also regarding the epidemiology of these conditions. The continuous discovery of novel autoantigens and related neurologic disease has broadened the association in classical PNS to include conditions such as paraneoplastic cerebellar degeneration. It has also brought into focus several other neurologic syndromes with a putative neoplastic association. These conditions are overall rare, making it difficult to capture large numbers of patients to study, and raising the question of whether incidence is increasing over time or improved identification is driving the increased numbers of cases. With the rise and increasing use of immunotherapy for cancer treatment, the incidence of these conditions is additionally expected to rise and may present with various clinical symptoms. As we enter an era of clinical trial intervention in these conditions, much work is needed to capture more granular data on population groups defined by socioeconomic characteristics such as age, ethnicity, economic resources, and gender to optimize care and clinical trial planning., (Copyright © 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Purpose of Review: To provide an overview and highlight recent updates in the field of paraneoplastic neurologic disorders., Recent Findings: The prevalence of paraneoplastic neurologic disorders is greater than previously reported and the incidence has been rising over time, due to improved recognition in the era of antibody biomarkers. Updated diagnostic criteria that are broadly inclusive and also contain diagnostic risk for clinical presentations (high and intermediate) and diagnostic antibodies (high, intermediate, and low) have replaced the original 2004 criteria. Antibody biomarkers continue to be characterized (e.g., KLHL-11 associated with seminoma in men with brainstem encephalitis). Some paraneoplastic antibodies also provide insight into likely immunotherapy response and prognosis. The rise of immune checkpoint inhibitors as cancer therapeutics has been associated with newly observed immune-mediated adverse effects including paraneoplastic neurological disorders. The therapeutic approach to paraneoplastic neurologic disorders is centered around cancer care and trials of immune therapy. The field of paraneoplastic neurologic disorders continues to be advanced by the identification of novel antibody biomarkers which have diagnostic utility, and give insight into likely treatment responses and outcomes., (© 2023. The Author(s).)

Objectives: Population-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., Methods: We 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])., Results: There 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., Discussion: PNSs 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., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Paraneoplastic neurological syndromes (PNS) are rare immune-mediated disorders, and the detection of onconeural antibodies is helpful for PNS diagnosis. The aim of this study was to investigate the clinical characteristics of patients with PNS with positive onconeural antibodies in a single center in Hubei, China. We retrospectively analyzed the clinical characteristics of 54 patients with positive onconeural antibodies from January 2016 to September 2020. Among 780 patients with suspected PNS, 54 (6.9%) had positive onconeural antibodies. Of those 54 patients, 28 (51.8%) were diagnosed with definite PNS and 13 (24.1%) with possible PNS. Eighteen (33.3%) patients were confirmed with cancer. Ten PNS syndromes were detected among the 28 patients with definite PNS, and they had either classical (12/28, 42.8%) or non-classical syndromes (17/28, 60.7%). Peripheral neuropathy (9/28, 32.1%), subacute cerebellar degeneration (4/28, 14.3%), and limbic encephalitis (4/28, 14.3%) were the most common PNS syndromes. The anti-CV2/CRMP5-antibody was observed most frequently. Lung cancer was the most common tumor type. For patients with possible PNS, peripheral neuropathy was the most common PNS syndrome, and the anti-Tr-antibody was the most frequent onconeural antibody. Immunotherapy was effective in treating PNS. The anti-CV2/CRMP5-antibody was the most subsequently observed antibody. The manifestations of PNS are diverse and include peripheral neuropathy, subacute cerebellar degeneration, and limbic encephalitis. In patients with PNS, lung cancer was the most common tumor., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: To evaluate the association between malignancy and frequently positive paraneoplastic antibodies., Methods: A retrospective cohort study was carried out for all patients who received paraneoplastic antibody testing in 2013-2014 at a tertiary referral center. Available medical records on included patients were reviewed through July 2020. Patients were divided into antibody positive and negative subgroups. Focused analysis was performed on the subgroup of patients who received testing via a commonly used antibody panel., Results: A total of 1860 patients (the full cohort) received 19,323 antibody testing via panel or individual antibody testing, and were followed-up for a mean period of 36.2 months (range 0-83 months). Altogether 229 antibodies in 196 patients were positive, and 9 (3.9%) in 7 patients were against onconeuronal antigens. The remaining 220 (96.1%) were positive for mostly antibodies against cell surface or synaptic antigens. A total of 1161 patients received Mayo Clinic paraneoplastic antibody panel tests (the panel cohort), and 14.9% (173) of these patients possessed one or more positive antibodies. For the panel cohort, no difference was found between antibody positive and negative groups with respect to the prevalence of previously existing malignancy (15.6% versus 16.6%, p = 0.745) or incidence of new malignancy (4.0% vs. 3.7%, p = 0.848) during the follow-up period. No difference was observed in the incidence of new malignancy during follow-up between the antibody positive and negative groups for the 7 most frequently positive antibodies., Conclusions: The presence of frequently positive antibodies, mostly to cell surface or synaptic antigens, is not clearly associated with the development of malignancy in the subsequent three years., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Paraneoplastic neurological syndromes (PNS) are a group of rare and severe immune-mediated disorders that affect the nervous system in patients with cancer. The best way to diagnose a paraneoplastic neurological disorder is to identify anti-onconeural protein antibodies that are specifically associated with various cancers. The aim of this multicentric study was to clinically and immunologically characterize patients with PNS and study their association with cancer. Patients suspected to have PNS were enrolled from various clinical centres and were characterized immunologically. This study population consisted of 112 patients. Onset of PNS was mainly subacute (76 %). PNS patients had various neurological disorders and symptoms. PNS developed before the diagnosis of cancer in 28 definite PNS patients and in six suspected PNS patients. The most frequent autoantibodies detected in PNS patients were anti-Hu and anti-Yo. One definite PNS patient with cerebellar syndrome had anti-Tr antibody and seven patients had atypical antibodies. The literature associates these antibodies with various neurological disorders and cancers. Our observations confirm the important role of autoantibodies in PNS and their importance for the early diagnosis of cancer in PNS patients.

