Presence Of Onconeural Antibodies Research Articles

Paraneoplastic neurological syndromes of the central nervous system: a single institution 7-year case series.

Paraneoplastic neurological syndromes (PNSs) are nonmetastatic complications of malignancy, defined by the presence of onconeural antibodies (ONAs). ONAs may be found in 60% of patients with central nervous system (CNS) involvement, and they are directed against intraneuronal antigens or channels, receptors or associated proteins located at the synaptic or extra-synaptic neuronal cell membrane. Given its rare incidence, there are few epidemiological case series on CNS-PNS. We aim to discuss the variability of CNS-PNSs etiology, clinical features, management and outcome, highlighting the importance of early recognition and appropriate treatment, leading to significant reduction of mortality and morbidity. We retrospectively reviewed our 7-years single-center experience, and specifically discussed the underlying etiology, parenchymal CNS involvement, and the acute treatment response. Only cases fulfilling PNS Euronetwork criteria for definitive PNS were included. A total of 26 probable PNSs cases involving CNS were identified. We reported medical records of eleven (42.3%) illustrative cases, meeting the criteria of definite PNS and presenting variable clinical spectrum and different radiological appearances. Our series has a relative paucity of the most common syndromes and larger portion of clinical diagnosis with ONAs. Well-characterized ONAs had been detected in CSF of six patients. Our case series supports the utmost importance of early recognition of CNS-PNSs. Screening for occult malignancies should not be limited to patients with classical CNS syndrome. Empiric immunomodulatory therapy may be considered before the diagnostic evaluation is completed, in order to prevent unfavorable outcome. Late presentations should not discourage initiation of treatment.

Whole-body computed tomography as first-line imaging procedure to exclude cancer in patients with neurological suspicion of paraneoplastic syndromes: shall clinical practice adhere to recommendations?

IntroductionTo assess the efficacy of whole-body computed tomography (WB-CT) as imaging procedure to exclude cancer in patients with neurological symptoms and signs at clinical onset. MethodsA retrospective observational study was designed to identify consecutive WB-CT requested by the Neurology Unit with a suspicion of an underlying tumor potentially linked to a paraneoplastic neurological syndrome (PNS) between January 2019 and February 2022. The following data were collected: diagnosis at admission and at discharge, the presence of onconeural antibodies, the scans dose length product (DLP), the estimated effective dose (ED), the total estimated time requested; the PNS-Care-Score was retrospectively calculated only in subjects with available antibodies. ResultsThe total number of patients included was 158. In 13/158 (positive group) a malignant or locally aggressive neoplasm was found while in 145/158 no malignant lesions were found on the WB-CT. Among the positive group, in 7/13 onconeural antibodies were diagnosed, resulting negative in all cases and the most frequent tumor was lung cancer (30.8%). PNS-Care-Score was of 6–7 in 2/7 (probable PNS) and in no case the PNS-Care-Score was ≥8 (definite PNS). The mean DLP for all the scans was 2798 ± 952 mGy cm (average estimated ED of 42 ± 14 mSv). The total estimated time requested for all scans was 11,060 min. ConclusionIf a PNS is suspected, we encourage the prescription of unenhanced chest CT and/or abdomen/testis/female pelvis ultrasound and/or mammography based on clinical picture. The WB-CT using a single portal phase would be appropriate as a second-line technique while magnetic resonance imaging might be indicated for the exclusion of nervous system diseases. Implications for practiceOur suggestion results in saving in terms of radiation exposure, financial resources and time.

BREAST CANCER ASSOCIATED ANTI YO-ANTIBODY MEDIATED PARANEOPLASTIC CEREBELLAR DEGENERATION: CASE SERIES AND REVIEW OF LITERATURE

Paraneoplastic cerebellar degeneration (PCD) is a rare immune mediated disorder characterized by progressive cerebellar ataxia in presence of onconeural antibodies which occurs due to an indirect effect of underlying malignancy i.e. small cell lung cancer (SCLC), breast and gynecologic cancer, and Hodgkin lymphoma. In about 50% of patients neurological manifestation of Paraneoplastic cerebellar degeneration occurs prior to detection of carcinoma. Anti-Yo Antibody is the commonest antibody present in patients with Paraneoplastic cerebellar degeneration which is associated with breast carcinoma. We describe 3 female patients with anti YO antibody mediated PCD with breast cancer. One patient had a previous diagnosis of breast cancer with post mastectomy status one year back. Two of them presented with ataxia and on further examination, breast lump was found. All three patients had symmetrical ataxia with one patient had severely debilitating ataxia and was not able to walk unassisted. Magnetic resonance imaging brain showed cerebellar atrophy in two patients while one patient had normal MRI. Anti- YO antibody was strongly positive in all the three patients. All patients were given immunotherapy (corticosteroids in 2, Intravenous immunoglobulin in 1) with 1 patient showed modest improvement These case highlights the need to consider for workup for paraneoplastic cerebellar degeneration in female patients presenting with subacute to chronic progressive ataxia, so that the tumors can be detected and treated in early stage with a good outcome.

