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Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, and the association with immune-related adverse events (irAEs) is well-established. However, cerebellar irAEs are poorly defined and their relationship with paraneoplastic disorders remains unclear. Our aim was (i) to characterize cerebellar irAE; (ii) to compare it with paraneoplastic cerebellar ataxia (PCA). We performed a multicenter, retrospective, cohort study of patients developing new-onset, immune-mediated, isolated/predominant cerebellar dysfunction after ICI administration. In addition, a systematic review following PRISMA guidelines was performed. Cerebellar irAE cases were compared with a consecutive cohort of patients with PCA. Overall, 35 patients were included, of whom 12 were original cases (males: 25/35 (71%), median age: 65 [range: 20–82]). The most frequent tumor was non-small cell lung cancer (12/35, 34%). Anti-PD1 were adopted in 19/35 (54%). Symptoms developed at a median of 11 weeks after ICI onset. Neuronal antibodies were detected in 15/31 patients tested (48%). Cerebrospinal fluid was inflammatory in 25/30 (83%). Magnetic resonance imaging showed cerebellar hyperintensities in 8/35 (23%). Immunotherapy was applied in 33/35 cases (94%), and most patients improved with residual disability (16/35, 46%). When compared with a series of PCA (n = 15), the cerebellar irAE group was significantly more associated with male sex, lung cancer (rather than gynecological/breast cancers), isolated ataxia, and a better outcome. We provide a detailed characterization of cerebellar irAE. Compared to PCA, differences exist in terms of tumor association, clinical features, and outcome. Clinical presentation-antibody-tumor triad in the ICI group only partially reflects the associations described in paraneoplastic disorders. [ABSTRACT FROM AUTHOR]

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

Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare neuroimmune disease with peak onset at 18 months, associated with neural crest tumors in 50% of patients. In part due to its rarity, misdiagnosis at onset is common, can delay treatment, and may contribute to adverse outcomes. Patient-reported registries may overcome some of these challenges in rare disease research. In this context, the OMSLife Foundation collaborated with the National Organization of Rare Diseases to create a patient-reported registry in OMAS. Retrospective analysis was performed of data entered by parents of patients with OMAS into nine online surveys assessing demographics, symptoms at onset, triggers, time of diagnosis, treatment, and additional therapies. A total of 194 patients were enrolled. There was a female predominance (54%) and high rate of parental autoimmunity (31%). Age at onset peaked between 12 and 18 months overall. The age of onset was older in female patients (median [interquartile range]: females 22 [15 to 31] vs males 18 [14 to 23], P = 0.0223, P = 0.0223). Symptoms at onset most commonly included ataxia (84%) and were typically severe. Initial misdiagnosis occurred in nearly 50% and tumor discovery was delayed in 18 patients, but overall median time to correct diagnosis was 25 days. Most patients (56%) received combination immunomodulatory therapies, and nearly all underwent supportive therapies. Patient- and parent-powered research is feasible in OMAS and created the second largest published cohort of pediatric patients with OMAS. Results were similar to other large cohorts and also validated findings from prior case reports and smaller case series. [ABSTRACT FROM AUTHOR]

Background. Paraneoplastic neurological syndromes (PNS) are a rare and diverse group of disorders caused by immune-mediated effects of malignancies. Affecting less than 1% of all cancer patients, these syndromes often present diagnostic and therapeutic challenges. Motor Neuron Disease as a paraneoplastic condition is particularly uncommon, especially in association with gastrointestinal malignancies like sigmoid colon adenocarcinoma. Case report. A 62-year-old male with Type 2 Diabetes Mellitus (T2DM) presented with chronic diarrhea and a three-year history of progressive bilateral limb weakness. Initial symptoms were attributed to diabetic neuropathy, but the rapid progression and severity warranted further investigation. Neurological examination revealed hypotonia, muscle wasting, and absent reflexes in all four limbs. Diagnostic tests, including electromyography (EMG) and nerve conduction studies, confirmed motor sensory axonal neuropathy. Colonoscopy revealed a mass in the sigmoid colon, and biopsy confirmed adenocarcinoma. The patient was managed with surgical resection of the tumor, adjuvant chemotherapy, and immunomodulatory treatments, resulting in stabilization of neurological symptoms. Conclusions. This case highlights the importance of considering paraneoplastic syndromes in patients with unexplained neurological symptoms, particularly when a malignancy is suspected or known. Early recognition and a multidisciplinary approach are crucial for improving patient outcomes. Further research is needed to understand the pathophysiological mechanisms and develop sensitive biomarkers for early detection. [ABSTRACT FROM AUTHOR]

Simple Summary: Autoantibodies against the metabotropic glutamate receptor 5 (mGluR5) have been linked to Ophelia syndrome, a combination of limbic encephalitis and Hodgkin lymphoma (HL). We studied mGluR5 expression in 57 pediatric HL and NHL by immunohistochemistry to explore the relationship between mGluR5 antibody formation and HL. All lymphoma tissues displayed mGluR5 staining, especially HL Reed–Sternberg cells. There was no staining in age-matched healthy lymph nodes, and we did not find GRM5 transcripts in RNA-sequencing data from normal lymphocytes. Lower mGluR5 levels in HL correlated with younger patients and EBV-positive tumors. Cases of paraneoplastic and neurological symptoms were found exclusively in the HL cohort. The frequent presence of mGluR5 in lymphoma tissue suggests a possible role in tumor development. This finding is in line with reports that glutamatergic signaling affects the outcome in other cancers. However, further studies in larger cohorts are needed to evaluate the impact of mGluR5 on HL severity. Autoantibodies targeting the neuronal antigen metabotropic glutamate receptor 5 (mGluR5) have been identified in patients with Ophelia syndrome, which describes a co-occurrence of paraneoplastic limbic encephalitis and Hodgkin lymphoma (HL). Little data exist regarding frequency and function of mGluR5 in HL and its potential role in causing seropositive paraneoplastic disease. We studied a representative cohort of pediatric HL and NHL patients (n = 57) using immunohistochemistry and fluorescence staining to investigate mGluR5 expression. All lymphoma tissues displayed positive mGluR5 staining, with focus on Hodgkin–Reed–Sternberg (H-RS) cells. We did not detect any mGluR5 staining in tumor-free lymph nodes, which is consistent with the absence of GRM5 transcripts in RNA-sequencing data from non-malignant B and T cells. The frequent presence in pediatric lymphoma falls in line with reports of mGluR5 expression and associated tumor progression in other malignancies. We tested for correlation with clinical features, focusing on disease progression and neurological symptoms. Low mGluR5 expression in H-RS cells correlated with young patient age (<15 years) and positive histology for EBV infection. Paraneoplastic or neurological symptoms were found exclusively in HL patients. While an impact of mGluR5 on HL severity remains possible, a prognostic value of mGluR5 expression levels requires further investigation. [ABSTRACT FROM AUTHOR]

