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Objectives Paraneoplastic arthritis (PA) is one of the paraneoplastic syndromes. Both laboratory and clinical findings similar to rheumatological diseases can be seen. In this study we aimed to present the clinical and laboratory findings, malignancy types and pathological diagnoses of patients with paraneoplastic arthritis. Methods In a multicentre retrospective study, 92 patients with PA from the last 10 years were included. Results Patients with PA and haematological malignancies exhibited the highest ratio of lymphomas (25.6%). The most common cancer detected in patients with solid malignancy and PA was lung cancer (41.5%). All malignant patients with PA had significant anti-CCP positivity compared with the healthy control group (P  = 0.014). Conclusion Although PA is a rare condition, it can be confused with many rheumatological diseases. The most commonly involved joint is the knee joint, followed by the ankle and hand/wrist. Autoantibody negativity, high lactate dehydrogenase level and arthritis unresponsive to treatment constitute important clues for diagnosis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Paraneoplastic neurological syndromes (PNS) are defined as remote neurologic immune-mediated effects triggered by underlying systemic tumors. While recognizing specific syndromes can aid early cancer detection, overutilization of paraneoplastic assays in the absence of a classic syndrome can precipitate overdiagnosis and overtreatment. PNS involve autoantibodies targeting intracellular or extracellular antigens, with variable immunotherapy responses based on antigen type. Diagnosing PNS is challenging, requiring exclusion of other differential diagnoses. New diagnostic criteria classify PNS into high-risk and intermediate-risk phenotypes based on clinical phenotype, neuronal antibodies, and cancer presence. Patients with cell surface antibodies respond better to immunotherapies compared to those with intracellular antigen targets. Understanding PNS syndromes, serological markers, and oncological features guides management, which facilitates initiation of immunosuppression for PNS alongside treatment of the underlying neoplasm, thereby improving neurologic and oncologic outcomes. Initial treatments often include intravenous methylprednisolone, plasma exchange, or intravenous immunoglobulins. Second-line immunosuppressants like rituximab or cyclophosphamide may be necessary if initial treatments fail. Specific therapies vary based on antibody target. Here, we summarize the current approach to the investigation, diagnosis, and treatment of patients with suspected PNS. [ABSTRACT FROM AUTHOR]

The heterogeneity of autoantibody targets in autoimmune encephalitides presents a challenge for understanding cellular and humoral pathophysiology, and the development of new treatment strategies. Thus, current treatment aims at autoantibody removal and immunosuppression, and is primarily based on data generated from other autoimmune neurological diseases and expert consensus. There are many subtypes of autoimmune encephalitides, which now entails both diseases with autoantibodies targeting extracellular antigens and classical paraneoplastic syndromes with autoantibodies targeting intracellular antigens. Here, we review the current knowledge of molecular and cellular effects of autoantibodies associated with autoimmune encephalitis, and evaluate the evidence behind the proposed pathophysiological mechanisms of autoantibodies in autoimmune encephalitis. [ABSTRACT FROM AUTHOR]

Among the different forms of cerebellar ataxia, autoimmune cerebellar ataxia (ACA) or immune‐mediated cerebellar ataxia (IMCA), which appears to be based on an autoimmune mechanism, has long been considered important from the viewpoint of paraneoplastic syndrome. With the expansion of the concept of immune‐mediated neurological diseases and the identification of many novel autoantibodies, ACA has recently become an important neurological syndrome. Although no definitive diagnostic criteria of ACA exist, Hadjivassilou et al suggested diagnostic criteria for primary ACA in 2020 and Dalmau and Graus showed proposed diagnostic criteria for ACA in 2022. The proposed diagnostic criteria for ACA by Dalmau and Graus emphasize the importance of antibody reliability. In the future, additional studies should be conducted to identify new antibodies associated with ACA and to clarify the importance of each antibody. Moreover, ACA is a disease for which immunological therapeutic intervention is feasible and requires early treatment to maintain cerebellar function. Many cases with ACA have reported the efficacy of immunotherapy. The concept of ACA may have the potential for further expansion and becomes increasingly important in the diagnosis of cerebellar ataxia. [ABSTRACT FROM AUTHOR]

Background: The literature describes a case of systemic lupus erythematosus (SLE) complicated with Castleman's disease (CD) and secondary paraneoplastic pemphigus (PNP). Case presentation: A 12-year-old female presented with a neck mass, rash, arthralgia, and skin and mouth ulceration for 5 years were admitted. All blood cells were low. Multiple autoantibodies associated with SLE were positive. The pathology of the neck mass revealed the classical manifestations of CD. She was treated with prednisone, hydroxychloroquine, leflunomide, thalidomide, and dressings. Pathological examination of the skin revealed PNP. The neck mass was removed and continued to take antirheumatic drugs. At subsequent follow-up, the patient's disease status was stable and the skin mucosal lesion did not recur. Conclusion: The case of simultaneous SLE, CD, and PNP in children was rarely reported, and the correct diagnosis of the disease will help to take timely treatment. [ABSTRACT FROM AUTHOR]

Background and purpose: Autoantibodies have been found to contribute to pathology and are used in the diagnosis of some neurological diseases. We examined the prevalence of autoantibodies in patients with various neurological diseases and whether patients who had autoantibodies differed in age, sex, or disability from those who did not. Methods: We examined the prevalence of neural surface and onconeural autoantibodies in cerebrospinal fluid (CSF) and serum from patients with multiple sclerosis (n = 64), Parkinson disease plus atypical parkinsonism (n = 150), amyotrophic lateral sclerosis (n = 43), or autoimmune encephalitis (positive control; n = 7) and a healthy control group (n = 37). A total of 12 onconeural autoantibodies and six neural surface autoantibodies were tested in all participants. Results: Autoantibodies were present in all cohorts. The prevalence of autoantibodies was high (>80%) in the autoimmune encephalitis cohort but low (<20%) in all other cohorts. When comparing patients within cohorts who were positive for autoantibodies to patients who were not, there was no difference in age, sex, and disability. This was apart from the multiple sclerosis and Parkinson disease plus atypical parkinsonism cohorts, where those with positivity for autoantibodies in the CSF were significantly older. Conclusions: The presence of the autoantibodies examined does not appear to have a substantial clinical impact within the diseases examined in this study. The presence of autoantibodies in all cohorts presents a risk for misdiagnosis when the method is used incorrectly on patients with atypical clinical presentation. [ABSTRACT FROM AUTHOR]

