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A 63-year-old man with symptoms of depression and sexual disinhibition was admitted to a psychiatric clinic for the elderly. Because the man’s symptoms rapidly became more severe he was referred to the emergency room. There, his illness was diagnosed as paraneoplastic limbic encephalitis with positive anti-Hu antibodies; this is a paraneoplastic neurological syndrome presenting with short-term memory loss, epileptic seizures and psychiatric symptoms. For the prognosis of the illness it is essential that the syndrome is diagnosed as early as possible. Since patients sometimes present with mainly psychiatric symptoms it is important that psychiatrists are fully informed about the symptoms and are able to make an accurate diagnosis.

Paraneoplastic neurological syndromes (PNS) are disorders of the nervous system that are associated with remote effects of malignancy. PNS are considered to have an autoimmune pathology. It has been suggested that immune antitumor responses are the origin of improved outcome in PNS. We describe cell-mediated immune responses in PNS and their potential contributions to antitumor reactions. Experimental and neuropathological studies have revealed infiltrates in nervous tissue and disturbances in lymphocyte populations in both cerebrospinal fluid and peripheral blood. A predominance of cytotoxic T lymphocytes (CTLs) over T helper cells has been observed. CTLs can be specifically aggressive against antigens shared by tumors and nervous tissue. Based on genetic studies, a common clonal origin of lymphocytes from blood, tumor, and nervous tissue is suggested. Suppressive regulatory T (Treg) lymphocytes are dysfunctional. Simultaneously, in tumor tissue, more intense cell-mediated immune responses are observed, which often coincide with a less aggressive course of neoplastic disease. An increased titer of onconeural antibodies is also related to better prognoses in patients without PNS. The evaluation of onconeural and neuronal surface antibodies was recommended in current guidelines. The link between PNS emergence and antitumor responses may result from more active CTLs and less functional Treg lymphocytes.

Lung cancer is recognized among the most frequent causes of paraneoplastic neurological syndromes (PNS). Neurological syndromes in subjects with systemic malignancy remain a clinical and diagnostic challenge. The aim of the study was to evaluate the frequency of NPS, their clinical manifestation and association with onconeural antibodies in patients with lung cancer. Fifty patients hospitalized with the diagnosis of PNS participated in the study. Neurological evaluation consisted of the Rankin scale (mRS), the Barthel index (BI), and testing for the presence of onconeural antibodies by means of indirect immunofluorescence, as screening, and Western blotting as confirmation. The majority of lung cancer patients (64%) aged 62 ± 10 had NPS symptoms. Their neurological condition and daily living activities were reasonable: mRS (1.0; 0.0-4.0) and BI (100; 7.4-100) scores. Classical PNS were found in 30% of cases and included sensory neuropathy (16%), paraneoplastic cerebellar degeneration (12%) as the most frequent symptoms. Autoimmune reaction was observed in 42% of lung cancer patients and in 20% was represented by well-characterized onconeural antibodies. Anti-Hu antibody was identified as the most frequent. In conclusion, PNS signs in lung cancer patients have both classical and non-classical features. In the course of SCLC only well-characterized onconeural antibodies were identified. The presence of well-characterized onconeural antibodies is strongly associated with classical features of PNS.

Langerhans cell histiocytosis (LCH) is a very rare disease in which granulation tissue forms in various organs and the central nervous system (CNS) due to monoclonal proliferation of Langerhans cells. Some patients develop ataxia, tremor, or neurodegenerative abnormalities (such as personality changes and mental deterioration) several years after the onset as the late effects of LCH. We report a case of a 4-year-old boy with LCH, showing speech disorder, truncal ataxia and a wide-based gait with abnormal findings of central nervous system in CT and MRI image. The results of auditory brain stem response revealed a conduction block in the auditory conduction pathway, suggesting an axonopathy of the brain stem. Disequilibrium may be due to brainstem dysfunction associated with paraneoplastic syndrome because an anti-GluRε2 antibody was seen. Paraneoplastic syndrome is a neuropathy induced through an autoimmune mechanism caused by an antibody directed against the nervous system. Neuro-otological examination is helpful for the assessment of CNS neurodegeneration associated with LCH., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Purpose of Review: This review describes relevant advances in paraneoplastic neurological syndromes (PNS) with emphasis on particular syndromes and the impact of antibodies against surface antigens in their management., Recent Findings: PNS may present with symptoms that do not raise the suspicion of a paraneoplastic origin. The best example is anti-N-methyl-D-aspartate receptor encephalitis that in adult women frequently associates with ovarian teratoma. An electroencephalogram pattern described as 'extreme delta brush' was recently identified in 30% of patients with this disorder. Isolated myelopathy may have a paraneoplastic origin associated with amphiphysin or CV2 (CRMP5) antibodies. Jaw dystonia and laryngospasm can be the predominant symptom of the brainstem encephalitis associated with Ri antibodies. γ-Aminobutyric acid (GABA)(B) receptor antibodies are the most common antibodies found in patients with limbic encephalitis and small cell lung cancer, and contactin-associated protein 2 antibodies in patients with Morvan's syndrome and thymoma. Lastly, a recent study identified delta/notch-like epidermal growth factor-related receptor (DNER) as the target antigen of Tr antibodies, a marker of cerebellar ataxia and Hodgkin's lymphoma., Summary: The number of antibodies relevant to PNS is now expanded to those against surface antigens. These antibodies do not confirm the paraneoplastic origin of the syndrome but predict a better response to immunotherapy.