The use of immune checkpoint inhibitors (ICIs) for the treatment of various advanced and aggressive types of malignancy has significantly increased both survival and long-term remission rates. ICIs block crucial inhibitory pathways of the immune system, in order to trigger an aggravated immune response against the tumor. However, this enhanced immune activation leads to the development of numerous immune-related adverse events (irAEs), which may affect any system. Although severe neurological irAEs are relatively rare, they carry a high disability burden, and they can be potentially life-threatening. Therefore, clinicians must be alert and act promptly when individuals receiving ICIs present with new-onset neurological symptoms. In this narrative review, we have collected all the currently available data regarding the epidemiology, pathogenesis, clinical manifestations, diagnosis, and treatment of post-ICI neurological irAEs. This review aims to raise physicians' awareness, enrich their knowledge regarding disease pathogenesis, and guide them through the diagnosis and management of post-ICI neurological irAEs. [ABSTRACT FROM AUTHOR]

Paraneoplastic neurological syndromes (PNSs) are an uncommon complication of cancer, affecting nearby 1/10,000 subjects with a tumour. PNSs can involve all the central and peripheral nervous systems, the muscular system, and the neuromuscular junction, causing extremely variable symptomatology. The diagnosis of the paraneoplastic disease usually precedes the clinical manifestations of cancer, making an immediate recognition of the pathology crucial to obtain a better prognosis. PNSs are autoimmune diseases caused by the expression of common antigens by the tumour and the nervous system. Specific antibodies can help clinicians diagnose them, but unfortunately, they are not always detectable. Immunosuppressive therapy and the treatment of cancer are the cornerstones of therapy for PNSs. This paper reports a case of PNSs associated with breast tumours and focuses on the most common paraneoplastic neurological syndromes. We report a case of a young female with a clinical syndrome of the occurrence of rigidity in the right lower limb with postural instability with walking supported and diplopia, with a final diagnosis of paraneoplastic cerebellar degeneration and seronegative rigid human syndrome associated with infiltrating ductal carcinoma of the breast. [ABSTRACT FROM AUTHOR]

Introduction. Rapidly progressive cerebellar syndrome (RPCS), previously referred to as “subacute cerebellar degeneration” or “paraneoplastic cerebellar degeneration”, is an autoimmune disorder, wich in the most cases is associated with a malignancy located outside the nervous system. RPCS is classified as one of the the paraneoplastic neurological syndromes and manifests in the early, often preclinical stages of oncopathology. Its diagnosis is difficult, but is necessary, since it can become a starting point for further screening for cancer. The article provides a clinical description of a 40-year-old patient with subacute development of hemiataxia and subsequent rapid progression of bilateral cerebellar deficiency associated with brainstem signs. The example of this case shows how difficult the diagnostic path is, since only the use of positron emission tomography and subsequent examination of a biopsy of the lesion in this patient made it possible to identify metastasis of poorly differentiated breast carcinoma in the axillary lymph node. The tumor itself was not found in the mammary gland. Since paraneoplastic antibodies were not detected in the patient’s blood and cerebrospinal fluid, a diagnosis of “probable” (not “definite”) RPCS was diagnosed in accordance with the diagnostic criteria proposed by the panel of experts in 2021. The treatment of cancer stopped progression of neurological deficit in the patient, but she remained severely disabled. Discussion. The approaches to the examination of patients with RPCS are discussed. Clinical assessment, neuronal antibodies testing and a targeted screening for cancer should be performed. Brief information is provided on the use of the PNS-Care scale in the diagnosis of paraneoplastic neurological syndromes. Conclusion. The presented case demonstrates the difficulties of diagnosing the RPCS and the associated cancer. The “definite” diagnosis of rapidly progressive cerebellar syndrome requires the presence of high or moderate risk antibodies and cancer that is consistent with the syndrome’s phenotype.

Paraneoplastic neurological syndromes, a diverse group of neurological syndromes, are associated with small cell lung, testicular, ovarian, and breast cancers; however, their association with neuroendocrine carcinoma of the small intestine remains unreported. In this report, we present the case of a 78-year-old man diagnosed with neuroendocrine carcinoma of the small intestine and experienced symptoms such as subacute progressive numbness of the extremities and impaired gait. These symptoms were diagnosed as tumor-associated neurological syndrome. The patient had also undergone pyloric gastrectomy for early-stage gastric cancer several years prior to the appearance of the neurological symptoms. Therefore, we could not determine whether the tumor-related neurologic syndrome was owing to gastric cancer or neuroendocrine carcinoma of the small intestine; however, one of these conditions was the cause of the neuropathy. The gait disturbance and numbness relatively improved after surgery for the neuroendocrine carcinoma of the small intestine, suggesting that the neuroendocrine carcinoma of the small intestine likely caused the paraneoplastic neurological syndrome. Collectively, we present a unique report highlighting the putative relationship between small bowel neuroendocrine carcinoma and tumor-associated neurologic syndromes. [ABSTRACT FROM AUTHOR]

The use of immune checkpoint inhibitors (ICIs) for the treatment of various advanced and aggressive types of malignancy has significantly increased both survival and long-term remission rates. ICIs block crucial inhibitory pathways of the immune system, in order to trigger an aggravated immune response against the tumor. However, this enhanced immune activation leads to the development of numerous immune-related adverse events (irAEs), which may affect any system. Although severe neurological irAEs are relatively rare, they carry a high disability burden, and they can be potentially life-threatening. Therefore, clinicians must be alert and act promptly when individuals receiving ICIs present with new-onset neurological symptoms. In this narrative review, we have collected all the currently available data regarding the epidemiology, pathogenesis, clinical manifestations, diagnosis, and treatment of post-ICI neurological irAEs. This review aims to raise physicians’ awareness, enrich their knowledge regarding disease pathogenesis, and guide them through the diagnosis and management of post-ICI neurological irAEs.

Abstract Background Opsoclonus-myoclonus syndrome (OMS) is a rare, immune-mediated neurological disorder. In adults, the pathogenesis can be idiopathic, post-infectious or paraneoplastic, the latter etiology belonging to the ever-expanding group of defined paraneoplastic neurological syndromes (PNS). In contrast to other phenotypes of PNS, OMS cannot be ascribed to a single pathogenic autoantibody. Here, we report the first detailed case of paraneoplastic, antibody-negative OMS occurring in association with a pancreatic neuroendocrine tumor (pNET). Case presentation A 33-year-old female presented with a two-week history of severe ataxia of stance and gait, dysarthria, head tremor, myoclonus of the extremities and opsoclonus. Her past medical history was notable for a metastatic pancreatic neuroendocrine tumor, and she was subsequently diagnosed with paraneoplastic opsoclonus-myoclonus syndrome. Further workup did not reveal a paraneoplastic autoantibody. She responded well to plasmapheresis, as she was refractory to the first-line therapy with corticosteroids. Conclusions This case expands current knowledge on tumors associated with paraneoplastic opsoclonus-myoclonus syndrome and the age group in which it can occur. It further adds evidence to the effectiveness of plasmapheresis in severe cases of opsoclonus-myoclonus syndrome with a lack of response to first-line therapy.