Objective: Seizures are a common manifestation of paraneoplastic neurologic syndromes. The objective of this study was to describe the seizure characteristics and outcomes in patients with high‐risk paraneoplastic autoantibodies (>70% cancer association) and to determine factors associated with ongoing seizures. Methods: Patients from 2000 to 2020 with seizures and high‐risk paraneoplastic autoantibodies were retrospectively identified. Factors associated with ongoing seizures at last follow‐up were evaluated. Results: Sixty patients were identified (34 males, median age at presentation = 52 years). ANNA1‐IgG (Hu; n = 24, 39%), Ma2‐IgG (n = 14, 23%), and CRMP5‐IgG (CV2; n = 11, 18%) were the most common underlying antibodies. Seizures were the initial presenting symptom in 26 (43%), and malignancy was present in 38 (63%). Seizures persisted for >1 month in 83%, and 60% had ongoing seizures, with almost all patients (55/60, 92%) still being on antiseizure medications at last follow‐up a median of 25 months after seizure onset. Ongoing seizures at last follow‐up were associated with Ma2‐IgG or ANNA1‐IgG compared to other antibodies (p =.04), highest seizure frequency being at least daily (p =.0002), seizures on electroencephalogram (EEG; p =.03), and imaging evidence of limbic encephalitis (LE; p =.03). Death occurred in 48% throughout the course of follow‐up, with a higher mortality in patients with LE than in those without LE (p =.04). Of 31 surviving patients at last follow‐up, 55% continued to have intermittent seizures. Significance: Seizures in the setting of high‐risk paraneoplastic antibodies are frequently resistant to treatment. Ongoing seizures are associated with ANNA1‐IgG and Ma2‐IgG, high seizure frequency, and EEG and imaging abnormalities. Although a subset of patients may respond to immunotherapy and achieve seizure freedom, poor outcomes are frequently encountered. Death was more common among patients with LE. [ABSTRACT FROM AUTHOR]

A 69‐year‐old Japanese male with advanced lung adenocarcinoma developed neurological symptoms after chemoradiotherapy and durvalumab maintenance therapy. He was positive for serum antiamphiphysin antibody, which is rarely seen in patients with lung adenocarcinoma. Additionally, his brain magnetic resonance images showed limbic encephalitis which led to the diagnosis of classic paraneoplastic neurological syndrome (PNS). Immune checkpoint inhibitors (ICIs) activate T cells and may also activate antineuronal antibodies that cause PNS. Durvalumab, which is an ICI, may have led to antiamphiphysin antibody‐positive PNS in our patient. Treatment with systemic high‐dose methylprednisolone was unsuccessful and he died 2 months later. PNS should be considered as one of the differential diagnoses in patients with lung cancer and neurological symptoms during, or after, ICI treatment. [ABSTRACT FROM AUTHOR]

Rapidly progressive cerebellar ataxia is a classical paraneoplastic neurological syndrome associated with different autoantibodies and typical demographic characteristics, extracerebellar signs, tumor association, and prognosis. Anti-Tr/anti-Delta/Notch-like epidermal growth factor-related receptor (DNER) antibody is one of the associated antibodies. Given the rarity of this condition, our current knowledge is based on case reports and small case series. In order to improve our understanding of these conditions, we conducted a systematic review of the literature. Our study followed the PRISMA reporting guidelines. Studies of patients with the presence of anti-Tr/DNER antibodies in serum or cerebrospinal fluid (CSF) were included. We extract data information related to study characteristics, demographics, clinical symptoms, tumor association, neuroimaging, and cerebrospinal fluid analysis. Out of 131 records, we analyzed 17 papers, including a total of 85 patients with anti-Tr/DNER antibody–associated cerebellar ataxia. We confirmed that this disease occurred mostly in middle-aged males. Isolated cerebellar ataxia was the most common presentation. Extracerebellar features were rare (8%). Ninety-one percent of the patients presented an associated tumor, being Hodgkin lymphoma the most common. Abnormal neuroimaging patterns included cerebellar atrophy (19%) and cerebellar hypersignal (6%). Cerebrospinal fluid was inflammatory in 64% of the patients. Oncological response was complete in 88%, but neurological prognosis was poor with only 41% of the patients presenting significant neurological improvement at the last follow up. Anti-Tr/DNER antibodies should be tested in rapid progressive cerebellar ataxia. Oncological response is excellent; however, many patients do not improve from their cerebellar ataxia. [ABSTRACT FROM AUTHOR]

Seizure is a rare symptom of paraneoplastic syndrome seen in neuroblastoma without a previous history. A 4-month-old male patient who was followed up with a preliminary diagnosis of an adrenal mass in pediatric oncology was admitted to hospital with a seizure. A diagnosis of undifferentiated neuroblastoma was made with a biopsy from an adrenal mass. Seizures were resistant to anti-epileptic therapy and they were completely under control with steroids on the 4th day of treatment. Electroencephalography (EEG) disturbances disappeared and no neurologic deficit was detected. This case, which presented with isolated seizure symptoms of neuroblastoma and was treated with steroids, was a very rare presentation in which symptoms and EEG disturbances disappeared. In neuroblastoma, autoimmunity may be involved in the pathogenesis of seizures, which is a rare finding of paraneoplastic syndrome and the option of immunotherapy should be considered. [ABSTRACT FROM AUTHOR]

Background: Autoimmune encephalitis (AIE) and paraneoplastic syndromes (PNS) are both rare groups of neurological diseases that are difficult to diagnose. Aim: We aimed to determine the common and distinct aspects of these two aetiologies of encephalitis as well as the characteristics of our patient group. Methods: We respectively analysed the records of the patients including symptoms, demographic features, neurological examination, cranial-magnetic-resonance-imaging (MRI), electroencephalography (EEG) findings, cerebrospinal fluid results (CSF) findings. Autoimmune/paraneoplastic autoantibodies in blood and/or CSF were all documented. Results: Forty-six patients fulfilled the diagnostic criteria. Thirty-eight of them were diagnosed with AIE, and 8 of them were diagnosed with PNS. The PNS group had higher nonconvulsive status epilepticus than the AIE (2/8 vs 0/38; p=0.027). PNS patients were diagnosed with a malignancy in their follow-ups more than those in the AIE group [4/38 vs 8/8] (p<0.001). When the symptoms of antibody-positive and negative patients were compared in the AIE group, the rates of consciousness/memory problems (13/15 vs 11/23; p=0.020) and speech impairment (8/15 vs 2/23; p=0.004) were significantly higher in patients without antibodies (n: 15) than in antibody-positive patients (n: 23). In antibody-negative groups, the rates of memory problems in neurological examination (13/15 vs 12/23 p=0.028) and temporal findings on electroencephalography were more prominent than antibody-positive groups (1/23 vs 5/15; p=0.027). The number of patients with cerebellar signs was higher in antibody-positive patients (6/23 vs 0/15; p=0.038). Conclusion: Although the positivity of autoantibodies is critical in the diagnosis of AIE and PNS, even minor differences in clinical and laboratory findings of patients are helpful in the diagnosis, especially in the autoantibody-negative patients. Comparing the data with other population studies has shown that several inherited and environmental factors may contribute to the pathophysiology of AIE and PNS, as well as clinical and laboratory differences. [ABSTRACT FROM AUTHOR]

