Antibody-positive autoimmune encephalitis and paraneoplastic neurological syndrome: A Swedish case series.

OBJECTIVE: This study aimed to explore the clinical characteristics and temporal disease course of patients with autoimmune encephalitis (AE) and paraneoplastic neurological syndrome (PNS) in Sweden. METHODS: Thirty-seven antibody-positive AE and PNS cases were identified in the Healthcare region Mid Sweden between 2015 and 2019. Clinical data were collected through a retrospective review of electronic health records. Patients were divided into three subgroups based on antibody type: neuronal surface antibodies (NSAbs), onconeural antibodies, and anti-GAD65 antibodies. RESULTS: Nineteen patients had NSAbs, 11 onconeural antibodies, and seven anti-GAD65 antibodies. Anti-LGI1 and anti-NMDAR were the most frequently detected NSAbs, with anti-NMDAR cases having an older-than-expected age distribution (median age 40, range 17-72). Only 11 of 32 (30%) of patients had findings suggesting encephalitis on initial MRI, but 28 of 31 (90%) had pathological findings on initial cerebrospinal fluid analysis. All patients but one had abnormal EEG findings. Median time to immunotherapy was comparable among the three subgroups, whereas patients with anti-LGI1, anti-CASPR2, and anti-IgLON5 had an eightfold longer time to immunotherapy than anti-NMDAR and anti-GABA-B (p = .0016). There was a seasonal variation in onset for patients with non-tumor-related NSAbs and anti-GAD65 antibodies, with most patients (72%) falling ill in spring or summer. CONCLUSION: Swedish patients with AE and PNS had similar clinical characteristics as previously described cohorts from other geographical regions except for anti-NMDAR encephalitis, with older onset than expected. The onset of non-tumor-related AE occurred predominantly in the warm seasons, and AE with a more insidious onset was associated with delayed treatment initiation.

Anti-Hu antibody associated paraneoplastic neurological syndrome in a child with ganglioneuroblastoma: A rare case report and literature review.

RATIONALE: Paraneoplastic neurological syndrome with anti-Hu antibody (Hu-PNS) is a neurological disorder that occur in patients with malignancy. The syndrome has a wide range of presentations and can present before diagnosis of primary malignancy. Familiarity with these paraneoplastic neurological syndromes can help early recognition and take appropriate regimens. PATIENTS CONCERNS: Diagnosis and treatment of Hu-PNS. DIAGNOSES: This is retrospective study that analyzed the clinical data of this case. Through retrospective analysis and targeted antibody screening, serum anti-Hu antibody was detected. Subsequent spinal imaging revealed a mass in the paraspinal region, which was confirmed as ganglioneuroblastoma by pathologic examination. INTERVENTIONS: The child was treated with a course of intravenous immunoglobulin and radical surgical operation without chemotherapy. OUTCOMES: The neurological symptoms were gradually improved and no signs indicate disease progression or tumor recurrence. LESSONS: Hu-PNS has rarely been reported in children with ganglioneuroblastomas. They can mimic non-neoplastic processes, making detection and diagnosis difficult. Serum and/or cerebrospinal fluid onconeural antibody can strongly indicate occult cancers. Early detection of paraneoplastic neurological syndromes can help take appropriate regimens and improve prognosis.

[Paraneoplastic Disorders of Peripheral Nervous System].

Paraneoplastic disorders of the peripheral nervous system are immune-mediated neurological syndromes associated with tumors. Several clinical phenotypes have been associated with these disorders. Sensory neuronopathy is the most well-known clinical phenotype, and is caused by neuronal cell injury to the dorsal root ganglia. Symptoms of the peripheral nervous system usually lead to the discovery of tumors. Antineuronal antibodies are occasionally identified in the serum and/or cerebrospinal fluid of these patients. The prevalence of small-cell lung cancer is notable in these patients. Early tumor resection, coupled with the initiation of immunotherapy, may prove effective in improving and stabilizing clinical symptoms.

