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Paraneoplastic cerebellar degeneration (PCD) is a rare immune-mediated disease that develops mostly in the setting of neoplasia and offers a unique prospect to explore the interplay between tumor immunity and autoimmunity. In PCD, the deleterious adaptive immune response targets self-antigens aberrantly expressed by tumor cells, mostly gynecological cancers, and physiologically expressed by the Purkinje neurons of the cerebellum. Highly specific anti-neuronal antibodies in the serum and cerebrospinal fluid represent key diagnostic biomarkers of PCD. Some anti-neuronal antibodies such as anti-Yo autoantibodies (recognizing the CDR2/CDR2L proteins) are only associated with PCD. Other anti-neuronal antibodies, such as anti-Hu, anti-Ri, and anti-Ma2, are detected in patients with PCD or other types of paraneoplastic neurological manifestations. Importantly, these autoantibodies cannot transfer disease and evidence for a pathogenic role of autoreactive T cells is accumulating. However, the precise mechanisms responsible for disruption of self-tolerance to neuronal self-antigens in the cancer setting and the pathways involved in pathogenesis within the cerebellum remain to be fully deciphered. Although the occurrence of PCD is rare, the risk for such severe complication may increase with wider use of cancer immunotherapy, notably immune checkpoint blockade. Here, we review recent literature pertaining to the pathophysiology of PCD and propose an immune scheme underlying this disabling disease. Additionally, based on observations from patients' samples and on the pre-clinical model we recently developed, we discuss potential therapeutic strategies that could blunt this cerebellum-specific autoimmune disease.

Encephalitis with anti-NMDAR antibodies (NMDAR-E) is a severe autoimmune neurological disorder, defined by a clinical presentation of encephalitis and the presence of IgG targeting the GluN1 subunit of NMDA receptors in the CSF. An underlying ovarian teratoma is commonly associated with this autoimmune disease suggesting a role of the tumor in immunopathogenesis. In this study, we characterized the salient histopathological features of 27 ovarian teratomas associated with NMDAR-E (3 immature and 24 mature teratomas) and 40 controls without associated encephalitis. All but one NMDAR-E-associated teratomas contained a nervous tissue component, while less than 40% of control teratomas did ( p  < 0.001). GluN1 expression by teratomatous nervous tissue seemed to be more often glial in NMDAR-E teratomas than in control teratomas (73% vs. 29%, p  < 0.05). Strikingly, 3 out of 24 NMDAR-E-associated mature teratomas contained neuroglial tissue exhibiting histopathological features of central nervous system neuroglial tumor, while such glioma-like features are exceptionally described in the literature on ovarian teratomas. Moreover, NMDAR-E associated teratomas differed from sporadic ovarian teratomas by consistent and prominent infiltration of the nervous tissue component by immune cells, comprised of T- and B-cells and mature dendritic cells organized in tertiary lymphoid structures, with IgG and IgA deposits and plasma cells in close contact to the neuroglial tissue. These data demonstrate an association between massive infiltration of NMDAR-E-associated teratomas by immune cells and particular glial features of its neuroglial component, suggesting that this glial tissue might be involved in triggering or sustaining the anti-tumor response associated with the auto-immune neurological disease.

This report is an assessment of the characteristics associated with cardiovascular dysautonomia (CVD) in the context of long Coronavirus disease (COVID), which is currently inadequately characterized. A retrospective cross-sectional study was performed involving 106 patients with long COVID, including 34 individuals diagnosed with CVD, among whom eight met the criteria for Postural Tachycardia Syndrome (PoTS). The variables assessed encompassed individual characteristics (e.g., age, sex, comorbidities), immunization parameters (e.g., vaccination/viral status, timing, frequency), cellular and humoral anti-Spike and anti-Nucleocapsid (Nuc) immune responses, inflammatory and allergic biomarkers, as well as an extensive panel of common autoantibodies comprising anti-nuclear antibodies, anti-central nervous system antibodies (cerebellum, brain), and anti-peripheral nervous system antibodies (gangliosides). An age < 45 years, body mass index, hyperventilation syndrome as well as a higher cumulative number of antigenic contacts (vaccinations plus infections ≥ 3) and an elevated basophil count (≥0.06 G/L) were independently associated with CVD. There was no association between CVD and inflammatory markers or common autoantibodies. Patients with PoTS criteria had a strong anti-Spike cellular immune response and increased IgG anti-Nuc humoral immunity when compared with CVD and non-CVD long COVID counterparts. Compared to other long COVID patients, patients with long COVID-associated CVD have distinctive clinical and immunovirological features. Our results suggest the potential role of the immune response against Spike and of allergic pathways rather than humoral autoimmunity against common autoantibodies in long COVID CVD.

