Neurological Autoimmunity Research Articles

Neurological disorders associated with glutamic acid decarboxylase 65 antibodies: Clinical spectrum and prognosis of a cohort from China.

ObjectiveTo describe clinical phenotypes and prognosis of neurological autoimmunity related to glutamic acid decarboxylase 65 (GAD65) antibodies in China.MethodIn this retrospective observational study from Peking Union Medical College Hospital, we identified patients with neurological disorders related to GAD65 antibodies (cell-based assay) from May 2015 to September 2021. Clinical manifestations, immunotherapy responsiveness, and outcomes were collected after obtaining informed consent from all patients.ResultsFifty-five patients were included: 40 (72.73%) were women and initial neurological symptoms developed at 42(34-55) years of age. The median time to the nadir of the disease was 5 months (range from 1 day to 48 months). The clinical syndromes included limbic encephalitis (LE) or epilepsy (Ep) (n = 34, 61.82%), stiff-person syndromes (SPS) (n = 18, 32.73%), autoimmune cerebellar ataxia (ACA) (n = 11, 20%), and overlap syndrome in eight (14.55%) patients. Thirty-two (58.2%) patients had comorbidities of other autoimmune diseases, including Hashimoto thyroiditis (n = 17, 53.13%), T1DM (n = 11, 34.78%), vitiligo (n = 6, 18.75%), and others (n=5, 15.63%). Two (3.64%) patients had tumors, including thymoma and small cell lung cancer. Fifty-one (92.7%) patients received first-line immunotherapy (glucocorticoids and/or IV immunoglobulin), and 4 (7.3%) received second-line immunotherapy (rituximab). Long-term immunotherapy (mycophenolate mofetil) was administered to 23 (41.8%) patients. At the median time of 15 months (IQR 6–33.75 month, range 3–96 month) of follow-up, the patients' median modified Rankin Score (mRS) had declined from 2 to 1. Thirty-eight (70.4%) patients experienced clinical improvement (mRS declined ≥1), 47 (87%) had favorable clinical outcomes (mRS ≤2), and nine were symptom-free (16.7%). The sustained response to immunotherapy ranged from 7/15 (63.63%) in ACA patients and 22/34 (64.7%) in LE/Ep patients to 14/17 (82.35%) in SPS patients.ConclusionsLE/Ep was the most common neurological phenotype of GAD65 antibody neurological autoimmunity in our cohort. Most patients had comorbidities of other autoimmune diseases, but underlying tumors were rare. Most patients responded to immunotherapy. However, the long-term prognosis varied among different clinical phenotypes.

Longitudinal COVID-19 immune trajectories in patients with neurological autoimmunity on anti-CD20 therapy

Background and objectivesDuring the COVID-19 pandemic, B cell depleting therapies pose a clinical concern for patients with neuroimmune conditions, as patients may not mount a sufficient immune response to SARS-CoV-2 infection and vaccinations. Studies to-date have reported conflicting results on the degree of antibody production post-SARS-CoV-2 infection and vaccinations in B cell depleted patients, focusing primarily on short-term immune profiling. Our objective was to follow longitudinal immune responses in COVID-19 B cell depleted patients with neuroimmune disorders post-COVID-19 and SARS-CoV-2-vaccination. MethodsCD20 B cell depleted autoimmune patients and age/sex-matched controls positive for SARS-CoV-2 were recruited at Dell Medical School, UT Austin between 2020 and 2021, followed prospectively for 12 months and evaluated at multiple time points for spike S1 receptor binding domain (RBD) antibody titers, B and T cell composition, and frequency of T cells specific for SARS-CoV-2 antigens. ResultsImmune responses post-SARS-CoV-2 infection and vaccination were evaluated in a cohort of COVID-19 B cell depleted neuroimmune patients (n = 5), COVID-19 non-B cell depleted autoimmune patients (n = 15), COVID-19 immunocompetent patients (n = 117), and healthy controls (n = 6) for a total of 259 samples in 137 participants. 4/5 B cell-depleted patients developed detectable anti-spike RBD antibodies, which were boosted by vaccination in 2 patients. While spike RBD antibodies were associated with presence of CD20+ B cells, very few B cells were required. In contrast, patients whose B cell compartment primarily consisted of CD19+CD20– Bcells during acute COVID-19 disease or vaccination did not seroconvert. Interestingly, circulating Bcells in B cell depleted patients were significantly CD38high with co-expression of CD24 and CD27, indicating that B cell depletion may impact B cell activation patterns. Additionally, all B cell depleted patients mounted a sustained T cell response to SARS-CoV-2 antigens, regardless of seroconversion. Specifically, all patients developed naïve, central memory, effector memory, and effector memory RA+ T cells, suggesting intact T cell memory conversion in B cell depleted patients compared to controls. DiscussionWe present the longest COVID-19 immune profiling analysis to date in B cell depleted patients, demonstrating that both humoral and cellular immune responses can be generated and sustained up to 12 months post SARS-CoV-2 infection and vaccination. Notably, failure to establish humoral immunity did not result in severe disease. We also highlight specific T and B cell signatures that could be used as clinical biomarkers to advise patients on timing of SARS-CoV-2 vaccinations.