Clinical Presentation, Management, and Diagnostic Performance of 2021 Criteria for Paraneoplastic Neurologic Syndromes in Childhood.

BACKGROUND AND OBJECTIVES: Paraneoplastic neurologic syndromes (PNSs) are remote neurologic immune-related effects of tumors. The clinical characteristics of pediatric PNSs remain unclear. We retrospectively examined the clinical characteristics of cases of pediatric PNSs and assessed the performance of the 2021 diagnostic criteria in children. METHODS: Patients hospitalized in the Beijing Children's Hospital between June 2015 and June 2023 and fulfilling the description of definite by 2004 diagnostic criteria of PNSs were included. A retrospective analysis of clinical characteristics was conducted, and the 2021 diagnostic criteria were applied to rediagnostic stratification. RESULTS: Among the 42 patients included, the most common neurologic syndrome was opsoclonus-myoclonus syndrome (OMS) (62%), followed by rapidly progressive cerebellar syndrome (26%). Most tumors were neuroblastomas (88%), with few being ovarian teratomas (10%). Approximately 71% (30/42) of patients were classified as definite and 24% (10/42) as probable according to the 2021 criteria. All cases judged as probable exhibited rapidly progressive cerebellar ataxia with neuroblastoma. For OMS, chemotherapy was administered based on the tumor's risk stage, accompanied by regular infusion of IV gamma globulin and oral steroids following tumor diagnosis. Twenty-one patients underwent regular follow-ups over 4.92 (0.58-7.58) years. The initial hospitalization recorded a median score of 12 (7-14) on the Mitchell and Pike OMS rating scale, decreasing to 0 (0-5) at the final follow-up. In cases of rapidly progressive cerebellar syndrome, a similar therapeutic regimen was used. Nine patients underwent regular follow-ups over 4.42 (1.17-7.50) years. The mean modified Rankin scale score at first hospitalization was 4 (3-4), reducing to 1 (0-4) at the final follow-up. Only 17% (5/30) of patients across both groups exhibited poor response to this regimen. Among these 5 patients, 4 belonged to the low-risk group (without chemotherapy). DISCUSSION: OMS followed by rapidly progressive cerebellar ataxia are the most common forms of PNSs in children and are associated with neuroblastoma. An aggressive approach with multiple immunotherapies may improve the prognosis of neuroblastoma-associated PNSs. The 2021 criteria perform well in pediatric PNSs. However, we propose upgrading the classification of antibody-negative rapidly progressive cerebellar ataxia with neuroblastoma to definite diagnosis. This adjustment aims to further improve the diagnostic efficacy of this diagnostic criterion in childhood.

Comparative Study of Paraneoplastic and Nonparaneoplastic Autoimmune Encephalitis With GABABR Antibodies.

