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We reported a 61-year-old man presented with 10-month progressing left sciatic neuropathy and 10-day right facial neuropathy. Serum amphiphysin-IgG was positive. 18 F-FDG PET/CT of the whole body showed no signs of malignancy. Treatment with plasma exchange and oral prednisone relieved the symptoms. Nine months later, right hemiparesis and seizure of right limbs developed. 18 F-FDG and 18 F-PBR06 (18 kDa translocator protein, TSPO) radioligand PET/MRI of the whole body revealed intense uptake in the intracranial lesions. Intracranial lymphoma was diagnosed by stereotactic needle brain biopsy. Mononeuropathies could be paraneoplastic syndromes. TSPO shows high uptake in intracranial lymphoma on 18 F-PBR06 PET images., Competing Interests: Declaration of Competing Interest All authors claimed that there were no conflicts of interest in this case., (Copyright © 2023. Published by Elsevier B.V.)

Background and Aims: SOX1 antibodies are generally associated with small cell lung cancer and anti-Hu antibody overlap is common. This case demonstrates isolated anti-SOX1 antibodies with an uncommon tumor type, and relapse of a paraneoplastic syndrome with recurrence of tumor., Methods: We describe a case of a 65-year-old male with a paraneoplastic peripheral neuropathy and anti-SOX1 antibody positivity in the context of a prior male breast Grade 2 ductal carcinoma, in remission at the time of the initial neurological presentation., Results: Treatment response to intravenous immunoglobulin (IVIg) was demonstrated. After period of clinical stability on IVIg in the context of remission of breast carcinoma, the patient experienced a relapse of his neuropathy. This was associated with tumor recurrence and again responded to tumor excision, radiotherapy and IVIg., Interpretation: Male breast carcinoma has not previously been associated with anti-SOX1 antibody positive paraneoplastic neuropathy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: Sensory ganglionopathies or sensory neuronopathies are subacute acquired diseases of the dorsal root ganglion, frequently associated with disinmune, paraneoplastic and toxic agents. Patients present sensory alteration of asymmetric distribution and early ataxia. Early identification is essential, as they may announce an underlying neoplasia or autoimmune disease., Aim: To study asymmetries of the sensory nervous action potential (SNAP) of nerve pairs and the relationship amplitude of ulnar sensory/ulnar motor potential (USMAR) with serial electroneurophysiological studies for the early diagnosis of sensory ganglionopathies., Patients and Methods: Six patients with sensory ganglionopathies were retrospectively studied with electroneurophysiological studies: four paraneoplastic cases with positivity for onconeuronal antibodies, one associated with Sjogren's syndrome and two idiopathic., Results: Electroneurophysiological studies showed axonal sensory involvement in all cases, with asymmetry > 50% in SNAP amplitude in two pairs of nerves in four cases and normal motor with USMAR < 0.71 in five cases. Serial electroneurophysiological studies were essential in the diagnosis of two cases in the beginning of the disease with mild sensory symptoms., Conclusions: This work evidences the importance of the study of asymmetries in the amplitude of the SNAP of nerve pairs, the USMAR and the serial electroneurophysiological studies in the early diagnosis of sensory ganglionopathies, to further identification of the disinmune and onconeuronal associated antibodies with the nervous system affection to search for hidden neoplasia.

Antibodies to the ganglioside GD1b have been reported in various forms of immune-mediated neuropathy, but their clinical relevance for diagnosis and prognosis is unknown. We investigated the prevalence of anti-GD1b antibodies in acute and chronic immune-mediated neuropathies, and the clinical presentation and outcome in Guillain-Barré syndrome (GBS) and Miller Fisher-GBS overlap syndrome (MF-GBS). Anti-GD1b, anti-GM1 and anti-GQ1b antibodies were tested in serum of patients with GBS (N = 165), Miller Fisher syndrome (N = 10), MF-GBS (N = 28), monoclonal gammopathy of unknown significance neuropathy (MGUS; N = 101), chronic inflammatory demyelinating polyneuropathy (N = 29), paraneoplastic syndrome with anti-Hu-associated neuropathy (PNS; N = 11), other auto-immune diseases (AID; N = 60), and healthy controls (HC; N = 60). All samples were tested by enzyme-linked immunosorbent assay according to the Inflammatory Neuropathy Cause and Treatment protocol. IgM anti-GD1b antibodies were found in GBS (N = 4; 2.4%), MGUS (N = 3; 3.0%), and PNS patients (N = 1; 9.1%). IgG anti-GD1b antibodies were found in GBS (N = 20; 12.1%) and MF-GBS (N = 4; 14.3%) patients, but not in the AID and HC group. In the combined group of MF-GBS and GBS patients ((MF-)GBS), 14/36 (38.9%) patients with IgG anti-GD1b antibodies also had IgG anti-GM1 antibodies, and IgG anti-GD1b and IgG anti-GQ1b antibodies were found in 3/29 (10.3%) patients. Patients with (MF-)GBS and anti-GD1b without anti-GM1 antibodies did not differ regarding sensory disturbances or disease severity but recovered faster regarding the ability to walk independently compared with patients without anti-GD1b antibodies (P = 0.031) and with patients with both anti-GD1b and anti-GM1 antibodies (P = 0.034). In conclusion, testing for anti-GD1b antibodies may identify a specific group of immune-mediated neuropathies and (MF-)GBS patients with only anti-GD1b antibodies tend to recover faster., (© 2018 Peripheral Nerve Society.)

