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.

PNMA2 forms immunogenic non-enveloped virus-like capsids associated with paraneoplastic neurological syndrome.

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

Paraneoplastic cochleovestibulopathy: clinical presentations, oncological and serological associations.

OBJECTIVE: Cochleovestibulopathy is a distinguishable paraneoplastic phenotype. In this study, we evaluate clinical presentation, serological/cancer associations and outcomes of paraneoplastic cochleovestibulopathy. METHODS: Retrospective chart review of patients with hearing impairment and/or vestibulopathy who underwent serological evaluations for paraneoplastic antibodies between January 2007 and February 2021 was performed. RESULTS: Twenty-six patients were identified (men, n=23; median age, 45 years, range: 28-70). Biomarkers detected included: KLHL11-IgG| |(n=20,| |77% (coexisting LUZP4-IgG, n=8)),| ||ANNA1-IgG| | |(n=3,| |12%),| |amphiphysin-IgG|| |(n=2,| |8%)| |and| |LUZP4-IgG|| |(n=1,| |4%). Most common neoplastic association was |testicular|/|extra-testicular| |seminoma| | (n=13,| |50%).|| Hearing| impairment (bilateral, 62%) was |present| |in| |all| |patients.| |Fifteen patients (58%) had cochleovestibular dysfunction as their initial presentation before rhombencephalitis/encephalomyelitis manifestations (hearing loss, four; acute vertigo, eight; both, three). |Brain| |MRI| |demonstrated| |internal| |auditory| |canal| |enhancement| |in| |four |patients.| Audiometry commonly revealed severe-profound bilateral sensorineural hearing loss. Most patients |had| a refractory course |despite| |immunotherapy| |and/or| |cancer| |treatment|. CONCLUSION: Cochleovestibulopathy commonly presents with rapidly progressive bilateral hearing loss and/or acute vertigo. However, in some patients, these symptoms present along with or following brainstem/cerebellar manifestations. KLHL11-IgG and seminoma are the most common serological and cancer associations, respectively. Recognition of this phenotype may aid in earlier diagnosis of paraneoplastic autoimmunity and associated cancer.

Immunophenotypical characterization of paraneoplastic neurological syndrome patients: a multicentric study.

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

Encefalitis límbica: clínica, patogenia y problemas diagnósticos / Limbic encephalitis: clinic, pathogenesis and diagnostic problems

La encefalitis límbica es una enfermedad infrecuente y potencialmente grave, que puede o no ser paraneoplásica y se caracteriza por déficit de la memoria reciente, alteraciones psiquiátricas y convulsiones. De origen autoinmunitario, está asociada a anticuerpos séricos e intratecales contra antígenos neuronales intracelulares y de superficie, con especial afectación de zonas límbicas. En este artículo se revisan aspectos históricos y epidemiológicos, patogenia, síndromes más frecuentes y mejor delimitados, histopatología y estudios complementarios. Se repasan también las dificultades del diagnóstico diferencial y la necesidad de descartar siempre un tumor subyacente. La detección de autoanticuerpos neuronales es importante para el diagnóstico, la planificación terapéutica y el pronóstico. La inmunoterapia y, si corresponde, el tratamiento de la neoplasia son cruciales para lograr una recuperación neurológica sustancial. La encefalitis límbica es una entidad probablemente subdiagnosticada, con un pronóstico más favorable si se trata de forma temprana. El actual conocimiento de su patogenia puede además aportar claridad para la mejor comprensión de otros síndromes neurológicos y psiquiátricos que puedan compartir mecanismos autoinmunitarios, como algunos trastornos psicóticos y epilepsias farmacorresistentes. (AU)