Objective: To determine the observed and expected incidence rates of paraneoplastic neurologic syndromes (PNSs) and autoimmune encephalitides (AEs) diagnosed in France between 2016 and 2018, we conducted a population-based epidemiologic study., Methods: Observed incidence rates were stratified by sex, age groups, region of care, year of diagnosis, and disease subgroups. National expected incidence rates were calculated based on rates obtained in the area directly adjacent to the Reference Center using a mixed Poisson model and compared with observed incidence rates., Results: Six hundred thirty-two patients with definite PNS or AE met the inclusion criteria. The observed incidence rate of definite PNS and AE in France was 3.2 per million person-years (CI 95% : 2.9-3.4) compared with an expected incidence rate of 7.1 per million person-years (CI 95% : 3.9-11.4). The national observed incidence rate for the antibody-positive AE subgroup increased from 1.4 per million person-years (CI 95% : 1.2-1.7) in 2016 to 2.1 per million person-years (CI 95% : 1.7-2.4) in 2018, thus surpassing the incidence rate of classical PNS (1.2 per million person-years [CI 95% : 1.0-1.5]) of 2018., Conclusions: There was a significant widespread year-to-year increase in the incidence of diagnoses registered with the Reference Center for all subgroups of PNS and AE studied. The national observed incidence rate is likely underestimated due to underdiagnosis and underreporting., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To describe the main syndrome and clinical course in a large cohort of patients with anti-Ri-associated paraneoplastic neurologic syndrome (Ri-PNS)., Methods: Twenty-year retrospective nationwide study and systematic review of the literature., Results: Thirty-six patients with complete clinical information were identified (median age 66 years, range: 47-87 years). In this French cohort, the majority were women (78%). At onset, 4 main patterns were observed: cerebellar syndrome (39%), isolated tremor (24%), oculomotor disturbances (17%), and other symptoms (19%). Course was multistep for 78% of cases. At the time the disease reached the plateau phase (median 12 weeks, range: 1-64 weeks; 28% >3 months), 24 (67%) showed an overt cerebellar syndrome, which was isolated in 3 patients, and was most frequently (21/24 cases) part of a multisystem neurologic disease. Patients manifested a variety of movement disorders, including myoclonus (33%), dystonia (17%), either cervical or oromandibular, and parkinsonism (17%). Most patients had cancer (92%), mainly breast cancer (n = 22). Misdiagnoses concerned 22% of patients (n = 8) and included atypical parkinsonism (n = 2), MS (n = 2), Bickerstaff encephalitis (n = 1), hyperekplexia (n = 1), vestibular neuritis (n = 1), and functional neurologic disorder (n = 1). Survival at 12 months was 73% (95% CI [0.54-0.85]), at 24 months 62% (95% CI [0.41-0.78]), and at 36 months 47% (95% CI [0.25-0.65]). There was no major clinical difference between cases retrieved from the systematic review of the literature (n = 55) and the French cohort., Conclusions: Ri-PNS is a multisystem neurologic syndrome with prominent cerebellum/brainstem involvement. Opsoclonus-myoclonus is less common than expected, and the disorder can mimic neurodegenerative diseases., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: The epidemiology of paraneoplastic neurological syndromes (PNS) remains to be defined. We present here the first population-based incidence study and report the clinical spectrum and antibody profile of PNS in a large area in Northeastern Italy., Methods: We performed a 9-year (2009-2017) population-based epidemiological study of PNS in the provinces of Udine, Pordenone and Gorizia, in the Friuli-Venezia Giulia region (983,190 people as of January 1, 2017). PNS diagnosis and subgroups were defined by the 2004 diagnostic criteria. Age- and sex-adjusted incidence rates were calculated., Results: We identified 89 patients with a diagnosis of definite PNS. Median age was 68 years (range 26-90), 52% were female. The incidence of PNS was 0.89/100,000 person-years. PNS incidence rates increased over time from 0.62/100,000 person-years (2009-2011), 0.81/100,000 person-years (2012-2014) to 1.22/100,000 person-years (2015-2017). The prevalence of PNS was 4.37 per 100,000. Most common PNS were limbic encephalitis (31%), cerebellar degeneration (28%) and encephalomyelitis (20%). Among antibody (Ab)-positive cases, most frequent specificities included: Yo (30%), Hu (26%), and Ma2 (22%), while the most frequent associated tumors were lung (17%) and breast cancer (16%), followed by lymphoma (12%). PNS developed in 1 in every 334 cancers in our region. Statistically significant associations were observed between cancer type and Ab-specificity (P < 0.001), and between neurological syndrome and Ab-specificity (P < 0.001)., Conclusions: This first population-based study found an incidence of PNS that approximates 1/100,000 person-years and a prevalence of 4/100,000. Moreover, the incidence of PNS is increasing over time, probably due to increased awareness and improved detection techniques.