BACKGROUND AND OBJECTIVES: While patients with paraneoplastic autoimmune encephalitis (AE) with gamma-aminobutyric-acid B receptor antibodies (GABABR-AE) have poor functional outcomes and high mortality, the prognosis of nonparaneoplastic cases has not been well studied. METHODS: Patients with GABABR-AE from the French and the Dutch Paraneoplastic Neurologic Syndromes Reference Centers databases were retrospectively included and their data collected; the neurologic outcomes of paraneoplastic and nonparaneoplastic cases were compared. Immunoglobulin G (IgG) isotyping and human leukocyte antigen (HLA) genotyping were performed in patients with available samples. RESULTS: A total of 111 patients (44/111 [40%] women) were enrolled, including 84 of 111 (76%) paraneoplastic and 18 of 111 (16%) nonparaneoplastic cases (cancer status was undetermined for 9 patients). Patients presented with seizures (88/111 [79%]), cognitive impairment (54/111 [49%]), and/or behavioral disorders (34/111 [31%]), and 54 of 111 (50%) were admitted in intensive care unit (ICU). Nonparaneoplastic patients were significantly younger (median age 54 years [range 19-88] vs 67 years [range 50-85] for paraneoplastic cases, p < 0.001) and showed a different demographic distribution. Nonparaneoplastic patients more often had CSF pleocytosis (17/17 [100%] vs 58/78 [74%], p = 0.02), were almost never associated with KTCD16-abs (1/16 [6%] vs 61/70 [87%], p < 0.001), and were more frequently treated with second-line immunotherapy (11/18 [61%] vs 18/82 [22%], p = 0.003). However, no difference of IgG subclass or HLA association was observed, although sample size was small (10 and 26 patients, respectively). After treatment, neurologic outcome was favorable (mRS ≤2) for 13 of 16 (81%) nonparaneoplastic and 37 of 84 (48%) paraneoplastic cases (p = 0.03), while 3 of 18 (17%) and 42 of 83 (51%) patients had died at last follow-up (p = 0.008), respectively. Neurologic outcome no longer differed after adjustment for confounding factors but seemed to be negatively associated with increased age and ICU admission. A better survival was associated with nonparaneoplastic cases, a younger age, and the use of immunosuppressive drugs. DISCUSSION: Nonparaneoplastic GABABR-AE involved younger patients without associated KCTD16-abs and carried better neurologic and vital prognoses than paraneoplastic GABABR-AE, which might be due to a more intensive treatment strategy. A better understanding of immunologic mechanisms underlying both forms is needed.

Changing landscape in the field of paraneoplastic neurology: Personal perspectives over a 35-year career.

Paraneoplastic neurologic syndromes are a group of rare disorders that have fascinated neurologists for more than a century. The discovery in the 1980s that many of these disorders occurred in association with antibodies against neuronal proteins revived the interest for these diseases. This chapter first traces the history of the paraneoplastic neurologic syndromes during the era that preceded the discovery of immune mechanisms and then reviews the immunologic period during which many of these syndromes were found to be associated with antibodies against intracellular onconeuronal proteins and pathogenic cytotoxic T-cell mechanisms. Alongside these developments, investigations on the antibody-mediated disorders of the peripheral nervous system, such as the myasthenic syndromes or neuromyotonia, provided suggestions for the study of the central nervous system (CNS) syndromes. These converging areas of research culminated with the groundbreaking discovery of a new category of CNS disorders mediated by antibodies against neuronal surface proteins or receptors. These disorders are not always paraneoplastic, and the understanding of these syndromes and mechanisms has changed the landscape of neurology and neurosciences.

Paraneoplastic autonomic neuropathies and GI dysmotility.

A number of the well-recognized autoimmune and paraneoplastic neurologic syndromes commonly involve the autonomic nervous system. In some cases, the autonomic nerves or ganglia are primary targets of neurologic autoimmunity, as in immune-mediated autonomic ganglionopathies. In other disorders such as encephalitis, autonomic centers in the brain may be affected. The presence of autonomic dysfunction (especially gastrointestinal dysmotility) is sometimes overlooked even though this may contribute significantly to the symptom burden in these paraneoplastic disorders. Additionally, recognition of autonomic features as part of the clinical syndrome can help point the diagnostic evaluation toward autoimmune and paraneoplastic etiologies. As with other paraneoplastic disorders, the clinical syndrome and the presence and type of neurologic autoantibodies help to secure the diagnosis and direct the most appropriate investigation for malignancy. Optimal management for these conditions typically includes aggressive treatment of the neoplasm, immunomodulatory therapy, and symptomatic treatments for orthostatic hypotension and gastrointestinal dysmotility.

Pathogenesis and immunopathology of paraneoplastic disorders.