Limbic encephalitis is a rare and potentially serious disease, which may or may not be paraneoplastic and is characterized by recent memory deficits, psychiatric disturbances and seizures. Of autoimmune origin, it is associated with serum and intrathecal antibodies against intracellular and surface neuronal antigens, with special involvement of limbic areas. This article reviews historical and epidemiological aspects, pathogenesis, more frequent and better defined syndromes, histopathology and complementary studies. The difficulties of differential diagnosis and the need to always rule out an underlying tumor are also reviewed. Detection of neuronal autoantibodies is important for diagnosis, therapeutic planning and prognosis. Immunotherapy and, if appropriate, neoplasm treatment, are crucial to achieve substantial neurological recovery. Limbic encephalitis is probably an underdiagnosed entity, with a more favorable prognosis if treated early. The current knowledge of its pathogenesis may also provide clarity for a better understanding of other neurological and psychiatric syndromes that may share autoimmune mechanisms, such as some psychotic disorders and drug-resistant epilepsies. (AU)

Imaging Review of Paraneoplastic Neurologic Syndromes.

Paraneoplastic syndromes are systemic reactions to neoplasms mediated by immunologic or hormonal mechanisms. The most well-recognized paraneoplastic neurologic syndrome, both clinically and on imaging, is limbic encephalitis. However, numerous additional clinically described syndromes affect the brain, spinal cord, and peripheral nerves. Many of these syndromes can have imaging findings that, though less well described, are important in making the correct diagnosis. Moreover, imaging in these syndromes frequently mimics more common pathology, which can be a diagnostic challenge for radiologists. Our goal is to review the imaging findings of paraneoplastic neurologic syndromes, including less well-known entities and atypical presentations of common entities. Specifically, we discuss limbic encephalitis, paraneoplastic cerebellar degeneration, paraneoplastic brain stem encephalitis, cranial neuropathy, myelitis, and polyneuropathy. We also demonstrate common diagnostic pitfalls that can be encountered when imaging these patients.

Significance of Autoantibodies in Autoimmune Encephalitis in Relation to Antigen Localization: An Outline of Frequently Reported Autoantibodies with a Non-Systematic Review.

Autoantibodies related to central nervous system (CNS) diseases propel research on paraneoplastic neurological syndrome (PNS). This syndrome develops autoantibodies in combination with certain neurological syndromes and cancers, such as anti-HuD antibodies in encephalomyelitis with small cell lung cancer and anti-Yo antibodies in cerebellar degeneration with gynecological cancer. These autoantibodies have roles in the diagnosis of neurological diseases and early detection of cancers that are usually occult. Most of these autoantibodies have no pathogenic roles in neuronal dysfunction directly. Instead, antigen-specific cytotoxic T lymphocytes are thought to have direct roles in neuronal damage. The recent discoveries of autoantibodies against neuronal synaptic receptors/channels produced in patients with autoimmune encephalomyelitis have highlighted insights into our understanding of the variable neurological symptoms in this disease. It has also improved our understanding of intractable epilepsy, atypical psychosis, and some demyelinating diseases that are ameliorated with immune therapies. The production and motility of these antibodies through the blood-brain barrier into the CNS remains unknown. Most of these recently identified autoantibodies bind to neuronal and glial cell surface synaptic receptors, potentially altering the synaptic signaling process. The clinical features differ among pathologies based on antibody targets. The investigation of these antibodies provides a deeper understanding of the background of neurological symptoms in addition to novel insights into their basic neuroscience.

Multiple intracranial lesions with lung adenocarcinoma: A rare case of MOG-IgG-associated encephalomyelitis.

BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG) is an important marker on the surface of oligodendrocytes and is associated with many demyelinating diseases. Recently, MOG-IgG-associated encephalomyelitis (MOG-EM) has been proposed as a disease entity with a preliminary diagnosis standard. Some patients with lung cancer have been reported to be seropositive for onconeural antibodies; however, lung cancer cases with MOG-EM have not been previously reported. METHODS: We report the case of a patient with lung adenocarcinoma with multiple intracranial lesions found during molecular targeted therapy. RESULTS: The patient tested positive for MOG antibody in her cerebrospinal fluid, and the therapeutic effect of steroids was excellent. CONCLUSION: This is the first reported case of MOG-EM coincident with lung cancer in a patient with multiple intracranial lesions. When patients present with a history of malignant tumors or suspected paraneoplastic neurological syndrome, clinicians should also be alert to the presence of other autoimmune antibodies such as MOG-IgG to avoid treatment delay.