Anti‐Zic4 encephalitis in endometrial cancer: Autoimmunity triggered by PD ‐1 inhibitor or recent CMV encephalitis?

Background Autoimmune encephalitis has been well described in oncological patients treated with immune checkpoint inhibitors (ICIs), as a paraneoplastic neurological syndrome. Central nervous system (CNS) infections from herpes viruses are also known to trigger secondary neurologic autoimmunity. Case Presentation We hereby describe a patient with a recent history of cytomegalovirus (CMV) CNS infection and ongoing immunotherapy with the programmed-cell-death-protein-1(PD-1) inhibitor pembrolizumab for metastatic endometrial cancer. The patient presented with progressive encephalopathy along with cerebellar signs, rapidly evolving to status epilepticus requiring mechanical ventilation and advanced care unit (ACU) support. A serum paraneoplastic antibody panel revealed strongly positive anti-Zic4 antibodies. Despite first-line immunotherapy and aggressive anticonvulsant treatment, the patient died a few days postintubation. Conclusion In anti-Zic4 encephalitis, both PD-1 inhibitor treatment and recent CMV viral insult may contribute to the development of neurological autoimmunity. Further research is needed to identify ways of predicting neurological damage in oncological patients treated with ICIs.

Anti-Neuronal Nuclear Antibody 3 Autoimmunity Targets Dachshund Homolog 1.

The antigen specificity of Anti-Neuronal Nuclear Antibody-type 3 (ANNA3)-IgG is unknown. We identified Dachshund-homolog 1 (DACH1) as the ANNA3 autoantigen and confirmed it by antigen-specific assays, immunohistochemical colocalization and immune absorption experiments. Patients' median age was 63.5 years (range, 49-88); 67% were female. Neurological manifestations (information available for 30 patients) included one or more of neuropathy, 12; cognitive difficulties, 11; ataxia, 8; dysautonomia, 7. Evidence of a neoplasm was present in 27 of 30 (90%), most of neuroendocrine lineage. DACH1-IgG is rare and represents a novel proposed biomarker of neurological autoimmunity and cancer. ANN NEUROL 2022;91:670-675.

Reactive oxygen species in cancer progression and its role in therapeutics

The redox status in pathogenesis is critically regulated by careful balance between the generation of reactive oxygen species (ROS) and their elimination. Increased ROS level above the cellular tolerability threshold results in apoptotic or necrotic cell death. ROS belongs to a group of highly reactive compounds that have evolved to play key roles in cellular signaling pathways. It’s widely assumed that a reasonable amount of ROS is essential for a variety of biological processes. Elevated levels of ROS are known to cause various pathologic conditions like neurological disorders, cardiovascular conditions, inflammation, autoimmunity, and cancer. ROS is well known to initiate and assist in progression of tumor by promoting proliferation and survival of cancer cells and thus facilitates pro-tumorigenic signaling in tumor microenvironment. As cancer cells become more resilient to the effects of ROS manipulating drugs, increased antioxidant capacity attenuates their susceptibility to cancer treatment. Excessive environmental stress, on the other hand, can cause cancer cells to die. This review summarizes various molecular mechanisms including the role of checkpoint inhibitors that can be harnessed to develop effective therapeutic strategies for targeting ROS related signaling in cancer.