Introduction: Antitumor immune responses are postulated to initiate paraneoplastic neurological disorders when proteins that are normally restricted to neural cells are expressed as oncoproteins. Mutated oncopeptides could bypass self-tolerant T cells to activate cytotoxic effector T lymphocytes and requisite helper T lymphocytes to stimulate autoantibody production by B lymphocytes., Methods: We investigated muscle-type nicotinic acetylcholine receptor (AChR) antigen expression at transcriptional and protein levels in a small-cell lung cancer line (SCLC) established from a patient with AChR-immunoglobulin G (IgG)-positive myasthenia gravis., Results: We identified messenger RNA transcripts encoding the 2 AChR α1-subunit isoforms and 7 alternative-splicing products, 3 of which yielded premature stop codons. Despite detecting native muscle-type AChR pentamers in the tumor, we did not identify mutant α1-peptides. However, we found α1-subunit-derived peptides bound to tumor major histocompatibility complex (MHC)1-protein. In a control SCLC from an antineuronal nuclear autoantibody, type 1 (anti-Hu)-IgG-positive patient, we identified MHC1-complexed Hu protein-derived peptides but not AChR peptides., Discussion: Our findings support onconeural protein products as pertinent immunogens initiating paraneoplastic neurological autoimmunity. Muscle Nerve 58: 600-604, 2018., (© 2018 Wiley Periodicals, Inc.)

Purpose of Review: To review recent advances in paraneoplastic neuropathies with emphasis on their definition, different forms and therapeutic development., Recent Findings: A strict definition of definite paraneoplastic neuropathies is necessary to avoid confusion. With carcinoma, seronegative sensory neuronopathies and neuronopathies and anti-Hu and anti-CV2/Contactin Response Mediator Protein 5 antibodies are the most frequent. With lymphomas, most neuropathies occur with monoclonal gammopathy including AL amyloidosis, Polyneuropathy-Organomegaly-Endocrinopathy-M component-Skin changes (POEMS) syndrome, type I cryoglobulinemia and antimyelin-associated glycoprotein (MAG) neuropathies and Waldenström's disease. Neuropathies improving with tumor treatment are occasional, occur with a variety of cancer and include motor neuron disease, chronic inflammatory demyelinating neuropathy and nerve vasculitis. If antibodies toward intracellular antigens are well characterized, it is not the case for antibodies toward cell membrane proteins. Contactin-associated protein-2 antibodies occur with neuromyotonia and thymoma with the Morvan's syndrome in addition to Netrin 1 receptor antibodies but may not be responsible for peripheral nerve hyperexcitability. The treatment of AL amyloidosis, POEMS syndrome, anti-MAG neuropathy and cryoglobulinemia is now relatively well established. It is not the case with onconeural antibodies for which the rarity of the disorders and a short therapeutic window are limiting factors for the development of clinical trials., Summary: A strict definition of paraneoplastic neuropathies helps their identification and is necessary to allow an early diagnosis of the underlying tumor.

Acute confusion is a common symptom of physical illness in the older patient. In the majority, it is transient and resolves on treatment of precipitants. In a subset of patients, however, neurological decline is progressive, raising concern about a serious underlying cause. We describe the case of a 71-year-old woman who developed progressive cognitive impairment following insertion of a permanent pacemaker for sinoatrial arrests. An initial diagnosis of delirium secondary to a urinary tract infection was suspected; however, the patient became increasingly confused despite treatment. Laboratory tests revealed serum anti-Hu paraneoplastic antibodies, and CT chest identified an occult lung tumour. Cervical lymph node histopathology confirmed a diagnosis of small cell carcinoma of the lung. Although a rare cause of confusion, paraneoplastic encephalomyelitis should be recognised early to allow timely identification and treatment of the associated cancer., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Introduction: Voltage-gated calcium-channel autoimmunity (VGCC-P/Q and VGCC-N types) occurs beyond Lambert-Eaton syndrome and lung cancer., Methods: We reviewed records for 236 Mayo Clinic patients with VGCC antibodies found in evaluation for paraneoplastic neurological autoimmunity (generally without myasthenic syndromes)., Results: VGCC autoantibodies were detected in 3.4% of neurological patients, 1.7% of healthy controls, and 4% of neurologically asymptomatic lung cancer controls. Fifty neurological patients (21%) had ≥ 1 neoplasm, historically (46) or detected prospectively [small-cell lung carcinoma (2), breast adenocarcinoma (2), lymphoma (1), and suspected tonsillar carcinoma (1)]. Autoimmune neurological diagnosis frequencies (encephalopathy, ataxia, myelopathy, neuropathy, neuromuscular junction disorder, and myopathy) among patients with medium values (24%; 0.10-0.99 nmol/L) or low values (19%; 0.03-0.10 nmol/L) were fewer than among patients with antibody values exceeding 1.00 nmol/L (71%; P = 0.02 and 0.004, respectively)., Conclusions: Among neuronal VGCC-autoantibody-seropositive patients, autoimmune neurological phenotypes and cancer types are diverse. Cautious interpretation of results (particularly medium and low values) is advised. Muscle Nerve, 2016 Muscle Nerve 54: 220-227, 2016., (© 2016 Wiley Periodicals, Inc.)