Neurological complications of pediatric cancer.

Both the onset of various malignancies as well as the treatment of cancer can lead to neurologic symptoms which can be difficult to diagnose. In this review, we highlight the varied ways in which neurologic sequelae of cancer and its treatment manifest in children. Initial neurologic presentation may be secondary to mass effect or to immune-mediated paraneoplastic syndromes. Treatment effects on the nervous system may arise from surgery, chemotherapy, radiation, or bone marrow transplantation. In addition, the rapidly expanding field of immunotherapies for cancer has generated numerous new approaches to eradicating cancer including monoclonal antibodies, checkpoint inhibitors, and chimeric antigen receptor T cells (CAR-T cells), which have neurologic side effects mediated by immune responses that are also being recognized. Here we review common consult questions to the neurologist and our general approach to these scenarios including altered mental status, headaches, seizures, and sensorimotor complaints, considering the multifactorial nature of each.

Pediatric Paraneoplastic Necrotizing Encephalitis Associated With Acute Lymphoblastic Leukemia.

BACKGROUND: Paraneoplastic encephalitis encompasses a diverse spectrum of neurological disorders associated with a variety of pediatric tumor types. METHODS: We describe a seven-year-old boy with paraneoplastic necrotizing encephalitis associated with precursor B-cell acute lymphoblastic leukemia. RESULTS: The initial presentation involved acute-onset upper extremity weakness, seizure-like activity, and agitation. Extensive evaluation revealed pancytopenia, elevated protein in the cerebrospinal fluid, and normal magnetic resonance imaging (MRI) consistent with a clinical diagnosis of encephalitis of presumed viral etiology. He was treated with antimicrobials and intravenous immunoglobulin and returned to his neurological baseline before discharge. One month later, he was diagnosed with precursor B-cell acute lymphoblastic leukemia. Before chemotherapy initiation, he again became encephalopathic. Repeat cerebrospinal fluid evaluation showed elevated protein, and MRI revealed findings consistent with diffuse necrotizing encephalitis. He received standard chemotherapy as well as immunotherapy with intravenous immunoglobulin and plasmapheresis, with resolution of MRI abnormalities and improvement in neurological status. At six years postpresentation, he is in remission for acute lymphoblastic leukemia, without significant neurocognitive deficits and mild right spastic hemiparesis. CONCLUSION: This is the first report of paraneoplastic encephalitis associated with pediatric leukemia. A hematologic malignancy should be considered in the differential diagnosis of paraneoplastic encephalitis.

Improved Prognosis and Increased Tumor-Infiltrating Lymphocytes in Patients Who Have SCLC With Neurologic Paraneoplastic Syndromes.

BACKGROUND: Approximately 10% of patients with SCLC develop a paraneoplastic syndrome (PNS). Neurologic PNS are thought to improve prognosis, which we hypothesized is related to increased tumor-infiltrating lymphocytes and immune recognition. METHODS: We queried 2,512,042 medical records from a single institution to identify patients who have SCLC with and without PNS and performed manual, retrospective chart review. We then performed multiplexed fluorescence immunohistochemistry and automated quantitative analysis (AQUA Technology) on tumors to assess CD3, CD4, and CD8 T cell infiltrates and programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) interactions. T cell infiltrates and PD-1/PD-L1 interaction scores were compared among patients with neurologic PNS, endocrinologic PNS, and a control group without PNS. Clinical outcomes were analyzed using the Kaplan-Meier method and Cox proportional hazards models. RESULTS: We evaluated 145 SCLC patients: 55 with PNS (25 neurologic and 30 endocrinologic) and 90 controls. Patients with neurologic PNS experienced improved overall survival compared to patients with endocrinologic PNS and controls (median overall survival of 24 months versus 12 months versus 13 months, respectively). Of the 145 patients, we identified tumor tissue from 34 patients that was adequate for AQUA analysis. Among 37 specimens from these 34 patients, patients with neurologic PNS had increased T cell infiltrates (p = 0.033) and PD-1/PD-L1 interaction (p = 0.014) compared to tumors from patients with endocrinologic PNS or controls. CONCLUSIONS: Tumor tissue from patients with SCLC with neurologic PNS showed increased tumor-infiltrating lymphocytes and PD-1/PD-L1 interaction consistent with an inflamed tumor microenvironment.

