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ObjectiveThe contemporary diagnosis of paraneoplastic neurologic syndromes (PNSs) requires an increasing understanding of their clinical, immunologic, and oncologic heterogeneity. The 2004 PNS criteria are partially outdated due to advances in PNS research in the last 16 years leading to the identification of new phenotypes and antibodies that have transformed the diagnostic approach to PNS. Here, we propose updated diagnostic criteria for PNS.MethodsA panel of experts developed by consensus a modified set of diagnostic PNS criteria for clinical decision making and research purposes. The panel reappraised the 2004 criteria alongside new knowledge on PNS obtained from published and unpublished data generated by the different laboratories involved in the project.ResultsThe panel proposed to substitute “classical syndromes” with the term “high-risk phenotypes” for cancer and introduce the concept of “intermediate-risk phenotypes.” The term “onconeural antibody” was replaced by “high risk” (>70% associated with cancer) and “intermediate risk” (30%–70% associated with cancer) antibodies. The panel classified 3 levels of evidence for PNS: definite, probable, and possible. Each level can be reached by using the PNS-Care Score, which combines clinical phenotype, antibody type, the presence or absence of cancer, and time of follow-up. With the exception of opsoclonus-myoclonus, the diagnosis of definite PNS requires the presence of high- or intermediate-risk antibodies. Specific recommendations for similar syndromes triggered by immune checkpoint inhibitors are also provided.ConclusionsThe proposed criteria and recommendations should be used to enhance the clinical care of patients with PNS and to encourage standardization of research initiatives addressing PNS.

These results suggest a link between high level of GAD-Ab and some cases of cerebellar ataxia, particularly women with IDDM. If high serum levels of GAD-Ab are detected, the cerebrospinal fluid should be evaluated for the presence of oligoclonal IgG bands and intrathecal synthesis of GAD-Ab to further prove an autoimmune origin of the syndrome.

Antibodies to mGluR5 should be considered in patients with symptoms of limbic encephalitis and HL (Ophelia syndrome). Recognition of this disorder is important because it can affect young individuals and is reversible.

Paraneoplastic neurological syndromes (PNS) are remote effects of cancer on the nervous system. An overview of the management of classical PNS, i.e. paraneoplastic limbic encephalitis, subacute sensory neuronopathy, paraneoplastic cerebellar degeneration, paraneoplastic opsoclonus-myoclonus, Lambert-Eaton myasthenic syndrome and paraneoplastic peripheral nerve hyperexcitability is given. Myasthenia gravis and paraproteinemic neuropathies are not included in this report. No evidence-based recommendations were possible, but good practice points were agreed by consensus. Urgent investigation is indicated, especially in central nervous system (CNS) syndromes, to allow tumour therapy to be started early and prevent progressive neuronal death and irreversible disability. Onconeural antibodies are of great importance in the investigation of PNS and can be used to focus tumour search. PDG-PET is useful if the initial radiological tumour screen is negative. Early detection and treatment of the tumour is the approach that seems to offer the greatest chance for PNS stabilization. Immune therapy usually has no or modest effect on the CNS syndromes, whereas such therapy is beneficial for PNS affecting the neuromuscular junction. Symptomatic therapy should be offered to all patients with PNS.

Background-Paraneoplastic neurological syndromes (PNS) are inflammatory disorders that probably depend on autoimmune processes. Several autoantibodies (anti-Hu, anti-Ri, and anti-Yo) have been characterised in PNS and proved to be helpful in the diagnosis. However, these do not account for all the cases and the possibility that other types of antibodies could be detected was investigated. Methods and results-Of 45 patients with PNS whose serum was probed on paraformaldehyde fixed rat brain sections, 11 patients were identified whose serum samples recognised a cytoplasmic antigen in a subpopulation of glial cells in the white matter of adult rat brainstem, cerebellum, and spinal cord that were double labelled with a monoclonal antibody specific for oligodendrocytes. All serum samples reacted with a 66 kDa protein of newborn rat brain on western blot analysis. These antibodies were designated as anti-CV2 antibodies. Only one of the 11 patients had one of the well characterised autoantibodies (anti-Hu). Five patients had cerebellar degeneration, three had limbic encephalitis, two had encephalomyelitis, and one had LambertEaton myasthenic syndrome. The tumours were small cell lung cancer or undifferentiated mediastinal cancer in seven patients, uterine sarcoma in two, and malignant thymoma in two. Among 1061 control serum samples, only two patients had anti-CV2 antibodies. One had small cell lung cancer and the other malignant thymoma. Conclusions-The detection of anti-CV2 antibodies in patients with neurological

To determine the usefulness of [18F]fluorodeoxyglucose (FDG) whole body FDG-PET in the diagnosis of tumours in patients with paraneoplastic neurological syndromes (PNS), we prospectively studied 20 patients with paraneoplastic antibodies in whom conventional imaging gave negative or inconclusive results for the presence of tumour. All 20 patients had neurological manifestations compatible with PNS and well-characterized paraneoplastic antibodies (12 anti-Hu, one anti-Hu and anti-CV2, one anti-CV2, four anti-Yo, one anti-Ri and one anti-amphiphysin). The mean delay between the onset of neurological symptoms and FDG-PET was 10 months (range 1-54). In these 20 patients, abnormal uptake was demonstrated in 18 patients, with some patients having abnormal signal in several areas. We observed abnormal uptake in the mediastinum (13 cases), lung (two cases), breast (two cases), parotid gland (one case), or the cervical, supraclavicular or axillary lymph nodes (seven cases). Following FDG-PET, the histological diagnosis of the tumour was made in 14 patients (small cell lung carcinoma in eight cases, breast adenocarcinoma in two, lung adenocarcinoma in two, axillary metastasis of ovary carcinoma in one, and malignant thymoma in one). Two other patients with abnormal FDG uptake showed radiological evidence of lung cancer, but a histological diagnosis could not be obtained. In two other patients, initial FDG-PET showed abnormal FDG uptake that was not confirmed a few months later by repeat FDG-PET. In the two patients with negative FDG-PET, peritoneal carcinomatosis was diagnosed in one and no tumour was found in the other. In our series, the sensitivity of FDG-PET for tumour detection was >83% demonstrating a clear role of this technique in the management of patients with PNS. However, in our series, the specificity of FDG uptake was only 25% due to unexplained abnormal FDG uptake in three patients and in abnormal FDG uptake due to a benign tumour in one patient. Over the study period, we saw 73 other patients with PNS and paraneoplastic antibodies. A tumour was demonstrated in 71 out of 73 by conventional techniques. Since false-positive and false-negative results are possible with FDG-PET and in most patients with PNS, the tumour is demonstrated by conventional techniques, we believe that FDG-PET should be reserved, at the moment, for patients with well-defined PNS antibodies when conventional imaging fails to identify a tumour or when lesions are difficult to biopsy.

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