Paraneoplastic neurological syndromes (PNSs) are group of disorders affecting one or multiple parts of the neuroaxis associated with underlying tumors. An antibody or autoantigen-specific cell-mediated immune response against neural antigen expressed in the tumor is the potential etiology for these rare but refractory disorders. In recent years, wide variety of neurological presentations and autoantibodies has been associated with paraneoplastic autoimmunity, leading to formulation of an updated expert consensus PNS diagnostic criteria. Recognition of these phenotypes and use of serological biomarkers may aid neurologists in early diagnosis of PNS cases encountered in the inpatient or outpatient practice. In this review article, we provide an overview of various clinical, radiological, and immunopathological characteristics of PNS. Furthermore, we discuss the updated PNS criteria and increasing recognition of neurological presentations resembling the PNS among patients receiving immune checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

Background: As a debilitating syndrome, paraneoplastic cerebellar degeneration (PCD) remains challenging to treat. Further, anti-Yo antibody (directed against human cerebellar degeneration-related protein 2) detection in patients with PCD is associated with unsatisfactory responses to existing therapies. Here, we present the case of a 60-year-old woman who developed PCD with anti-Yo antibodies and a submandibular gland tumor.Case Presentation: A 60-year-old woman presented with a 5-day history of unsteadiness of gait and inadequate coordination of her extremities, along with truncal instability. Although walking without aid was possible, dysmetria of all four limbs, trunk, and gait ataxia was observed. While routine biochemical and hematological examinations were normal, the patient's blood was positive for anti-Yo antibodies. When the neurological symptoms deteriorated despite administration of intravenous methylprednisolone, fluorodeoxyglucose-positron emission tomography (FDG-PET) and computed tomography (CT) images with contrast enhancement were performed, which showed a tumor in the left submaxillary gland. She underwent total left submandibular gland resection, including the tumor; histological and immunohistochemical results revealed a salivary duct carcinoma. She was administered intravenous methylprednisolone, followed by 10 plasma exchange sessions, intravenous immunoglobulins, and cyclophosphamide therapy. Following treatment, her symptoms were not alleviated, even after the reduction of anti-Yo titers.Conclusions: Although tumor detection was delayed, early tumor detection, diagnosis, and PCD treatment are essential because any delay can result in the progression of the disorder and irreversible neurological damage. Therefore, we recommend that the possibility of a salivary gland tumor should be considered, and whole-body dual-modality CT, including the head and neck, and FDG-PET should be performed at the earliest for patients with well-characterized paraneoplastic antibodies when conventional imaging fails to identify a tumor. [ABSTRACT FROM AUTHOR]

Cytosolic 5′-nucleotidase IA (cN-IA) plays a central role in the regulation of the purine nucleotide pool in skeletal muscle, preferentially converting adenosine monophosphate to adenosine. cN-IA can act as an autoantigen in muscle diseases, including the paraneoplastic syndrome related to breast cancer (BC). As a result of myocyte damage, released cN-IA protein may trigger the production of anti-cN-IA antibodies (anti-NT5C1A). This work aimed to develop an effective method to measure cN-IA activity in the serum and analyze it in BC patients. Our study demonstrated that serum cN-IA activity was decreased in BC patients and we assumed it is due to the presence of specific autoantibodies. We found correlations between cN-IA activity and parameters of inflammatory muscle damage. Thus, cN-IA is worth further attention to clarify its usefulness as a biomarker of BC-associated polymyositis. [ABSTRACT FROM AUTHOR]

Paraneoplastic pemphigus is a rare and severe autoimmune blistering disease characterized by a recalcitrant and severe mucositis, and polymorphic cutaneous lesions, associated with benign and malignant neoplasms. Paraneoplastic pemphigus is caused by production of autoantibodies against various epidermal proteins involved in cell adhesion. Bronchiolitis obliterans (BO) is one of the leading causes of mortality in these patients. Recent advances have associated the presence of anti-epiplakin antibodies with the development of BO in adult patients. Here we describe the first pediatric patient in whom the association of anti-epiplakin antibodies and BO have been reported so far. [ABSTRACT FROM AUTHOR]

Paraneoplastic neurological syndromes (PNS) are the immune-mediated effects of a remote cancer and are characterised by an autoantibody response against antigens expressed by the tumour. Classically, well-characterised 'onconeuronal' antibodies target intracellular antigens and hence cannot access their antigens across intact cell membranes. The pathogenic mediators are likely to be neuronal-specific T cells. There is a variable response to immunotherapies and the clinical syndrome helps to direct the search for a specific set of tumours. By contrast, many newly emerging autoantibodies with oncological associations target cell surface epitopes and can exert direct pathogenic effects on both the central and peripheral nervous systems. Patients with these cell- surface directed autoantibodies often clearly respond to immunotherapies. Overall, the clinical, serological and oncological features in an individual patient help to determine the clinical relevance of the syndrome and hence guide its management. We summarise current knowledge and a practical approach to the investigation, diagnosis, treatment and outcomes of patients with suspected PNS. [ABSTRACT FROM AUTHOR]

Purkinje cell cytoplasmic autoantibody type 1 (PCA1), also known as anti-Yo, is a 'high-risk' paraneoplastic antibody, associated with rapidly progressive cerebellar syndrome. In patients with this syndrome, various MRI abnormalities have been documented, including atrophy in the cerebellum and brainstem, T2 hyperintensity in the brainstem and spinal cord, and cranial nerve enhancement. This report introduces an imaging finding, cerebellar leptomeningeal enhancement, which was observed in all three cases at early stages. Despite neurological deterioration, all patients underwent immunotherapy, and subsequent follow-up MRI revealed resolution of the leptomeningeal enhancement, suggesting that this feature is distinct from meningeal carcinomatosis. • Cerebellar leptomeningeal enhancement can be observed in the early stages of PCA1 autoimmunity [ABSTRACT FROM AUTHOR]

The paraneoplastic Ma antigen (PNMA) proteins are associated with cancer-induced paraneoplastic syndromes that present with an autoimmune response and neurological symptoms. Why PNMA proteins are associated with this severe autoimmune disease is unclear. PNMA genes are predominantly expressed in the central nervous system and are ectopically expressed in some tumors. We show that PNMA2 , which has been co-opted from a Ty3 retrotransposon, encodes a protein that is released from cells as non-enveloped virus-like capsids. Recombinant PNMA2 capsids injected into mice induce autoantibodies that preferentially bind external "spike" PNMA2 capsid epitopes, whereas a capsid-assembly-defective PNMA2 protein is not immunogenic. PNMA2 autoantibodies in cerebrospinal fluid of patients with anti-Ma2 paraneoplastic disease show similar preferential binding to spike capsid epitopes. PNMA2 capsid-injected mice develop learning and memory deficits. These observations suggest that PNMA2 capsids act as an extracellular antigen, capable of generating an autoimmune response that results in neurological deficits. [Display omitted] • Gag-derived PNMA2 protein is released from cells as non-enveloped virus-like capsids • Recombinant PNMA2 capsids injected into mice induce an autoimmune reaction • Mouse and paraneoplastic patient PNMA2 autoantibodies bind to external capsid epitopes • Mice injected with PNMA2 capsids develop learning and memory deficits PNMA2 is a domesticated retrotransposon gene associated with cancer-induced paraneoplastic neurological syndromes. Findings here show that PNMA2 protein is exclusively expressed in the brain of mammals and is released as non-enveloped virus-like capsids, which are immunogenic and induce an autoimmune response that leads to neurological deficits when injected into mice. [ABSTRACT FROM AUTHOR]