Presence of onconeural antibodies in sarcoidosis patients with parasarcoidosis syndrome.

Bothersome symptoms from sarcoidosis can develop in the absence of identified granulomas. These parasarcoidosis complaints can include small fiber neuropathy, diaphoresis, dysautonomia, and fatigue. Similar issues are also encountered in some cancer patients, especially those with onconeural antibodies. Serum was obtained for onconeural antibody testing from sarcoidosis patients with parasarcoidosis symptoms seen at the University of Cincinnati Sarcoidosis clinic during a six month period. Detection of antibodies was performed using an onconeural antibody panel. A total of 268 patients with sarcoidosis and one or more features suggesting parasarcoidosis symptoms were enrolled in the study. Of these, 60 (22.4%) had one or more positive onconeural antibodies. In a control group of 46 non sarcoidosis patients seen in the interstitial lung disease clinic, there were only three patients with a positive antibody (Chi square=6.143, p=0.0132). A subgroup of sarcoidosis and control patients completed the small fiber neuropathy screening list. Sarcoidosis patients had a significantly higher score than the control patients (sarcoidosis: 7 [0-49] (Median [range] versus non sarcoidosis: 3 [0-31], p=0.0074). However, no significant differences were measured in the SFNL scores for sarcoidosis patients with an onconeural antibody (9 [3-36]) versus without (7 [0-49]). In patients with parasarcoidosis symptoms, approximately 30% have evidence of onconeural antibody production. This may be a potential cause for parasarcoidosis symptoms in some patients.

Autoimmune response in lung cancer patients with neurological paraneoplastic syndromes.

The aim of this study was to evaluate granzyme B, perforin and FasL expression in peripheral blood mononuclear cells (PBMCs) in lung cancer patients and in paraneoplastic neurological syndromes (PNS). Cellular immune response is activated as part of anti-tumour reaction of the malignancy-bearing host. Paraneoplastic neurological syndromes (PNS) are defined as indirect effects of cancer on the nervous system and are considered immune-mediated. Such stimulation of the immune system may limit the aggressiveness of cancer and the development of metastasis, and thereby improve survival. Granzyme B and perforin pathway, and Fas ligand (FasL) - Fas receptor interaction play an important role in cytotoxic response. Fifty-two patients were included in the study: 28 subjects with PNS and 24 subjects with lung cancer. PNS cases were diagnosed according to the Graus criteria. The presence of onconeural antibodies (anti-Hu/anti-Ri/anti-Yo/anti-Ma/Ta/anti-CV2/anti-amphiphysin/anti-myelin/anti-neuroendothelium/anti-MAG/anti-GAD) was detected with indirect immunofluorescence and confirmed with Line Blotting. The expression of granzyme B, perforin and FasL was detected in PBMCs with ELISA. PPBMC-FasL expression was increased in lung cancer compared to other patient groups. The granzyme to FasL ratio was significantly higher in lung cancer patients with peripheral than with central PNS involvement. In a multiple regression model, sex was an independent factor influencing PBMC expression of granzyme and perforin. FasL expression in PBMCs is up-regulated in lung cancer patients. The interplay between granzyme B and FasL may be involved in the development of PNS at the level of the peripheral and the central nervous systems in different manners. Gender is associated with PBMC expression of granzyme B and perforin in lung cancer patients. The novel findings that we report broaden the current knowledge on PNS pathomechanism, with aspects that have not been previously explored. Our findings provide a rationale for further exploration of the granzyme B/FasL pathway with regards to its potential diagnostic value. However, our study is preliminary and needs further research, especially in the context of the prognostic value of the proposed markers.

18F-fluorodeoxyglucose positron emission tomography in the diagnosis of malignancy in patients with paraneoplastic neurological syndrome: a systematic review and meta-analysis.

