Inflammatory sensory neuronopathies.

Inflammatory sensory neuronopathies are rare disorders mediated by dysimmune mechanisms targeting sensory neurons in the dorsal root ganglia. They constitute a heterogeneous group of disorders with acute, subacute, or chronic courses, and occur with cancer, systemic autoimmune diseases, notably Sjögren syndrome, and viral infections but a noticeable proportion of them remains isolated. Identifying inflammatory sensory neuronopathies is crucial because they have the potential to be stabilized or even to improve with immunomodulatory or immunosuppressant treatments provided that the treatment is applied at an early stage of the disease, before a definitive degeneration of neurons. Biomarkers, and notably antibodies, are crucial for this early identification, which is the first step to develop therapeutic trials.

Autonomic nervous system involvement in autoimmune encephalitis and paraneoplastic neurological syndromes.

In autoimmune neurological diseases, the autonomic nervous system can be the primary target of autoimmunity (e.g. autoimmune autonomic ganglionopathy), or, more frequently, be damaged together with other areas of the nervous system (e.g. Guillain-Barré syndrome). Patients with autoimmune encephalitis and paraneoplastic neurological syndromes (PNS) often develop dysautonomia; however, the frequency and spectrum of autonomic signs and symptoms remain ill defined except for those scenarios in which dysautonomia is a core feature of the disease. Such is the case of Lambert-Eaton myasthenic syndrome, Morvan syndrome or anti-NMDAR encephalitis; in the latter, patients with dysautonomia have been reported to carry a more severe disease and to retain higher disability than those without autonomic dysfunction. Likewise, the presence of autonomic involvement indicates a higher risk of death due to neurological cause in patients with anti-Hu PNS. However, in anti-Hu and other PNS, as well as in the context of immune checkpoint inhibitors' toxicities, the characterization of autonomic involvement is frequently overshadowed by the severity of other neurological symptoms and signs. When evaluated with tests specific for autonomic function, patients with autoimmune encephalitis or PNS usually show a more widespread autonomic involvement than clinically suggested, which may reflect a potential gap of care when it comes to diagnosing dysautonomia. This review aims to revise the autonomic involvement in patients with autoimmune encephalitis and PNS, using for that purpose an antibody-based approach. We also discuss and provide general recommendations for the evaluation and management of dysautonomia in these patients.

Septin-3 autoimmunity in patients with paraneoplastic cerebellar ataxia.

BACKGROUND: Septins are cytoskeletal proteins with filament forming capabilities, which have multiple roles during cell division, cellular polarization, morphogenesis, and membrane trafficking. Autoantibodies against septin-5 are associated with non-paraneoplastic cerebellar ataxia, and autoantibodies against septin-7 with encephalopathy with prominent neuropsychiatric features. Here, we report on newly identified autoantibodies against septin-3 in patients with paraneoplastic cerebellar ataxia. We also propose a strategy for anti-septin autoantibody determination. METHODS: Sera from three patients producing similar immunofluorescence staining patterns on cerebellar and hippocampal sections were subjected to immunoprecipitation followed by mass spectrometry. The identified candidate antigens, all of which were septins, were expressed recombinantly in HEK293 cells either individually, as complexes, or combinations missing individual septins, for use in recombinant cell-based indirect immunofluorescence assays (RC-IIFA). Specificity for septin-3 was further confirmed by tissue IIFA neutralization experiments. Finally, tumor tissue sections were analyzed immunohistochemically for septin-3 expression. RESULTS: Immunoprecipitation with rat cerebellum lysate revealed septin-3, -5, -6, -7, and -11 as candidate target antigens. Sera of all three patients reacted with recombinant cells co-expressing septin-3/5/6/7/11, while none of 149 healthy control sera was similarly reactive. In RC-IIFAs the patient sera recognized only cells expressing septin-3, individually and in complexes. Incubation of patient sera with five different septin combinations, each missing one of the five septins, confirmed the autoantibodies' specificity for septin-3. The tissue IIFA reactivity of patient serum was abolished by pre-incubation with HEK293 cell lysates overexpressing the septin-3/5/6/7/11 complex or septin-3 alone, but not with HEK293 cell lysates overexpressing septin-5 as control. All three patients had cancers (2 × melanoma, 1 × small cell lung cancer), presented with progressive cerebellar syndromes, and responded poorly to immunotherapy. Expression of septin-3 was demonstrated in resected tumor tissue available from one patient. CONCLUSIONS: Septin-3 is a novel autoantibody target in patients with paraneoplastic cerebellar syndromes. Based on our findings, RC-IIFA with HEK293 cells expressing the septin-3/5/6/7/11 complex may serve as a screening tool to investigate anti-septin autoantibodies in serological samples with a characteristic staining pattern on neuronal tissue sections. Autoantibodies against individual septins can then be confirmed by RC-IIFA expressing single septins.