Abstract Background The anti-SOX-1 antibodies have been mainly associated with Lambert-Eaton Myasthenic Syndrome (LETMS) and Small-Cell Lung Cancer (SCLC). In this report, we describe the interesting case of a patient with serum anti-SOX-1 antibodies and Crohn’s Disease (CD) with ensuing neurological symptoms. Case presentation A Caucasian 67-year-old female was admitted to the Emergency Department with seizures, vertigo, emesis, nausea, postural instability and recurrent falls, over a period of 10 days. She had been affected by Crohn’s Disease since 1991. A CT scan failed to detect any ischemic or haemorrhagic lesion. A brain MRI revealed signs of leukoencephalopathy. Western blot analysis of her serum revealed a high titre of the onconeural antibody anti-SOX1, consistent with a neurological, cerebellar type, paraneoplastic syndrome. In spite of multiple efforts to unmask a possible underlying malignancy, no neoplastic lesion cropped up during hospitalization. Her clinical conditions progressively deteriorated, up to respiratory failure; a few days later she died, due to ensuing septic shock and Multiple Organ Failure. Conclusions Our experience may usher and reveal a new role of anti-neural antibodies, so far reckoned an early indicator of associated malignancy, suggesting that neurological syndromes associated with such antibodies may complicate also chronic Gastrointestinal (GI) diseases. As of now, testing for anti-neuronal antibodies appeared unnecessary within the diagnostic assessment of gastroenterological disorders, which may lead to overlooking incident neurologic autoimmune diseases. Further exploration of such research hypothesis in clinical grounds appears intriguing.

SOX1 antibodies (SOX1-abs) are associated with paraneoplastic neurological syndromes (PNS) and small cell lung cancer (SCLC). In many clinical laboratories SOX1-abs are determined by commercial line blots without confirmation by cell-based assay (CBA) with HEK293 cells expressing SOX1. However, the diagnostic yield of commercial line blots is low and the accessibility to the CBA, that is not commercially available, limited. Here, we evaluated if the addition of the band intensity data of the line blot and the immunoreactivity in a tissue-based assay (TBA) improve the diagnostic performance of the line blot. We examined serum of 34 consecutive patients with adequate clinical information that tested positive for SOX1-abs in a commercial line blot. Samples were also assessed by TBA and CBA. SOX1-abs were confirmed by CBA in 17 (50%) patients, all (100%) had lung cancer (SCLC in 16) and 15/17 (88%) had a PNS. In the remaining 17 patients the CBA was negative and none had PNS associated with lung cancer. TBA was assessable in 30/34 patients and SOX1-abs reactivity was detected in 15/17 (88%) with positive and in 0/13 (0%) with negative CBA. Only 2 (13%) of the 15 TBA-negative patients were CBA-positive. The frequency of TBAnegative but CBA-positive increased from 10% (1/10) when the band intensity of the line blot was weak to 20% (1/5) in patients with a moderate or strong intensity band. Confirmation by CBA should be mandatory for samples (56% in this series) not assessable (4/34; 12%) or negative in the TBA (15/34; 44%). [ABSTRACT FROM AUTHOR]

Paraneoplastic neurological syndromes (PNS) include any symptomatic and non-metastatic neurological manifestations associated with a neoplasm. PNS associated with antibodies against intracellular antigens, known as "high-risk" antibodies, show frequent association with underlying cancer. PNS associated with antibodies against neural surface antigens, known as "intermediate- or low-risk" antibodies, are less frequently associated with cancer. In this narrative review, we will focus on PNS of the central nervous system (CNS). Clinicians should have a high index of suspicion with acute/subacute encephalopathies to achieve a prompt diagnosis and treatment. PNS of the CNS exhibit a range of overlapping "high-risk" clinical syndromes, including but not limited to latent and overt rapidly progressive cerebellar syndrome, opsoclonus-myoclonus-ataxia syndrome, paraneoplastic (and limbic) encephalitis/encephalomyelitis, and stiff-person spectrum disorders. Some of these phenotypes may also arise from recent anti-cancer treatments, namely immune-checkpoint inhibitors and CAR T-cell therapies, as a consequence of boosting of the immune system against cancer cells. Here, we highlight the clinical features of PNS of the CNS, their associated tumors and antibodies, and the diagnostic and therapeutic strategies. The potential and the advance of this review consists on a broad description on how the field of PNS of the CNS is constantly expanding with newly discovered antibodies and syndromes. Standardized diagnostic criteria and disease biomarkers are fundamental to quickly recognize PNS to allow prompt treatment initiation, thus improving the long-term outcome of these conditions. [ABSTRACT FROM AUTHOR]

Paraneoplastic neurological syndromes (PNSs) are an uncommon complication of cancer, affecting nearby 1/10,000 subjects with a tumour. PNSs can involve all the central and peripheral nervous systems, the muscular system, and the neuromuscular junction, causing extremely variable symptomatology. The diagnosis of the paraneoplastic disease usually precedes the clinical manifestations of cancer, making an immediate recognition of the pathology crucial to obtain a better prognosis. PNSs are autoimmune diseases caused by the expression of common antigens by the tumour and the nervous system. Specific antibodies can help clinicians diagnose them, but unfortunately, they are not always detectable. Immunosuppressive therapy and the treatment of cancer are the cornerstones of therapy for PNSs. This paper reports a case of PNSs associated with breast tumours and focuses on the most common paraneoplastic neurological syndromes. We report a case of a young female with a clinical syndrome of the occurrence of rigidity in the right lower limb with postural instability with walking supported and diplopia, with a final diagnosis of paraneoplastic cerebellar degeneration and seronegative rigid human syndrome associated with infiltrating ductal carcinoma of the breast.

Abstract Background In 2014, we first described novel autoantibodies to the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1-IgG/anti-Sj) in patients with autoimmune cerebellar ataxia (ACA) in this journal. Here, we provide a review of the available literature on ITPR1-IgG/anti-Sj, covering clinical and paraclinical presentation, tumour association, serological findings, and immunopathogenesis. Methods Review of the peer-reviewed and PubMed-listed English language literature on ITPR1-IgG/anti-Sj. In addition, we provide an illustrative report on a new patient with ITPR1-IgG-associated encephalitis with cognitive decline and psychosis. Results So far, at least 31 patients with serum ITPR1-IgG/anti-Sj have been identified (clinical information available for 21). The most common manifestations were ACA, encephalopathy with seizures, myelopathy, and (radiculo)neuropathy, including autonomic neuropathy. In 45% of cases, an underlying tumour was present, making the condition a facultative paraneoplastic neurological disorder. The neurological syndrome preceded tumour diagnosis in all but one case. In most cases, immunotherapy had only moderate or no effect. The association of ITPR1-IgG/anti-Sj with manifestations other than ACA is corroborated by the case of a 48-year-old woman with high-titre ITPR1-IgG/anti-Sj antibodies and rapid cognitive decline, affecting memory, attention and executive function, and psychotic manifestations, including hallucinations, investigated here in detail. FDG-PET revealed right-temporal glucose hypermetabolism compatible with limbic encephalitis. Interestingly, ITPR1-IgG/anti-Sj mainly belonged to the IgG2 subclass in both serum and cerebrospinal fluid (CSF) in this and further patients, while it was predominantly IgG1 in other patients, including those with more severe outcome, and remained detectable over the entire course of disease. Immunotherapy with intravenous methylprednisolone, plasma exchange, and intravenous immunoglobulins, was repeatedly followed by partial or complete recovery. Long-term treatment with cyclophosphamide was paralleled by relative stabilization, although the patient noted clinical worsening at the end of each treatment cycle. Conclusions The spectrum of neurological manifestations associated with ITPR1 autoimmunity is broader than initially thought. Immunotherapy may be effective in some cases. Studies evaluating the frequency of ITPR1-IgG/anti-Sj in patients with cognitive decline and/or psychosis of unknown aetiology are warranted. Tumour screening is essential in patients presenting with ITPR1-IgG/anti-Sj.