Anti-SRP (signal recognition particle) positive necrotizing myopathy is commonly not associated with neoplasms. We demonstrate two histologically confirmed cases with unusual manifestations of anti-SRP positive necrotizing myopathy. A 65-year-old man presented with rapidly progressing weakness and mild difficulties in swallowing and speaking. Screening for underlying disorders revealed a moderately differentiated renal adenocarcinoma. The muscular symptoms partially improved after tumor nephrectomy and prednisone treatment. However, the patient developed pulmonary metastases and died of the sequelae of pneumonia 11 months after the diagnosis of renal cancer. The second patient developed rapidly complete external ophthalmoplegia, severe bulbar dysarthrophonia and dysphagia, bilateral facial palsy, loss of patellar and ankle jerk reflexes, and severe symmetrical tetraparesis of both proximal and distal muscles. CSF showed mildly increased protein levels, neurography axonal impairment of motor nerves. Screening revealed no evidence for infections, ganglioside antibodies, and carcinoma. MRI was normal. The disease course suggested an overlap syndrome of Miller-Fisher-syndrome, axonal Guillain-Barré-syndrome and Bickerstaff brainstem encephalitis. In conclusion SRP antibodies might be found in necrotizing myopathies associated with autoimmune mediated overlap syndromes and neoplasms. The pathomechanism is not clear. Any otherwise unexplained evidence of necrotizing myopathy should prompt the screening for SRP antibodies., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Anti-Hu antibody-associated paraneoplastic neurological syndromes (Hu-PNSs) are severe and often precede the detection of a malignancy, usually small-cell lung cancer. In Hu-PNS, it is hypothesized that neuronal cells are destroyed by T cells targeted against HuD, a protein expressed by small-cell lung cancer cells and neurons. There is only limited evidence for the existence of HuD-specific T cells. To detect these T cells in the blood of Hu-PNS patients, we employed 3 highly sensitive assays that included T cell stimulation with dendritic cells (DCs) to specifically expand the number of any HuD-specific T cells. A total of 17 Hu-PNS patients were tested with 1 or more of the following 3 assays: (1) tetramer staining after stimulation of T cells with conventionally generated DCs (n = 9), (2) interleukin (IL)-13 enzyme-linked immunosorbent spot (ELISpot; n = 3), IL-4 and IL-5 and interferon (IFN)-γ multiplex cytokine bead array (n = 2) to assay cytokine production by T cells after stimulation with conventionally generated DCs, and (iii) IFN-γ ELISpot and tetramer staining after T cell stimulation with accelerated co-cultured DCs (n = 11). No circulating HuD-specific T cells were found. We suggest that either autoaggressive T cells in Hu-PNS are not targeted against HuD or that their numbers in the blood are too low for detection by highly sensitive techniques.

Paraneoplastic neurological syndromes (PNS) are severe immune mediated effects of cancer. The presence of IgG autoantibodies against onconeural antigens in serum is a hallmark of the disease. Multiple paraneoplastic antibodies have been described, including antibodies against HuD, Yo, amphiphysin and CV2. In this study, we test the hypothesis that primary amino-acid structures of the antigen binding part of antibodies from various individuals share common sequences that are specific for each auto-antigen. We selected 60 patients with PNS, associated with antibodies against HuD, Yo, Amp or CV2. Affinity purified IgG was separated using SDS-PAGE and IgG heavy chains were excised, trypsinized and subjected to tandem mass spectrometry. We selected masses that uniquely identified a PNS autoantibody group, and used MS/MS fragmentation spectra to obtain information on peptide sequences. Out of 19,173 unique masses, 28 immunoglobulin-derived peptides were found exclusively in samples from a single autoantibody defined PNS group. Our results confirm that specific peptide structures exist in the antigen binding site of IgG that are shared between individuals harboring autoantibodies against the same onconeural antigen. Thus, the immune response in these patients followed converging paths during the rearrangement, selection and maturation of immunoglobulin sequences. The identified peptides can be applied in the diagnosis of PNS, but these data also indicate that a similar approach in a variety of other diseases involving an immune response would have an appealing outlook., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis is a recently described potentially lethal but treatable disorder that often occurs as a paraneoplastic manifestation of ovarian teratomas. We report three women with this disorder who presented with subacute onset of delirium, seizures and autonomic instability. Anti-NMDA receptor antibodies were detectable in the serum or cerebrospinal fluid of each patient. Ovarian masses were detected in two patients, and subsequently excised. In the third patient, an empirical bilateral salpingo-oophorectomy was performed and revealed a microscopic neoplasm. All patients experienced slow reversal of the neurological symptoms following surgery and immunotherapy. Our experience suggests that prompt syndrome recognition followed by tumor removal and immunotherapy usually results in neurological recovery., (© 2012 The Authors Acta Obstetricia et Gynecologica Scandinavica© 2012 Nordic Federation of Societies of Obstetrics and Gynecology.)