A Case of Anti-Ma2 Encephalitis Presenting with Pendular Torsional Nystagmus.

Antibodies against the neuronal protein Ma2 have been reported in a peculiar form of paraneoplastic encephalitis with prominent involvement of the limbic, brainstem, and diencephalic structures and usually associated with germ cell testicular, lung, or breast cancer. The diagnosis is frequently challenged by atypical clinical manifestations including parkinsonism, sleep disturbances, hypothalamic-pituitary dysfunctions, and motor neuron-like syndrome. In recent years, the advent of monoclonal antibodies targeting immune checkpoints has deeply changed the treatment of different tumors, especially melanoma and lung cancer. However, given their nature, an increasing number of neurological immune-related adverse events, including ocular motor abnormalities, have been described. Here, we report a woman with advanced non-small cell lung cancer treated with anti-PD-L1 durvalumab, presenting with an isolated pendular torsional nystagmus, in association with anti-Ma2 antibodies. This peculiar case widens our knowledge on the clinical presentation of anti-Ma2 encephalitis associated with checkpoint inhibitors.

Cerebellar involvement associated with immune checkpoint inhibitors: A systematic review.

BACKGROUND AND PURPOSE: Immune checkpoint inhibitors (ICIs) targeting programmed death receptor 1 (PD-1), cytotoxic T-lymphocyte-associated-4 (CTLA-4) and programmed cell death ligand 1 can be associated with immune-related adverse events (iRAEs). Amongst neurological iRAEs, cerebellar involvement seems to be rare and currently lacks a proper characterization. The aim of this study was to phenotype cerebellar iRAEs. METHODS: A systematic review was performed according to PRISMA guidelines including reported patients with cerebellar involvement related to ICIs and with available individual data. RESULTS: After screening 2765 records, 32 studies with 46 patients were included. Median age was 63 years (20-82), and most patients were male (63.0%). Isolated cerebellitis was observed in 32.6% of cases, whilst the remaining cases had "cerebellitis plus", mostly associated with encephalitis/encephalopathy. Associated tumors included most frequently lung cancer, melanoma and Merkel cell carcinoma. PD-1 inhibitor was the most administered treatment (n = 29, 64.4%), whilst exposure to CTLA-4 inhibitor was rare (n = 2, 4.5%). Magnetic resonance imaging was abnormal in 43.2% of patients and inflammatory cerebrospinal fluid findings were frequently observed. Autoantibodies were detected in 61.9% of patients and included novel reactivities. Amongst treatment strategies, the most common were steroids (n = 36) and ICI discontinuation (n = 28, 90.3%). Relapses were reported in 10% of patients. Most patients showed improvement/remission (n = 31) but, at last follow-up, 12 had died. Isolated cerebellitis versus cerebellitis-plus differed in terms of outcomes, whilst seropositive versus seronegative patients had distinct tumor associations. DISCUSSION: Cerebellar iRAEs are usually multifocal, have heterogeneous tumor associations, are most associated with PD-1 inhibitor exposure and are related to autoantibodies, including novel reactivities.