Paraneoplastic neurologic syndromes (PNS) represent a rare group of immune-mediated complications associated with an underlying tumor. Ectopic protein expression in neoplastic cells or an aberrant immune regulation in the course of hematooncologic diseases or thymomas trigger an autoimmune response that may affect any part of the central and/or peripheral nervous system. Recent advances in drug therapies as well as novel animal models and neuropathologic studies have led to further insights on the immune pathomechanisms of PNS. Although the syndromes share common paths in pathogenesis, they may differ in the disease course, prognosis, and therapy targets, depending on the localization and type of antibody epitope. Neuropathologic hallmarks of PNS associated with antibodies directed against intracellular epitopes are characterized by T cell-dominated inflammation, reactive gliosis including microglial nodules, and neuronal degeneration. By contrast, the neuropathology of cell surface antibody-mediated PNS strongly depends on the targeted antigen and varies from B cell/plasma cell-dominated inflammation and well-preserved neurons together with a reduced expression of the target antigen in anti-NMDAR encephalitis to irreversible Purkinje cell loss in anti-P/Q-type VGCC antibody-associated paraneoplastic cerebellar degeneration. The understanding of different pathomechanisms in PNS is important because they strongly correspond with therapy response and prognosis, and should guide treatment decisions.

Antibodies to neural cell surface and synaptic proteins in paraneoplastic neurologic syndromes.

Among patients with paraneoplastic neurologic syndromes (PNS), emphasis has historically been placed on neural antibodies against intracellular proteins that have a strong association with malignancy. Because of the intracellular location of their antigenic targets, these antibodies are typically considered to be non-pathogenic surrogate markers of immune cell-mediated neural injury. Unfortunately, patients with these antibodies often have suboptimal response to immunotherapy and poor prognosis. Over the last two decades, however, dramatic advancements have been made in the discovery and clinical characterization of neural antibodies against extracellular targets. These antibodies are generally considered to be pathogenic, given their potential to directly alter antigen structure or function, and patients with these antibodies often respond favorably to prompt immunotherapy. These antibodies also associate with tumors and may thus occur as PNS, albeit more variably than neural antibodies against intracellular targets. The updated 2021 PNS diagnostic criteria, which classifies antibodies as high-risk, intermediate-risk, or lower-risk for an associated cancer, better clarifies how neural antibodies against extracellular targets relate to PNS. Using this recently created framework, the clinical presentations, ancillary test findings, oncologic associations, and treatment responses of syndromes associated with these antibodies are discussed.

Paraneoplastic antibodies targeting intracellular antigens.

Although they are relatively rare, the diagnosis of paraneoplastic neurologic syndromes (PNS) can be aided by the identification of neural autoantibodies in patients' serum and cerebrospinal fluid (CSF). They often clinically manifest as characteristic syndromes, including limbic encephalitis, opsoclonus-myoclonus syndrome, paraneoplastic cerebellar degeneration, and paraneoplastic encephalomyelitis. The antibodies are directed either toward intracellular targets, or epitopes on the cell surface. As compared to cell surface antibodies, intracellular paraneoplastic autoantibodies are more classically associated with cancer, most often lung, breast, thymoma, gynecologic, testicular, and/or neuroendocrine cancers. The malignancies themselves tend to be small and regionally contained, attesting to the strength of the immune system in cancer immunosurveillance. Typically, the intracellular antibodies are not directly pathogenic and tend to be associated with PNS that are poorly responsive to treatment. With some notable exceptions, including patients with PNS associated with testicular cancer, patients with intracellular antibodies are typically older individuals, in their 7th decade of life and beyond. Many of them are current or former smokers. Treatment strategies include tumor removal as well as immunotherapy to treat the concomitant PNS. Newer technologies and the ever-broadening use of cancer immunotherapies are contributing to the continued identification of novel intracellularly targeted autoantibodies.

Hematologic malignancies and hematopoietic stem cell transplantation.