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

Isolated case reports suggest that breast tumors from patients with paraneoplastic cerebellar degeneration (PCD) and Yo antibodies overexpress human epidermal growth factor receptor 2 (HER2). HER2 overexpression is present in 15%-25% of breast cancers and is associated with poor prognosis. We retrospectively analyzed the status of HER2 in breast tumors of 27 patients with anti-Yo-associated PCD to evaluate whether HER2 overexpression in this group of patients is higher than expected. In addition, we analyzed HER2 status of 19 breast tumors from patients with paraneoplastic neurological syndromes and Ri antibodies to see whether HER2 was specifically related to anti-Yo-associated PCD. We also assessed cdr2 expression (the onconeural antigen recognized by Yo antibodies) in 21 HER2-positive breast tumors from patients without paraneoplastic neurological syndromes. HER2 was overexpressed in 26 patients (96.3%) with anti-Yo-associated PCD but only in 2 patients (10.5%) with paraneoplastic neurological syndromes associated with Ri antibodies (P< .0001). Only 5 (23.8%) of the 21 HER2-positive breast tumors showed cdr2 immunoreactivity. This study shows a very high frequency of HER2 overexpression in breast cancers in patients with anti-Yo-associated PCD but not in those from patients with Ri antibodies. Although the expression of cdr2 onconeural antigen is not high in HER2-positive breast cancers, HER2 overexpression seems to be an important requirement to develop an anti-Yo-associated PCD.

Tissues of the CNS, such as the brain, optic nerves, and spinal cord, may be affected by a range of insults including genetic, autoimmune, infectious, or neurodegenerative diseases and cancer. The immune system is involved in the pathogenesis of many of these, either by causing tissue damage or alternatively by responding to disease and contributing to repair. It is clearly vital that cells of the immune system patrol the CNS and protect against infection. However, in contrast to other tissues, damage caused by immune pathology in the CNS can be irreparable. The nervous and immune systems have, therefore, coevolved to permit effective immune surveillance while limiting immune pathology. Here we will consider aspects of adaptive immunity in the CNS and the retina, both in the context of protection from infection as well as cancer and autoimmunity, while focusing on immune responses that compromise health and lead to significant morbidity.

Introduction: Paraneoplastic neurological syndrome associated with anti-CV2/CRMP5 antibodies are rare. Various clinical manifestations can occur, cerebellar ataxia, polyneuropathy, optic neuritis with NORB or uveitis. Small cell lung carcinoma is generally responsible., Case Report: We report the case of a 64-year-old man who developed visual symptoms with papilledema, cerebellar signs, polyneuropathy confirmed with a neurophysiological studies. Anti-CV2/CRMP5 antibodies were present. A small cell lung carcinoma was responsible for this paraneoplastic syndrome revealing the cancer. The paraneoplastic syndrome improved with radio chemotherapy of the cancer alone., Conclusion: A paraneoplastic neurological syndrome must be evoked in case of an atypic neurological syndrome. This diagnostic can be confirmed by the presence of anti-neuronal antibodies. In this case, a small cells cancer of the lung must be research., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Purpose of Review: This article provides an update on classic paraneoplastic syndromes of the CNS and autoimmune encephalitis syndromes associated with antibodies against synaptic proteins, including the NMDA receptor, LGI1, and Caspr2, among others., Recent Findings: Most classic paraneoplastic syndromes are associated with antibodies against intracellular (onconeuronal) antigens, appear to be mediated by cytotoxic T-cell responses, and have limited response to treatment. The autoimmune synaptic disorders are associated with antibodies against extracellular epitopes, appear to be directly mediated by antibodies, and are responsive to immunotherapy. The syndromes associated with antibodies against intracellular antigens almost always occur in conjunction with cancer, and their clinical course is usually monophasic. In contrast, syndromes associated with antibodies against synaptic proteins may occur with or without cancer and often relapse., Summary: The spectrum of autoimmune disorders of the CNS with distinct clinical and immunologic associations is expanding. Prompt diagnosis and treatment can result in recovery from some syndromes.

Neurological dysfunction results from vascular, inflammatory, degenerative, neoplastic, metabolic or genetic causes. Of particular interest is a group of neurological symptoms thought to be linked to an underlying tumour, the so-called paraneoplastic syndromes. It is considered to be due to an attempt by the immune system to subjugate the growth of the tumour by triggering an antibody response against the neuronal antigens expressed by the neoplasm. The unfortunate consequence of this is an assault by the immune components on the nervous tissue, thereby rapidly precipitating a variety of neurological deficits. Every level of the nervous system is potentially vulnerable, with the disability being considered as irreversible due to the lack of regenerative capacity of the neurons. This phenomenon is rare, occurring at an approximate frequency of less than 1% of all tumours and often accompanied by the presence of specific high-titre autoantibodies in both the cerebrospinal fluid and blood. This group of antibodies are non-pathogenic markers for paraneoplastic neurological syndromes, which have expanded to almost 20 since the discovery, in 1986, of the first clinically relevant syndrome. More recently, a new generation of antineuronal antibodies against cell surface antigens, having a direct pathogenic role in causing the disease, has emerged to complement the existing repertoire. Neuronal antibodies are useful diagnostic markers of the brain disease and also, in some cases, may reveal an underlying malignancy, thus facilitating faster diagnosis and earlier treatment with consequently better prognosis.

A 63-year-old woman had anti-Hu-associated paraneoplastic encephalomyelitis (anti-Hu syndrome) caused by esophageal small cell carcinoma (SCC). The patient developed bilateral limbic encephalitis, followed by myelitis, brain stem encephalitis, and autonomic failure. Extensive examination demonstrated SCC of the abdominal lymph nodes that was retrospectively diagnosed as metastasis of esophageal SCC on autopsy. The neuropathological findings were characterized by widespread neuronal loss and gliosis in the central nervous system, as well as patchy loss of myelin and axons in the spinal nerve roots with perivascular lymphocytic infiltration. This is the first detailed clinical and neuropathological report of anti-Hu syndrome caused by esophageal SCC.