Kelch-like protein 11 antibody-associated paraneoplastic neurological syndrome: A state-of-the-art review.

The Kelch-like protein 11 antibody-associated paraneoplastic neurological syndrome (KLHL 11-PNS) was first identified in 2019. This novel antibody, targeting the intracellular KLHL 11 antigen, can be detected in serum and cerebrospinal fluid using tissue-based and cell-based assays. It is thought to be a biomarker for a T-cell autoimmunity response. The most likely immunopathogenesis of KLHL 11-PNS appears to be linked to cytotoxic T-cell-mediated neuronal injury and loss. Patients have adult-male predilection, rhombencephalitis (brainstem and / or cerebellar involvement), and a robust oncological correlation with testicular germ cell tumors (predominately seminoma). Brain magnetic resonance imaging demonstrated T2 / fluid-attenuated inversion recovery hyperintensities and atrophy of the temporal lobe, cerebellum, and brainstem. Most patients responded poorly to immunotherapy and oncotherapy and thus had a poor long-term prognosis. We review the literature and provide an update of current knowledge regarding KLHL 11-PNS, including epidemiology, underlying mechanism, clinical presentations, paraclinical and oncological findings, diagnostic workup, and treatment approaches.

Paraneoplastic neurological syndromes associated with non-Hodgkin lymphoma: a case series.

BACKGROUND: Paraneoplastic neurological syndromes (PNS) associated with lymphoma are rare diseases that usually have different peculiar features when compared to PNS associated with solid neoplasms. METHODS: We retrospectively identified patients with NHL-associated PNS. Clinical and demographic data are reported. RESULTS: We report two cases of NHL-associated PNS: a 72-years old female that presented with rapidly progressive cerebellar syndrome (RCPS) and a 65-years old male that presented with encephalomyelitis (confusion, sensory neuropathy, lower motor neuron involvement). Both PNS were associated with a NHL, small lymphocytic lymphoma and nodal marginal zone lymphoma respectively, and onconeural antibodies tested negative. All patients received first-line immunotherapy with absent or minimal benefit and died of intercurrent infection before cancer or immunosuppressive treatment. DISCUSSION: RCPS and encephalomyelitis rarely present in association with NHL. In our cases, those syndromes took place in the setting of non-aggressive advanced hematological disorders, had an unfavorable prognosis with minimal benefit from immunotherapy, and were seronegative for onconeural antibodies. Our patients fulfilled the criteria for "definite PNS" in the 2004 PNS criteria, but they would be classified as "probable", in the new 2021 PNS criteria. The newest criteria rely on onconeural antibodies testing and on the evidence of antigen expression in cancer cells, features that are usually absent in NHL-associated PNS. New antibodies are being discovered but are still not available to promptly test yet. CONCLUSION: NHL-associated PNS are rare and bear unfavorable prognosis. The diagnosis should not be overlooked even in seronegative patients.

Myasthenia gravis after glioblastoma resection: paraneoplastic syndrome or coincidence? A unique case report and review of the literature.

Paraneoplastic neurological syndromes (PNS) can manifest with every type of malignancy. A well-known syndrome is myasthenia gravis (MG) in combination with thymomas. No association between primary brain tumors and neuromuscular disorders has been described. Here, we present a case of a 65-year-old patient who developed MG, following an uncomplicated, gross-total resection of a glioblastoma. To our knowledge, this is the first case describing the onset of MG during the early postoperative phase after glioblastoma resection. Current criteria of PNS are insufficient when the neurological syndrome is diagnosed at the time of a malignancy or shortly thereafter and should be revisited.

Anti-neuron antibody syndrome: clinical features, cytokines/chemokines and predictors.

