Phosphodiesterase 10A IgG: A novel biomarker of paraneoplastic neurologic autoimmunity.

OBJECTIVE: To describe a novel antibody biomarker of neurologic paraneoplastic autoimmunity specific for phosphodiesterase 10A (PDE10A), a striatum-enriched phosphodiesterase, and to characterize the clinical phenotype of patients with PDE10A immunoglobulin G (IgG). METHODS: We describe 7 patients with autoantibodies specific for PDE10A identified in the Mayo Clinic Neuroimmunology Laboratory. Patient specimens (sera, 7; CSF, 4) produced identical basal ganglia-predominant synaptic staining of murine brain tissue by indirect immunofluorescence. The autoantigen was identified by immunoprecipitation and mass spectrometry as PDE10A, and confirmed by antigen-specific recombinant Western blot and cell-based assays, and immune absorption experiments. RESULTS: The median patient age was 70 years (range 66-76); 4 were men. Four patients with clinical information available had movement disorders (hyperkinetic in 3 [chorea, ballismus, dystonia] and parkinsonism in 1). All patients but one had cancer (lung [adenocarcinoma 1, squamous cell carcinoma 1, poorly differentiated mesenchymal carcinoma 1], renal adenocarcinoma 2, and pancreatic adenocarcinoma 1). Two of the 7 patients developed hyperkinetic movement disorders during treatment with immune checkpoint inhibitors (nivolumab and pembrolizumab), though none of 26 cancer control patients treated with immune checkpoint inhibitors harbored PDE10A IgG in their serum. MRIs from those 2 patients with hyperkinetic movement disorders demonstrated fluid-attenuated inversion recovery/T2 basal ganglia hyperintensities, and their CSF harbored unique oligoclonal bands. One of those 2 patients had substantial improvement after corticosteroids. One patient's renal adenocarcinoma expressed PDE10A by immunohistochemistry. CONCLUSIONS: PDE10A IgG defines a novel rare neurologic autoimmune syndrome and expands the spectrum of diagnosable paraneoplastic CNS disorders. The intracellular location of PDE10A suggests a T-cell-mediated pathology targeting cells displaying MHC1-bound PDE10A peptides.

Orthostatic Hypotension and Albuminocytologic Dissociation as Primary Manifestations of the Paraneoplastic Syndrome.

BACKGROUND: Orthostatic hypotension (OH) is the key manifestation of autonomic dysfunction with many causes. Systemic neurological causes such as paraneoplastic syndrome are usually ignored. METHODS: We retrospectively analyzed clinical and examination data of 2 patients who were hospitalized, with onset symptom of OH and who were diagnosed as paraneoplastic syndrome. RESULTS: The patients were characteristic of an initial symptom of OH, positive anti-Hu antibody and albuminocytologic dissociation in the cerebrospinal fluid. Patient 2 died and Patient 1 worsened during follow-up. CONCLUSIONS: The diagnosis of paraneoplastic syndrome is usually neglected when the onset symptoms are autonomic dysfunctions such as OH. Neurologists should improve their knowledge to diagnose accurately.

Lower motor neuron syndrome in a patient with HER2-positive metastatic breast cancer: A case report and review of the literature.

Paraneoplastic neurological syndromes are very rare and often associated to breast, ovarian and small cells lung cancers. Paraneoplastic motor neuron diseases (MNDs) are even rarer, and frequently described in patients with breast cancer. We presented the first case of patient affected by HER2-positive breast tumor and possible paraneoplastic lower motor neuron disease. In literature, few cases are reported but no one highlights the tumor receptors' profile. Instead, HER2-positive breast cancers are prone to be related to anti-Yo-associated paraneoplastic cerebellar disorders. Anti-onconeural antibodies positivity can be rarely found, confirming that paraneoplastic MND have no specific biomarkers. The presence of CSF oligoclonal bands (OBs) suggests the presence of immune-mediated mechanism, in absence of other possible OBs causes.

(18)F-FDG PET/CT and MRI findings in a patient with anti-GABA(B) receptor encephalitis.

Autoimmune synaptic encephalitis can occur as paraneoplastic neurological syndromes, which are dysfunctions of the nervous system in cancer patients. One such rare but treatable form is associated with GABAB (γ-aminobutyric acid-B) receptor antibody. We report a 55-year-old man with small cell lung cancer who presented with 3 weeks of progressive seizures, memory impairment, and behavioral disorder. His cerebrospinal fluid anti-GABAB receptor antibody titer was elevated. F-FDG PET/CT revealed pronounced medial temporal hypermetabolism with gross hypometabolism in the rest of the brain. There were no associated abnormalities on MRI. He showed improvement after immunotherapy and chemoradiotherapy.

[Diagnosis of paraneoplastic neurological syndromes]. / Paraneoplasztikus neurológiai kórképek diagnosztikája.