Paraneoplastic neurological syndromes (PNS) are rare nervous system dysfunctions in cancer patients, which are not due to a local effect of the tumour or its metastases. PNS in adults are mainly associated with lung cancer, especially small cell lung cancer, lymphoma and gynaecological tumours. In some cases an overlapping of different clinical syndromes can be observed. Since autoantibodies directed against tumour and nervous system tissue can be observed, an autoimmune aetiology has been suspected in PNS patients. Currently, one group of patients exhibit surface-binding receptor or ion channel autoantibodies which are thought to be pathogenic and many of these patients respond well to immunotherapies. Another group of PNS is associated with highly specific autoantibodies directed against intracellular onconeuronal antigens. The latter group seem to be T-cell-mediated and do not respond well to immunotherapies. The childhood PNS, especially the neuroblastoma-associated opsoclonus-myoclonus syndrome also respond to immunosuppressive therapies, plasmapheresis and intravenous immunoglobulins. The current review summarizes recent developments in physiopathology, diagnosis and treatment of paraneoplastic neurological syndromes.

We report a case of elderly-onset neuromyelitis optica (NMO) positive for the anti-aquaporin-4 (AQP-4) antibody; symptoms developed after the diagnosis of prostate adenocarcinoma and relapsed after a 23-valent pneumococcal polysaccharide vaccination. We suggest that activation of CD4-positive T cells and secretion of interferon-gamma induced by adenocarcinoma and complement activation induced by vaccination are responsible for the onset and relapse of NMO, even if a patient is positive for the anti-AQP-4 antibody. This case supports the previous experimental finding that the anti-AQP-4 antibody does not cause NMO-like lesions when injected alone, but does so after the induction of T cell-mediated experimental autoimmune encephalomyelitis or when co-injected with human complement.

Paraneoplastic neurological syndrome (PNS) is a rare disorder caused by the remote effects of cancer and is considered as immune-responses to the molecules on cancer which cross-react with self-antigens in the nervous system. Since the 1980s, several specific anti onconeural antibodies have been reported, which are useful diagnostic markers of PNS and occult cancer. Only a few onconeural antibodies have been identified as primary effectors of neurological damage. Recently sophisticated methods for the detection of new or low titer antibodies have been developed. Several new auto-antibodies against receptors or ion channels on the surface of neuronal membrane, such as NMDA receptors, AMPA receptors, GABA(B) receptors and VGKC complexes, have been reported in the patients with encephalopathy including limbic encephalitis. These diseases can be associated with tumor, but they are more often non-paraneoplastic. These antibodies are generally good biomarkers for effective immunomodulatory treatment for immune-mediated encephalitis with not only consciousness disturbance but also dementia, seizures and psychiatric symptoms which sometimes mimic schizophrenia. Further studies are required to clarify the exact mechanisms underlying neuronal damage in immune-mediated neurological diseases including PNS, which may lead to the development of more rational therapies and greater understanding of immunology in the nervous system.

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

The last three decades have seen major advances in the understanding of paraneoplastic and idiopathic autoimmune disorders affecting the central nervous system (CNS). Neural-specific autoantibodies and their target antigens have been discovered, immunopathology and neuroimaging patterns recognized and pathogenic mechanisms elucidated. Disorders accompanied by autoantibody markers of neural peptide-specific cytotoxic effector T cells [such as anti-neuronal nuclear antibody type 1 (ANNA-1, aka anti-Hu), Purkinje cell antibody type 1 (PCA-1, aka anti-Yo) and CRMP-5 IgG] are generally poorly responsive to immunotherapy. Disorders accompanied by neural plasma membrane-reactive autoantibodies [the effectors of synaptic disorders, which include antibodies targeting voltage-gated potassium channel (VGKC) complex proteins, NMDA and GABA-B receptors] generally respond well to early immunotherapy. Here we describe in detail the neuropathological findings and pathophysiology of paraneoplastic CNS disorders with reference to antigen-specific serology and neurological and oncological contexts.

Purpose of Review: The most relevant advances in immune-mediated movement disorders are described, with emphasis on the clinical--immunological associations, novel antigens, and treatment., Recent Findings: Many movement disorders previously considered idiopathic or degenerative are now recognized as immune-mediated. Some disorders are paraneoplastic, such as anti-CRMP5-associated chorea, anti-Ma2 hypokinesis and rigidity, anti-Yo cerebellar ataxia and tremor, and anti-Hu ataxia and pesudoathetosis. Other disorders such as Sydenham's chorea, or chorea related to systemic lupus erythematosus and antiphospholipid syndrome occur in association with multiple antibodies, are not paraneoplastic, and are triggered by molecular mimicry or unknown mechanisms. Recent studies have revealed a new category of disorders that can be paraneoplastic or not, and associate with antibodies against cell-surface or synaptic proteins. They include anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, which may cause dyskinesias, chorea, ballismus or dystonia (NMDAR antibodies), the spectrum of Stiff-person syndrome/muscle rigidity (glutamic acid decarboxylase, amphiphysin, GABA(A)-receptor-associated protein, or glycine receptor antibodies), neuromyotonia (Caspr2 antibodies), and opsoclonus--myoclonus--ataxia (unknown antigens)., Summary: Neurologists should be aware that many movement disorders are immune-mediated. Recognition of these disorders is important because it may lead to the diagnosis of an occult cancer, and a substantial number of patients, mainly those with antibodies to cell-surface or synaptic proteins, respond to immunotherapy.