BACKGROUND: Neuroimmunology is a rapidly expanding field, and there have been recent discoveries of new antibodies and neurological syndromes. Most of the current clinical studies have focused on disorders involving one specific antibody. We have summarized a class of antibodies that target common neuronal epitopes, and we have proposed the term "anti-neuron antibody syndrome" (ANAS). In this study, we aimed to clarify the clinical range and analyse the clinical features, cytokines/chemokines and predictors in ANAS. METHODS: This was a retrospective cohort study investigating patients with neurological manifestations that were positive for anti-neuron antibodies. RESULTS: A total of 110 patients were identified, of which 43 patients were classified as having autoimmune encephalitis (AE) and the other 67 were classified as having paraneoplastic neurological syndrome (PNS). With regards to anti-neuron antibodies, 42 patients tested positive for anti-N-methyl-D-aspartate receptor (NMDAR) antibody, 19 for anti-Hu, 14 for anti-Yo and 12 for anti-PNMA2 (Ma2). There were significant differences between the ANAS and control groups in serum B cell-activating factor (BAFF) levels and in cerebrospinal fluid (CSF) C-X-C motif chemokine10 (CXCL10), CXCL13, interleukin10 (IL10), BAFF and transforming growth factor ß1 (TGFß1) levels. Predictors of poor outcomes included having tumours (P = 0.0193) and having a chronic onset (P = 0.0306), and predictors of relapses included having lower levels of CSF BAFF (P = 0.0491) and having a larger ratio of serum TGFß1/serum CXCL13 (P = 0.0182). CONCLUSIONS: Most patients with ANAS had a relatively good prognosis. Having tumours and a chronic onset were both associated with poor outcomes. CSF BAFF and the ratio of serum TGFß1/serum CXCL13 were associated with relapses.

Paraneoplastic cerebellar degeneration as a presenting manifestation of non-Hodgkin's lymphoma.

BACKGROUND: Paraneoplastic Cerebellar degeneration (PCD) is one of the classical paraneoplastic syndromes (PNS) which is characterised by subacute onset, progressive cerebellar ataxia and is usually associated with small cell lung carcinoma, adeno carcinoma of breast and ovary followed by Hodgkin's lymphoma. OBJECTIVE: We herein report a case of subacute onset, progressive cerebellar ataxia in a 37-year-old female, who on evaluation was found to have non-Hodgkin's lymphoma and experienced good clinical response to treatment. DISCUSSION: As compared to solid tumours, chances of association of PNS with Lymphomas is quite low and there are only few case reports in the literature showing association of PCD with non-Hodgkin's lymphoma. As PCD is one of the classical PNS, it is very important to identify subtle cerebellar manifestations in an otherwise apparently normal individual, as early diagnosis and aggressive treatment can immensely improve the mortality and morbidity associated with this syndrome. CONCLUSION: This case signifies the importance of suspecting PNS as an important differential diagnosis in a young patient presenting with subacute onset progressive cerebellar ataxia and evaluating her extensively for malignancy in spite of no paraneoplastic antibody been detected as early diagnosis and treatment can lead to gratifying response. We do agree that 2 weeks follow up is a short time interval to determine whether the response was sustained or not, for which a long term follow up is required.

The Association of Ovarian Teratoma and Anti-N-Methyl-D-Aspartate Receptor Encephalitis: An Updated Integrative Review.

Ovarian teratomas are by far the most common ovarian germ cell tumor. Most teratomas are benign unless a somatic transformation occurs. The designation of teratoma refers to a neoplasm that differentiates toward somatic-type cell populations. Recent research shows a striking association between ovarian teratomas and anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, a rare and understudied paraneoplastic neurological syndrome (PNS). Among teratomas, mature teratomas are thought to have a greater relevance with those neurological impairments. PNS is described as a neurologic deficit triggered by an underlying remote tumor, whereas anti-NMDAR encephalitis is characterized by a complex neuropsychiatric syndrome and the presence of autoantibodies in cerebral spinal fluid against the GluN1 subunit of the NMDAR. This review aims to summarize recent reports on the association between anti-NMDAR encephalitis and ovarian teratoma. In particular, the molecular pathway of pathogenesis and the updated mechanism and disease models would be discussed. We hope to provide an in-depth review of this issue and, therefore, to better understand its epidemiology, diagnostic approach, and treatment strategies.