Introduction: Paraneoplastic neurological syndromes (PNS) are rare neurological conditions and they are mostly triggered by autoimmune mechanisms. Cancer-related retinopathies (CAR) are even rarer and commonly related with breast tumor in woman. This limits our knowledge about pathophysiology of CAR. In this study, we question the association between histopathological findings and onconeural antibodies in breast cancer. Method: Thirty-two patients with newly diagnosed breast cancer admitted to the oncology outpatient clinic were included in the study. None of the participants have visual complaints. After the neurological examination of the patients, two tubes of 5 cc venous blood were obtained by screening onconeuronal antibodies. Samples were investigated in ASDETAE (İstanbul University Experimental Medicine Research Institute). Results: Patients included in the study included one patinet (3.1%) with grade 1, 14 patients (43.8%) with grade 2 and 17 patients (53.1%) with grade 3 invasive breast cancer. Perineural invasion was detected in 5 (15.6%) patients. Progesterone receptor positivity was found in 26 (81.2%) patients and estrogen receptor positivity was found in 27 (84.4%) patients. In 7 (21.9%) patients, CERBB2 was positive and in 25 (78.1%) patients, Ki 67 was positive. A total of 12 (37.5%) patients had onconeuroneal antibody positivity. Antibody positivity was significantly higher in patients with high grade tumor (p=0.008). Conclusion: There may be a relationship between tumor grade and the presence of onconeuronal antibodies in breast cancer patients. By the detection of new biochemical markers, significant contribution can be made to the early diagnosis and treatment of underlying cancer. [ABSTRACT FROM AUTHOR]

Paraneoplastic optic neuropathy is a relatively rare ocular manifestation. We report the case of a patient with bilateral papilledema revealing a pulmonary squamous cell carcinoma. Paraneoplastic neuropathy is linked to an immune reaction by the presence of autoantibodies against collapsin responsive mediator protein 5. Diagnosis is based on the determination of these autoantibodies and the search for occult cancer by PET scan.Treatment is often based on corticosteroid therapy and sometimes immunosuppressive treatment is necessary in the case of corticosteroid unresponsiveness. [ABSTRACT FROM AUTHOR]

Melanoma-associated retinopathy (MAR) is a paraneoplastic syndrome that involves the production of autoantibodies which can cross-react with retinal epitopes leading to visual symptoms. Autoantibodies can target intracellular proteins, and only a few are directed against membrane proteins. This discrepancy in autoantibody–protein target can translate into different immune responses (T-cell mediated vs B-cell mediated). Historically, treatment of MAR has focused on surgical reduction or immunosuppressive medication, mainly glucocorticoids. However, tumor resection is not relevant in metastatic melanoma in which MAR is mostly encountered. Moreover, the use of glucocorticoids can reduce the efficacy of immunotherapy. We report the first case to our knowledge with subjective resolution of visual symptoms and objective evidence of normalization of electroretinogram of MAR with undetectable autoantibodies after administration of programmed death-1 (PD-1) inhibitor (pembrolizumab) without the use of surgical reduction or systemic immunosuppression. This case highlights the potential improvement and resolution of negative autoantibody MAR with the use of PD-1 inhibitors and emphasizes the importance of multidisciplinary approach and team discussion to avoid interventions that can decrease immunotherapy-mediated anti-tumor effect. [ABSTRACT FROM AUTHOR]

Limbic encephalitis with antibodies against adenylate kinase 5 (AK5) has been difficult to characterize because of its rarity. In this study, we identified 10 new cases and reviewed 16 previously reported patients, investigating clinical features, IgG subclasses, human leucocyte antigen and CSF proteomic profiles. Patients with anti-AK5 limbic encephalitis were mostly male (20/26, 76.9%) with a median age of 66 years (range 48-94). The predominant symptom was severe episodic amnesia in all patients, and this was frequently associated with depression (17/25, 68.0%). Weight loss, asthenia and anorexia were also highly characteristic, being present in 11/25 (44.0%) patients. Although epilepsy was always lacking at disease onset, seizures developed later in a subset of patients (4/25, 16.0%). All patients presented CSF abnormalities, such as pleocytosis (18/25, 72.0%), oligoclonal bands (18/25, 72.0%) and increased Tau (11/14, 78.6%). Temporal lobe hyperintensities were almost always present at disease onset (23/26, 88.5%), evolving nearly invariably towards severe atrophy in subsequent MRIs (17/19, 89.5%). This finding was in line with a poor response to immunotherapy, with only 5/25 (20.0%) patients responding. IgG1 was the predominant subclass, being the most frequently detected and the one with the highest titres in nine CSF-serum paired samples. A temporal biopsy from one of our new cases showed massive lymphocytic infiltrates dominated by both CD4+ and CT8+ T cells, intense granzyme B expression and abundant macrophages/microglia. Human leucocyte antigen (HLA) analysis in 11 patients showed a striking association with HLA-B*08:01 [7/11, 63.6%; odds ratio (OR) = 13.4, 95% confidence interval (CI): 3.8-47.4], C*07:01 (8/11, 72.7%; OR = 11.0, 95% CI: 2.9-42.5), DRB1*03:01 (8/11, 72.7%; OR = 14.4, 95% CI: 3.7-55.7), DQB1*02:01 (8/11, 72.7%; OR = 13.5, 95% CI: 3.5-52.0) and DQA1*05:01 (8/11, 72.7%; OR = 14.4, 95% CI: 3.7-55.7) alleles, which formed the extended haplotype B8-C7-DR3-DQ2 in 6/11 (54.5%) patients (OR = 16.5, 95% CI: 4.8-57.1). Finally, we compared the CSF proteomic profile of five anti-AK5 patients with that of 40 control subjects and 10 cases with other more common non-paraneoplastic limbic encephalitis (five with antibodies against leucine-rich glioma inactivated 1 and five against contactin-associated protein-like 2), as well as 10 cases with paraneoplastic neurological syndromes (five with antibodies against Yo and five against Ma2). These comparisons revealed 31 and seven significantly upregulated proteins in anti-AK5 limbic encephalitis, respectively mapping to apoptosis pathways and innate/adaptive immune responses. These findings suggest that the clinical manifestations of anti-AK5 limbic encephalitis result from a distinct T cell-mediated pathogenesis, with major cytotoxicity-induced apoptosis leading to a prompt and aggressive neuronal loss, likely explaining the poor prognosis and response to immunotherapy. [ABSTRACT FROM AUTHOR]

An association between immunoglobulin G4-related disease (IgG4-RD) and malignancy has been suggested. We report two cases of IgG4-RD with suspected paraneoplastic syndrome. In both patients, malignancy was observed immediately after diagnosis of IgG4-RD, and surgical resection resulted in spontaneous regression of IgG4-RD. We review the reports on IgG4-RD associated with malignancy, including these two cases, and discuss their relevance. [ABSTRACT FROM AUTHOR]