Anti-titin antibodies indicate a paraneoplastic etiology pointing towards a thymoma in myasthenia gravis (MG), but their seroprevalence and potential diagnostic value in patients with other paraneoplastic neurological syndromes (PNS) is unknown. Therefore, we screened the sera of 44 PNS patients with well-characterized onconeural antibodies (anti-Hu, Yo, Ri, CV2/CRMP5, Ma1, Ma2/Ta, or amphiphysin) for anti-titin reactivity. Two patients (4.5%) were positive for anti-titin antibodies: both patients differed regarding the PNS (sensorimotor neuropathy and subacute cerebellar degeneration vs. chorea), well-characterized onconeural antibodies (CV2/CRMP5 vs. Ri), and malignoma (small cell lung cancer vs. breast cancer). However, retrospectively, the patients neither showed any symptoms of MG nor a thymoma on a computed tomographic (CT) scan. The results of this study indicate that anti-titin antibodies without a predictive relevance for MG or thymoma may be present in a small proportion of patients with PNS., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Introduction: Sural nerve biopsy is an important means of establishing the diagnosis of inflammatory neuropathies. We investigated the diagnostic value of endoneurial edema., Methods: Diagnostic sural nerve biopsies from 42 patients with inflammatory and 28 patients with noninflammatory neuropathies were re-evaluated for the presence of endoneurial edema. Edema was assessed on hematoxylin-eosin stained paraffin and frozen sections and on azure II-methylene blue stained semithin sections. We determined the area of endoneurial edema on digitized images in relation to the entire endoneurial area of each fascicle., Results: Edema was more extensive in neuropathies with short disease duration (≤12 months) as compared to long duration (>12 months; P < 0.01). Edema in inflammatory neuropathies of ≤12 months duration covered a larger area than in noninflammatory neuropathies (P < 0.01), and the extent of edema correlated negatively with disease duration (P < 0.05)., Conclusions: Endoneurial edema may be a useful additional disease marker in inflammatory neuropathies of recent onset., (© 2016 Wiley Periodicals, Inc.)

Tonsillar metastatic small cell lung cancer (SCLC) is rare, while anti-Hu antibodies are frequently found in SCLC. A 66-year-old man was admitted to our hospital with painful dysesthesia and muscle weakness in the distal extremities for over 1 year, progressive dysphagia for over 1 month, and severe cough and dyspnea for over 1 week. He was diagnosed with SCLC accompanied by tonsillar metastasis and anti-Hu antibody-associated paraneoplastic sensory neuropathy (PSN). The patient tolerated 6 cycles of sequential chemoradiotherapy and gradually recovered. The patient's disease remained in remission 2 years after the diagnosis with a remarkable reduction of tumor burden and a persisting high titer of anti-Hu antibodies. To our knowledge, this is the first case of tonsillar metastatic SCLC accompanied by anti-Hu antibody-associated PSN, whereby the anticancer immune response was presumed to play a vital role in disease control. Unilateral tonsillar metastasis of SCLC accompanied by anti-Hu antibody-associated PSN can occur and in certain circumstances, may have a favorable prognosis., Competing Interests: The authors have no conflicts of interest to disclose.

Objectives: To study possibilities of immunological and electrophysiological methods for the diagnosis of paraneoplastic polyneuropathy in cancer., Methods: We studied 88 cancer patients using electromyography and immunological assay (serum neuronal antibodies)., Results: A symmetrical, distal, sensory-motor, axonal-demyelinating form of polyneuropathy can develop in breast cancer and small cell lung cancer. Onconeural antibodies were detected in the serum of more than half of study participants as well as in some healthy donors. Symptoms of polyneuropathy appeared earlier than the diagnosed tumor., Conclusion: The diagnostic value of the methods used for the early diagnosis of breast cancer and small cell lung cancer is emphasized.