Neural Antibody Testing in Patients with Suspected Autoimmune Encephalitis.

BACKGROUND: Autoimmunity is an increasingly recognized cause of encephalitis with a similar prevalence to that of infectious etiologies. Over the past decade there has been a rapidly expanding list of antibody biomarker discoveries that have aided in the identification and characterization of autoimmune encephalitis. As the number of antibody biomarkers transitioning from the research setting into clinical laboratories has accelerated, so has the demand and complexity of panel-based testing. Clinical laboratories are increasingly involved in discussions related to test utilization and providing guidance on which testing methodologies provide the best clinical performance. CONTENT: To ensure optimal clinical sensitivity and specificity, comprehensive panel-based reflexive testing based on the predominant neurological phenotypic presentation (e.g., encephalopathy) is ideal in the workup of cases of suspected autoimmune neurological disease. Predictive scores based on the clinical workup can aid in deciding when to order a test. Testing of both CSF and serum is recommended with few exceptions. Appropriate test ordering and interpretation requires an understanding of both testing methodologies and performance of antibody testing in different specimen types. SUMMARY: This review discusses important considerations in the design and selection of neural antibody testing methodologies and panels. Increased collaboration between pathologists, laboratorians, and neurologists will lead to improved utilization of complex autoimmune neurology antibody testing panels.

Diagnosis and treatment of limbic encephalitis in the cancer patient.

Limbic encephalitis is an inflammatory process involving the limbic structures of the brain, manifested with short-term memory deficits, confusion, depression and seizures. It is usually a paraneoplastic condition but it may also appear as a nonparaneoplastic syndrome. Patients with this condition may exhibit a variety of antibodies in their serum or/and cerebrospinal fluid targeting basement membrane components that bind to a variety of neurotransmitter receptors such as α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid and GABA B and proteins associated to the ion channels such as LGI1, Caspr2 or intracellular components. Flurodeoxyglucose PET/computed tomography usually demonstrates increased uptake in the limbic structures, and it may reveal the site of the primary tumor. Treatment consists of tumor removal if possible. Symptomatic treatment includes steroids, gamma immune globulin, plasma exchange, immunosuppressive therapies and anti-epileptic drugs. Prognosis is better when it is associated with antibodies against basement membrane rather than intracellular antibodies.

The associations between serum vascular endothelial growth factor, tumor necrosis factor and interleukin 4 with the markers of blood-brain barrier breakdown in patients with paraneoplastic neurological syndromes.

The blood-brain barrier (BBB) disruption is a critical step in paraneoplastic neurological syndrome (PNS) development. Several cytokines have been implicated in BBB breakdown. However, the exact step-by-step mechanism in which PNS develops is unknown, and the relationship between a systemic neoplasm and BBB is multilevel. The aim of the present study was to examine serum markers of BBB breakdown (S100B protein, neuron-specific enolase, NSE) and concentrations of proinflammatory (TNF-alpha, VEGF) and anti-inflammatory/immunosuppressive cytokines (IL-4), and to establish their interrelationship in patients with PNS. We analyzed 84 patients seropositive for onconeural antibodies that originated from a cohort of 250 cases with suspected PNS. Onconeural antibodies were estimated with indirect immunofluorescence and confirmed with Western blotting. Serum S-100B was estimated using electrochemiluminescence immunoassay. NSE, VEGF, TNF-alpha and IL-4 were analyzed with ELISA. We found that S-100B protein and NSE serum concentrations were elevated in PNS patients without diagnosed malignancy, and S-100B additionally in patients with peripheral nervous system manifestation of PNS. Serum VEGF levels showed several abnormalities, including a decrease in anti-Hu positive patients and increase in PNS patients with typical manifestation and/or central nervous system involvement. Increase in TNF-alpha was observed in patients with undetermined antibodies. To conclude, the presence of paraneoplastic neurological syndrome in seropositive patients does not affect serum markers of BBB breakdown, with the exception of the group without clinically demonstrated malignancy and patients with peripheral manifestation of PNS. S-100B and NSE might increase during early phase of PNS. VEGF may be involved in typical PNS pathophysiology.