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., (© 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Given its rare incidence, there are few epidemiological case series on paraneoplastic neurologic syndromes (PNS)., Methods: We present a 10-year series compiled in the Section of Neuro-Oncology, Yale Cancer Center between 2002 and 2012., Results: Twenty-five cases met the PNS Euro-network criteria for definitive PNS. Most (64%; 16/25) had no known neoplasm. Cerebrospinal fluid pleocytosis declined logarithmically over time. Neuroimaging abnormalities were seen in 88% of cases (15/17), but with delayed onset. Therapeutic benefit correlated strongly to pre-treatment modified Rankin Scale (mRS) (p < 0.01), but not with time elapsed between syndrome onset to treatment (p = 0.8), first immunotherapy modality (corticosteroids: n = 10; IVIG: n = 10; PLEX: n = 3; p = 0.37), or number of immunotherapy modalities provided (p = 0.17). PNS-related mortality was high (24%; 6/25). Nonetheless, 16% (3/18; 7 living patients censored) survived over 6 times the anticipated median expected by tumor type and stage., Conclusions: PNS are rare, at an estimated incidence of 3.1 cases per million-person-years. Detection of CSF pleocytosis and MRI abnormalities depend on time of analysis. While PNS-related mortality was high, immunotherapy benefit correlated strongly with pre-treatment mRS and long-term survival is possible.

To describe and analyze the clinical features and prognosis of patients with anti-Hu associated paraneoplastic neurological syndromes (PNS).The symptoms, MRI findings, cerebrospinal fluid (CSF) changes, electroencephalogram (EEG) characteristics and prognoses of 9 well-diagnosed anti-Hu associated PNS patients were analyzed.The study enrolled 6 female and 3 male patients. Three patients presented with vertigo and 6 patients exhibited a depressed mood, numbness of the lower limbs, generalized pains, seizures, mental disturbances, and a temporary unilateral hand tremor on initial presentation. Three patients presented with MRI abnormalities localized in the mesial temporal lobe and the thalamus. Abnormal interictal EEG readings were observed in all 5 patients who underwent EEG study. Four patients were found lung cancer (3 during hospitalization, 1 during follow-up). Seven patients were treated with immunotherapy and improved in symptoms. Three patients died during follow-up (2 with lung cancer).The clinical manifestation of anti-Hu associated PNS is diverse and multifocal. EEG may be more sensitive than MRI for early diagnosis of PNS. Long-term follow-up for patients with CT-negative anti-Hu associated PNS is necessary.

Paraneoplastic neurological disorders associated with onconeural antibodies often appear with neuropsychiatric symptoms. To study the prevalence of onconeural antibodies in patients admitted to acute psychiatric inpatient care, the serum of 585 such patients was tested for antibodies targeting MOG, GLRA1B, DPPX, GRM1, GRM5, DNER, Yo, ZIC4, GAD67, amphiphysin, CV2, Hu, Ri, Ma2, and recoverin. Only one sample was positive (antirecoverin IgG). The present findings suggest that serum onconeural antibody positivity is rare among patients acutely admitted for inpatient psychiatric care. The clinical implications of this finding are discussed.