Discovery and characterization of serologic biomarkers has revolutionized the diagnostic framework of systemic and paraneoplastic autoimmune neuro-ophthalmic diseases. Expanding recognition of the multiple ocular and visual manifestations of these conditions highlights the important role of the referring provider in identifying potential cases. Increasing ease of access to serologic testing also enables these practitioners to initiate the diagnostic work-up in suspected cases. We aimed to provide an update on the current knowledge surrounding and use of relevant autoimmune biomarkers by correlating specific clinical neuro-ophthalmic manifestations with autoantibody biomarkers. The utility of select biomarkers for myasthenia gravis, neuromyelitis optica spectrum disorder, myelin oligodendrocyte glycoprotein-IgGassociated disorder, opsoclonus-myoclonus syndrome, anti-collapsin-response mediator protein-5 optic neuropathy, and glial fibrillary acidic protein-IgG-associated disease are discussed with particular focus on the clinical contexts in which to consider testing. [ABSTRACT FROM AUTHOR]

Background Paraneoplastic cerebellar degeneration (PCD) is a clinical syndrome in which cerebellar dysfunction is associated with identifiable or occult cancer but without the direct involvement of the nervous system by cancer.1,2 Typically, the disorder evolves sub-acutely, causes severe immune-mediated pan cerebellar dysfunction, and is associated with extensive purkinje cell loss, sometimes accompanied by meningeal and deep cerebellar nuclear inflammatory infiltrates.1 It has been linked to elevated anti-yo antibody serum titre in affected patients. It is most commonly associated with breast and other gynaecological cancers and often presents in patients prior to their cancer diagnosis. Hence, an aggressive search for an underlying malignancy would confirm the diagnosis and provide a basis for treatment, which is what this case series intends to highlight. Materials and method We present three cases of patients (aged 50-70 years) presenting with cerebellar features; truncal and/or limb ataxia, dysarthria and nystagmus. All of them have a rise in anti-yo antibody titre, as well as a positive oligoclonal band in the CSF, raising a strong suspicion of PCD.3,4 Their preliminary CT TAP and MRI brain were unyielding. However, the high index of suspicion prompted a positron emission tomographic (PET) scan, which identified the origin of the malignancy as breast in the first two cases and fallopian tube in the third case (metastatic deposits in the pelvic side wall were seen here on the PET scan necessitating an exploratory laparotomy). All the cancers were confirmed on histology. Results All three patients received intravenous immunoglobulin (IVIg) as part of their treatment. Of the two breast cancer cases, one was a grade 3 non-invasive DCIS, hence mastectomy was offered in addition. Unfortunately, none of the patients improved despite treatment at the time this information was collected, although there was no long-term follow up. Conclusion The case series demonstrated the need for a high index of suspicion of underlying malignancy in patients presenting with features of PCD and the need to pursue it aggressively. This would not only help to confirm the diagnosis but would aid in management. However, further studies are needed to explore alternative treatment options. [ABSTRACT FROM AUTHOR]

Purpose: To describe outcomes of combined rituximab and bortezomib treatment for non-paraneoplastic autoimmune retinopathy.Case: A 37-year-old female developed photopsias and reduced vision. Electroretinography, optical coherence tomography, and positive serum anti-retinal antibodies were consistent with autoimmune retinopathy. A negative malignancy work-up specified her non-paraneoplastic presentation. Given absence of response to periocular steroids, azathioprine, and methotrexate, a combination of rituximab and bortezomib was initiated as fifth-line therapy.Results: There was no significant improvement in the patient's symptoms or visual function following treatment. The full field electroretinogram amplitudes were reduced with progressive outer retinal degeneration evident on optical coherence tomography. Post-treatment anti-retinal antibody testing demonstrated the persistence of antibodies and revealed additional antibodies not previously detected.Conclusion: Combined rituximab and bortezomib treatment did not result in significant clinical improvement and there was evidence of disease progression. Further prospective studies are required to assess the efficacy of immunotherapy in patients with autoimmune retinopathy. [ABSTRACT FROM AUTHOR]

The article describes the case of a 52-year-old female with a history of asymmetrical weakness in both the lower limbs. Topics include the detection of lump in the right breast of the patient on general physical examination, development of jaw-closing oromandibular dystonia in the patient, and first step in management of paraneoplastic jaw dystonia and myelopathy with anti-Ri/antineuronal nuclear antibody type 2 (ANNA-2) antibody.

The reported case is a 61-year-old woman, admitted for gradual onset of gait disturbances and dysphonia. The serum immunological panel revealed anti-Yo autoantibodies, suggestive of a paraneoplastic syndrome (PNS). A PET-CT revealed a suspicious left ovarian mass with retroperitoneal nodal involvement, and the histological assessment of surgical samples confirmed a FIGO IIIC high-grade serous ovarian cancer (HGSOC). Deemed inoperable at first, the patient was treated by carboplatin and paclitaxel chemotherapy, after which she refused surgical debulking. At the end of her systemic treatment, the patient only experienced a transient improvement of the cerebellar ataxia. Despite the suboptimal oncological treatment, the patient still presents stable disease and is free of progression 7 years from her diagnosis. This case study illustrates the favorable effect of PNS occurrence on oncological outcome in a patient with advanced HGSOC. The absence of recurrence despite the presence of residual disease after the systemic treatment is unusual and could be related to the PNS. [ABSTRACT FROM AUTHOR]

Paraneoplastic neurological syndromes (PNS) are rare disorders affecting any part of the central, peripheral or autonomic nervous system that occur in association with cancer. Among cancer patients, less than 1% overall develop PNS. Anti‐SOX1 antibodies' positive paraneoplastic neurological disorders are rare and are usually associated with small cell lung cancer (SCLC). Here, we report a case of a 61‐year‐old male patient who presented with an unusual anti‐SOX1 positive PNS. The right tibialis anterior showed noticeable low‐amplitude motor unit potentials and high amplitude motor potentials in electrodiagnostic study, suggesting the presence of Lambert‐Eaton myasthenic syndrome (LEMS). Typical MRI and PET‐CT found a hyperintense lesion with contrast enhancement in the thorax in front of 5–6 centrum of vertebrae, and thoracoscopic biopsy revealed pathological findings for SCLC. The patient underwent several lines of chemotherapy and radiotherapy and survived for 15 months after the diagnosis of SCLC. [ABSTRACT FROM AUTHOR]