Acquired neuromyotonia in thymoma-associated myasthenia gravis: a clinical and serological study.

BACKGROUND AND PURPOSE: Acquired neuromyotonia can occur in patients with thymoma, alone or in association with myasthenia gravis (MG), but the clinical prognostic significance of such comorbidity is largely unknown. The clinico-pathological features were investigated along with the occurrence of neuromyotonia as predictors of tumour recurrence in patients with thymoma-associated myasthenia. METHODS: A total number of 268 patients with thymomatous MG were studied retrospectively. Patients with symptoms of spontaneous muscle overactivity were selected for autoantibody testing using immunohistology for neuronal cell-surface proteins and cell-based assays for contactin-associated protein 2 (CASPR2), leucine-rich glioma inactivated 1 (LGI1), glycine receptor and Netrin-1 receptor antibodies. Neuromyotonia was diagnosed according to the presence of typical electromyography abnormalities and/or autoantibodies against LGI1/CASPR2. RESULTS: Overall, 33/268 (12%) MG patients had a thymoma recurrence. Five/268 (2%) had neuromyotonia, four with typical autoantibodies, including LGI1 (n = 1), CASPR2 (n = 1) or both (n = 2). Three patients had Netrin-1 receptor antibodies, two with neuromyotonia and concomitant CASPR2+LGI1 antibodies and one with spontaneous muscle overactivity without electromyography evidence of neuromyotonia. Thymoma recurrence was more frequent in those with (4/5, 80%) than in those without (28/263, 10%, P < 0.001) neuromyotonia. Neuromyotonia preceded the recurrence in 4/5 patients. In univariate analysis, predictors of thymoma recurrence were age at thymectomy [odds ratio (OR) 0.95, 95% confidence interval (CI) 0.93-0.97], Masaoka stage ≥IIb (OR 10.73, 95% CI 2.38-48.36) and neuromyotonia (OR 41.78, 95% CI 4.71-370.58). CONCLUSIONS: De novo occurrence of neuromyotonia in MG patients with previous thymomas is a rare event and may herald tumour recurrence. Neuronal autoantibodies can be helpful to assess the diagnosis. These observations provide pragmatic risk stratification for tumour vigilance in patients with thymomatous MG.

Anti-Ri-associated paraneoplastic neurological syndrome: Initial symptom of breast cancer with HER2 overexpression and treatment by dual HER2 blockade.

Paraneoplastic neurological syndrome is associated with anti-Ri antibodies, which are typically present with opsoclonus-myoclonus-ataxia. Human epidermal growth factor receptor 2 (HER2) overexpression is present in 15%-25% of breast cancer and is associated with poor prognosis. There are a few reports of paraneoplastic neurological syndrome associated with HER2-positive breast cancer in the literature, of which most are anti-Yo-associated paraneoplastic neurological syndrome. We present herein the case of a female patient with HER2-positive breast cancer who had atypical anti-Ri antibody associated with opsoclonus-myoclonus paraneoplastic neurological syndrome. Following the diagnosis of paraneoplastic syndrome, chemotherapy with dual HER2 blockade and immunomodulating treatment including intravenous immunoglobulin and oral prednisolone were administered. Although the patient was negative for serum anti-Ri antibodies, there was partial clinical improvement and her neurological deficit persisted. To our knowledge, this is the first case report of female patient with HER2-positive breast cancer who had atypical anti-Ri antibody associated with opsoclonus-myoclonus paraneoplastic neurological syndrome and treated with dual HER2 blockade.