Paraneoplastic syndromes are indirect manifestations of cancer due to functional peptides/hormones produced by a tumour, or due to cross reactivity between tumour and host antigens. Here the case of a 58-year-old woman presenting with ataxia, paraesthesia and subacute and progressive loss of vision is reported. The patient exhibited strong serum positivity for anti-Hu and anti-CV2 antibodies, and a chest CT scan showed a hypodense nodule in proximity of the right upper lobe bronchus and an enlarged ipsilateral paratracheal lymph node that was not visible on a lung x-ray. Histopathological examination of a biopsy specimen from this lymph node showed that small cell carcinoma of the lung was present. The patient's deficits were subsequently diagnosed as three coexisting paraneoplastic neurological syndromes (PNSs): subacute cerebellar ataxia, sensory neuropathy and retinopathy, respectively. Although rare, PNSs can be the first manifestations of cancer, and their rapid recognition facilitates an early treatment.

Thymoma, a common anterior mediastinal tumour, may present with paraneoplastic neurological symptoms. The presence of neuronal anti-Hu paraneoplastic antibodies in thymoma patients is very rare. Here, we describe a patient who presented with symptoms of a sensory peripheral neuropathy in the presence of onconeural antibodies cross-reactive with Hu antigen, in whom an underlying thymoma was diagnosed. Subsequent minimally invasive thymomectomy improved her neurological symptoms significantly.

IgG4-RSD should be suspected in any patient presenting with lacrimal or salivary gland enlargement, particularly if male and manifesting mild glandular dysfunction. A serum IgG4 level, if increased, may be helpful, although a gland biopsy staining for IgG4-positive plasma cells is the definitive test. Primary low-grade B cell lymphomas of the glandular tissue, specifically MALT lymphoma and other glandular malignancy, should be considered, particularly in patients with asymmetric glandular enlargement. Patients with idiopathic uveitis should have a thorough evaluation to exclude malignancy, in particular PIOL and melanoma in adults, and diffuse retinoblastoma and ALL in children. RF remains a diagnostic challenge and atypical features such as outward displacement of the retroperitoneal structures should raise the suspicion for a malignant infiltrative process. CRPS rarely may be the first presentation of an occult malignancy and requires a thorough review of age-appropriate cancer screening. Carpal tunnel syndrome, if bilateral or associated with other systemic features, should prompt a search for amyloidosis., (Published by Elsevier Inc.)

Objective: To describe a patient with diencephalic and mesencephalic presentation of a Ma1 and Ma2 antibody-associated paraneoplastic neurological disorder., Design: Case report., Setting: The Colorado Neurological Institute Movement Disorders Center in Englewood, Colorado, and the Mayo Clinic in Rochester, Minnesota., Patient: A 55-year-old man with a paraneoplastic neurological disorder characterized by rapid eye movement sleep behavior disorder, narcolepsy, and a progressive supranuclear palsy-like syndrome in the setting of tonsillar carcinoma., Intervention: Immunotherapy for paraneoplastic neurological disorder, surgery and radiotherapy for cancer, and symptomatic treatment for parkinsonism and sleep disorders., Main Outcome Measures: Polysomnography, multiple sleep latency test, and neurological examination., Results: The cancer was detected at a limited stage and treatable. After oncological therapy and immunotherapy, symptoms stabilized. Treatment with modafinil improved daytime somnolence., Conclusions: Rapid onset and progression of multifocal deficits may be a clue to paraneoplastic etiology. Early treatment of a limited stage cancer (with or without immunotherapy) may possibly slow progression of neurological symptoms. Symptomatic treatment may be beneficial.

Objective: We studied a case series of peripheral nerve hyperexcitability (PNH) aiming to describe clinical characteristics, immunologic and cancer associations, antibodies against neuronal antigens (voltage-gated potassium channel antibodies [VGKC-Abs] and other), and muscle biopsy findings., Methods: Patients presenting with clinical and electrophysiologic signs of PNH were selected. We studied clinical and electrophysiologic features; a panel of non-neuronal organ-specific antibodies, immunofluorescence on rat nervous tissues, and radioimmunoprecipitation for VGKC-Abs; and muscle biopsies., Results: Thirty-eight patients were included. After the exclusion of 6 cases with axonopathy of known origin, patients were subdivided according to the presence of electrophysiologic findings of motor axonopathy and association with cancer: axonopathic-PNH (group A: 12 patients), isolated nonparaneoplastic PNH (group B: 16 patients), and isolated paraneoplastic PNH (3 with thymoma and myasthenia gravis, 1 with thyroid carcinoma). PNH clinical features were similar in groups A and B. We found an overall high prevalence of clinical autoimmunity (33% of group A and 63% of group B) and systemic non-neuronal autoantibodies (42% of group A and 75% of group B). However, VGKC-Abs were only positive in 2 patients of group B. Ten patients underwent muscle biopsy, which showed inflammatory changes in 2 cases and nonspecific myopathic features in 8., Conclusions: PNH is a heterogeneous disorder involving the peripheral nerves in patients with a high propensity for developing autoimmunity. Associated muscle diseases are frequent in the form of myositis, myasthenia gravis, or nonspecific myopathic pathologic findings. VGKC-Abs were uncommon in this series.

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.

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.)