The detection of occult cancer in patients suspected of having a paraneoplastic neurological syndrome (PNS) poses a diagnostic challenge. The aim of our study was to perform a systematic review and meta-analysis to assess the diagnostic performance of FDG PET for the detection of occult malignant disease responsible for PNS. A systematic review of the literature (MEDLINE, EMBASE, Cochrane, and DARE) was undertaken to identify studies published in any language. The search strategy was structured after addressing clinical questions regarding the validity or usefulness of the test, following the PICO framework. Inclusion criteria were studies involving patients with PNS in whom FDG PET was performed to detect malignancy, and which reported sufficient primary data to allow calculation of diagnostic accuracy parameters. When possible, a meta-analysis was performed to calculate the joint sensitivity, specificity, and detection rate for malignancy (with 95% confidence intervals [CIs]), as well as a subgroup analysis based on patient characteristics (antibodies, syndrome). The comprehensive literature search revealed 700 references. Sixteen studies met the inclusion criteria and were ultimately selected. Most of the studies were retrospective (12/16). For the quality assessment, the QUADAS-2 tool was applied to assess the risk of bias. Across 16 studies (793 patients), the joint sensitivity, specificity, and detection rate for malignancy with FDG PET were 0.87 (95% CI: 0.80-0.93), 0.86 (95% CI: 0.83-0.89), and 14.9% (95% CI: 11.5-18.7), respectively. The area under the curve (AUC) of the summary ROC curve was 0.917. Homogeneity of results was observed for sensitivity but not for specificity. Some of the individual studies showed large 95% CIs as a result of small sample size. The results of our meta-analysis reveal high diagnostic performance of FDG PET in the detection of malignancy responsible for PNS, not affected by the presence of onconeural antibodies or clinical characteristics.

Paraneoplastic neurological syndromes in lymphoid neoplasms: a clinical and laboratorial challenge.

Paraneoplastic neurological syndromes in lymphoid neoplasms: a clinical and laboratorial challenge.

The Anti-Neuronal Autoantibodies in Patients with Endometrial and Breast Cancer (P06.007)

Objective: To evaluate the spectrum of neurological deficits and onconeural antibodies in patients with endometrial cancer and breast cancer. Background The detection of onconeural antibodies is crucial in definite diagnosis of neurological paraneoplastic syndromes (NPS). However, cancer-associated autoimmunity can be directed against other antigens expressed in nervous system. The aim of this study was to analyze the spectrum of onconeural and other neural antibodies in women with endometrial cancer (EC) and breast cancer (BC). Design/Methods: The study included 42 patients with EC hospitalized in Department of Gynecological Surgery Poznan University of Medical Sciences in Poznan and 15 patients with BC identified among 1552 subjects with suspicion of NPS and admitted to Department of Neurology at Poznan University of Medical Sciences. Indirect fluorescence was performed as a screening test and Western blotting (EUROIMMUN) as a confirmation test for the presence of onconeural antibodies in patients9 sera. Well-defined onconeural antibodies tested were : anti-Hu, anti-Yo, anti-Ri, anti-amphiphysin, anti-Ma/Ta, anti-CV2. The spectrum of evaluated anti-neural antigens included: anti-MAG (Myelin-Associated Glycoprotein), anti-GAD (Glutamic Acid Decarboxylase), anti-myelin, anti-neuroendothelium, and anti-GFAP (Glial Fibrillary Acidic Protein) antibodies. Results: EC patients frequently manifested neuropathy (21.4%), upper motor neuron syndrome (UMNS) (4.8%), bulbar palsy (2.4%), coexisting neuropathy with paraneoplastic cerebellar degeneration (PCD) (2.4%). In BC subjects PCD was the most frequent syndrome (33.3%), followed by neuropathy (13.3%), coexisting PCD with UMNS (6.7%) and plexopathy (6.6%). Anti-neural antibodies were the most frequent among EC patients (anti-myelin-9.5%, anti-MAG-7.1%) and onconeural antibodies were detected in 7.1% of patients (anti-Tr and coexisting anti-Ma/Ta with anti-CV2). In BC subjects anti-Ri were identified (26.6%), coexisting anti-Ri with anti-Yo (6.7%) as onconeural antibodies, and in 20% - anti-neural antibodies. Conclusions: Anti-neural autoimmunity is predominant in EC, while BC is associated with well defined onconeural antibodies. The dominating NPS manifestation in the course EC is neuropathy, but PCD in BC. Disclosure: Dr. Michalak has nothing to disclose. Dr. Poplawska has nothing to disclose. Dr. Szpurek has nothing to disclose. Dr. Michalak has nothing to disclose. Dr. Englert-Golon has nothing to disclose. Dr. Sajdak has nothing to disclose. Dr. Kozubski has nothing to disclose.