Integrated treatment for autonomic paraneoplastic syndrome improves performance status in a patient with small lung cell carcinoma: a case report.

BACKGROUND: Paraneoplastic neurological syndromes (PNS) are rare disorders associated with cancer and are believed to be immune mediated. Patients with autonomic PNS suffer from variable combinations of parasympathetic and sympathetic failure. Autonomic PNS are usually associated with other PNS, such as encephalomyelitis and sensory neuropathy; however, autonomic symptoms may rarely manifest as PNS symptoms. Autonomic symptoms, therefore, may be overlooked in patients with cancer. CASE PRESENTATION: We described a 65-year-old Japanese man who was diagnosed with autonomic PNS due to small-cell lung carcinoma (SCLC) with Eastern Cooperative Oncology Group (ECOG) performance status 3, who suffered from orthostatic hypotension, and urinary retention needing a urethral balloon. Laboratory studies showed decreased levels of noradrenaline, and were positive for anti-ganglionic acetylcholine receptor antibody, type 1 antineuronal nuclear antibody, and sry-like high mobility group box 1 antibody. Nerve conduction evaluations and 123I-metaiodobenzylguanidine myocardial scintigraphy showed no abnormalities. Abdominal contrast-enhanced computed tomography revealed marked colonic distention. The patient's autonomic symptoms resolved following integrated treatment (symptomatic treatment, immunotherapy, and additional chemotherapy) enabling the patient to walk, remove the urethral balloon, and endure further chemotherapy. ECOG performance status remained at 1, 10 months after admission. CONCLUSIONS: Integrated treatment for autonomic PNS may improve autonomic symptoms and ECOG performance status of patients with cancer.

Autoimmune encephalitis and psychiatric disorders.

Autoimmune encephalitis (AE) refers to a rare, newly described, group of diseases associated with specific circulating autoantibodies directed against neuronal proteins used as biomarkers of the disease. Characterization of the associated autoantibodies present in the patients' cerebrospinal fluid (CSF) and/or sera can differentiate the various AE subgroups, which have specific clinical presentations and prognoses, and is therefore essential for proposing appropriate treatments. As psychiatric symptoms may predominate at the onset or over the course of these diseases, the diagnosis is frequently delayed. Yet, patients' prognoses depend on the speed with which the disease is detected, identified and managed. A wide range of neuropsychiatric symptoms is observed according to the patient's AE subgroup, and some are highly suggestive of an immune origin and should be recognized as such by physicians. Because the presence of pronounced psychiatric symptoms drives patients to psychiatric institutions, which can hinder the diagnosis, physicians need to be aware of AE and propose the detection of autoantibodies as early as possible to provide optimal medical care to such patients. In fact, the description of AE subgroups over the past decade has allowed the present overview of their incidence in psychiatric diseases and some general guidelines for the management of these patients.

Movement disorders in autoimmune encephalitis and paraneoplastic neurological syndromes.

Movement disorders are extremely common and diverse in autoimmune encephalitis (AE) and paraneoplastic neurological syndromes (PNS). They can sometimes represent the main neurological disorder of a given patient, or just be part of a larger neurological syndrome. Early diagnosis of AE or PNS is essential, as the associated abnormal movements can be effectively treated with immunomodulators. Nevertheless, the diagnosis is often delayed because of the large number of differential diagnoses (infections, metabolic disorders, genetic and degenerative diseases) and because the semiology of abnormal movements arising during AE and PNS is often not well known. However, there are highly specific clinical features, depending on the associated autoantibodies, age and gender of the patient, and associated cancers. Such features are likely to rely on specific mechanisms, the knowledge of which could lead to new therapeutic proposals. Also, the growing body of work on AE and PNS provides a better understanding of the links between immunity and neuronal degeneration, and immunity and genetic specificities. Thus, the purpose of this article is to present the current knowledge and different subtypes of movement disorders associated with AE and PNS, as well as the mechanisms that can lead to neuronal dysfunction.

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

PURPOSE: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.