Autoimmune bullous diseases are a group of chronic inflammatory disorders caused by autoantibodies targeted against structural proteins of the desmosomal and hemidesmosomal plaques in the skin and mucosa, leading to intra-epithelial or subepithelial blistering. The oral mucosa is frequently affected in these diseases, in particular, in mucous membrane pemphigoid, pemphigus vulgaris, and paraneoplastic pemphigus. The clinical symptoms are heterogeneous and may present with erythema, blisters, erosions, and ulcers localized anywhere on the oral mucosa, and lead to severe complaints for the patients including pain, dysphagia, and foetor. Therefore, a quick and proper diagnosis with adequate treatment is needed. Clinical presentations of autoimmune bullous diseases often overlap and diagnosis cannot be made based on clinical features alone. Immunodiagnostic tests are of great importance in differentiating between the different diseases. Direct immunofluorescence microscopy shows depositions of autoantibodies along the epithelial basement membrane zone in mucous membrane pemphigoid subtypes, or depositions on the epithelial cell surface in pemphigus variants. Additional immunoserological tests are useful to discriminate between the different subtypes of pemphigoid, and are essential to differentiate between pemphigus and paraneoplastic pemphigus. This review gives an overview of the clinical characteristics of oral lesions and the diagnostic procedures in autoimmune blistering diseases, and provides a diagnostic algorithm for daily practice. [ABSTRACT FROM AUTHOR]

The pathogenesis of Yo-mediated paraneoplastic cerebellar degeneration (PCD) is unclear. We applied cerebrospinal fluid and serum from PCD patients as well as CDR2 and CDR2L antibodies to neuronal tissue, cancer cell lines, and cells transfected with recombinant CDR2 and CDR2L to elucidate which is the major antigen of Yo antibodies. We found that Yo antibodies bound endogenous CDR2L, but not endogenous CDR2. However, Yo antibodies can bind the recombinant CDR2 protein used in routine clinical testing for these antibodies. Because Yo antibodies only bind endogenous CDR2L, we conclude that CDR2L is the major antigen of Yo antibodies in PCD. ANN NEUROL 2019;86:316-321. [ABSTRACT FROM AUTHOR]

To describe autoantibodies (Abs) against tripartite motif-containing (TRIM) protein 9 and 67 in two patients with paraneoplastic cerebellar degeneration (PCD) associated with lung adenocarcinoma. Abs were characterized using immunohistochemistry, Western blotting, cultures of murine cortical, and hippocampal neurons, immunoprecipitation, mass spectrometry, knockout mice for Trim9 and 67, and cell-based assay. Control samples included sera from 63 patients with small cell lung cancer without any paraneoplastic neurological syndrome, 36 patients with lung adenocarcinoma and PNS, CSF from 100 patients with autoimmune encephalitis, and CSF from 165 patients with neurodegenerative diseases. We found Abs targeting TRIM9 and TRIM67 at high concentration in the serum and the cerebrospinal fluid (CSF) of a 78-year-old woman and a 65-year-old man. Both developed subacute severe cerebellar ataxia. Brain magnetic resonance imaging found no abnormality and no cerebellar atrophy. Both had CSF inflammation with mild pleiocytosis and a few oligoclonal bands. We identified a pulmonary adenocarcinoma, confirming the paraneoplastic neurological syndrome in both patients. They received immunomodulatory and cancer treatments without improvement of cerebellar ataxia, even though both were in remission of their cancer (for more than 10 years in one patient). Anti-TRIM9 and anti-TRIM67 Abs were specific to these two patients. All control serum and CSF samples tested were negative for anti-TRIM9 and 67. Anti-TRIM9 and anti-TRIM67 Abs appeared to be specific biomarkers of PCD and should be added to the panel of antigens tested when this is suspected. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract Background Paraneoplastic neurological syndromes (PNS) are a group of syndromes that affect the central and peripheral neuromuscular system in association with cancer. Specific antibodies may assist in the diagnosis of PNS. The antibodies tested can be classified into those directed against intracellular neuronal proteins ("well characterized" PNS: Hu, Yo, RI, CV2, amphiphysin, Ma1, Ma2) and those directed against neural surface antigens (autoimmune encephalitis syndromes: NMDA, AMPA, LGI1, CASPR2, GABAR). We aimed to characterize patients with unexplained neuropsychiatric symptoms, in whom positive PNS antibodies were detected in the Sheba medical center, a large referral hospital. Methods Clinical and demographic data of patients with positive PNS antibodies were collected during the years 2002–2016. Antibodies were tested by either Line immunoassay or by cell-based indirect immunofluorscent assay. Results During the follow up of 14 years, 4010 PNS tests were performed in patients with unexplained neuropsychiatric symptoms. Seventy-two were found to be positive; among them we had full clinical data access to 44. The most frequent antibodies were anti-Hu (31.8%), anti-Yo (18.2%), anti-CV2 (13.6%), and anti-NMDA (9.1%), and the most common cancers were small-cell lung (SCLC) and ovarian cancers. In the well characterized paraneoplastic group, cancer was diagnosed in 55.9% of the patients, and in the autoimmune encephalitis group, 40.0% were diagnosed with cancer. A positive correlation between antibody titer and the presence of cancer was found. Ninety percent of the tests in patients who were found positive were ordered by a neurologist or neuro-oncologist. Conclusions The titers of PNS auto-antibodies can predict cancer in patients whom anti-PNS antibodies are tested. In addition, consultation with a specialist should be considered before this test is ordered. [ABSTRACT FROM AUTHOR]

Antibodies to the ganglioside GD1b have been reported in various forms of immune‐mediated neuropathy, but their clinical relevance for diagnosis and prognosis is unknown. We investigated the prevalence of anti‐GD1b antibodies in acute and chronic immune‐mediated neuropathies, and the clinical presentation and outcome in Guillain‐Barré syndrome (GBS) and Miller Fisher‐GBS overlap syndrome (MF‐GBS). Anti‐GD1b, anti‐GM1 and anti‐GQ1b antibodies were tested in serum of patients with GBS (N = 165), Miller Fisher syndrome (N = 10), MF‐GBS (N = 28), monoclonal gammopathy of unknown significance neuropathy (MGUS; N = 101), chronic inflammatory demyelinating polyneuropathy (N = 29), paraneoplastic syndrome with anti‐Hu‐associated neuropathy (PNS; N = 11), other auto‐immune diseases (AID; N = 60), and healthy controls (HC; N = 60). All samples were tested by enzyme‐linked immunosorbent assay according to the Inflammatory Neuropathy Cause and Treatment protocol. IgM anti‐GD1b antibodies were found in GBS (N = 4; 2.4%), MGUS (N = 3; 3.0%), and PNS patients (N = 1; 9.1%). IgG anti‐GD1b antibodies were found in GBS (N = 20; 12.1%) and MF‐GBS (N = 4; 14.3%) patients, but not in the AID and HC group. In the combined group of MF‐GBS and GBS patients ((MF‐)GBS), 14/36 (38.9%) patients with IgG anti‐GD1b antibodies also had IgG anti‐GM1 antibodies, and IgG anti‐GD1b and IgG anti‐GQ1b antibodies were found in 3/29 (10.3%) patients. Patients with (MF‐)GBS and anti‐GD1b without anti‐GM1 antibodies did not differ regarding sensory disturbances or disease severity but recovered faster regarding the ability to walk independently compared with patients without anti‐GD1b antibodies (P = 0.031) and with patients with both anti‐GD1b and anti‐GM1 antibodies (P = 0.034). In conclusion, testing for anti‐GD1b antibodies may identify a specific group of immune‐mediated neuropathies and (MF‐)GBS patients with only anti‐GD1b antibodies tend to recover faster. [ABSTRACT FROM AUTHOR]