Background: The glycoprotein CD226 plays a key role in regulating immune cell function. Soluble CD226 (sCD226) is increased in sera of patients with several chronic inflammatory diseases but its levels in neuroinflammatory diseases such as multiple sclerosis (MS) are unknown. Objective: To investigate the presence and functional implications of sCD226 in persons with multiple sclerosis (pwMS) and other neurological diseases. Methods: The mechanisms of sCD226 production were first investigated by analyzing CD226 surface expression levels and supernatants of CD3/CD226-coactivated T cells. The role of sCD226 on dendritic cell maturation was evaluated. The concentration of sCD226 in the sera from healthy donors (HD), pwMS, neuromyelitis optica (NMO), and Alzheimer’s disease (AD) was measured. Results: CD3/CD226-costimulation induced CD226 shedding. Addition of sCD226 to dendritic cells during their maturation led to an increased production of the pro-inflammatory cytokine interleukin (IL)-23. We observed a significant increase in sCD226 in sera from pwMS and NMO compared to HD and AD. In MS, levels were increased in both relapsing–remitting multiple sclerosis (RRMS) and secondary-progressive multiple sclerosis (SPMS) compared to clinically isolated syndrome (CIS). Conclusion: Our data suggest that T-cell activation leads to release of sCD226 that could promote inflammation and raises the possibility of using sCD226 as a biomarker for neuroinflammation.

Objective Because of its heterogeneity in clinical presentation and course, predicting autoimmune encephalitis (AIE) evolution remains challenging. Hence, our aim was to explore the correlation of several biomarkers with the clinical course of disease. Methods Thirty‐seven cases of AIE were selected retrospectively and divided into active (N = 9), improved (N = 12) and remission (N = 16) AIE according to their disease evolution. Nine proteins were tested in both serum and cerebrospinal fluid (CSF) at diagnosis (T0) and during the follow‐up (T1), in particular activated MMP‐9 (MMP‐9A) and YKL‐40 (or chitinase 3‐like 1). Results From diagnosis to revaluation, AIE remission was associated with decreased YKL‐40 and MMP‐9A levels in the CSF, and with decreased NfL and NfH levels in the serum. The changes in YKL‐40 concentrations in the CSF were associated with (1) still active AIE when increasing >10% (P‐value = 0.0093); (2) partial improvement or remission when the changes were between +9% and −20% (P‐value = 0.0173); and remission with a reduction > −20% (P‐value = 0.0072; overall difference between the three groups: P‐value = 0.0088). At T1, the CSF YKL‐40 levels were significantly decreased between active and improved as well as improved and remission AIE groups but with no calculable threshold because of patient heterogeneity. Conclusion The concentration of YKL‐40, a cytokine‐like proinflammatory protein produced by glial cells, is correlated in the CSF with the clinical course of AIE. Its introduction as a biomarker may assist in following disease activity and in evaluating therapeutic response. In this cohort of various types of autoimmune encephalitis (AIE), we showed that the levels of cytokine‐like YKL‐40 in the CSF correlated with the clinical course. From diagnosis (T0) to re‐evaluation point (T1), CSF YKL‐40 levels were increased by more than 10% when AIE was still active, remained stable (between +9% and −20%) when AIE was only partially improved, and decreased by more than 20% in case of complete remission. YKL‐40 could thus be useful for the follow‐up of these rare diseases and for the management of the treatment.

BackgroundIt is currently unknown whether early B cell reconstitution (EBR) in MS patients under rituximab is associated with a risk of relapse or progression.ObjectivesAnalyzing EBR in rituximab-treated patients and its putative association with clinical findings.MethodsProspective lymphocytes immunophenotyping was performed in a monocentric cohort of MS patients treated by rituximab for 2 years. EBR was defined when B cells concentration was > 5 cells/mm3. B cell subsets were retrospectively associated with clinical data. Clinical and radiological monitoring included relapses, EDSS (Expanded Disability Status Scale), SDMT (Symbol Digit Modalities Test), and MRI.Results182 patients were analyzed (61 remitting-relapsing and 121 progressive-active). 38.5% experienced EBR at least once, but very few (7/182) showed systematic reconstitution. Most patients remained stable upon treatment, regardless of the occurrence of EBR. Dynamics of B cell reconstitution featured increased naïve/transitional B cells, and decreased memory subsets. Homeostasis of the B cell compartment differed at baseline between patients experiencing or not EBR upon treatment. In patients with EBR, reciprocal dynamics of transitional and pro-inflammatory double-negative B cell subsets was associated with better response to rituximab treatment.ConclusionEBR is common in rituximab-treated MS patients and is not associated with clinical disease activity. EBR in the peripheral blood may reflect regulatory immunological phenomena in subgroup of patients.