The diagnosis of anti-Hu-associated encephalomyelitis/sensory neuropathy may be particularly difficult when cranial nerve involvement represents the first clinical manifestation of the disease. We report a case of a patient who presented with facial pain as the first manifestation of an anti-Hu paraneoplastic syndrome, which needs a rapid detection and treatment of the underlying tumour. We suggest that paraneoplastic neuropathy should be considered during the management of trigeminal neuropathic pain, especially when brain imagery is normal.

Introduction: The anti-Hu associated syndrome is a rare paraneoplastic neurological syndrome, which is principally associated with small-cell lung cancer., Observation: We report the case of a patient with the following clinical features: dysautonomia with severe gastroparesis, sensory neuropathy and a rhombencephalitis. Tumour regression was obtained with chemotherapy but the patient ultimately died from the neurological complications., Conclusion: Neurological syndromes associated in small cell lung cancer with anti-Hu antibodies are very diverse. Cancer evolution is generally speaking more benign than usual with the prognosis linked to the severity of the neurological involvement., (Copyright 2010 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Although small cell cancer of the lung may have protean manifestations, tumor embolization and inability to identify the primary sites are unusual features. We present a patient with anti-Hu antibody-associated paraneoplastic sensory polyneuropathy and tumor embolism diagnosed by endovascular biopsy to be due to small cell cancer, the primary site of which was not evident. To our knowledge, this patient represents only the second individual to be described with tumor embolization complicating small cell cancer and reminds clinicians of the extended spectrum of this disease., (2009 S. Karger AG, Basel.)

Extraskeletal myxoid chondrosarcomas usually arise deep in the proximal extremities and limb girdles. Patients with this type of sarcoma have high rates of local recurrence and metastases, but do not typically have paraneoplastic syndromes. We report an unusual case of a 49-year-old man with anti-Hu syndrome in the setting of an extraskeletal myxoid chondrosarcoma. This case shows the importance of searching for antineural antibodies in oncologic patients with new neurologic deficits, and of having a judicious workup for occult malignancies in patients with known antineural antibodies.

Along with myasthenia, other paraneoplastic neurological syndromes (PNS) may occur in thymoma. Anti-Hu antibodies and a clinical "anti-Hu syndrome" characterized by encephalitis and/or painful neuropathies have been reported in only three patients at the time of the diagnosis of thymoma. We describe a severe anti-Hu-related autonomic neuropathy with gastrointestinal paresis and intestinal pseudo-obstruction with malabsorption that occurred concomitantly with the worsening of myasthenic symptoms long after the initial diagnosis of thymoma in a young patient. The clinical anti-Hu syndrome preceded the radiological diagnosis of thymoma recurrence. Treatment with plasma exchange led to a transient improvement of neurological symptoms.

The PNS Euronet group criteria have classified paraneoplastic peripheral neuropathies as definite or possible according as to whether the neuropathy is a classical paraneoplastic disorder, the presence of onconeural antibodies, the delay between tumor and neuropathy, and improvement of the neuropathy with tumor treatment. Denny Brown's subacute sensory neuronopathy and neuropathies with anti-Hu or anti-CV2 antibodies are definite paraneoplastic disorders. Possible paraneoplastic neuropathies are heterogeneous. This classification is useful for the diagnostic of these disorders and the selection of patients in whom a search for cancer is warranted.

The association of high levels of autoantibodies to glutamic acid decarboxylase (GAD-ab) and stiff-person syndrome (SPS) is well known. However, the full spectrum of neurological syndromes associated with GAD-ab is not well established. In addition, these patients usually present type 1 diabetes mellitus (DM1) that could justify the presence of high GAD-ab levels. To clarify these issues, we reviewed the clinical and immunological features of patients in whom high GAD-ab levels were detected in a reference centre for DM1 and for the detection of antineuronal antibodies in suspected paraneoplastic neurological syndromes (PNS). High GAD-ab levels were defined as values > or =2000 U/ml by radioimmunoassay. Intrathecal synthesis (IS) of GAD-ab was calculated in paired serum/CSF samples. Values higher than the IgG index were considered indicators for positive GAD-ab-specific IS. High GAD-ab levels were identified in 61 patients, 22 (36%) had SPS, 17 (28%) cerebellar ataxia, 11 (18%) other neurological disorders (epilepsy -- four, PNS -- four; idiopathic limbic encephalitis -- two; myasthenia gravis -- one), and 11 (18%) isolated DM1. Patients with SPS and cerebellar ataxia had the same frequency of female gender (86% vs 94%), DM1 (59% vs 53%), CSF oligoclonal bands (35% vs 69%). Three of the four PNS patients, with paraneoplastic encephalomyelitis, a predominant gait cerebellar ataxia, and limbic encephalitis, had neuroendocrine carcinomas. GAD expression was confirmed in the two tumours in which the study was done. The fourth patient presented with paraneoplastic cerebellar degeneration antedating a lung adenocarcinoma. The frequency of increased IS of GAD-ab was 85% in SPS, 100% in cerebellar ataxia, and 86% in other neurological disorders. In conclusion, our study emphasizes that high GAD-ab levels associate with other neurological disorders besides SPS. Cerebellar ataxia, the second most common syndrome associated with high GAD-ab levels, shares with SPS the same demographic, clinical and immunological features. The demonstration of an increased IS of GAD-ab is important to confirm that the GAD autoimmunity is related to the neurological syndrome particularly when there is a concomitant DM1 that could justify the presence of high GAD-ab levels. Lastly, in patients who develop neurological syndromes that suggest a PNS, the finding of GAD-ab does not rule out this possibility and appropriate studies should be done to confirm an underlying cancer.