Paraneoplastic neurologic syndromes are rarely associated with hematologic malignancies. In their rarity, lymphomas are the diseases with more frequent paraneoplastic neurologic syndrome. High-risk antibodies are absent in most lymphoma-associated paraneoplastic neurologic syndromes, with the exception of antibodies to Tr/DNER in paraneoplastic cerebellar degeneration, mGluR5 in limbic encephalitis, and mGluR1 in some cerebellar ataxias. Peripheral nervous system paraneoplastic neurologic syndromes are rare and heterogeneous, with a prevalence of demyelinating polyradiculoneuropathy in non-Hodgkin lymphoma. Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes (POEMS) is a rare, paraneoplastic syndrome due to an underlying plasma cell disorder. The diagnosis is based on defined criteria, and vascular endothelial growth factor (VEGF), not an antibody, is considered a reliable diagnostic marker that also mirrors therapy response. As with the paraneoplastic neurologic syndromes in solid tumors, therapies rely on cancer treatment associated with immunomodulatory treatment with better response in PNS with antibodies to surface antigens. The best outcome is generally present in Ophelia syndrome/limbic encephalitis with anti-mGluR5 antibodies, with frequent complete recovery. Besides patients with isolated osteosclerotic lesions (where radiotherapy is indicated), hematopoietic stem-cell transplantation is the therapy of choice in patients with POEMS syndrome. In the paraneoplastic neurologic syndromes secondary to immune checkpoint inhibitors, discontinuation of the drug together with immunomodulatory treatment is recommended.

Paraneoplastic neurologic manifestations of neuroendocrine tumors.

Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors arising from the transformation of neuroendocrine cells in several organs, most notably the gastro-entero-pancreatic system and respiratory tract. The classification was recently revised in the 5th Edition of the WHO Classification of Endocrine and Neuroendocrine Tumors. NENs can rarely spread to the central or peripheral nervous systems. Neurologic involvement is determined by the rare development of paraneoplastic syndromes, which are remote effects of cancer. Mechanisms depend on immunologic response to a tumor, leading to the immune attack on the nervous system or the production of biologically active ("functioning") substances, which can determine humoral (endocrine) effects with neurologic manifestations. Paraneoplastic neurologic syndromes (PNS) are immunologically mediated and frequently detected in small cell lung cancer but rarely seen in other forms of NEN. PNS and Merkel cell carcinoma is increasingly reported, especially with Lambert Eaton myasthenic syndrome. Endocrine manifestations are found in a wide spectrum of NENs. They can develop at any stage of the diseases and determine neurologic manifestations. Patient outcomes are influenced by tumor prognosis, neurologic complications, and the severity of endocrine effects.

Clinical approach to diagnosis of paraneoplastic neurologic syndromes.

The correct diagnosis of a paraneoplastic neurologic syndrome (PNS) first requires the identification of the syndrome as one of those defined as high-risk (previously called classical) or intermediate-risk for cancer in the 2021 PNS diagnostic criteria. Testing for neuronal antibodies should be restricted to these syndromes as indiscriminate request decreases the diagnostic value of the antibodies. Identifying onconeural (high-risk for cancer) or intermediate-risk for cancer antibodies supports the paraneoplastic diagnosis and mandates the search for an underlying cancer. Tumor screening must follow the published guidelines. Repeated screening is indicated in neurologic syndromes with onconeural antibodies and patients with high-risk for cancer neurologic syndromes unless they present neuronal antibodies which are not associated with cancer. Neuronal antibodies should be screened by immunohistochemistry and confirmed by immunoblot (intracellular antigens) or cell-based assay (CBA) (surface antigens). Positive results only by immunoblot or CBA should be taken with caution. Although the 2021 diagnostic criteria for PNS do not capture all PNS, as they do not allow to diagnose definite PNS neurologic syndromes without neuronal antibodies, the updated criteria represent a step forward to differentiate true PNS from neurologic syndromes that coincide in time with cancer diagnosis without having a pathogenic link.

Epidemiology of paraneoplastic neurologic syndromes.

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

Paraneoplastic neurologic syndrome and autoantibody accompaniments of germ cell tumors.