A recent case report described the radiological features of a suspected COVID-19 necrotising haemorrhagic encephalopathy.1 We present here a description of clinical, biological, radiological and immunological features of a COVID-19 patient case, evocative of virus-associated acute necrotising encephalopathy (ANE) possibly mediated by antibodies. Patient’s representative consent has been obtained in agreement with the journal’s policy.

ObjectiveThe aim of this study was to describe specificities of patients with NMDA receptor antibody (NMDAR-Ab) encephalitis associated with a malignant tumor.MethodsRetrospective observational study of 252 patients with NMDAR-Ab encephalitis of the French Paraneoplastic Neurological Syndrome Reference Center. Patients were classified in three groups: (1) non-malignant ovarian teratomas, (2) malignant ovarian teratomas (immature), and (3) other malignant tumors.ResultsSixty patients (23.8%) had an associated tumor and 15 (6%) were malignant. No particular neurological symptom was observed in these patients. Ovarian teratomas were the most frequent (51 cases) with 6 of them immature (11.8% of teratomas). Nine patients (3.6%) developed other malignant tumors (3 small cell lung carcinomas, 1 uterine adenocarcinoma, 1 prostate adenocarcinoma, 1 Hodgkin lymphoma, 1 pineal dysgerminoma, 1 neuroblastoma and 1 pancreatic neuroendocrine tumor). Among patients with a cancer other than teratoma, 6/9 were elderly patients (median age 65 years, representing 30% of elderly patients with such encephalitis) compared to a median age of 26 years in adult patients included herein. The clinical course was similar in the three groups, other than a higher death rate among patients with malignant tumors (86 versus 2%; p < 0.001) mainly due to tumor progression (5/7 deaths).ConclusionImmature ovarian teratomas represent 11.8% of all teratomas in patients with NDMAR-Ab encephalitis. The other malignant tumors are mainly observed in elderly patients. The presence of a malignant tumor does not impact the neurological presentation but is directly associated with a higher risk of death.

Autoimmune encephalitis is a rare and newly described group of diseases involving autoantibodies directed against synaptic and neuronal cell surface antigens. It comprises a wide range of neuropsychiatric symptoms. Sensitive and specific diagnostic tests such as cell-based assay are primordial for the detection of neuronal cell surface antibodies in patients' cerebrospinal fluid or serum and determine the treatment and follow-up of the patients. As neurological symptoms are fairly well described in the literature, this review focuses on the nature of psychiatric symptoms occurring at the onset or during the course of the diseases. In order to help the diagnosis, the main neurological symptoms of the most representative synaptic and neuronal cell surface autoantibodies were detailed. Finally, the exploration of these autoantibodies for almost a decade allowed us to present an overview of autoimmune encephalitis incidence in psychiatric disease and the general guidelines for the management of psychiatric manifestations. For the majority of autoimmune encephalitis, the prognosis depends on the rapidity of the detection, identification, and the management of the disease. Because the presence of pronounced psychiatric symptoms drives patients to psychiatric institutions and can hinder the diagnosis, the aim of this work is to provide clues to help earlier detection by physicians and thus provide better medical care to patients.

Leucine-rich glioma-inactivated 1 (LGI1) encephalitis is a rare entity. Its typical features are seizures, faciobrachial dystonic seizures (FBDS), cognitive impairment, and personality changes. We report the case of a 66-year-old man with an unusual presentation, consisting of two types of FBDS, one starting in the foot and the other consisting of asynchronous myoclonic and dystonic jerks of the face triggered by noise and chin stimulation. The patient displayed no personality changes or cognitive impairment. LGI1 encephalitis is a heterogeneous disease. Many different forms of FBDS may be observed, and these seizures can be the only symptom. This type of encephalitis should be suspected in presenting very frequent episodic events with dystonic features, regardless of the part of the body affected.