In 10-30% of MDS and CMML cases, autoimmune or auto-inflammatory disorders (AID) could occur concomitantly, before or after the MDS/CMML diagnosis [[1]]. Our purpose was to evaluate the frequencies of autoantibodies in MDS/CMML patients without clinical AID in comparison to MDS/CMML patients with various AID and to healthy controls. The MDS/CMML patients with AID were younger (75 (16-90) years vs. 77 (37-94) than MDS/CMML patients without AID ( I p i <.001) and had higher levels of C-reactive protein (41 (0-210) mg/L vs. 4 (1-39); I p i <.00001). [Extracted from the article]

Abstract: A 55‐year‐old postmenopausal and multiparous woman presented to our department with recent memory disturbances associated with rapidly progressive positive Anti‐Hu antibodies. She was subsequently diagnosed with anti‐Hu antibody‐related paraneoplastic limbic encephalitis. Clinical examination and imaging studies revealed a bulky cervical tumor with both parametrial and vaginal fornix extension; biopsy confirmed the tumor as cervical squamous cell carcinoma. In this case, we encountered a patient with anti‐Hu‐mediated paraneoplastic limbic encephalitis with a subsequent diagnosis of cervical cancer. [ABSTRACT FROM AUTHOR]

Objectives: To analyse the influence of genetic alterations and differential expression of transcription intermediary factor 1 (TIF1) genes in the pathophysiology of cancer-associated myositis (CAM). Methods: Paired blood and tumour DNA samples from patients with anti-TIF1γ-positive CAM and from controls were analysed by whole-exome sequencing for the presence of somatic mutations and loss of heterozygosity (LOH) in their TIF1 genes. The genesis and maintenance of the autoimmune process were investigated immunohistochemically by studying TIF1γ expression in the different tissues involved in CAM (skin, muscle and tumour) based on the immunohistochemical H-score. Results: From seven patients with anti-TIF1γ-positive CAM, we detected one somatic mutation and five cases of LOH in one or more of the four TIF1 genes compared with just one case of LOH in tumours from TIF1γ-negative myositis patients (86% vs 17%; P = 0.03). Compared with type-matched control tumours from non-myositis patients, TIF1γ staining was more intense in tumours from anti-TIF1γ-positive patients (H-score 255 vs 196; P = 0.01). Also, TIF1γ staining in muscle was slightly more intense in anti-TIF1γ-positive than in anti-TIF1γ-negative myositis (H-score 22 vs 5; P = 0.03). In contrast, intense TIF1γ staining was detected in the skin of both myositis and control patients. Conclusion: Tumours from paraneoplastic anti-TIF1γ-positive patients showed an increased number of genetic alterations, such as mutations and LOH, in TIF1 genes. These genetic alterations, in the context of a high expression of TIF1γ in the tumour, muscle and skin of these patients may be key to understanding the genesis of paraneoplastic myositis. [ABSTRACT FROM AUTHOR]

The aim of this study is to compare the rates of clinically relevant and clinically irrelevant neuronal autoantibodies among patients presenting with new neurological symptoms. We reviewed 401 neurological patients who were tested for the Mayo-Clinic paraneoplastic panel from January 2014 to December 2014 at the Johns Hopkins Hospital. We divided antibody-positive patients into two groups: clinically relevant (CR), in which a recognizable autoimmune or paraneoplastic syndrome was confirmed, and clinically irrelevant (CI), in which an autoimmune/paraneoplastic etiology was initially suspected but an alternative diagnosis was eventually found. We used Fisher's exact test for categorical variables and Mann-Whitney U test for continuous variables to identify differences between the two groups. Fifty-three patients tested positive for one or more neuronal autoantibodies. There were 17 CR (65% females, mean age 56 years), 33 CI, and 3 indeterminate patients. Compared to CI patients, CR patients were more likely to present with movement disorders or stiff person syndrome, have inflammatory CSF markers, cancer or smoking history, concomitant hyponatremia, and classical onconeuronal antibodies. CI patients were more likely to have a neuromuscular presentation, a chronic course, and antibodies against synaptic antigens. By combining the most robust differentiating factors, we developed a simple scale that predicted clinical relevance with an odds ratio of 50.3 (CI 8.2-309.9, P < 0.0001) if the score was ≥ 2. Up to 62% of neuronal autoantibody-positive patients are ultimately found to have an alternative diagnosis. Several clinical and laboratory factors can differentiate CR from CI patients to aid in interpretation of positive results. [ABSTRACT FROM AUTHOR]

This document presents the guidelines for onconeural antibody testing that have been developed following a consensus process built on questionnaire-based surveys, internet contacts, and discussions at workshops of the sponsoring Italian Association of Neuroimmunology (AINI) congresses. Essential clinical information on paraneoplastic neurological syndromes, indications and limits of onconeural antibody testing, instructions for result interpretation, and an agreed laboratory protocol (Appendix) are reported for the communicative community of neurologists and clinical pathologists. [ABSTRACT FROM AUTHOR]

The recent discovery of neuronal cell-surface antibodies profoundly expanded the clinical spectrum of paraneoplastic neurological syndromes. Many of these syndromes are associated with impaired cognitive function, a clinical symptom that is of increasing concern in cancer patients. However, the frequency of these antibodies in cancer patients and their relation to clinical syndromes is currently unknown. Here, we investigated the prevalence of neuronal cell-surface antibodies and associated paraneoplastic neurological syndromes in 323 patients with different cancer types and in 105 controls. Cerebrospinal fluid and serum samples were analysed for a large panel of anti-neuronal antibodies and all patients were screened for cognitive deficits. Blood-brain barrier integrity was assessed using the age-normalized albumin cerebrospinal fluid/serum ratio. Anti-neuronal autoantibodies were observed in 24.5% of cancer patients (in contrast to 3.1% in neurological control patients without cancer and 2.5% in healthy controls) and were almost exclusively detected in serum. The majority of antibodies were directed against cell-surface antigens (75.9%), most frequently IgA/IgM isotypes targeting the N-methyl- d-aspartate (NMDA) receptor. Cognitive deficits and cerebellar syndromes were significantly more prevalent in antibody-positive in comparison with antibody-negative patients (21 vs. 7%, p = 2.7 × 10; 11 vs. 2%, p = 3.0 × 10). Antibody-positive patients with cognitive deficits had a significantly increased albumin cerebrospinal fluid/serum ratio in comparison with antibody-positive patients with other neurological deficits, indicating blood-brain barrier dysfunction (49.1 × 10 vs. 12.0 × 10; p = 0.036). Our results show that anti-neuronal antibodies have a high prevalence in a wide range of different tumour types and are associated with distinct neurological deficits. Specifically, the results suggest a so far undefined cognitive paraneoplastic syndrome in patients with antibodies targeting neuronal surface antigens and concurrent blood-brain barrier dysfunction. Anti-neuronal antibodies might thus serve as a biomarker for potentially treatment-responsive cognitive impairments in cancer patients. [ABSTRACT FROM AUTHOR]