Paraneoplastic myasthenia gravis (MG) is accompanied by a neoplasm, usually thymoma. In patients with thymoma and a specific genetic make-up, the paraneoplastic immune response develops further in thymic remnant or peripheral lymphatic tissue. Paraneoplastic MG and late-onset MG (age >or= 50 years) share a similar immunological profile with high titin and ryanodine receptor (RyR) antibody prevalence. This profile is the most important predictor of clinical outcome in paraneoplastic MG. The presence of a thymoma per se does not cause more severe MG. MG severity is linked to the patient's immunological profile. Paraneoplastic MG causes a distinctive non-limb symptom profile at MG onset, characterized by bulbar, ocular, neck, and respiratory symptoms. When the diagnosis of paraneoplastic MG is established, the neoplasm should be removed surgically. Pre-thymectomy plasmapheresis or iv-IgG should be considered in these patients to minimize post-thymectomy MG exacerbation risk. Paraneoplastic MG usually continues after thymectomy. The pharmacological treatment of paraneoplastic MG does not differ from non-paraneoplastic MG, except for tacrolimus that should be considered in difficult cases. Tacrolimus is an immunosuppressant acting specifically in RyR antibody positive patients through enhancing RyR-related sarcoplasmic calcium release that in theory might be blocked by RyR antibodies, causing symptomatic relief in paraneoplastic MG.

Despite high-dose intravenous immunoglobulin (IVIG) is widely used in treatment of a number of immune-mediated neurological diseases, the consensus on its optimal use is insufficient. To define the evidence-based optimal use of IVIG in neurology, the recent papers of high relevance were reviewed and consensus recommendations are given according to EFNS guidance regulations. The efficacy of IVIG has been proven in Guillain-Barré syndrome (level A), chronic inflammatory demyelinating polyradiculoneuropathy (level A), multifocal mononeuropathy (level A), acute exacerbations of myasthenia gravis (MG) and short-term treatment of severe MG (level A recommendation), and some paraneoplastic neuropathies (level B). IVIG is recommended as a second-line treatment in combination with prednisone in dermatomyositis (level B) and treatment option in polymyositis (level C). IVIG should be considered as a second or third-line therapy in relapsing-remitting multiple sclerosis, if conventional immunomodulatory therapies are not tolerated (level B), and in relapses during pregnancy or post-partum period (good clinical practice point). IVIG seems to have a favourable effect also in paraneoplastic neurological diseases (good practice point) [corrected],stiff-person syndrome (level A), some acute-demyelinating diseases and childhood refractory epilepsy (good practice point).

Paraneoplastic neurological syndromes (PNS) are often associated with antineuronal autoantibodies and many of them could be identified in the recent years. However, there are still new antineuronal binding patterns with yet unidentified autoantigens. We here describe a new autoantibody associated with paraneoplastic sensorimotor and autonomic neuropathy in a patient with small cell lung cancer. In indirect immunofluorescence test, the patient's serum colocalised with the synaptic protein synaptophysin in the cerebellum and myenteric plexus of the gut. Immunoblotting showed a 38 kDa reactivity, which is also the molecular weight of synaptophysin. Therefore a Western Blot with recombinant synaptophysin has been used and revealed reactivity of the serum against synaptophysin. In patients with non-paraneoplastic neuropathies or healthy controls, anti-synaptophysin autoantibodies were not detectable. In 20 SCLC patients without neurological syndromes, two patients had low-titer anti-synaptophysin autoantibodies. The patient's serum and IgG fraction showed cytotoxicity to primary cultured myenteric plexus neurons. We conclude that synaptophysin is an autoantigen in paraneoplastic neurological syndromes.

Anti-Hu antibodies, also known as ANNA-1, are well characterized in paraneoplastic neuropathies. We present here the first known case of anti-Hu seropositivity, cerebellar ataxia, and sensory neuropathy in association with cervical cancer.