Paraneoplastic neurologic syndromes (PNSs) are a group of diseases affecting the central and/or peripheral nervous system caused by immune-mediated processes directed toward antigens with shared expression in tumor and neural tissue. Germ cell tumors (GCTs) are associated with PNSs with varied clinical phenotypes. Early diagnosis of PNS is vital to potentially uncover and treat underlying tumors, improving the chances of recovery, and preventing permanent neurologic complications. In this chapter, we outline the pathophysiology and epidemiology of PNS. We briefly provide a summary of GCTs in males and females. We review the neural-specific autoantibodies and PNSs associated with GCTs and their clinical and radiologic accompaniments. We also provide an overview of the treatment and prognosis of these disorders.

Genetic predisposition to autoimmune encephalitis and paraneoplastic neurological syndromes.

PURPOSE OF REVIEW: We summarize the recent discoveries on genetic predisposition to autoimmune encephalitis and paraneoplastic neurological syndromes (PNS), emphasizing clinical and pathophysiological implications. RECENT FINDINGS: The human leukocyte antigen (HLA) is the most studied genetic factor in autoimmune encephalitis and PNS. The HLA haplotype 8.1, which is widely known to be related to systemic autoimmunity, has been only weakly associated with a few types of autoimmune encephalitis and PNS. However, the strongest and most specific associations have been reported in a subgroup of autoimmune encephalitis that comprises antileucine-rich glioma-inactivated 1 (LGI1) limbic encephalitis, associated with DRB1∗07 : 01 , anticontactin-associated protein-like 2 (CASPR2) limbic encephalitis, associated with DRB1∗11 : 01 , and anti-IgLON5 disease, associated with DRB1∗10 : 01∼DQA1∗01∼DQB1∗05 . Non-HLA genes have been poorly investigated so far in autoimmune encephalitis, mainly in those lacking HLA associations such as anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, with only a few genome-wide association studies (GWAS) reporting equivocal results principally limited by small sample size. SUMMARY: Genetic predisposition seems to be driven mostly by HLA in a group of autoimmune encephalitis characterized by being nonparaneoplastic and having predominantly IgG4 autoantibodies. The contribution of non-HLA genes, especially in those diseases lacking known or strong HLA associations, will require large cohorts enabling GWAS to be powerful enough to render meaningful results.

Interest of rare autoantibodies in autoimmune encephalitis and paraneoplastic neurological syndromes: the utility (or futility) of rare antibody discovery.

PURPOSE OF REVIEW: The increasing recognition and diagnosis of autoimmune encephalitis (AE) and paraneoplastic neurological syndromes (PNS) is partly due to neural autoantibody testing and discovery. The past two decades witnessed an exponential growth in the number of identified neural antibodies. This review aims to summarize recent rare antibody discoveries in the context of central nervous system (CNS) autoimmunity and evaluate the ongoing debate about their utility. RECENT FINDINGS: In the last 5 years alone 15 novel neural autoantibody specificities were identified. These include rare neural antibody biomarkers of autoimmune encephalitis, cerebellar ataxia or other movement disorders, including multifocal presentations. SUMMARY: Although the clinical applications of these rare antibody discoveries may be limited by the low number of positive cases, they still provide important diagnostic, prognostic, and therapeutic insights.

Neurological autoimmunity in patients with non-pulmonary neuroendocrine neoplasms: clinical manifestations and neural autoantibody profiles.

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.

Neurological autoimmunity in melanoma patients: a comparison between those exposed and non-exposed to immune checkpoint inhibitors.