Homer-3 Antibody Disease: A Potentially Treatable MSA-C Mimic.

Homer-3 Antibody Disease: A Potentially Treatable MSA-C Mimic.

Autoimmune/Paraneoplastic Encephalitis Antibody Biomarkers: Frequency, Age, and Sex Associations

ObjectiveTo determine the frequency of detection and the age and sex associations of autoimmune/paraneoplastic encephalitis antibody biomarkers (AE-Abs). MethodsThere were 42,032 patients tested in the Mayo Clinic Neuroimmunology Laboratory between January 2018 and December 2019 for AE-Abs in serum or cerebrospinal fluid (CSF), including NMDA-R-IgG, AMPA-R-IgG, GABAB-R-IgG, CASPR2-IgG, LGI1-IgG, GAD65-IgG, CRMP5-IgG, amphiphysin-IgG, PCA1/2/Tr-IgGs, ANNA1/2/3-IgGs, GFAP-IgG, mGluR1-IgG, DPPX-IgG, and MOG-IgG1. Results were examined to determine frequency of antibody positivity. Age and sex associations were examined by multivariable logistic regression. ResultsAdult serum analysis (22,472 patients; 56% female) revealed that 814 (3.6%) were positive: NMDA-R-IgG (24.6%) > GAD65-IgG (21.5%) > LGI1-IgG (20.5%) > others. Of children (5649; 50% female), 251 (4.4%) were positive: NMDA-R-IgG (53.1%) > MOG-IgG1 (32%) > GAD65-IgG (7.1%) > others. Adult CSF analysis (18,745 patients; 54% female) revealed that 796 (4.2%) were positive: NMDA-R-IgG (39.7%) > GAD65-IgG (28.5%) > LGI1-IgG (11.4%) > others. Of children (5136; 50% female), 282 (5.5%) were positive: NMDA-R-IgG (88.1%) > GAD65-IgG (8.7%) > others. Age younger than 20 years was associated with NMDA-R-IgG and MOG-IgG1 (odds ratio [OR], 8.11 and 7.84, respectively; P<.001). Age older than 65 years was associated with GABAB-R-IgG, LGI1-IgG, CASPR2-IgG, and ANNA1-IgG (OR, 7.33, 14.98, 3.67, and 14.53; P<.001). Women accounted for 60% of NMDA-R-IgG (CSF) and 78% of GAD65-IgG (CSF and serum) cohorts (OR, 1.32 [P=.002] and 2.23 [P<.001], respectively). Men accounted for 62% of the LGI1-IgG cohort (OR, 1.87; P<.001). Age and sex interacted for NMDA-R-IgG, particularly in female patients younger than 20 years (OR, 7.72; P<.001). ConclusionThe most frequent AE-Abs detected were NMDA-R-IgG, GAD65-IgG, LGI1-IgG, and MOG-IgG1. Age and sex associations may suggest paraneoplastic, or aging influences on neurologic autoimmunity.

Neurological autoimmune diseases following vaccinations against SARS-CoV-2: a case series.