Motor neuron involvement in anti-Ma2-associated paraneoplastic neurological syndrome.

OBJECTIVE: To present clinical, radiological, and pathological features of a cohort of patients with motor neuron involvement in association with anti-Ma2 antibodies (Ma2-Ab). METHODS: Retrospective case-series of patients with definite paraneoplastic neurological syndrome (PNS) and Ma2-Ab, and cases identified from a review of the literature. RESULTS: Among 33 Ma2-Ab patients referred between 2002 and 2016, we retrospectively identified three patients (9.1%) with a motor neuron syndrome (MNS). Seven additional cases were retrieved among the 75 Ma2-patients reported in the literature (9.3%). A total of ten patients are, therefore, described herein. MNS was evident as combined upper and lower MNS in four patients, isolated upper MNS in two, and isolated lower MNS in one; three patients were diagnosed with myeloradiculopathy. The most common MNS signs/symptoms were: hyperreflexia (80%), proximal weakness (60%), proximal upper-limb fasciculations (50%), head drop (40%), and dysarthria/dysphagia (30%). Brain MRI abnormalities included bilateral pyramidal tract T2-weighted/FLAIR hyperintensities (three patients). Spine MRI found bilateral, symmetric, T2-weighted signal abnormalities in the anterior horn in two patients. CSF examination was abnormal in nine patients. Cancer was found in seven patients (four testicular, two lung, and one mesothelioma). Eight patients underwent first-line immunotherapy. Second-line immunotherapy was adopted in all our patients and in none of those identified in the literature. Motor improvement was observed in 33% of our patients, and 20% in the literature series. CONCLUSIONS: Motor neuron involvement could complicate Ma2-Ab-associated PNS in almost 10% of patients and must be carefully studied to adapt treatment. This disorder differs from amyotrophic lateral sclerosis.

Principales complicaciones neurológicas de los cánceres nefrourológicos / Major neurological complications of genitourinary cancers

Introducción. Los cánceres nefrourológicos constituyen un conjunto heterogéneo y cada vez más frecuente de tumores malignos que poseen el potencial de derivar directamente, e indirectamente por el tratamiento aplicado, en una serie de complicaciones neurológicas que impactan negativamente sobre la calidad de vida de los pacientes. Objetivo. Exponer los datos más relevantes sobre las principales complicaciones neurológicas de los cánceres nefrourológicos. Desarrollo. Búsqueda de artículos en PubMed, últimos libros y principales guías de práctica clínica y sociedades científicas publicados referentes al diagnóstico y tratamiento de dichas complicaciones. Conclusiones. Las complicaciones neurológicas de los cánceres nefrourológicos generan una carga importante de morbimortalidad en los pacientes oncológicos. Paradójicamente, gracias al aumento de su supervivencia, también se incrementa la probabilidad de producirse metástasis en el sistema nervioso o efectos adversos por el tratamiento, en especial la quimioterapia. Actualmente, el diagnóstico y el tratamiento de las complicaciones neurológicas asociadas a los cánceres nefrourológicos suponen un área muy importante de interés creciente para el desarrollo de trabajos de investigación que permitan mejorar el pronóstico y la calidad de vida de estos pacientes y de sus familiares o cuidadores. Para ello, es preciso conocer mejor la etiopatogenia y la fisiopatología que llevan a la aparición de este tipo de complicaciones, particularmente los síndromes paraneoplásicos, y, por otro lado, la realización de ensayos clínicos controlados, aleatorizados, bien diseñados, que amplíen el arsenal terapéutico con nuevos fármacos quimioterápicos con mayor efectividad antineoplásica y mejor seguridad relativa a los efectos secundarios neurotóxicos