SOX1 antibodies (SOX1-abs) are associated with paraneoplastic neurological syndromes (PNS) and small cell lung cancer (SCLC). In many clinical laboratories SOX1-abs are determined by commercial line blots without confirmation by cell-based assay (CBA) with HEK293 cells expressing SOX1. However, the diagnostic yield of commercial line blots is low and the accessibility to the CBA, that is not commercially available, limited. Here, we evaluated if the addition of the band intensity data of the line blot and the immunoreactivity in a tissue-based assay (TBA) improve the diagnostic performance of the line blot. We examined serum of 34 consecutive patients with adequate clinical information that tested positive for SOX1-abs in a commercial line blot. Samples were also assessed by TBA and CBA. SOX1-abs were confirmed by CBA in 17 (50%) patients, all (100%) had lung cancer (SCLC in 16) and 15/17 (88%) had a PNS. In the remaining 17 patients the CBA was negative and none had PNS associated with lung cancer. TBA was assessable in 30/34 patients and SOX1-abs reactivity was detected in 15/17 (88%) with positive and in 0/13 (0%) with negative CBA. Only 2 (13%) of the 15 TBA-negative patients were CBA-positive. The frequency of TBA-negative but CBA-positive increased from 10% (1/10) when the band intensity of the line blot was weak to 20% (1/5) in patients with a moderate or strong intensity band. Confirmation by CBA should be mandatory for samples (56% in this series) not assessable (4/34; 12%) or negative in the TBA (15/34; 44%).

Objective: To describe the clinical associations of SOX1 antibodies (SOX1-Abs), determine the accuracy of various detection techniques, and propose laboratory criteria to identify definite paraneoplastic neurological syndromes (PNS) associated with SOX1-Abs. Methods: Single-center, retrospective study of patients referred to the French Reference Center between 2009 and 2019 for confirmation of SOX1-Ab positivity, without concurrent neural antibodies. Patients were classified according to the updated diagnostic PNS criteria; biological samples were systematically retested with three distinct techniques (line blot, cell-based assay, indirect immunofluorescence). Results: Among 77 patients with isolated SOX1-Ab positivity, 23 (29.9%) fulfilled the criteria for definite PNS; all of them had lung cancer (mostly small-cell) and presented mainly with Lambert-Eaton myasthenic syndrome (10/23) and rapidly progressive cerebellar ataxia (6/23). SOX1-Ab positivity varied depending on the laboratory methods which were used, and a single technique was not sufficient to draw conclusions about the PNS diagnosis. The combination of an antigen-specific test (line blot and/or cell-based assay) and immunofluorescence showed the highest accuracy (81.5%, 95% CI 70.0–90.1) in identifying definite PNS. Moreover, when the PNS-Care score was recalculated assigning three points at the laboratory-level only to patients with positive "antigenic-specific test + immunofluorescence" and 0 points to the remaining cases, a higher certainty for definite and non-PNS was achieved (from 41/77, 53.2%, to 60/77, 77.9%; p < 0.001). Conclusion: SOX1-Abs should be considered high-risk antibodies only when detected with a positive antigenic-specific test and immunofluorescence. Other laboratory results and clinical associations different from Lambert-Eaton myasthenic syndrome and rapidly progressive cerebellar ataxia should be carefully reassessed to rule out false positivity and alternative diagnoses. [ABSTRACT FROM AUTHOR]

Background: Appendiceal goblet cell carcinoma (aGCC) is a rare neoplasm with mixed endocrine and exocrine features. No paraneoplastic neurological syndromes or autoantibodies have been identified in cases of aGCC or even appendiceal tumors. Amphiphysin-immunoglobulin G (IgG) autoimmunity was first described in stiff-person syndrome with breast cancer. We firstly described the clinical course and pathological findings of a patient with aGCC-associated amphiphysin-IgG autoimmunity. Case presentation: A 54-year-old man who developed aGCC was admitted for acute disturbance of consciousness, psychiatric symptoms, cognitive impairment, seizure and hypotension. Amphiphysin-IgG was detected in the patient's serum and CSF by immunoblotting and tissue-based indirect immunofluorescence assay confirming the diagnosis of definite paraneoplastic amphiphysin-IgG-positive encephalitis. Histopathology revealed amphiphysin protein expression and accompanying immune cell infiltration (predominantly CD20+ B cells, CD3+ and CD8+ T cells) within the tumor tissue, suggesting a possible paraneoplastic origin of amphiphysin-associated paraneoplastic neurological syndromes (PNSs) in this case. Although the patient's symptoms resolved after high-dose corticosteroid therapy, he experienced recurrence 6 months later, manifesting as paraneoplastic cerebellar dysfunction. Despite treatment with IV cyclophosphamide and oral mycophenolate mofetil, no improvement was noted. Conclusions: This case suggests that aGCC may trigger amphiphysin-IgG autoimmunity. [ABSTRACT FROM AUTHOR]

Background: The link between paraneoplastic neurological syndromes (PNS) and renal cell and bladder cancer (RCC/BC) is rare and uncertain. Our aim was to clinically evaluate, in light of the updated PNS criteria, these uncommon associations. Methods: Retrospective nationwide cohort chart review study and systematic review of the literature. Results: After excluding 5 patients due to the diagnosis of another co-occurrent malignancy, 10/18 patients with RCC and 8/18 patients with BC were identified. A total of 31 cases were previously published, yielding an overall series of 27/49 RCC and 22/49 BC patients. There was a predominance of cerebellar syndromes in both cancers (10/27, 37% for RCC; 9/22, 41% for BC), followed by encephalitis in 9/27 (33%) patients with RCC and encephalomyelitis/sensory neuronopathy in 5/22 (23%) patients with BC. The detection of high-risk Abs was more frequent among BC patients (16/19, 84% vs. 3/13, 23% in RCC, p = 0.0009), Ri antibodies being the most frequent thereof. After applying the updated PNS criteria, patients with BC met highest degrees (possible, probable, and definite) of certainty for PNS diagnosis (20/22, 91% vs. 16/27, 59% in RCC, p = 0.021). Conclusion: A second neoplasm should always be ruled out before establishing the diagnosis of PNS in patients with RCC or BC. However, while this association remains dubious for most patients with RCC, a casual role is more probable in patients with BC and high-risk antibodies presenting with cerebellar ataxia, brainstem encephalitis or encephalomyelitis/sensory neuronopathy. [ABSTRACT FROM AUTHOR]

The most recent International League Against Epilepsy (ILAE) classification has included "immune etiology" along with other well-known causes of epilepsy. This was possible thanks to the progress in detection of pathogenic neural antibodies (Abs) in a subset of patients, and resulted in an increased interest in identifying potentially treatable causes of otherwise refractory seizures. Most autoimmune encephalitides (AE) present with seizures, but only a minority of cases evolve to long-term epilepsy. The risk of epilepsy is higher for patients harboring Abs targeting intracellular antigens (T cell-mediated and mostly paraneoplastic, such as Hu, CV2/CRMP5, Ma2, GAD65 Abs), compared with patients with neuronal surface Abs (antibody-mediated and less frequently paraneoplastic, such as NMDAR, GABAbR, LGI1, CASPR2 Abs). To consider these aspects, conceptual definitions for two entities were provided: acute symptomatic seizures secondary to AE, and autoimmune-associated epilepsy, which reflect the different pathophysiology and prognoses. Through this manuscript, we provide an up-to-date review on the current state of knowledge concerning diagnosis and management of patients with Ab-mediated encephalitis and associated epilepsy. Special emphasis is placed on clinical aspects, such as brain magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) specificities, electroencephalographic (EEG) findings, cancer screening and suggestions for a rational therapeutic approach. [ABSTRACT FROM AUTHOR]