BACKGROUND: The clinical spectrum of melanoma-associated neurological autoimmunity, whether melanoma-associated paraneoplastic neurological syndromes (PNS) or induced by immune checkpoint inhibitors (ICI), is not well characterized. We aim to describe the clinical spectrum of melanoma-associated neurological autoimmunity. METHODS: A systematic review of the literature combined with patients from French databases of paraneoplastic neurological syndromes was conducted. All melanoma patients with a possible immune-mediated neurologic syndrome were included and classified according to whether they had previously been exposed to ICI (ICI-neurotoxicity) or not (ICI-naïve) at first neurological symptoms. RESULTS: Seventy ICI-naïve (literature: n = 61) and 241 ICI-neurotoxicity patients (literature: n = 180) were identified. Neuromuscular manifestations predominated in both groups, but peripheral neuropathies were more frequent in ICI-neurotoxicity patients (39.4% vs 21.4%, p = 0.005) whereas myositis was more frequent in ICI-naïve patients (42.9% vs 18.7%, p < 0.001). ICI-naïve patients had also more frequent central nervous system (CNS) involvement (35.7% vs 23.7%, p = 0.045), classical paraneoplastic syndrome (25.7% vs 5.8%, p < 0.001), and more frequently positive for anti-neuron antibodies (24/32, 75.0% vs 38/90, 42.2%, p = 0.001). Although more ICI-neurotoxicity patients died during the acute phase (22/202, 10.9% vs 1/51, 2.0%, p = 0.047), mostly myositis patients (14/22, 63.6%), mortality during follow-up was higher in ICI-naïve patients (58.5% vs 29.8%, p < 0.001). There was no significant difference in the frequency of life independence (mRS ≤ 2) in the surviving patients in both groups (95.5% vs 91.0%, p = 0.437). CONCLUSIONS: Melanoma-associated PNS appear remarkably rare. The clinical similarities observed in neurological autoimmunity between ICI-treated and ICI-naïve patients, characterized predominantly by demyelinating polyradiculoneuropathy and myositis, suggest a potential prior immunization against melanoma antigens contributing to ICI-related neurotoxicity.

Dysautonomia in anti-Hu paraneoplastic neurological syndromes.

BACKGROUND AND OBJECTIVES: Dysautonomia has been associated with paraneoplastic neurological syndrome (PNS)-related mortality in anti-Hu PNS, but its frequency and spectrum remain ill-defined. We describe anti-Hu patients with dysautonomia, estimate its frequency, and compare them to patients without dysautonomia. METHODS: Patients with anti-Hu antibodies diagnosed in the study centre (1990-2022) were retrospectively reviewed; those with autonomic signs and symptoms were identified. RESULTS: Among 477 anti-Hu patients, 126 (26%) had dysautonomia (the only PNS manifestation in 7/126, 6%); gastrointestinal (82/126, 65%), cardiovascular (64/126, 51%), urogenital (24/126, 19%), pupillomotor/secretomotor (each, 11/126, 9%), and central hypoventilation (10/126, 8%). Patients with isolated CNS involvement less frequently had gastrointestinal dysautonomia than those with peripheral (alone or combined with CNS) involvement (7/23, 30% vs. 31/44, 70% vs. 37/52, 71%; P = 0.002); while more frequently central hypoventilation (7/23, 30% vs. 1/44, 2.3% vs. 2/52, 4%; P < 0.001) and/or cardiovascular alterations (18/23, 78% vs. 20/44, 45% vs. 26/52, 50%; P = 0.055). Median [95% CI] overall survival was not significantly different between patients with (37 [17; 91] months) or without dysautonomia (28 [22; 39] months; P = 0.78). Cardiovascular dysautonomia (HR: 1.57, 95% CI [1.05; 2.36]; P = 0.030) and central hypoventilation (HR: 3.51, 95% CI [1.54; 8.01]; P = 0.003) were associated with a higher risk of death, and secretomotor dysautonomia a lower risk (HR: 0.28, 95% CI [0.09; 0.89]; P = 0.032). Patients with cardiovascular dysautonomia dying ≤ 1 year from clinical onset had severe CNS (21/27, 78%), frequently brainstem (13/27, 48%), involvement. DISCUSSION: Anti-Hu PNS dysautonomia is rarely isolated, frequently gastrointestinal, cardiovascular and urogenital. CNS dysfunction, particularly brainstem, associates with lethal cardiovascular alterations and central hypoventilation, while peripheral involvement preferentially associates with gastrointestinal or secretomotor dysautonomia, being the latest more indolent.