Immune responses targeting self-proteins (autoantigens) can lead to a variety of autoimmune diseases. Identification of these antigens is important for both diagnostic and therapeutic reasons. However, current approaches to characterize autoantigens have, in most cases, met only with limited success. Here we present a synthetic representation of the complete human proteome, the T7 peptidome phage display library (T7-Pep), and demonstrate its application to autoantigen discovery. T7-Pep is composed of >413,000 36-residue, overlapping peptides that cover all open reading frames in the human genome, and can be analyzed using high-throughput DNA sequencing. We developed a phage immunoprecipitation sequencing (PhIP-Seq) methodology to identify known and previously unreported autoantibodies contained in the spinal fluid of three individuals with paraneoplastic neurological syndromes. We also show how T7-Pep can be used more generally to identify peptide-protein interactions, suggesting the broader utility of our approach for proteomic research.

Introduction: A paraneoplastic syndrome characterized by neuropsychiatric symptoms, involuntary movements and seizures has been recently associated with antibodies targeting NMDA (N-methyl-D-aspartate) receptor in patients with an ovarian teratoma. Severe neurological impairment is frequent and treatment in the intensive care unit is often required because of ventilatory failure and life-threatening autonomic instability. Tumor removal is curative in many cases and neurological improvement is demonstrated shortly after surgery., Case Report: Here we report on a patient with paraneoplastic encephalitis manifested by unconsciousness and coreo-athetosic movements related to NMDA receptor antibodies associated with an immature ovarian teratoma grade III. She made a complete recovery after oophorectomy, intravenous immunoglobulin and corticosteroids., Conclusions: Treatment of paraneoplastic syndromes is based on specific therapy for underlying tumor associated to immunomodulators. As in this case, anti-NMDA encephalitis may significantly improve after tumor removal and intra-venous immunoglobuline.

Recent identification of syndromes encompassing psychiatric symptoms, seizures, and movement disorders has led to effective treatments for several previously obscure conditions now known to be immune-mediated encephalopathies. In contrast to long-recognized paraneoplastic neurologic syndromes associated with antibodies to intracellular antigens, these more recently described disorders are not always paraneoplastic, are associated with cell surface antibodies, and may respond to immunosuppressive therapies. In this review, the author discusses clinical presentations, differential diagnosis, immunologic evaluation, and therapeutic options for both groups of disorders., (© Thieme Medical Publishers.)

Paraneoplastic neurologic syndromes are rare disorders that have potentially devastating effects on the developing brain. Recently, there has been increased interest in possible immunotherapy for these disorders. Recognition of paraneoplastic syndromes in children may lead to early detection and treatment of the pediatric cancer and may diminish the neurologic damage that is the major source of morbidity in children with successfully treated tumors. This article reviews the presenting symptoms, immunology, long-term sequelae, and management options for paraneoplastic neurologic syndromes, focusing on those most commonly reported in children: opsoclonus-myoclonus ataxia, limbic encephalitis, and anti-NMDAR encephalitis. The child neurologist plays an important role in recognizing these disorders, initiating a tumor search, and directing ongoing treatment and management of neurologic symptoms after oncologic treatment is complete. Given the rarity of these conditions, multisite collaborative efforts are needed to develop standardized approaches to characterization and treatment.

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

Background: Onconeural antibodies are strongly associated with cancer and paraneoplastic neurological syndromes (PNS). Most of these antibodies are well-characterized (antibodies against Hu, Yo, Ri, CRMP5, amphiphysin, Ma2 and Tr) and are in common use for the diagnosis of definite PNS., Materials and Methods: Literature on detection and clinical significance of onconeural antibodies were identified by using relevant search terms in PubMed and reviewed., Conclusions: The onconeural antibodies are directed against intracellular antigens and their pathogenic role is still largely unknown. They are highly specific markers of paraneoplastic aetiology in patients with neurological symptoms. Detection of an onconeural antibody in a patient with neurological symptoms should lead to prompt investigation for cancer. However, absence of detectable onconeural antibodies does not exclude the PNS diagnosis. In particular, failure to detect antibodies in patients without classical PNS symptoms may result in less vigorous cancer screening and diagnostic delay. Neuronal antibodies that are directed to synaptic proteins or proteins of the cell membrane are also associated with neurological symptoms, and probably have pathogenic effects. The association between these antibodies and cancer is less robust, and they are usually not included among the onconeural antibodies., (© 2011 John Wiley & Sons A/S.)

Objective: Paraneoplastic neurological syndromes associated with anti-Hu antibodies (Hu-PNS) are mediated by a T-cell immune response that is directed against the Hu antigens. In pregnancy, many Th1-mediated autoimmune diseases such as rheumatoid arthritis and multiple sclerosis regress. We hypothesised that this decreased disease activity during pregnancy may be related to high human chorionic gonadotropin (hCG) levels., Methods: 15 Hu-PNS patients were treated in a prospective, uncontrolled and unblinded trial with 10,000 IU daily of hCG administered by intramuscular injection during 12 weeks. Primary outcome measures were functional improvement defined as a decrease of one or more points on the modified Rankin Scale (mRS) or stabilisation in patients with mRS score ≤3 and improvement of neurological impairment assessed with the Edinburgh Functional Impairment Tests (EFIT). Secondary end points included the change in activities of daily living as evaluated using the Barthel Index., Results: Seven of 15 patients (47%) improved on the mRS or stabilised at mRS score ≤3. Four patients (27%) showed significant improvement of neurological impairment as indicated by an overall Edinburgh Functional Impairment Tests score of ≥1 point. Five patients improved on the Barthel Index (33%)., Conclusion: Comparison with previous studies suggests that hCG may have immunomodulatory activity and may modify the course of Hu-PNS, although well-established confounding factors may have contributed in this uncontrolled trial.