Antibodies against brain proteins were identified in the plasma of cancer patients and are defined to cause paraneoplastic neurological syndromes. The profiles of brain-directed antibodies in non-small cell lung cancer (NSCLC) are largely unknown. Here, for the first time, we compared autoantibodies against brain proteins in NSCLC (n = 18) against those present in age-matched non-cancer control subjects (n = 18) with a similar life-style, habit, and medical history. Self-recognizing immunoglobulin (IgG) are primarily directed against cells in the cortex (P = 0.008), hippocampus (P = 0.003–0.05), and cerebellum (P = 0.02). More specifically, IgG targets were prominent in the pyramidal, Purkinje, and granule cell layers. Furthermore, autoimmune IgG signals were localized to neurons (81%), astrocytes (48%), and endothelial (29%) cells. While cancer sera yielded overall higher intensity signals, autoantigens of 100, 65, 45, 37, and 30 kDa molecular weights were the most represented. Additionally, a group of 100 kDa proteins seem more prevalent in female adenocarcinoma patients (4/5, 80%). In conclusion, our results revealed autoantigen specificity in NSCLC, which implicitly depends on patient’s demographics and disease history. Patients at risk for lung cancer but with no active disease revealed that the immune profile in NSCLC is disease-dependent. [ABSTRACT FROM AUTHOR]

Background: Experts in the autoimmune paraneoplastic field recommend autoantibody testing as “panels” to improve the poor sensitivity of individual autoantibodies in detecting paraneoplastic neurological syndromes (PNS). The sensitivity of those panels was not reported to date in a fashion devoid of incorporation bias. We aimed to assess the collective sensitivity and specificity of one of the commonly used panels in detecting PNS.Methods: A single-centered retrospective cohort of all patients tested for paraneoplastic evaluation panel (PAVAL; test ID: 83380) over one year for the suspicion of PNS. Case adjudication was based on newly proposed diagnostic criteria in line with previously published literature, but modified to exclude serological status to avoid incorporation bias. Measures of diagnostic accuracy were subsequently calculated. Cases that failed to show association with malignancy within the follow-up time studied, reflecting a possibly pure autoimmune process was considered paraneoplastic-like syndromes.Results: Out of 321 patients tested, 51 patients tested positive. Thirty-two patients met diagnostic criteria for paraneoplastic/paraneoplastic-like syndromes. The calculated collective sensitivity was 34% (95% CI: 17–53), specificity was 86% (95% CI: 81–90), Youden's index 0.2 and a positive clinical utility index 0.07 suggesting poor utility for case-detection.Conclusion: This is the first reported diagnostic accuracy measures of paraneoplastic panels without incorporation bias. Despite recommended panel testing to improve detection of PNS, sensitivity remains low with poor utility for case-detection. The high-calculated specificity suggests a possible role in confirming the condition in difficult cases suspicious for PNS, when enough supportive evidence is lacking on ancillary testing. [ABSTRACT FROM PUBLISHER]

Autoantibodies are important in the diagnosis of dermatomyositis. They can be divided in two different groups: myositis-associated autoantibodies (MAA) prevailing in overlap syndromes, and myositis-specific autoantibodies (MSA), with diagnostic specificity exceeding 90%. Our purpose was to detect retrospectively the prevalence of the most common MSAs in a group of 19 adult DM patients (13 women, 6 men). A severe DM (SDM), with extensive cutaneous and muscular manifestations, dysphagia, and sometimes pneumopathy, was detected in ten cases. Three patients had a mild DM (MDM), with little muscle and skin impairment, and a short course. Four patients suffered from amyopathic DM (ADM), two from paraneoplastic DM (PDM). Each serum was tested for ANA, ENA, MAAs, MSAs. Myositis-specific autoantibodies were detected in 15 cases. The most frequent was anti-TIF1γ, associated with SDM or PDM in four out of seven cases. Anti-MDA5 antibodies were recorded in a SDM and in a ADM with lung fibrosis. Anti-Mi2 and anti-SRP antibodies were both detected in a MDM and in a SDM, whereas anti-SAE1 in a amyopathic form. Other antibodies (anti-NXP2, -Jo1, -PL7, -PL12, -OJ) were found in single patients with SDM. Our series confirmed that specific autoantibodies could be helpful to classify different clinical subsets, particularly in the case of paraneoplastic forms or association with pneumopathy. Moreover, they can help in predicting the disease evolution and influence therapeutic strategies. A greater number of cases should be useful to highlight the clinical and pathogenic role of these antibodies, and develop a homogeneous protocol for diagnosis and treatment. [ABSTRACT FROM AUTHOR]

A 68-year-old male presented with blurred vision in both eyes. Ophthalmoscopy revealed bilateral prominent disc swelling and vitritis. No systematic neurological symptoms were observed. Magnetic resonance imaging revealed bilateral meningeal enhancement of the optic nerve. Small cell carcinoma was found, and antibodies against collapsing response-mediating protein-5 (CRMP-5) were detected in the serum. Ophthalmological manifestations disappeared during a decrease in tumour size with treatment for the malignancy. This case report describes this rare case of anti-CRMP-5 antibody–positive paraneoplastic perioptic neuritis without neurological symptoms, showing that prompt diagnosis and timely treatment of the underlying tumour are crucial to prevent increased levels of autoantibodies and irreversible damage to the nervous system. [ABSTRACT FROM AUTHOR]

Autoimmune paraneoplastic and neoplasm-associated skin syndromes are characterized by autoimmune-mediated cutaneous lesions in the presence of a neoplasm. The identification of these syndromes provides information about the underlying tumor, systemic symptoms, and debilitating complications. The recognition of these syndromes is particularly helpful in cases of skin lesions presenting as the first sign of the malignancy, and the underlying malignancy can be treated in a timely manner. Autoimmune paraneoplastic and neoplasm-associated bullous skin syndromes are characterized by blister formation due to an autoimmune response to components of the epidermis or basement membrane in the context of a neoplasm. The clinical manifestations, histopathology and immunopathology findings, target antigens, associated neoplasm, current diagnostic criteria, current understanding of pathogenesis, and treatment options for a selection of four diseases are reviewed. Paraneoplastic pemphigus manifests with clinically distinct painful mucosal erosions and polymorphic cutaneous lesions, and is often associated with lymphoproliferative neoplasm. In contrast, bullous pemphigoid associated with neoplasm presents with large tense subepidermal bullae of the skin, and mild mucosal involvement, but without unique clinical features. Mucous membrane pemphigoid associated with neoplasm is a disorder of chronic subepithelial blisters that evolve into erosions and ulcerations that heal with scarring, and involves stratified squamous mucosal surfaces. Linear IgA dermatosis associated with neoplasm is characterized by annularly grouped pruritic papules, vesicles, and bullae along the extensor surfaces of elbows, knees, and buttocks. Physicians should be aware that these autoimmune paraneoplastic and neoplasm-associated syndromes can manifest distinct or similar clinical features as compared with the non-neoplastic counterparts. [ABSTRACT FROM AUTHOR]