Objective: To characterize the clinicopathologic features of ataxic and painful forms of paraneoplastic neuropathy., Methods: Clinical, electrophysiologic, and histopathologic findings were assessed in 17 patients with paraneoplastic neuropathy., Results: Clinical features can be categorized into two groups: one group (13 patients) with predominantly deep sensory disturbance and a second group (4 patients) with predominantly superficial sensory disturbance. The former group showed severe sensory ataxia and predominantly large myelinated fiber loss in the sural nerve. The latter group showed marked pain, in particular, severe mechanical hyperalgesia, and predominantly small myelinated and unmyelinated fiber loss. Nerve conduction assessment indicated an axonal neuropathy pattern in both groups, while sensory action potentials were more markedly diminished in the sensory ataxic form. Anti-Hu antibodies were detected in half of the patients in both groups. Treatment for cancer was effective to improve or stabilize neuropathic symptoms in some cases from both groups. Immunotherapy was effective only for a short time., Conclusions: Paraneoplastic neuropathy can be characterized into two groups by the presence of sensory ataxia or severe spontaneous pain and severe mechanical hyperalgesia. Preferential small myelinated and unmyelinated fiber loss correlated to the cases of severe pain.

Neurological paraneoplastic syndromes (NPS) are rare disorders in association with malignancy and the presence of various antineuronal antibodies. The persistence of antineuronal antibodies for years after the eradication of the tumor without clinical manifestations of a NPS has not been reported. In a 64-year-old woman with a history of gynecologic malignancy, treated by surgery and chemotherapy with docetaxel and carboplatin, ptosis, hypertelorism, dysarthria, short stature, upper and lower limb weakness, exaggerated tendon reflexes and recurrent creatine-kinase elevation were found. Nerve conduction studies disclosed polyneuropathy and muscle biopsy nonspecific myopathic features. Though anti-Yo antibodies were repeatedly positive, the clinical findings and polyneuropathy were rather attributed to a suspected metabolic myopathy or chemotherapy than a NPS. Anti-Yo antibodies remained positive at 5 further determinations. During the 5 years of follow up there was improvement of polyneuropathy and no relapse of the malignancy, as assessed clinically, by tumor markers, computed tomography scans and 18-fluorodeoxyglucose positron emission tomography. Anti-Yo antibodies may occur without the typical clinical manifestations of a NPS and may persist for years without the development of a NPS or relapse of the tumor.

Combining clinical and immunological information, a neurological syndrome can now be diagnosed as a "definite" or "possible" paraneoplastic syndrome according to the newly suggested diagnostic criteria of the PNS Euronetwork. Differentiated diagnosis of a paraneoplastic syndrome is essential for differential therapy in patients. According to the response to IVIG therapy, paraneoplastic disorders may be subgrouped in group A, a clinical response is the rule (prototype Lambert-Eaton myasthenic syndrome), and in group B, IVIG may be helpful in single patients and is indicated in specific clinical settings (prototype anti-Hu associated neurological syndromes). The mode of action of IVIG may range from direct anti-idiotype effect to indirect effects on the cellular part of the pathogenesis of paraneoplastic syndromes. Due to the therapeutic relevance, it is therefore important to diagnose a PND as early as possible, and start immunotherapy including IVIG immediately.

The aim of the study was to search for novel targets of autoantibodies in patients with paraneoplastic neurological syndromes (PNS). PNS are mediated by immune reactions against autoantigen(s) shared by the cancer cells and the nervous system. By serological screening of a rat cerebellum cDNA expression library using anti-Hu-positive sera from three patients with paraneoplastic encephalomyelitis (PEM), we identified an open reading frame encoding an isoform of the BTB-kelch protein KLHL7. Immunohistochemical studies demonstrated that the KLHL7 protein is expressed in the nuclei of neurones, but not in other tissues including various cancers. However, the KLHL7 protein was detected in the nuclei of cancer cell lines. Antibodies to KLHL7 were detected by an immunoprecipitation assay in sera from 12 of 254 (4.7%) patients with various cancers and 2 of 170 blood donors (1.2%). None of 50 sera from patients with multiple sclerosis were positive for KLHL7 antibodies. Sixteen patients with classical PNS and anti-Hu or anti-Yo antibodies were also negative for KLHL7 antibodies. Seven cancer patients with KLHL7 antibodies had various signs of neurological disease that could be related to cancer, whereas the remaining five seropositive cancer patients had no clinical signs of possible PNS. The present results indicate that KLHL7 antibodies are associated with various cancers, and in some patients also with neurological disease. Whether KLHL7 antibodies can be used as paraneoplastic markers for PNS remains to be determined.