An elderly female smoker presented with nausea and anorexia. Imaging and histopathology were consistent with a diagnosis of small cell lung cancer (SCLC). She subsequently developed a progressive sensorimotor neuropathy with high titres of anti-Hu antibodies. Development of the neuropathy was associated with marked regression in the lung neoplasm. Repeat investigation with radioimaging and bronchoscopy showed no evidence of neoplasia. Paraneoplastic sensorimotor neuropathies are commonly associated with SCLC particularly in the presence of anti-Hu antibodies. Regression of SCLC with anti-Hu antibodies has only been reported twice previously. The authors believe this case supports the theory that anti-Hu antibodies confer anti-tumour activity causing tumour regression.

The article provides an overview on the diagnosis and pathogenesis of paraneoplastic neurological disorders (PNDs), and subsequently the current therapeutic strategies in these patients. PNDs are nervous system dysfunctions in cancer patients, which are not due to a local effect of the tumor or its metastases. Most of these clinically defined syndromes in adults are associated with lung cancer, especially small-cell lung cancer, lymphoma and gynecological tumors. In a part of the PND, an overlapping of different clinical syndromes can be observed. Highly specific autoantibodies directed against onconeuronal antigens led to the current hypothesis of an autoimmune pathophysiology. Whereas the most central nervous PNDs are more T-cell-mediated, limbic encephalitis can be caused by pathogenic receptor autoantibodies. The PND of the neuromuscular junction and paraneoplastic autonomic neuropathy are mainly associated with receptor or ion channel autoantibodies. The childhood opsoclonus-myoclonus syndrome and the PNDs associated with receptor/ion channel autoantibodies often respond to immunosuppressive therapies, plasmapheresis and intravenous immunoglobulins. By contrast, most CNS PNDs associated with defined antineuronal antibodies directed against intracellular antigens only stabilize after tumor treatment.

A 17-year-old boy, with acute myelomonocytic leukemia and inversion 16(p13q22) developed polyneuropathy and isolated central nervous system relapse. Scoliosis and high-arched feet suggested a diagnosis of Charcot Marie Tooth (CMT) syndrome and genetic testing confirmed duplication at the PMP22 locus at chromosome 17p11.12. No mutation was found in another CMT gene, the CMT C1 LITAF locus at 16p13.2, to suggest that this association is anything more than chance. Titres to VGKC, a paraneoplastic autoantibody, were elevated, suggesting an additional mechanism for the polyneuropathy. This case extends the clinical spectrum of cancer with CMT, and of paraneoplastic disorders.

Brainstem encephalitis is not a classic paraneoplastic syndrome and usually involves monophasic neurological deterioration and has negative magnetic resonance imaging (MRI) findings. We describe a patient with brainstem encephalitis who had elevated anti-Ri antibody levels and double-step neurological deterioration associated with different abnormal lesions on MRI. Immunosuppression with steroids and intravenous immune globulin combined with aggressive treatment of the tumor successfully led to the resolution of brainstem symptoms and MRI lesions. In patients with unusual signs and symptoms of paraneoplastic encephalitis mimicking multiple sclerosis, onconeural antibody studies are recommended.

Introduction: Paraneoplastic neurological syndromes (PNS) are uncommon and imperfectly understood and, therefore, are frequently underdiagnosed., Methods: We review the current literature on the clinical presentation, diagnosis, pathophysiology and treatment of PNS., Results: PNS are a heterogeneous group of neurologic disorders caused by an immune response to an underlying malignancy. A 3-step diagnostic process is necessary to establish the diagnosis. We review the role of onconeural antibodies in the diagnosis and pathogenesis of PNS and describe recent advances in treatment, focusing on paraneoplastic encephalomyelitis, limbic encephalitis, paraneoplastic cerebellar degeneration, opsoclonus-myoclonus syndrome, subacute sensory neuronopathy and Lambert-Eaton myasthenic syndrome, Conclusion: PNS often antedate the diagnosis of cancer, offering an opportunity for detecting cancer at an earlier and curable stage. Tests for paraneoplastic antibodies are often negative and do not rule out the diagnosis of a paraneoplastic syndrome. Certain clinical presentations should suggest a paraneoplastic syndrome, even in the absence of paraneoplastic antibodies, and prompt a thorough search for occult malignancy.