Background: Neurology has been continuously transforming by the refinement of molecular diagnostics and the development of disease-modifying treatments. The discovery of new antibody markers has elucidated the pathogenesis, provided the means of diagnostics, and offered cure or treatment for several immune-mediated neurological and neuropsychiatric disorders. The identification of pathogenic and marker autoantibodies has also facilitated defining the associated phenotypic spectra and the overlap among the phenotypes linked to individual immune markers., Review Summary: This survey presents the list of currently known autoimmune encephalitis entities along with the associated marker autoantibodies, highlights the phenotypic and immune pathogenic relationships, calls attention to the recently described rare syndromes, discusses the biological significance of the autoantibodies and targeted molecules, points out the potential postinfectious origin of immune pathogenesis in several of the disorders, and directs the readers to the latest diagnostic guidelines as well as to the generally used treatment approaches., Conclusions and Future Directions: Owing to the successful and usually combined use of various methods to detect serum and cerebrospinal fluid autoantibodies on rodent brain sections, in primary neuronal cell culture, in immune precipitation, and cell-based assays, or in other antigen-specific immune assays (Western blot, enzyme-linked immunosorbent assay, and radioimmune assay), the subgroup of antibody marker-negative autoimmune encephalopathy syndromes is contracting, whereas the numbers of entities within the overall group are expanding. Recognition of the correct diagnosis is becoming increasingly rewarding not only for neurologists, but also for pediatric neurologists and psychiatrists.

Paraneoplastic neurological syndromes (PNS) are remote effects of cancer. They are much less common, but are nevertheless important because they cause severe neurological morbidity and mortality. The present cases were studied to characterize the clinical features of patients of suspected PNS and to study their association with different types of tumors. In this study conducted from a super speciality teaching institute from South India, forty five (incidence-0.25%) patients were diagnosed with PNS based on the clinical data. They were subdivided into two groups patients with central nervous system (CNS) manifestations and those with neuromuscular manifestations. Immunological markers were assessed in a subset of patients. Majority of them (75.6%) were above 40 years. There was no sex predilection and a chronic presentation was common (42.2%). While more than half had involvement of peripheral nervous system (64.4%), CNS manifestations were present in 16 (35.6%) cases. Immunological markers were present in 10 out of 14 (58.8%) patients. Classic PNS was seen 22 cases (48.9%), while 23 (51.1%) were non classical. Most common tumor was lung cancer followed by myeloma and breast carcinoma. Present study construed that, in patients with neurological syndromes of unknown cause, search should be focused for occult malignancy based on the phenotype and onconeural antibodies, targeting the lung and breast in particular.

Objective: To determine the frequency and range of paraneoplastic neurologic disorders (PNDs) and neuronal antibodies in small cell lung carcinoma (SCLC)., Methods: Two hundred sixty-four consecutive patients with biopsy-proven SCLC were recruited at the time of tumor diagnosis. All patients underwent full neurologic examination. Serum samples were taken prior to chemotherapy and analyzed for 15 neuronal antibodies. Thirty-eight healthy controls were analyzed in parallel., Results: PNDs were quite prevalent (n = 24, 9.4%), most frequently Lambert-Eaton myasthenic syndrome (3.8%), sensory neuronopathy (1.9%), and limbic encephalitis (1.5%). Eighty-seven percent of all patients with PNDs had antibodies to SOX2 (62.5%), HuD (41.7%), or P/Q VGCC (50%), irrespective of their syndrome. Other neuronal antibodies were found at lower frequencies (GABAb receptor [12.5%] and N-type VGCC [20.8%]) or very rarely (GAD65, amphiphysin, Ri, CRMP5, Ma2, Yo, VGKC complex, CASPR2, LGI1, and NMDA receptor [all <5%])., Conclusions: The spectrum of PNDs is broader and the frequency is higher than previously appreciated, and selected antibody tests (SOX2, HuD, VGCC) can help determine the presence of an SCLC., (© 2015 American Academy of Neurology.)

Importance: Purkinje cell cytoplasmic antibody type 1 (PCA-1)-IgG (or anti-Yo) is characteristically detected in women with gynecological or breast adenocarcinoma. We describe 2 unique scenarios occurring in 1 patient: PCA-1 paraneoplastic autoimmunity in a child, and a paraneoplastic neurological disorder in the context of Down syndrome., Observations: A child with Down syndrome and a history of adrenocortical carcinoma resected at age 1 year presented at age 7 years with cerebellar ataxia of subacute onset. Paraneoplastic serological and cerebrospinal fluid evaluations revealed PCA-1. Serological and biochemical studies also supported a diagnosis of subclinical autoimmune hypothyroidism. Extensive serum, urine, and radiological testing did not reveal a new or recurrent neoplasm. Neurological improvements after standard immunotherapy were lacking., Conclusions and Relevance: Solid organ neoplasms are uncommon among patients with Down syndrome, but organ-specific autoimmune diseases are common. In our patient, Down syndrome-related impaired T regulatory lymphocyte function (previously reported) may have resulted in both enhanced immunity against an undetected solid neoplasm and paraneoplastic neurological (PCA-1) autoimmunity.