Background: Opsoclonus-myoclonus syndrome (OMS) is a rare, immune-mediated neurological disorder. In adults, the pathogenesis can be idiopathic, post-infectious or paraneoplastic, the latter etiology belonging to the ever-expanding group of defined paraneoplastic neurological syndromes (PNS). In contrast to other phenotypes of PNS, OMS cannot be ascribed to a single pathogenic autoantibody. Here, we report the first detailed case of paraneoplastic, antibody-negative OMS occurring in association with a pancreatic neuroendocrine tumor (pNET). Case presentation: A 33-year-old female presented with a two-week history of severe ataxia of stance and gait, dysarthria, head tremor, myoclonus of the extremities and opsoclonus. Her past medical history was notable for a metastatic pancreatic neuroendocrine tumor, and she was subsequently diagnosed with paraneoplastic opsoclonus-myoclonus syndrome. Further workup did not reveal a paraneoplastic autoantibody. She responded well to plasmapheresis, as she was refractory to the first-line therapy with corticosteroids. Conclusions: This case expands current knowledge on tumors associated with paraneoplastic opsoclonus-myoclonus syndrome and the age group in which it can occur. It further adds evidence to the effectiveness of plasmapheresis in severe cases of opsoclonus-myoclonus syndrome with a lack of response to first-line therapy. [ABSTRACT FROM AUTHOR]

Background: The anti-SOX-1 antibodies have been mainly associated with Lambert-Eaton Myasthenic Syndrome (LETMS) and Small-Cell Lung Cancer (SCLC). In this report, we describe the interesting case of a patient with serum anti-SOX-1 antibodies and Crohn's Disease (CD) with ensuing neurological symptoms.Case Presentation: A Caucasian 67-year-old female was admitted to the Emergency Department with seizures, vertigo, emesis, nausea, postural instability and recurrent falls, over a period of 10 days. She had been affected by Crohn's Disease since 1991. A CT scan failed to detect any ischemic or haemorrhagic lesion. A brain MRI revealed signs of leukoencephalopathy. Western blot analysis of her serum revealed a high titre of the onconeural antibody anti-SOX1, consistent with a neurological, cerebellar type, paraneoplastic syndrome. In spite of multiple efforts to unmask a possible underlying malignancy, no neoplastic lesion cropped up during hospitalization. Her clinical conditions progressively deteriorated, up to respiratory failure; a few days later she died, due to ensuing septic shock and Multiple Organ Failure.Conclusions: Our experience may usher and reveal a new role of anti-neural antibodies, so far reckoned an early indicator of associated malignancy, suggesting that neurological syndromes associated with such antibodies may complicate also chronic Gastrointestinal (GI) diseases. As of now, testing for anti-neuronal antibodies appeared unnecessary within the diagnostic assessment of gastroenterological disorders, which may lead to overlooking incident neurologic autoimmune diseases. Further exploration of such research hypothesis in clinical grounds appears intriguing. [ABSTRACT FROM AUTHOR]

Purpose of Review: Paraneoplastic neurological syndromes (PNS) are caused by nervous system-targeting aberrant anti-tumoral immune responses. We review the updated criteria for PNS diagnosis, incorporating novel information on clinical phenotypes, neuronal autoantibodies (Nabs), and tumors. The impact of the oncologic use of immune checkpoint inhibitors (ICI) on PNS occurrence is also addressed. Recent Findings: Clinical phenotypes and Nabs are redefined as "high/intermediate/low" risk, following the frequency of cancer association. Nabs, the diagnostic hallmark of PNS, can target intracellular or surface neuronal proteins, with important prognostic and pathogenic implications. Many novel assays have been incorporated into laboratory diagnostics, that is becoming increasingly complex. ICI fight tumors, but favor autoimmunity, thus increasing the incidence of PNS-like disorders. Summary: Overcoming the old PNS criteria, the new ones are centered around the presence of tumor. Clinical presentation, Nabs, and tumor findings are translated in diagnostic scores, providing a useful tool for PNS diagnosis and management. [ABSTRACT FROM AUTHOR]

Antibody-associated autoimmune neurological diseases are a group of disorders with various immune effector mechanisms that result in significant differences in disease course and prognosis. Paraneoplastic or idiopathic autoimmune encephalitis associated with antibodies against intracellular antigens are mostly characterized by a T-cell-dominated inflammation with neuronal loss, astrogliosis, and microglial nodules. In anti-Yo paraneoplastic cerebellar degeneration CD8+/granzymeB+ T cells were demonstrated in close apposition to neurons along with a nuclear upregulation of the activator of transcription 1, suggesting an important role of interferon-gamma in disease pathogenesis. Early and late disease stages may show different lesion types. For example, tissue samples from patients with temporal lobe epilepsy associated with antiglutamic acid decarboxylase 65 antibodies in early disease stages show numerous infiltrating T cells targeting hippocampal neurons and high numbers of B cells and plasma cells, while in chronic stages inflammation gets less and is followed by hippocampal sclerosis. Similarly, antiglial fibrillary acidic protein meningoencephalomyelitis may show loss of astrocytes only in the very early lesions, whereas in subacute and chronic stages astrocytes can get replenished most likely due to their high regeneration potential. In contrast, neuropathology of autoimmune neurological diseases mediated by surface antibodies is mostly characterized by a dysfunction of neurons in the absence of immune-mediated neuronal damage. The interaction of surface antibodies with their target antigen and the resulting downstream mechanisms are variable and can range from an internalization of the receptor in well-preserved neurons in anti-N-methyl-D-aspartate receptor encephalitis to an irreversible internalization and blocking of the receptor that may be associated with an accumulation of phosphorylated tau in specific brain regions in anti-IgLON5 disease. Interestingly, anti-IgLON5 patients with short disease duration were shown to present prominent deposition of IgG4 in the neuropil and on neuronal membranes in the absence of neuronal tau deposits, suggesting that the immune mechanisms precede neurodegeneration. Knowledge about pathomechanisms and patterns of tissue damage in different disease stages of antibody-associated autoimmune diseases will help to identify novel biomarkers and can give important clues for possible therapeutic interventions., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

This article presents a clinical review of a patient with an extremely rare assotiation of opticoneuromyelitis and skin melanoma. The paper noted the typical clinical and neuroimaging signs of opticoneuromyelitis and the rare manifestations of myelitic syndrome such as segmental muscle hypertonicity and hand hyperkinesis. The question remains open as to whether these two processes in a patient are linked by a single pathogenesis in the form of a paraneoplastic neurological syndrome or whether two independent diseases are represent there. Two observations of a combination of melanoma and opticoneuromyelitis as a manifestation of the paraneoplastic syndrome have been analysed in the literature. The article highlights the difficulties in the treatment of this patient, as the immunomodulatory therapy used for both diseases has a different vectorial focus. Immunosuppression is recommended for the treatment of opticoneuromyelitis, while immune activation is recommended for melanoma.