Paraneoplastic limbic encephalitis – a case report

Abstract Introduction Paraneoplastic neurological syndromes (PNS) refer to a diverse group of nervous system disorders associated with tumors. They are not directly caused by a tumor's immediate expansion, compression resulting from it, infiltration or anticancer treatment. Their pathomechanism involves damage to the nervous system as a result of the organism's immune response directed against cancer antigens, and also against antigens occurring physiologically in the nervous system. Onconeural antibodies and cytotoxic T lymphocytes are responsible for the immune response. These conditions are quite rare – fewer than 1 person out of 100 patients suffering from cancer develops PNS. They often precede a direct manifestation of cancer. The best known PNS conditions include: Lambert–Eaton myasthenic syndrome, paraneoplastic cerebellar degeneration, and polyneuropathies. PNS was identified for the first time in 1949. Nowadays, the criteria established in 2004 by Graus et al. have been followed in diagnostics. These define the conditions for arriving at a possible and definite diagnosis based on the presence of a characteristic neurological syndrome, the presence of onconeural antibodies, and detecting neoplasm before or after the manifestation of neurological symptoms. Diagnosis is difficult due to the lack of laboratory markers (onconeural antibodies are present in serum only in 50–60% of cases) or direct cancer symptoms in the first phase of the disease. Aim This paper aimed at recounting the existence of a very rare neurological syndrome, limbic encephalitis, which can develop in the course of a neoplastic disease. Awareness of PNS and detecting neoplasm before its direct clinical manifestation can contribute to a better prognosis for patients. Materials and Methods This paper is based on a case analysis concerning a patient manifesting symptoms of the limbic system involvement. The medical history has been interpreted, additional examination results have been analyzed, and the developing clinical manifestations have been investigated. Case study The presented patient is a 45-year old man in whose case limbic encephalitis exceeded detecting abdominal cancer by a year. Diagnostic difficulties were caused by a synchronous pituitary microadenoma and hormonal disturbances involving cortisol and prolactin, which suggested Cushing's syndrome. The main clinical symptoms, intensifying in time during the course of the disease lasting several months included: recent memory disturbances, allopsychic disorientation, depression, and periodical aggression. Results and discussion Conducted serum tests to screen for onconeural antibodies did not confirm their presence. However, a magnetic resonance imaginig (MRI) scan revealed bilateral hippocampal damage. On the basis of a typical clinical syndrome, and cancer identified after a year following the occurrence of the symptoms, a definite, according to Graus’ criterion, diagnosis of PNS was established. Conclusions Awareness and knowledge of PNS contributes to an early diagnosis and detection of cancer. This creates an opportunity to introduce adequate treatment and improves the prognosis for the patient.

Onconeural antibodies in sera from patients with various types of tumours.

We assessed the frequency and levels of onconeural antibodies in 974 patients with various types of tumours, but without apparent paraneoplastic neurological syndromes (PNS). We included patients with the following tumours: 200 small-cell lung cancer (SCLC) patients, 253 breast cancer patients, 182 ovarian cancer patients, 266 uterine cancer patients and 73 thymoma patients, as well as 52 patients with PNS and cancer and 300 healthy blood donors. Sera were screened for amphiphysin, CRMP5, Hu, Ma2, Ri and Yo antibodies using a multi-well immunoprecipitation technique. The most frequently detected antibodies were Hu followed by CRMP5. Ma2, Yo, amphiphysin and Ri antibodies were less common, but each was found at similar frequencies. Onconeural antibodies were present at similar levels in sera from the PNS control group and from cancer patients. Hu antibodies were rare in cancers other than SCLC. CRMP5 was the only antibody found in patients with thymoma and this antibody was more common among patients with thymoma than in other tumour patients. With one exception, coexisting antibodies were only found in patients with SCLC. The presence of onconeural antibodies in SCLC patients was not associated with prolonged survival. Onconeural antibodies are associated with various types of tumours suggesting that all antibodies should be included in the serological screening for possible PNS. The levels of onconeural antibody are not sufficiently sensitive to discriminate between cancer patients with PNS and those without.

Les neuropathies périphériques paranéoplasiques

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.

Paraneoplastic cerebellar degeneration as a presentation of breast cancer – a case report and review of the literature

Paraneoplastic cerebellar degeneration is part of a rare spectrum of neurological syndromes whereby gynaecological, lung or breast cancers present primarily with neurological manifestations. The presence of onconeural antibodies and PET scanning help in the challenging diagnosis of these conditions but despite the treatment of the primary cancer, the prognosis for the neurological symptoms is poor.