Aim: Paraneoplastic neurological diseases (PND) are rare, but potentially treatable disorders. Paraneoplastic encephalitis is rapidly emerging as an important but likely under-recognized condition in children. The aim of this study was to assess the prevalence and spectrum of PND in children with benign ovary tumor and the long-term outcome., Patients and Methods: We retrospectively reviewed the charts of all female patients below 18years of age diagnosed with a benign ovarian tumor proven by pathology between January 1993 and December 2010. All the clinical symptoms developed within 5years of tumor diagnosis and the related investigations were recorded., Results: There were total 133 children and adolescents with benign ovarian tumors, mostly mature teratoma. Six patients (4.5%) had neuropsychiatric manifestations and all but one were beyond age 10years. The most common neuropsychiatric presentations were depression or low mood (84%), headache (50%), mutism (50%), hypoventilation (50%), seizures (30%), hallucination (30%), vomiting and hypersalivation (30%). Three patients (2.2%) had serious PND including acute disseminated encephalomyelitis in 1 and anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis in 2. Although all of three improved after tumor removal, one without immunotherapy had neurological sequelae and prolonged ICU stay., Conclusion: The prevalence of PND in benign ovary tumor is not so uncommon in children. It is important to survey ovary tumors in female adolescents with subacute presentation of multiple-level involvement of neuraxis where no clear alternate diagnosis is possible. Treatment of serious PND associated with ovary tumors should include immunotherapy in addition to tumor removal., (Copyright © 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Paraneoplatic neurologic syndromes (PNS) have been seminally defined as acute or subacute neurological syndromes resulting from nervous system dysfunction that is remote from the site of a malignant neoplasm or its metastases. However, in respect to our current understanding of their pathogenesis we may redefine these disorders as cancer-related dysimmune neurologic syndromes. We first deal with the epidemiology and the pathogenesis of PNS, then the different classic PNS are reviewed with clinical features according to the associated onconeuronal antibodies. Finally, therapeutic approaches are discussed., (© 2014 Elsevier B.V. All rights reserved.)

This study determined the prevalence of classical onconeural Ab in a series of 2063 consecutive patients that were investigated because of suspicion of PNS as well as evaluated individual onconeural Ab in relationship to the clinical spectrum of associated neurological syndromes and tumor types detected in 70 patients finally diagnosed with PNS. We conclude that detectability of onconeural Ab is low among patients suspected with PNS. Specification of Ab is helpful in defining a neurological syndrome as paraneoplastic as well as in searching of underlying tumor. The success in tumor screening depends on the type of onconeural Ab., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Introduction: Encephalitis is an inflammatory or infectious disease with an acute or subacute presentation. Immunological abnormalities in serum can be found but may be underdiagnosed. In several cases, a paraneoplastic origin with anti-neuron antibodies is noted. In all cases, other auto-antibodies can be found with or without any neoplastic mechanism., Objectives: The aim of our study was to describe a clinical, radiological and immunological cohort of patients with autoimmune encephalitis and suggest a diagnostic and therapeutic algorithm., Patients and Method: We performed a retrospective study in an immunological unit of neurology. All patients with autoimmune encephalitis between March 2000 and October 2009 were included. The clinical, imaging and immunological evaluations were recorded for each patient., Results: Our cohort included 16 patients (eight men and eight women), mean age 45.3±10years. All patients had acute or subacute neuropsychological or neuropsychiatric impairment and all patients but one had temporal lobe dysfunction confirmed by cerebral MRI, PET or SPECT. Epilepsy was observed in 56% of cases, extra-temporal lobe impairment in 50%, including sleep disturbances. A cancer was found in only 25% (two small-cell lung cancers, one testis seminoma, one non-small-cell lung cancer with Merckel cells cancer). Anti-neuron antibodies were noted in 56% of cases (two with anti-voltage gate potassium channel complex antibodies (ab), two with anti-NMDA-R ab, two with anti-glutamate acid decarboxylase ab, one with anti-Ma2, two with anti-Hu ab and two remained uncharacterized). Systemic antibodies were found in 50% (one anti-gangliosides, one anti-SSA and one anti-DNA and four antinuclear ab uncharacterized, two anti-TPO and two anti-phospholipids). All patients received immunomodulatory treatments, including intravenous immunoglobulins (IgIV) and cancer was treated. Five patients achieved complete recovery, partial improvement was observed in 10 patients and two patients died., Discussion: Despite clinical homogeneity at presentation, clinical outcome seems to be different between patients with antibodies against neuronal surface antigens and those with antibodies against intracellular antigens, which are more likely refractory to immunotherapy and paraneoplastic. The frequency of extra-temporal lobe impairment suggests that the term of limbic encephalitis should be changed to autoimmune encephalitis., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

The objective of this paper is to review the literature published in 2011 in the field of intensive care and emergency related to oncology. Are discussed because of new original publications: prognosis, resuscitation techniques, oncologic emergencies, serious toxicities of cytotoxic chemotherapy and targeted therapies, complicated aplastic anemia, toxicity of bisphosphonates, respiratory complications, pulmonary embolism and neurological complications.