Major advances in our knowledge concerning autoimmune and paraneoplastic cerebellar ataxias have occurred in the last 20 years. The discovery of several neural antibodies represents an undeniable contribution to this field, especially those serving as good biomarkers of paraneoplastic neurological syndromes and those showing direct pathogenic effects. Yet, many patients still lack detectable or known antibodies, and also many antibodies have only been reported in few patients, which makes it difficult to define in detail their clinical value. Nevertheless, a notable progress has additionally been made in the clinical characterization of patients with the main neural antibodies, which, although typically present with a subacute pancerebellar syndrome, may also show either hyperacute or chronic onsets that complicate the differential diagnoses. However, prodromal and transient features could be useful clues for an early recognition, and extracerebellar involvement may also be highly indicative of the associated antibody. Moreover, important advances in our understanding of the pathogenesis of cerebellar ataxias include the description of antibody effects, especially those targeting cell-surface antigens, and first attempts to isolate antigen-specific T-cells. Furthermore, genetic predisposition seems relevant, although differently involved according to cancer association, with particular HLA observed in non-paraneoplastic cases and genetic abnormalities in the tumor cells in paraneoplastic ones. Finally, immune checkpoint inhibitors used as cancer immunotherapy may rarely induce cerebellar ataxias, but even this undesirable effect may in turn serve to shed some light on their physiopathology. Herein, we review the principal novelties of the last 20 years regarding autoimmune and paraneoplastic cerebellar ataxias. [ABSTRACT FROM AUTHOR]

Background: In 2014, we first described novel autoantibodies to the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1-IgG/anti-Sj) in patients with autoimmune cerebellar ataxia (ACA) in this journal. Here, we provide a review of the available literature on ITPR1-IgG/anti-Sj, covering clinical and paraclinical presentation, tumour association, serological findings, and immunopathogenesis.Methods: Review of the peer-reviewed and PubMed-listed English language literature on ITPR1-IgG/anti-Sj. In addition, we provide an illustrative report on a new patient with ITPR1-IgG-associated encephalitis with cognitive decline and psychosis.Results: So far, at least 31 patients with serum ITPR1-IgG/anti-Sj have been identified (clinical information available for 21). The most common manifestations were ACA, encephalopathy with seizures, myelopathy, and (radiculo)neuropathy, including autonomic neuropathy. In 45% of cases, an underlying tumour was present, making the condition a facultative paraneoplastic neurological disorder. The neurological syndrome preceded tumour diagnosis in all but one case. In most cases, immunotherapy had only moderate or no effect. The association of ITPR1-IgG/anti-Sj with manifestations other than ACA is corroborated by the case of a 48-year-old woman with high-titre ITPR1-IgG/anti-Sj antibodies and rapid cognitive decline, affecting memory, attention and executive function, and psychotic manifestations, including hallucinations, investigated here in detail. FDG-PET revealed right-temporal glucose hypermetabolism compatible with limbic encephalitis. Interestingly, ITPR1-IgG/anti-Sj mainly belonged to the IgG2 subclass in both serum and cerebrospinal fluid (CSF) in this and further patients, while it was predominantly IgG1 in other patients, including those with more severe outcome, and remained detectable over the entire course of disease. Immunotherapy with intravenous methylprednisolone, plasma exchange, and intravenous immunoglobulins, was repeatedly followed by partial or complete recovery. Long-term treatment with cyclophosphamide was paralleled by relative stabilization, although the patient noted clinical worsening at the end of each treatment cycle.Conclusions: The spectrum of neurological manifestations associated with ITPR1 autoimmunity is broader than initially thought. Immunotherapy may be effective in some cases. Studies evaluating the frequency of ITPR1-IgG/anti-Sj in patients with cognitive decline and/or psychosis of unknown aetiology are warranted. Tumour screening is essential in patients presenting with ITPR1-IgG/anti-Sj. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy represents a novel anticancer strategy that acts directly on the immune system, promoting its activation toward cancer cells to enhance its natural ability to fight cancer. Among various treatments currently used or investigated, chimeric antigen receptors (CAR) T-cell therapy and immune checkpoint inhibitors (ICIs) have consistently proven their efficacy. These innovations are progressively improving the standard of care in cancer treatment, yet they are hampered by novel neurological adverse events, attributing to neurologists a key role in the multidisciplinary oncological team. Indeed, neurotoxicity may develop in up to 77% of patients who received CAR T-cell therapy and usually presents with encephalopathy characterized by a predominant frontal lobe dysfunction. This neurotoxicity is related to cytokine release syndrome, a systemic hyperinflammatory condition triggered by CAR T-cells. On the other hand, following treatment with ICIs, unrestrained T-cells may lead to central and peripheral neurological disorders by antigen-directed autoimmunity. Notably, biological and clinical similarities have been underlined between neurotoxicity related to CAR T-cell therapy and neurological manifestations of cytokine storms (e.g. COVID-19-related encephalopathy), as well as between a subgroup of ICI-related neurological adverse events and paraneoplastic neurological syndromes. Therefore, these cancer immunotherapy-related neurological syndromes may provide an unprecedented, perhaps transitory, opportunity to shed light on the underlying pathogenicmechanisms of a wide spectrumof neurological syndromes and to push forward our knowledge in neuroimmunology. [ABSTRACT FROM AUTHOR]

Paraneoplastic neurological syndrome (PNS) is uncommon and not well known. PNS can reveal cancer, but its role in seminomas has not been described explicitly. We report the case of a 36-year-old man with unremarkable medical history and no comorbidities who was diagnosed with a retroperitoneal metastatic seminoma. The patient's general condition deteriorated, and he developed progressive neurological palsy without other clinical anomalies. Electromyography revealed demyelinating, non-lengthy neuropathy. Guillain-Barré syndrome was initially suspected. However, a positron emission tomography scan revealed a retroperitoneal mass, and blood markers revealed increased human chorionic gonadotropin. The patient was diagnosed with PNS, and a computed tomography-guided biopsy revealed a metastatic seminoma without a primary tumor. No circulating neural antibodies were detected. Human polyvalent immunoglobulin was simultaneously administered with chemotherapy. After three cycles of a cisplatin-etoposide-bleomycin, a complete biological and metabolic response rate was observed, and his neurological symptoms rapidly improved. Four years later, the patient responded completely, without any neurological complaints. Paraneoplastic demyelinating inflammatory neuropathy can lead to advanced seminoma diagnosis. Prompt management of seminomas with cisplatin-based regimens provides the best chance of cure for both advanced seminoma and paraneoplastic syndrome. [ABSTRACT FROM AUTHOR]

Paraneoplastic neurologic syndromes (PNS) caused by anti-Ma2/Ta antibodies have diverse presentations. Myeloradiculopathy is one anti-Ma2/Ta-associated PNS manifestation. We report the case of a patient with chronic relapsing anti-Ma2/Ta paraneoplastic myeloradiculopathy. The patient was successfully treated with low-dose human recombinant interleukin-2, despite having chronic relapsing symptoms and a refractory response to conventional immunotherapy.