INTRODUCTION: Paraneoplastic neurological syndromes are rare non-metastatic manifestations of malignancy. They are differentiated from side effects of tumor therapy, tumor-associated coagulopathy, infections, metabolic, and nutritional disorders. In the majority of cases neurological symptoms precede diagnosis of associated malignancy. Detection of anti-neuronal antibodies suggests a paraneoplastic mechanism. OBJECTIVES: To summarize syndromes, diagnostic steps, and currently available diagnostic possibilities. METHODS AND RESULTS: Serum and/or cerebrospinal fluid is analysed using indirect immunfluorescence and Western blotting. The pattern of immunoreactivity suggests the type of antibody. Anti-Hu antibody immunolabels predominantly nuclei, and less the cytoplasm of central and peripheral nervous system neurons. Anti-Yo shows cytoplasmic immunoreactivity primarily of cerebellar Purkinje cells, while anti-Ri is somewhat similar to anti-Hu except that peripheral nervous tissue lacks immunoreactivity. Examination of non-neural tissue allows exclusion of nuclear immunostaining caused by other antinuclear antibodies. Western blot examination specifies the anti-neuronal antibody. CONCLUSIONS: 1. Paraneoplastic neurological syndromes may occur without defined malignancy. 2. Clinical diagnosis is supported by immunofluorescent/Western blot/ELISA detection of antibodies. 3. Knowledge of antibody may suggest the origin of malignancy. 4. Tumor and immunomodulatory therapy may be considered, however, prognosis is different in distinct tumors and syndromes.

Paraneoplastic antibodies detected by isoelectric focusing of cerebrospinal fluid and serum.

Patients with paraneoplastic neurological syndromes often produce intrathecal antibodies. We have employed isoelectric focusing and peroxidase-labeled anti-IgG or 35S-labeled Hu or Yo antigens to identify oligoclonal bands (OCB) representing either total IgG or Hu or Yo antibodies in serum and CSF of patients with paraneoplastic encephalomyelitis (PEM) or paraneoplastic cerebellar degeneration (PCD). OCBs representing paraneoplastic antibodies were found in all CSF, but in only three sera. Yo antibodies represented the majority of IgG bands in PCD-CSF, which may reflect a limited immune response, whereas in PEM/SN, there were numerous additonal IgG bands of unknown specificity, indicating a broader immune response in these patients.

Response to cancer therapy in a patient with a paraneoplastic choreiform disorder.

The authors report a patient with chorea and multifocal neurologic abnormalities associated with a small-cell lung carcinoma. A previously unreported antibody directed at a 76-kD neuronal protein antigen was identified in both serum and CSF. Antitumor treatment resulted in dramatic and sustained clinical neurologic and serologic responses.

Cytotoxic T lymphocyte-mediated cell death in paraneoplastic sensory neuronopathy with anti-Hu antibody.

Paraneoplastic sensory neuronopathy (PSN) has been shown to harbor characteristic anti-neuronal autoantibody 'anti-Hu' in their sera and cerebrospinal fluid. Creation of animal models exhibiting clinical or pathological features seen in PSN by means of passive transfer of anti-Hu positive IgG has not been achieved. Although, anti-Hu antibody was shown to induce neuronal cell lysis in vitro, this result has not been reproduced so far. Since prominent T cell infiltration are seen in the central nervous system and posterior spinal ganglion of the patients with anti-Hu syndrome, we studied cytotoxic T cell (CTL) activity in peripheral mononuclear cells from a patient with PSN harboring anti-Hu antibody. The activated CD8+ T cells from the patient's venous blood were shown to lyse her own fibroblasts which were incubated with interferon-gamma to induce HLA class I molecules on their surface and the recombinant HuD protein was injected into the cells by microinjector. This is the first report showing the existence of CTL in a patient with PSN.

Failure to detect cytotoxic T cell activity against recombinant Yo protein using autologous dendritic cells as the target in a patient with paraneoplastic cerebellar degeneration and anti-Yo antibody.

Paraneoplastic neurological syndromes are believed to be autoimmune neuronal degenerations that develop in some patients with systemic cancer. Although a high titer of anti-Yo antibody has been found in the sera and cerebrospinal fluid of patients with paraneoplastic cerebellar degeneration (PCD), the role of anti-Yo antibody in Purkinje cell loss has not been shown. Previously we found that all of nine Japanese patients with PCD who harbored anti-Yo antibody had HLA A24. In this present study we have examined cytotoxic T cell (CTL) activity against recombinant Yo protein in peripheral blood of a patient with PCD and anti-Yo antibody using autologous dendritic cells as the target. We did not detect CTL activity against Yo protein, though, this study does not exclude the possibility of the involvement of CTL in the development of PCD.

Antineuronal antibody in a patient with neuroblastoma and opsoclonus-myoclonus-ataxia: a case report.

We describe a case of a patient with neuroblastoma and opsoclonus- myoclonus ataxia displaying serum and CSF anti-Hu antibodies that were able to recognize antigens of the patient's own tumor.

Immunological characterization of a neuronal antibody (anti-Tr) associated with paraneoplastic cerebellar degeneration and Hodgkin's disease.