Objectives: SOX1 antibodies have been described in patients with Lambert-Eaton myasthenic syndrome (LEMS) in association with voltage-gated calcium channel antibodies as serological markers of small cell lung cancer (SCLC). This study was aimed to screen for additional SOX1 autoimmunity in onconeural antibody-positive sera from patients with paraneoplastic neurological syndromes (PNS) other than LEMS and to identify the clinical-immunological profile and associated tumours of patients with coexisting SOX1 antibodies., Methods: We retrospectively analysed sera from 55 patients with different PNS positive for well-characterized antineuronal antibodies for the presence of SOX1 antibodies by recombinant ELISA and immunoblot., Results: Eight (14.5%) patients showed additional SOX1 antibodies in the ELISA and the recombinant immunoblot. Five patients had coexisting Hu antibodies, while the other three showed coexisting CV2/CRMP5, amphiphysin, and coexisting CV2/CRMP5 and Hu antibodies, respectively. PNS included (partially overlapping) subacute sensory neuropathy, subacute sensorimotor neuropathy, cerebellar degeneration, brainstem encephalitis, encephalomyelitis and limbic encephalitis. No tumour was detected in two patients, while the others had lung cancer (four SCLC and two non-SCLC). One patient showed SOX1-specific intrathecal antibody synthesis., Conclusions: We describe SOX1 reactivity for the first time overlapping with CV2/CRMP5 and amphiphysin antibodies. SOX1 reactivity is predominantly associated with Hu antibodies and SCLC, but can occur also in other types of lung cancer. Neurological manifestations present in patients with coexisting SOX1 antibodies and well-characterized antineuronal antibodies do not differ from those previously described in patients positive for antineuronal antibodies but no SOX1-specific anti-glial antibodies., (© 2011 John Wiley & Sons A/S.)

Paraneoplastic neurological syndromes (PNS) are rare diseases defined so far by the presence of a neurological disorder associated with cancer in the absence of invasion of the nervous system by tumor cells. Discovery of circulating autoantibodies specific for these patients has revolutionized the diagnosis and understanding of these syndromes and demonstrated a role of the immune system in the neurological syndromes. Until recent years, we thought that these autoantibodies were only markers of the disease and had no role in the pathophysiology. The recent description of autoantibodies directed against membrane receptors or channels and playing a direct pathological role has transformed the concept of PNS. Especially, it appears that many patients may have a neurological syndrome and autoantibodies without cancer. This results in a classification based on the nature of the autoantibodies associated with neurological syndrome. In case of autoantibodies targeting intracellular antigens, cancer is almost always associated, the neurological disorders are mainly related to neuronal death, patients are rarely sensitive to immunomodulatory treatments and cellular immunity appears to play a major role. In contrast, patients with autoantibodies targeting membrane antigens (receptors, channels or receptor associated proteins) have rarely cancer, neurological disorders are related to a reversible neuronal dysfunction, patients are mostly sensitive to immunomodulatory treatments and it seems that humoral immunity and autoantibodies play a major role., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Objective: To define the frequency and clinical and immunologic characteristics of patients affected by paraneoplastic neurologic syndromes (PNS) and lymphoma., Methods: Patients fulfilling the criteria for PNS associated with lymphoma collected from the European Commission-funded PNS Euronetwork group database were analyzed., Results: Fifty-three patients with Hodgkin lymphoma (HL) (24 patients, mean age 51, range 16-84) or non-Hodgkin lymphoma (NHL) (29 patients, mean age 64, range 31-82) and PNS were analyzed. The most commonly associated PNS was paraneoplastic cerebellar degeneration, present in 21 cases, with a higher prevalence in HL (16/24 cases). Peripheral nervous system (mainly demyelinating polyradiculopathies) and motor neuron involvement were more common in NHL. Onconeural antibodies were more frequent in patients with paraneoplastic cerebellar degeneration, most commonly against the Tr antigen. Fifty percent of the patients with PNS and HL responded to chemotherapy, whereas neurologic improvement was less frequent (24%) in patients with PNS and NHL. In both groups, the survival rate was good. Overall, 10 out of 53 patients eventually died, with only 2 patients (1 with HL, 1 with NHL) dying from PNS., Conclusions: PNS in patients with lymphoma are relatively rare. Paraneoplastic cerebellar degeneration, mainly associated with anti-Tr antibodies, is more prevalent in HL and NHL, followed in our study by motor neuron disease in patients with NHL. Involvement of the peripheral nervous system is heterogeneous, with a prevalence of polyradiculoneuritis in patients with NHL.