Cancer immunotherapy represents a novel anticancer strategy that acts directly on the immune system, promoting its activation toward cancer cells to enhance its natural ability to fight cancer. Among various treatments currently used or investigated, chimeric antigen receptors (CAR) T-cell therapy and immune checkpoint inhibitors (ICIs) have consistently proven their efficacy. These innovations are progressively improving the standard of care in cancer treatment, yet they are hampered by novel neurological adverse events, attributing to neurologists a key role in the multidisciplinary oncological team. Indeed, neurotoxicity may develop in up to 77% of patients who received CAR T-cell therapy and usually presents with encephalopathy characterized by a predominant frontal lobe dysfunction. This neurotoxicity is related to cytokine release syndrome, a systemic hyperinflammatory condition triggered by CAR T-cells. On the other hand, following treatment with ICIs, unrestrained T-cells may lead to central and peripheral neurological disorders by antigen-directed autoimmunity. Notably, biological and clinical similarities have been underlined between neurotoxicity related to CAR T-cell therapy and neurological manifestations of cytokine storms (e.g. COVID-19-related encephalopathy), as well as between a subgroup of ICI-related neurological adverse events and paraneoplastic neurological syndromes. Therefore, these cancer immunotherapy-related neurological syndromes may provide an unprecedented, perhaps transitory, opportunity to shed light on the underlying pathogenic mechanisms of a wide spectrum of neurological syndromes and to push forward our knowledge in neuroimmunology.

Paraneoplastic neurological syndromes (PNS) include any symptomatic and non-metastatic neurological manifestations associated with a neoplasm. PNS associated with antibodies against intracellular antigens, known as “high-risk” antibodies, show frequent association with underlying cancer. PNS associated with antibodies against neural surface antigens, known as “intermediate- or low-risk” antibodies, are less frequently associated with cancer. In this narrative review, we will focus on PNS of the central nervous system (CNS). Clinicians should have a high index of suspicion with acute/subacute encephalopathies to achieve a prompt diagnosis and treatment. PNS of the CNS exhibit a range of overlapping “high-risk” clinical syndromes, including but not limited to latent and overt rapidly progressive cerebellar syndrome, opsoclonus-myoclonus-ataxia syndrome, paraneoplastic (and limbic) encephalitis/encephalomyelitis, and stiff-person spectrum disorders. Some of these phenotypes may also arise from recent anti-cancer treatments, namely immune-checkpoint inhibitors and CAR T-cell therapies, as a consequence of boosting of the immune system against cancer cells. Here, we highlight the clinical features of PNS of the CNS, their associated tumors and antibodies, and the diagnostic and therapeutic strategies. The potential and the advance of this review consists on a broad description on how the field of PNS of the CNS is constantly expanding with newly discovered antibodies and syndromes. Standardized diagnostic criteria and disease biomarkers are fundamental to quickly recognize PNS to allow prompt treatment initiation, thus improving the long-term outcome of these conditions.

Objective: Paraneoplastic neurological syndromes (PNSs) are a diverse group of neurological disorders affecting any part of the nervous system before or during cancer. Case: A 78-year-old man first experienced pain and burning in the upper extremity three years previously, to which muscle weakness was added a short time later. The same symptoms developed in the lower extremities one year previously. He was admitted to the intensive care unit due to pneumonia and was conscious but quadriplegic with a modified Rankin score of 5. Abdominal computed tomography showed mass lesions in the liver and pancreas. Biopsies revealed pancreatic small cell neuroendocrine carcinoma. Electrophysiological studies revealed severe sensorimotor axonal polyneuropathy. Paraneoplastic sensorimotor axonal polyneuropathy was diagnosed since other causes of polyneuropathy had been excluded. Palliative care was considered due to the patient's poor functional state. Conclusions: Early diagnosis of cancer is of paramount importance in patients with PNSs if appropriate treatment is to be provided. [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]

Paraneoplastic neurological syndromes (PNSs) are a group of neurological disorders triggered by an underlying remote tumor. Ovarian teratoma (OT) is the most common histologic type of germ cell tumor in females. The most common PNSs associated with OT is anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. However, with the increasing number of new antibodies reported over the last decade, the clinical spectrum of OT-related PNSs is also expanding. Our knowledge of OT-related PNSs is still far from complete. Here, we provide a comprehensive review of the most recent findings in the field of OT-related PNSs, with a particular focus on their clinical and pathological characteristics. Overall, the description of neuronal antibodies in PNSs associated with OT strongly suggests that antibodies may be responsible for the clinical symptoms in some cases. OT-related PNSs are associated with various clinical manifestations, including anti-NMDAR encephalitis, limbic encephalitis, encephalomyelitis, progressive cerebellar syndrome and opsoclonus-myoclonus syndrome. The pathological characteristics of the OT suggest that the mechanism of PNSs is probably due to heteromorphic neurons in the tumor tissue, the ectopic expression of the antigens in neural tissue within the teratomas and patients' unusual immune response. Despite the severity of the neurological syndromes, most patients with OT-related PNSs showed good neurologic response to early tumor resection combined with immunotherapy. To further advance the management of OT-related PNSs, additional studies are needed to explore this complex topic. [ABSTRACT FROM AUTHOR]

The introduction of immune checkpoint inhibitors (ICIs) in oncologic therapies has led to a paradigm shift in cancer treatment. ICIs have increased the overall survival in patients with malignant melanoma, small-cell lung cancer, and many other tumor entities. Despite their clinical benefits, these novel cancer immunotherapies can induce neurological immune-related adverse events (irAEs). Such immune-mediated complications can manifest within the spectrum of paraneoplastic neurological syndromes (PNSs). PNSs are rare immune-mediated complications of systemic cancers that can involve every aspect of the nervous system. The emergence of PNSs with ICI treatment opens further pathways to study the complex immunopathological interplay of cancer immunity, cross-reactive neurological autoimmune phenomena, and effects of ICIs on the immune system. ICI-induced PNSs comprise a diverse antibody repertoire and phenotypic spectrum with severe and life-threatening disease progression in some cases. Timely diagnosis and urgent interventions are pivotal for a favorable neurologic and oncologic outcome. This review focuses on the pathogenesis of cancer immunotherapy and the disruption of immune tolerance in PNSs and provides an overview of the most pertinent clinical manifestations and principles of diagnostic and therapeutic managements in light of the expected increase in PNSs due to the widespread use of ICIs in clinical practice. This review further discusses potential and evolving concepts of therapeutic monoclonal antibodies for the treatment of PNSs. [ABSTRACT FROM AUTHOR]

Background: Paraneoplastic Neurological Syndromes (PNSs) are a heterogeneous group of immune-mediated disorders that often precede tumor diagnosis. There are few systematic studies on the spectrum and follow-up of PNSs. Objective: To analyze the clinical spectrum, associated tumors, antibody profile, outcomes, and prognostic predictors in a cohort of PNSs admitted in a tertiary care center. Methods: This retrospective study included 97 patients (2008-2019). PNSs were further classified as “classical,” “nonclassical,” “definite,” and “possible.” Clinical profile, diagnostic strategies, therapeutic options, and predictors of outcomes were identified. Results: The median age was 54 years (range 17–81). Thirty-nine (40.2%) had classical PNS, and 58 (59.8%) had nonclassical PNS, 74 (76.3%) had “Definite” PNS while 23 (23.7%) had “Possible” PNS. Cerebellar degeneration, peripheral neuropathy, and encephalopathy were the three most common neurological syndromes. Tumors were diagnosed in 66 (68%) patients; Lung cancer was the most common primary tumor. Antibodies were positive in 52 (53.6%). Anti-Yo antibody and anti-Ma2 antibody were the most common antibodies. The majority (57.7%) received immunotherapy in addition to definitive treatment for the tumor. A good outcome was seen in 53 (54.6%). Factors associated with good outcome were: early diagnosis, mRS