We studied an autoantibody (called anti-Tr), found in the serum and CSF of five patients with paraneoplastic cerebellar degeneration (PCD) and Hodgkin's disease (HD). Anti-Tr antibodies labelled the cytoplasm of Purkinje cells of human and rat cerebellum. The molecular layer of rat cerebellum showed a characteristic dotted pattern suggestive of immunoreactivity of dendritic spines of Purkinje cells. Patients with cerebellar disorders without HD (159) or HD without PCD (30) did not harbor anti-Tr antibodies. Immunoblots of human Purkinje cells or rat and mouse cerebellum were negative. Anti-Tr antibodies, as defined in this study, appear specific for HD-associated PCD. The immunohistochemical pattern described in the rat cerebellum coupled with the absence of reactivity in the immunoblot may be used to identify anti-Tr antibodies.

Intrathecal synthesis of the anti-Hu antibody in patients with paraneoplastic encephalomyelitis or sensory neuronopathy: clinical-immunologic correlation.

We studied the intrathecal synthesis of the anti-Hu antibody (also called type 1 antineuronal nuclear autoantibody) in 14 patients with isolated paraneoplastic subacute sensory neuronopathy (SSN) and 16 with paraneoplastic encephalomyelitis (PEM). Patients with PEM had higher anti-Hu titers in the CSF (p = 0.003) but not in the serum than those with SSN. Only one patient (7%) with SSN had a positive intrathecal anti-Hu antibody synthesis whereas this was present in 14 (88%) of the 16 patients with PEM (p < 0.0001). The correlation between the intrathecal production of anti-Hu antibodies and PEM supports the role of autoimmune mechanisms in the pathogenesis of PEM. The absent intrathecal synthesis of anti-Hu antibodies in patients with SSN suggests easier accessibility of the systemic immune reaction to the sensory neurons probably due to the partial absence of blood-nerve barrier in the dorsal root ganglia.

Circulating autoantibodies against central nervous system (CNS) antigens in neurological diseases.

A number of investigators have reported the detection of circulating autoantibodies directed against serum and cerebrospinal fluid (CSF) neuronal antigens in certain neurological clinical conditions. Using an immunohistochemical technique, we examined the sera and (when available) the CSF from 120 patients with several neurological disorders and 40 controls in order to analyze the incidence and specificity of the detection of these autoantibodies. Circulating autoantibodies were found in 3 patients with cerebellar degeneration and in 3 patients with stiff-man syndrome, and different staining patterns were revealed in the same disease. Our findings confirm the reported disease-specificity of the detection of these autoantibodies in biological fluids, suggesting that a standardized immunohistochemical technique could constitute an easy and reproducible diagnostic tool in selected neurological conditions. These procedures enable the identification of an immunological pathogenesis of the disease and, in some case, early cancer detection. When atypical staining patterns of staining are found at immunohistochemistry, Western blot characterization of the recognized neuronal antigens is recommended.

Paraneoplastic sensorimotor neuropathy associated with breast cancer.

Paraneoplastic sensorimotor neuropathy occurs in association with many different types of cancer. The clinical findings are heterogeneous, and the pathogenesis is unknown. We have encountered 9 women with breast cancer and shared neurological features that suggest a distinct paraneoplastic syndrome. The syndrome is characterized by upper and lower extremity paresthesias and numbness, itching, muscle weakness and cramps, and in some, radicular symptoms and signs. Serum and CSF inflammatory changes suggested an immune pathogenesis but none had detectable antibodies directed at nervous system elements. Six patients presented with neuropathy 2 months to 8 years before the discovery of the breast cancer. In 7 the neoplastic disease was localized to the breast and axillary lymph nodes. The neurologic course was chronic in all, and while symptoms were annoying, disability was minimal until late. One improved transiently with plasmapheresis, and three had mild transient improvement with treatment of the cancer. Recognition of this paraneoplastic syndrome may forewarn the physician of an underlying breast malignancy.

Autopsy report of acute necrotizing opticomyelopathy associated with thyroid cancer.

We report an autopsied case of paraneoplastic necrotizing myelopathy. The patient had bilateral blindness, quadriplegia, and dyspnea of acute onset and died without remission 7 weeks later. The severe tissue necrosis and demyelination were found in the optic chiasm and from the medulla oblongata throughout the whole length of spinal cord. A papillary carcinoma was found in the thyroid gland at autopsy. In the present case IgG, myelin basic protein and activated helper T cells were increased in the CSF at onset, suggesting a mechanism of autoimmune demyelination for the condition.

Cerebrospinal fluid pheresis in Guillain Barré syndrome.

While plasmapheresis is established in the treatment of acute polyneuroradiculitis, disabling pareses may last long, persisting neurological deficits remain frequent, and costs and side-effects are considerable. Repeated filtration of cerebrospinal fluid may remove pathogenetically relevant cells and polypeptides. Observations in 12 severe Guillain-Barré patients treated with CSF pheresis indicate that it is a safe and effective procedure. We hypothesize mechanisms of action of and potential indications for CSF pheresis as a more general concept. In inflammatory demyelinating polyneuropathy, CSF filtration could be combined with 'dynamic' cerebrospinal fluid pheresis, intravenous immunoglobulin therapy, cryoprecipitation, and/or immuno-adsorption to increase its effectiveness.