Background: Hypothetically, T cells are involved in the pathogenesis of paraneoplastic neurological syndromes associated with Hu-antibodies (Hu-PNS)., Objective: To identify genetic risk factors for Hu-PNS and investigate the role of T cells., Methods: HLA-A, B, DRB1 and DQB1 alleles were compared in 53 Hu-PNS patients with 24 small-cell lung-cancer (SCLC) patients and 2440 healthy controls (HC)., Results: The frequency of both HLA-DQ2 and HLA-DR3 was significantly higher in Hu-PNS patients than in HC., Conclusions: This study indicates an association between Hu-PNS and presence of HLA-DQ2 and HLA-DR3, which supports a role for CD4(+) T cells in the pathogenesis of Hu-PNS., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Anti-SOX1 antibodies have been described to be positive in patients with paraneoplastic Lambert-Eaton myasthenic syndrome and, in a lower amount, in patients with anti-Hu positive paraneoplastic neurological syndromes, and with SCLC alone, respectively. We found 5/32 patients with paraneoplastic neuropathy and, surprisingly, 4/22 patients with neuropathy of unknown origin positive for anti-SOX1 antibodies, whereas no patient with inflammatory neuropathy and no healthy controls showed any reactivity (p=0.007). All patients with neuropathy of unknown origin where followed up for four years without diagnosis of a tumour so far. Anti-SOX1 antibodies are associated with paraneoplastic neuropathies and may define another group of non-paraneoplastic, immune-mediated neuropathies., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Paraneoplastic disorders of the CNS result from immune responses to neuronal proteins expressed by tumors found elsewhere in the body. Limbic encephalitis, one of the most common manifestations of paraneoplastic disorders, is characterized by rapid onset of psychiatric and neurological symptoms that often culminate in severe neurological deterioration. Recent work has described paraneoplastic syndromes with prominent, and sometimes isolated, psychiatric symptoms for which patients are fi rst seen by a psychiatrist. Here the authors review the existing literature on psychiatric and behavioral manifestations of paraneoplastic disorders, the cellular mechanisms underlying these syndromes, and current treatment and outcomes. They also discuss the broad behavioral findings that highlight the need for psychiatrists to be aware of initial presentations of paraneoplastic disorders.

Background: The occurrence of a second delayed paraneoplastic neurological syndrome (PNS), different from the first, in the same patient, is not well known. However, recognition of this possibility is important in the management of the patient with PNS., Objective: To describe eight patients who presented with two different PNS with a time delay of months to years., Design, Setting and Patients: Retrospective analysis of eight patients, included in the European PNS database, with two different PNS that occurred months to years apart., Results: The median delay between the two different PNS was 15 months. The antibody repertoire did not change between the two episodes. Anti-Hu was detected in five patients, and anti-CV2 and anti-Ri in one each. One patient did not present onconeural antibodies. Lung cancer was diagnosed in six patients. In five patients, the second PNS revealed a cancer relapse (n=4) or a second cancer (n=1) and in three it occurred without evidence of tumour recurrence. In these three patients, all with anti-Hu antibodies, the second episode consisted of a lower motor neuron disease. Median survival was not reached after a median follow-up of 5 years., Conclusions: A second PNS can reveal a cancer relapse but can also arise in its absence. The long survival of patients with a second PNS suggests that the immune response might be more effective in controlling the cancer.

Paraneoplastic autoimmune diseases associate occasionally with small cell lung cancers and gynecologic tumors. However, myasthenia gravis (MG) occurs in at least 30% of all patients with thymomas (usually present at MG diagnosis). These epithelial neoplasms almost always have numerous admixed maturing polyclonal T cells (thymocytes). This thymopoiesis-and export of mature CD4(+)T cells-particularly associates with MG, though there are rare/puzzling exceptions in apparently pure epithelial WHO type A thymomas. Other features potentially leading to inefficient self-tolerance induction include defective epithelial expression of the autoimmune regulator (AIRE) gene and/or of major histocompatibility complex class II molecules in thymomas, absence of myoid cells, failure to generate FOXP3(+) regulatory T cells, and genetic polymorphisms affecting T-cell signaling. However, the strong focus on MG/neuromuscular targets remains unexplained and suggests some biased autoantigen expression, T-cell selection, or autoimmunization within thymomas. There must be further clues in the intriguing serological and cellular parallels in some patients with late-onset MG but without thymomas-and in others with AIRE mutations-and in the contrasts with early-onset MG, as discussed here.

Although the discovery of antineuronal antibodies has facilitated the diagnosis of paraneoplastic neurologic disorders, the recognition and treatment of these disorders remain a challenge. Some antibodies are more syndrome-specific than others, and some syndromes suggest a paraneoplastic etiology more frequently than others. Because some antineuronal antibodies may occur in cancer patients without paraneoplastic neurologic disorders, their detection does not necessarily imply that a neurologic disorder is paraneoplastic. Moreover, there is an emerging group of encephalitides that appear to be mediated by antibodies against cell surface or synaptic proteins, may occur with or without tumor association, and are responsive to treatment. This review analyzes the immune responses associated with paraneoplastic and nonparaneoplastic disorders of the central nervous system, and the main clinical features and response to treatment., (Thieme Medical Publishers.)