The coincidence of stroke and cancer is frequently encountered. From recent epidemiological data, the stroke risk in cancer patients seems to be equally distributed as compared to the non-cancer population. However, there are several clinical conditions in cancer patients which increase the risk for stroke: Trousseau's syndrome, non-bacterial thrombotic endocarditis and disseminated intravascular coagulation. Also some tumour-specific conditions such as coagulopathies, changes of viscosity and cellular mechanisms such as leukocytosis or thrombocytopathies must be considered. In several types of tumour treatment, such as various anticancer drugs, an increased occurrence of stroke has been reported. Presently there is no indication that stroke and cancer are related to the immune-mediated "classic" paraneoplastic syndromes. However, there are several cancer-specific types and causes of stroke which need to be considered in each patient, as they can be of significance in the treatment.

Objective: Anti-Hu antibodies (Hu-Ab) and anti-CV2/CRMP5 antibodies (CV2/CRMP5-Ab) have been identified in association with paraneoplastic neurological disorders. However, it is not clear whether these antibodies are associated with specific neurological symptoms or are only markers of anti-cancer immune reaction., Methods: To address this question, 37 patients with CV2/CRMP5-Ab and 324 patients with Hu-Ab were compared., Results: Whereas the age and sex ratio were the same between the two groups, the distribution of neurological symptoms was not. Patients with CV2/CRMP5-Ab presented more frequently cerebellar ataxia, chorea, uveo/retinal symptoms and myasthenic syndrome (Lambert-Eaton myasthenic syndrome LEMS or myasthenia gravis). They also had a better Rankin score. In contrast, dysautonomia, brainstem encephalitis and peripheral neuropathy were more frequent in patients with Hu-Ab. Limbic encephalitis occurred similarly in both groups. Small-cell lung cancer was the most frequently associated tumour in both groups of patients, while malignant thymoma was observed only in patients with CV2/CRMP5-Ab. In particular, patients with CV2/CRMP5-Ab and thymoma developed myasthenic syndrome more frequently, while patients with SCLC developed neuropathies more frequently. Chorea and myasthenic syndrome were only seen in patients with CV2/CRMP5-Ab. The median survival time was significantly longer in patients with CV2/CRMP5-Ab, and this effect was not dependent on the type of tumour., Interpretation: The data demonstrate that in patients with paraneoplastic neurological syndromes, the neurological symptoms and survival vary with both the type of associated onco-neural antibody and the type of tumour.

Background: The neuromyelitis optica IgG autoantibody (NMO-IgG) is a validated biomarker for NMO and an emerging spectrum of inflammatory central nervous system-demyelinating disorders. Its antigen is the astrocytic water channel aquaporin-4; NMO-IgG has not been described in a cancer context., Objectives: To report (1) neurologic and oncologic correlates for patients incidentally identified as NMO-IgG seropositive in a blinded evaluation for paraneoplastic autoantibodies and (2) the frequency of cancer in NMO-IgG-seropositive patients., Design: Observational, retrospective case series., Setting: Neuroimmunology Laboratory and Neurology Clinical Practice, Mayo Clinic College of Medicine., Patients and Methods: From 1998 to 2007, we detected NMO-IgG in 2 patient groups: (1) 31 patients (88% female) identified incidentally among 180 000 patients evaluated for paraneoplastic autoantibodies and (2) 141 patients identified through physician-requested serological evaluation for a suspected NMO-spectrum disorder., Results: In the first group, clinical information was available for 28 patients (90%). An NMO-spectrum disorder was diagnosed in 26 patients (93%), of whom 6 had a neoplasm (5 carcinomas [2 breast, 1 lung, 1 thymic, and 1 uterine cervical] and 1 B-cell lymphoma) and 1 had monoclonal gammopathy. In 4 patients, NMO-related symptoms followed neoplasia detection (median, 14 [range 3-18] months), and in 2 patients, symptoms preceded neoplasia detection (by 5 and 3 months). Two patients had carcinoma (1 breast and 1 lung) without neurological evidence of an NMO-spectrum disorder. In the second group, neoplasms were recorded in 7 seropositive patients (5.0%) with a clinically diagnosed NMO-spectrum disorder: 3 carcinomas (all breast), 1 thyroid Hürthle cell, 1 carcinoid, 1 pituitary somatotropinoma, and 1 B-cell lymphoma. An eighth patient had monoclonal gammopathy., Conclusions: Aquaporin-4-specific IgG in some cases of NMO may reflect a paraneoplastic immune response. The clinical utility of this autoantibody as a cancer marker warrants prospective investigation.