Introduction. Genitourinary cancers constitute a heterogeneous and increasingly frequent group of malignant tumors that have the potential to derive directly, or indirectly from the treatment applied, in a series of neurological complications that negatively impact on the quality of life of the patients who suff er them. Aims. To report the most relevant data on the main neurological complications of genitourinary cancers. Development. We conducted a PubMed search for articles, latest books, leading clinical practice guidelines, and scientific societies, regarding the appearance of such complications. Conclusions. Neurological complications of genitourinary cancers generate a signifi cant burden of morbidity and ortality in cancer patients. In a paradoxical manner, owing to the raised survival of these patients, the likelihood of metastatization at the nervous system level and/or adverse eff ects related to the treatment received, especially due to chemotherapy, is also increased. Currently, diagnosis and management of neurological complications associated with genitourinary cancers represent a very important area of growing interest for the development of research projects that allow to improve the prognosis and quality of life genitourinary cancers subjects and their relatives and/or caregivers. For this purpose, it is necessary to know more about the etiopathogenesis and pathophysiology that lead to the occurrence of these type of complications in genitourinary cancers individuals, in particular paraneoplastic syndromes. Moreover, on the other hand, to carry out further well-designed randomized controlled clinical trials that expand the therapeutic arsenal with new chemotherapeutic drugs that possess a better antineoplastic eff ectiveness and improve the safety related to the neurotoxic side effects

Updates in the Diagnosis and Treatment of Paraneoplastic Neurologic Syndromes.

The disorders of the central nervous system associated with cancer by remote immune-mediated mechanisms are a heterogeneous group. These disorders encompass the classic paraneoplastic disorders and the recently recognized autoimmune encephalitis associated with antibodies against neuronal cell surface or synaptic proteins that occur with or without cancer association. In the last decade, the new surge of interest in neuronal diseases associated with anti-neuronal antibodies led to the rapid discovery of new forms of disease that have different manifestations and were not previously suspected to be immune mediated. The recognition of these syndromes is important because it may lead to early detection of an underlying malignancy and prompt initiation of treatment, improving chances for a better outcome.

Autopsy-proven case of paraneoplastic lower motor neuron disease with sensorimotor neuropathy due to Waldenström's macroglobulinemia.

We report a case of a male patient with a 19-year history of monoclonal and later polyclonal gammopathy who subsequently developed tetraparesis, bulbar palsy, and respiratory failure. Autopsy findings showed degeneration of the hypoglossal nuclei, prominent neuronal loss and atrophy in the anterior horn of the whole spinal cord despite the presence of mild astrocytosis, degeneration of the gracilis on one side, and infiltration of inflammatory cells, which included B cells and plasma cells in the anterior and posterior roots of the lumbar spinal cord, iliopsoas muscle, and perivascular area of the cervical cord. On immunostaining, cytoplasmic inclusions of phosphorylated transactivation response DNA-binding protein of 43 kDa were observed in the motor neurons and astrocytes of the hypoglossal nuclei and whole spinal cord. The final diagnosis was paraneoplastic lower motor neuron disease with sensorimotor neuropathy due to Waldenström's macroglobulinemia.

Neurological paraneoplastic syndromes: an update.

PURPOSE OF REVIEW: To describe recent advances in the diagnosis and treatment of paraneoplastic neurological syndromes (PNS). RECENT FINDINGS: PNS are rare complications of cancer caused by an immune cross-reaction between antigens expressed by tumor cells and neurons. The target of the immune attack can be an intracellular antigen or a cell-surface antigen. Although both types of autoimmunity are 'paraneoplastic', as indirectly triggered by the presence of a tumor, they profoundly differ in terms of clinical profile, pathogenesis and outcome. PNS associated with antibodies to intracellular antigens (icPNS) are characterized by relentless progression and poor response to treatment, because of rapid and permanent neuronal loss. PNS associated with antibodies to cell-surface antigens (csPNS) generally show favorable response to immune therapy and good functional outcome, as they result from reversible neuronal dysfunction. SUMMARY: The spectrum of paraneoplastic autoimmunity has dramatically expanded following the discovery of cell-surface antibodies. Novel antibodies are incessantly discovered, some of which have a solid association with cancer. As csPNS usually respond to immune therapy, the optimization of current treatment strategies should have high priority to improve therapeutic results and prevent relapses.