Antibodies to the N-methyl-d-aspartate subtype of glutamate receptor have been associated with a newly-described encephalopathy that has been mainly identified in young females with ovarian tumours. However, the full clinical spectrum and treatment responses are not yet clear. We established a sensitive cell-based assay for detection of N-methyl-d-aspartate receptor antibodies in serum or cerebrospinal fluid, and a quantitative fluorescent immunoprecipitation assay for serial studies. Although there was marked intrathecal synthesis of N-methyl-d-aspartate receptor antibodies, the absolute levels of N-methyl-d-aspartate receptor antibodies were higher in serum than in cerebrospinal fluid. N-methyl-d-aspartate receptor antibodies were of the immunoglobulin G1 subclass and were able to activate complement on N-methyl d-aspartate receptor-expressing human embryonic kidney cells. From questionnaires returned on 44 N-methyl-d-aspartate receptor antibody-positive patients, we identified a high proportion without a detected tumour (35/44, 80%: follow-up 3.6-121 months, median 16 months). Among the latter were 15 adult females (43%), 10 adult males (29%) and 10 children (29%), with four in the first decade of life. Overall, there was a high proportion (29%) of non-Caucasians. Good clinical outcomes, as defined by reductions in modified Rankin scores, correlated with decreased N-methyl-d-aspartate receptor antibody levels and were associated with early (<40 days) administration of immunotherapies in non-paraneoplastic patients (P < 0.0001) and earlier tumour removal in paraneoplastic patients (P = 0.02). Ten patients (23%) who were first diagnosed during relapses had no evidence of tumours but had received minimal or no immunotherapy during earlier episodes. Temporal analysis of the onset of the neurological features suggested progression through two main stages. The time of onset of the early features, characterized by neuropsychiatric symptoms and seizures preceded by a median of 10-20 days, the onset of movement disorders, reduction in consciousness and dysautonomia. This temporal dichotomy was also seen in the timing of cerebrospinal fluid, electroencephalographic and in the rather infrequent cerebral imaging changes. Overall, our data support a model in which the early features are associated with cerebrospinal fluid lymphocytosis, and the later features with appearance of oligoclonal bands. The immunological events and neuronal mechanisms underlying these observations need to be explored further, but one possibility is that the early stage represents diffusion of serum antibodies into the cortical grey matter, whereas the later stage results from secondary expansion of the immunological repertoire within the intrathecal compartment acting on subcortical neurons. Four patients, who only had temporal lobe epilepsy without oligoclonal bands, may represent restriction to the first stage.

The remote effects of malignant tumors in most cases of paraneoplastic neurological syndromes(PNS)are mediated by autoimmune processes against antigens shared by the tumor cells and the nervous tissue(onconeural antigens). Onconeural (or paraneoplastic)antibodies are broadly categorized into two groups according to the location of the corresponding onconeural antigens, inside or on the surface of neurons. Antibodies established as clinically relevant diagnostic markers for PNS are designated as well-characterized onconeural antibodies (or classical antibodies)that target intracellular antigens(Hu, Yo, Ri, CV2/CRMP5,Ma2, and amphiphysin). They also serve as useful markers in detecting primary tumors. Recent identification of new antibodies as markers of subtypes of limbic encephalitis has also expanded the concept of autoimmune limbic encephalitis. These autoantibodies are directed to neuronal cell-surface antigens including neurotransmitter receptors(NMDA, AMPA, and GABAB receptors)and ion channels(VGKC). They are less frequently associated with cancer, so that they cannot be used as specific markers for PNS. Autoimmune limbic encephalitis with anti-neuronal cell surface antobodies and paraneoplastic limbic encephalitis with classical antibodies overlap in some clinical features but are pathophysiologically distinct. Classical antibodies are not simple tumor markers. They seem to be closely related to the disease mechanisms because specific intrathecal synthesis has been shown in PNS patients. However, attempts to produce an animal model of PNS by passive transfer of these antibodies have been unsuccessful, and there is no direct evidence demonstrating the pathogenic role of classical antibodies. Instead, some circumstantial evidence, including pathological studies showing extensive infiltrates of T cells in the CNS of the patients, supports the hypothesis that cytotoxic-T cell mechanisms cause irreversible neuronal damage. On the other hand, humoral immune response is probably the principal mechanism in autoimmune encephalitis associated with antibodies against neuronal cell-surface antigens. Those antibodies are supposed to mediate neural dysfunction which may be reversed by immunosuppression therapy, while the exact mechanism remains to be elucidated. Further accumulation of the cases and longer observation would be necessary to delineate the clinical spectrum of each type of newly-identified autoimmune limbic encephalitis. Early diagnosis and optimal oncological treatment is a prerequisite for better prognosis of PNS patients. Detection of the primary tumor at very early stages including carcinoma in situ is a challenging issue. Optimization of immunosuppression/ immunomodulation therapy for each patient according to the underlying pathophysiological processes is another important clinical issue.

Paraneoplastic neurological syndromes (PNS) are thought to be caused by autoimmune processes triggered by the cancer and directed against antigens common to both the cancer and nervous system. There are several clinical phenotypes in combinations with the neurological syndromes, origin of cancer and the specific autoantibodies. In most patients, the neurological disorder develops before the cancer becomes clinically overt together with autoantibodies. As these antibodies are associated with a restricted range of cancers, the presence of the antibodies requires physicians in charge to search the underlying cancers. The early cancer treatment and active immunotherapy tended to ameliorate the neurological symptoms, especially in those harboring antibodies against cell surface antigens like NMDAR. VGKC, VGCC. The group of PNS having antibodies against intracellular antigens might be caused via cytotoxic T cell activation.

Background: The role of antibodies in neuromuscular junction disorders is well established with antibodies to acetylcholine receptor, muscle-specific kinase, and voltage-gated calcium channels. The diseases associated with these antibodies, myasthenia gravis and the Lambert-Eaton myasthenic syndrome, respond well to symptomatic treatments (e.g., cholinesterase inhibitors) and to immunotherapies such as plasma exchange, intravenous immunoglobulin, oral steroids, and steroid-sparing drugs. The role of the antibodies has been established by a variety of in vitro and in vivo approaches. More recently, antibodies to voltage-gated potassium channels have been identified in patients with autoimmune forms of acquired neuromyotonia. Over the last decade, antibodies to CNS membrane receptors or ion channels have begun to be identified and these antibodies define antibody-mediated CNS diseases that also respond to immunotherapies., Summary: The paradigms gained from the study of the peripheral conditions has led to a better appreciation of the role of antibodies in neurological disorders and a growing recognition of their role in central nervous system (CNS) diseases.