Purpose of Review: Acute transverse myelitis is a pathogenetically heterogeneous inflammatory disorder of the spinal cord. Here we describe recent advances in inflammatory non-infectious transverse myelitis. Particular attention will be paid to the serum autoantibody marker NMO-IgG and its application to acute transverse myelitis., Recent Findings: The recent identification of neuromyelitis optica-IgG, a novel marker of neuromyelitis optica spectrum disorders (including longitudinally extensive transverse myelitis), contributes to an evolving understanding of acute transverse myelitis. Other serological markers, such as collapsin response-mediator protein-5 -IgG and amphiphysin-IgG, predict specific cancers in the setting of a paraneoplastic acute transverse myelitis. Furthermore, novel inflammatory markers such as interleukin-6 or other proteins in their signaling pathways may represent markers of disease severity and potential therapeutic targets. Additional cerebrospinal fluid biomarkers, such as protein 14-3-3 and neuron-specific enolase, may be useful prognostic indicators in transverse myelitis. Acute transverse myelitis in children, in contrast to adults, is more likely to be longitudinally extensive, and has a better prognosis and lower likelihood of recurrence. Prognostic factors in pediatric transverse myelitis are reviewed., Summary: The recent identification of novel biomarkers associated with acute transverse myelitis has led to a better understanding of the spectrum of disorders associated with inflammatory transverse myelitis, as well as a greater appreciation of its diverse and complex pathogenetic basis.

Paraneoplastic Neurologic Diseases (PND) are remote complications of certain neoplastic diseases characterized by distinct neurological deficits in the central as well as the peripheral nervous system. The neurological disorders are usually clinically evident before the cancer is identified. PND are rare syndromes believed to have an immunological link where antibodies or activated T cells are acting against self antigens shared by the tumor cells and neurons. Most of these onconeural antigens are located in the cytoplasm-nuclear compartment of the cell, whereas others are located at the membrane and act as receptors or ion channels. This short review discusses the autoimmune mechanisms involved in PND in general and in opsoclonus-myoclonus-ataxia in particular. The article attempts to clarify why in most PND the immune effector mechanisms against onconeural antigens detected in sera of patients may not be the direct cause of the neurological deficit. We elaborate on the difference between the immune response against cytoplasmic-nuclear antigens as opposed to membranal antigens with regard to the fact that: a) the nervous system is considered immune privileged; b) neither the tumors nor the neurons have an optimal expression of MHC class I antigens and onconeural epitopes on the membrane. The availability of onconeural antigens to the immune effectors mechanisms is probably the main reason why there are few animal models for PND.

Objective: Paraneoplastic neuropathy is a clinical and immunological heterogeneous disorder and attempts have been made to classify subgroups of this disease. Only 30-50% of the clinical defined cases have antineuronal antibodies., Methods: The clinical and immunological features of 36 patients with paraneoplastic neuropathy from the authors' database were analysed including the type and course of the neuropathy, associated tumours, and the presence of antineuronal and other autoantibodies., Results: Antineuronal antibodies were detected in 17/36 patients (47%) and anti-Hu was the most frequent antineuronal antibody. Nine patients had high titre antinuclear antibodies (ANA, median titre 1/1000) without antineuronal antibodies. ANA reactivities were different in most patients. Comparison of the ANA positive and ANA negative patients revealed that ANA positive paraneoplastic neuropathy is more frequently associated with breast cancer but is not associated with lung cancer (p<0.05). The main clinical type in these patients was sensorimotor neuropathy. No ANA positive patient had central nervous system involvement. Although the Rankin score at the time of diagnosis was not different, the functional outcome in ANA positive patients was better than in ANA negative patients (p<0.05)., Conclusions: Paraneoplastic neuropathy is a heterogeneous disorder. ANA may define a subgroup of paraneoplastic neuropathy with different clinical and immunological features and may be related to better prognosis of the neuropathic symptoms.

Background: Paraneoplastic peripheral neuropathy is sometimes associated with unidentified neuronal autoantibodies., Objective: To examine the effects of serum from a patient with subacute sensory axonopathy on the function of the Trk high-affinity nerve growth factor receptor., Patient: An 86-year-old man with sensory neuropathy exhibiting an autoantibody to Trk., Methods: Immunoblot analyses of the brain homogenates and immunoprecipitation were performed with human sera. We further examined the effect of sera on nerve growth factor-induced neurite outgrowth and Trk autophosphorylation., Results: The patient showed sensory nerve axonopathy without well-known paraneoplastic autoantibodies. His serum inhibited nerve growth factor-induced neurite outgrowth and Trk autophosphorylation in PCtrk cells. Moreover, the patient's serum, but not control serum, immunoprecipitated Trk and recognized Trk in brain homogenates as well as in Trk immunoprecipitates., Conclusion: These data strongly suggest that an anti-Trk autoantibody might cause subacute sensory neuropathy.

Anti-Hu syndrome is a paraneoplastic neurological syndrome, most frequently associated with small cell carcinoma of the lung. Subacute sensory neuronopathy is thought to be the most frequent presentation of the anti-Hu syndrome, but it seems that sensory-motor neuropathy is the most common form in the anti-Hu neuropathy. Neurological symptoms often appear before the associated cancer has been identified. Sometimes the tumor is discovered months or even a few years after the appearance of the neurological syndrome. FDG-PET scan seems a better method for finding the tumor in patients with paraneoplastic neurological syndrome and anti-Hu antibodies who had negative test results after an initial workup using radiological methods. In this case report we present a patient with the anti-Hu syndrome associated with an unclassified rhabdomyosarcoma with epitheloid cellular morphology and neuroendocrine differentiation.