Antineuronal antibodies are associated with rare paraneoplastic neurological syndromes, and their identification alerts clinicians to examine for the presence of a tumor. Presented here is laboratory experience (prevalence, difficulties, and procedures) and several interesting but inconclusive results. A total of 1045 samples were screened over a 2-year period; 91 showed a degree of binding of antibodies to the cerebellum, and 22 of these 91 were confirmed, by Western blot, to have specific antineuronal antibodies. Thirteen of 22 were Hu-positive, and 6 of these also had antinuclear antibodies. Six were Yo-positive, 2 had anti-Ma antibodies, and 1 was Tr-positive. An additional 27 of 91 patients had cerebellar antibodies giving recognized staining patterns (Hu, Yo, and Ma). However, Western blot did not confirm these specificities, and hence they were reported as atypical. Six of 27 of these patients had neoplasms; 3 of the 6 gave nucleolar patterns (not Ma). Two appeared similar to Yo, and 1 similar to Hu. Antineuronal antibodies are rare, and in the absence of a specific etiology patients should be examined further for the possible presence of an underlying tumor. Methodical classification of the antibodies must be conducted to avoid incorrect reporting. Further criteria on the typing/reporting of atypical results may aid diagnosis of paraneoplastic neurological syndromes.

Opsoclonus-myoclonus syndrome (OMS) is a rare, autoimmune neurological disorder that is poorly recognized and undertreated. Neuroblastoma is found in one half of the cases. Because of the high incidence of spontaneous regression of neuroblastoma, it is unknown whether not finding a tumor means there was none. To define demographic trends and the standard of care in the first large series of OMS, 105 children were recruited over a 13-year period in a retrospective questionnaire survey. Children with and without a tumor differed little in viral-like prodrome and neurological symptoms. Earliest neurological symptoms were staggering and falling, leading to a misdiagnosis of acute cerebellitis. Later symptoms included body jerks, drooling, refusal to walk or sit, speech problems, decreased muscle tone, opsoclonus, and inability to sleep. Tumor resection alone did not provide adequate therapy for most. Adrenocorticotropic hormone (ACTH), prednisone, and intravenous immunoglobulin were used with equal frequency, but ACTH was associated with the best early response. More than one half of the children had relapses. Residual behavioral, language, and cognitive problems occurred in the majority. The delay in diagnosis (11 weeks) and initiation of treatment (17 weeks) is unacceptably long.

Various paraneoplastic autoantibodies have been linked to discrete neurologic syndromes and tumors in adults, but little is known about their incidence in children. We report a cross-sectional study of known paraneoplastic antibodies in 59 children with opsoclonus-myoclonus-ataxia, 86% of whom were moderately or severely symptomatic, and 68% of whom had relapsed at the time of testing. This total number of patients includes 18 children with low-stage neuroblastoma (tested after tumor resection), six of whom had never been treated with immunosuppressants. All were seronegative for anti-Hu, anti-Ri, and anti-Yo, the three paraneoplastic antibodies most associated with opsoclonus-myoclonus or ataxia in adults. These data contrast with reports of anti-Hu-positive sera in children with high-stage tumors and suggest that anti-Hu, anti-Ri, and anti-Yo do not explain relapses in pediatric opsoclonus-myoclonus-ataxia. They underscore the need to search for unique autoantibodies, as well as cellular mechanisms of pediatric paraneoplastic disease.

In a retrospective study, we determined clinical and serological findings, associated tumours, outcome and prognostic factors in 73 Hu-Ab positive patients detected in a Dutch reference laboratory. The most frequent signs and symptoms at presentation were sensory neuropathy (55 %), cerebellar degeneration (22 %), limbic encephalitis (15 %) and brainstem encephalitis (16 %). 23 % developed autonomic dysfunction including gastro-intestinal motility disorders in 14 %. In 85 % a tumour was detected, which was a lung tumour in 77 %. Signs, symptoms and associated tumours did not differ in six patients with additional neuronal antibodies (anti-amphiphysine, anti-CV2, anti-Ri). The overall 3 months, one-year and three-year survival rates from the time of diagnosis were 64 %, 40 % and 22 %. Rankin Scale Score (RS) at diagnosis and presence of tumour at the time of diagnosis predicted mortality with hazard ratios (95 % CI) of 2.6 (1.5-4.6) and 1.5 (1.1-2). The median delay between onset of symptoms and Hu-Ab diagnosis was 4 months. There was a negative association between delay RS at diagnosis (P=0.03). In a logistic regression analysis, only older age (OR=0.15; 0.02-0.63) and a higher RS at diagnosis (OR=0.29; 0.11-0.73) were associated with a lower probability of successful functional outcome. Adjusted for these factors, antitumour therapy showed a higher but statistically not significant probability of successful outcome (OR=3.5; 0.87-14.3). Our study underlines the importance of early diagnosis and start of antitumour treatment when the patient is still in a better functional state. The delay between onset of symptoms and diagnosis of PEM/SN suggests a window for improving outcome in these patients.