Paraneoplastic neurological syndromes (PNSs) are a group of neurological disorders triggered by an underlying remote tumor. Ovarian teratoma (OT) is the most common histologic type of germ cell tumor in females. The most common PNSs associated with OT is anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. However, with the increasing number of new antibodies reported over the last decade, the clinical spectrum of OT-related PNSs is also expanding. Our knowledge of OT-related PNSs is still far from complete. Here, we provide a comprehensive review of the most recent findings in the field of OT-related PNSs, with a particular focus on their clinical and pathological characteristics. Overall, the description of neuronal antibodies in PNSs associated with OT strongly suggests that antibodies may be responsible for the clinical symptoms in some cases. OT-related PNSs are associated with various clinical manifestations, including anti-NMDAR encephalitis, limbic encephalitis, encephalomyelitis, progressive cerebellar syndrome and opsoclonus-myoclonus syndrome. The pathological characteristics of the OT suggest that the mechanism of PNSs is probably due to heteromorphic neurons in the tumor tissue, the ectopic expression of the antigens in neural tissue within the teratomas and patients’ unusual immune response. Despite the severity of the neurological syndromes, most patients with OT-related PNSs showed good neurologic response to early tumor resection combined with immunotherapy. To further advance the management of OT-related PNSs, additional studies are needed to explore this complex topic.

Autoimmune and paraneoplastic encephalitides represent an increasingly recognized cause of devastating human illness as well as an emerging area of neurological injury associated with immune checkpoint inhibitors. Two groups of antibodies have been detected in affected patients. Antibodies in the first group are directed against neuronal cell surface membrane proteins and are exemplified by antibodies directed against the N-methyl-D-aspartate receptor (anti-NMDAR), found in patients with autoimmune encephalitis, and antibodies directed against the leucine-rich glioma-inactivated 1 protein (anti-LGI1), associated with faciobrachial dystonic seizures and limbic encephalitis. Antibodies in this group produce non-lethal neuronal dysfunction, and their associated conditions often respond to treatment. Antibodies in the second group, as exemplified by anti-Yo antibody, found in patients with rapidly progressive cerebellar syndrome, and anti-Hu antibody, associated with encephalomyelitis, react with intracellular neuronal antigens. These antibodies are characteristically found in patients with underlying malignancy, and neurological impairment is the result of neuronal death. Within the last few years, major advances have been made in understanding the pathogenesis of neurological disorders associated with antibodies against neuronal cell surface antigens. In contrast, the events that lead to neuronal death in conditions associated with antibodies directed against intracellular antigens, such as anti-Yo and anti-Hu, remain poorly understood, and the respective roles of antibodies and T lymphocytes in causing neuronal injury have not been defined in an animal model. In this review, we discuss current knowledge of these two groups of antibodies in terms of their discovery, how they arise, the interaction of both types of antibodies with their molecular targets, and the attempts that have been made to reproduce human neuronal injury in tissue culture models and experimental animals. We then discuss the emerging area of autoimmune neuronal injury associated with immune checkpoint inhibitors and the implications of current research for the treatment of affected patients. [ABSTRACT FROM AUTHOR]

Abstract Background Breast cancer is the most common cancer in women. However, in the management of breast cancer, paraneoplastic neurological syndromes represent a diagnostic and therapeutic challenge. The diagnosis of paraneoplastic neurological syndromes is difficult due to the heterogeneity of symptoms, the timing of presentation, and the absence of antibodies, and it generally occurs before the diagnosis of breast cancer in 80% of patients who develop paraneoplastic neurological syndromes. We describe a 72-year-old woman with subacute ophthalmoplegia-ataxia syndrome who was subsequently diagnosed as having breast cancer and anti-Ri antibodies. Case presentation A 72-year-old post-menopausal Caucasian woman, with a positive medical history for diabetes mellitus and hypertension, presented with a 3-month onset of blurred vision, diplopia, and progressive gait disturbance. Serological tests were positive for well-characterized onconeural antibodies (anti-Ri). A whole-body computed tomography scan revealed a nodular opacity under her left nipple and axillary adenopathy. A biopsy of her left breast was performed, and histological examination showed ductal carcinoma. She underwent a superoexternal quadrantectomy with left axillary dissection. The final diagnosis showed infiltrating ductal carcinoma of the breast (T1c N1 M0, stage IIA) associated with paraneoplastic ophthalmoplegia-ataxia syndrome. At a 6-month follow-up, she showed no clinical or instrumental evidence of neoplastic recurrence with partial clinical improvement of neurological symptoms, such as ataxia and diplopia. Conclusion The diagnosis of paraneoplastic neurological syndromes is often late, as in this patient, but treatment at an early stage may provide a good prognosis. Furthermore, this is one of several cases of an anti-Ri paraneoplastic neurological syndrome not associated with myoclonus, which reinforces the belief that opsoclonus myoclonus syndrome is not pathognomonic of the associated anti-Ri paraneoplastic neurological syndromes.

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.

Autoimmune and paraneoplastic encephalitides represent an increasingly recognized cause of devastating human illness as well as an emerging area of neurological injury associated with immune checkpoint inhibitors. Two groups of antibodies have been detected in affected patients. Antibodies in the first group are directed against neuronal cell surface membrane proteins and are exemplified by antibodies directed against the N-methyl-D-aspartate receptor (anti-NMDAR), found in patients with autoimmune encephalitis, and antibodies directed against the leucine-rich glioma-inactivated 1 protein (anti-LGI1), associated with faciobrachial dystonic seizures and limbic encephalitis. Antibodies in this group produce non-lethal neuronal dysfunction, and their associated conditions often respond to treatment. Antibodies in the second group, as exemplified by anti-Yo antibody, found in patients with rapidly progressive cerebellar syndrome, and anti-Hu antibody, associated with encephalomyelitis, react with intracellular neuronal antigens. These antibodies are characteristically found in patients with underlying malignancy, and neurological impairment is the result of neuronal death. Within the last few years, major advances have been made in understanding the pathogenesis of neurological disorders associated with antibodies against neuronal cell surface antigens. In contrast, the events that lead to neuronal death in conditions associated with antibodies directed against intracellular antigens, such as anti-Yo and anti-Hu, remain poorly understood, and the respective roles of antibodies and T lymphocytes in causing neuronal injury have not been defined in an animal model. In this review, we discuss current knowledge of these two groups of antibodies in terms of their discovery, how they arise, the interaction of both types of antibodies with their molecular targets, and the attempts that have been made to reproduce human neuronal injury in tissue culture models and experimental animals. We then discuss the emerging area of autoimmune neuronal injury associated with immune checkpoint inhibitors and the implications of current research for the treatment of affected patients.