Background and purposePopulation‐based studies suggest that severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccines may trigger immune‐mediated thrombotic thrombocytopenia (VITT) raising concerns for other autoimmune responses. The aim was to characterize neurological autoimmunity after SARS‐CoV‐2 vaccinations.MethodsIn this single‐centre prospective case study patients with neurological autoimmunity in temporal association (≤6 weeks) with SARS‐CoV‐2 vaccinations and without other triggers are reported. Clinical, laboratory and imaging data were collected with a median follow‐up of 49 days.ResultsIn the study period 232,603 inhabitants from the main catchment area of our hospital (Rhein‐Neckar‐Kreis, county) received SARS‐CoV‐2 vaccinations. Twenty‐one cases (new onset n = 17, flares n = 4) diagnosed a median of 11 days (range 3–23) following SARS‐CoV‐2 vaccinations (BNT162b2 n = 12, ChAdOx1 n = 8, mRNA‐1273 n = 1) were identified. Cases included VITT with cerebral venous sinus thrombosis (n = 3), central nervous system demyelinating diseases (n = 8), inflammatory peripheral neuropathies (n = 4), myositis (n = 3), myasthenia (n = 1), limbic encephalitis (n = 1) and giant cell arteritis (n = 1). Patients were predominantly female (ratio 3.2:1) and the median age at diagnosis was 50 years (range 22–86). Therapy included administration of steroids (n = 15), intravenous immunoglobulins in patients with Guillain–Barré syndrome or VITT (n = 4), plasma exchange in cases unresponsive to steroids (n = 3) and anticoagulation in VITT. Outcomes were favourable with partial and complete remissions achieved in 71% and 24%, respectively. Two patients received their second vaccination without further aggravation of autoimmune symptoms under low‐dose immunosuppressants.ConclusionsIn this study various neurological autoimmune disorders encountered following SARS‐CoV‐2 vaccinations are characterized. Given the assumed low incidence and mostly favourable outcome of autoimmune responses, the benefits of vaccinations outweigh the comparatively small risks.

Clinical Features and Outcomes in Pediatric Autoimmune Encephalitis Associated With CASPR2 Antibody.

Background: Contactin-associated protein-like 2 (CASPR2) neurological autoimmunity has been associated with various clinical syndromes involving central and peripheral nervous system. CASPR2 antibody-associated autoimmune encephalitis is mostly reported in adults. Analysis of the clinical presentation and prognostic data of CASPR2 antibody-associated autoimmune encephalitis in children remains important.Methods: A single-center retrospective review of children diagnosed with CASPR2 antibody-associated autoimmune encephalitis from June 1st, 2018 to October 31st, 2020.Results: Six patients were identified. The median age was 12 years (range 1.8–14), with an overall male predominance of 83% (5/6). Commonest clinical features were psychiatric symptoms (6/6), movement disorders (4/6), altered consciousness (3/6), sleep disorders (3/6), and headache (3/6). Four patients (4/6) received first-line therapy alone (steroids combined with intravenous immunoglobulins), and two patients (2/6) received second-line therapy (rituximab, mycophenolate mofetil, or cyclophosphamide). All patients showed no peripheral nervous system involvement. One patient had comorbidities with systemic lupus erythematosus. No evidence of neoplastic disease was found in the whole cohort. All patients had favorable outcomes (modified Rankin Score 0–2) with recurrence rate at 0%, respectively.Conclusion: CASPR2 antibody-associated autoimmune encephalitis is rare in children. Our findings suggest that this type of encephalitis seems to occur more frequently in older children. Patients respond well to immunotherapy and usually demonstrate a favorable clinical outcome. Associated tumors are extremely rare.

Neurological Autoimmunity Associated With Homer-3 Antibody: A Case Series From China.

Background and ObjectiveTo present 6 new cases with Homer-3 antibodies that expand their clinical spectra and to evaluate the effect of immunotherapy.MethodsPatients with suspected autoimmune cerebellar disorder were tested for rare autoimmune cerebellar ataxia (ACA) antibodies (anti-Tr(DNER)/Zic4/ITPR1/Homer-3/NCDN/PKCγ/PCA-2/AP3B2/mGluR1/ATP1A3 antibodies) using both cell-based and tissue-based assays. Patients with positive serum or CSF results who were diagnosed with ACA were registered and followed up. This study reports and analyzes cases with Homer-3 antibodies.ResultsOf the serum and CSF samples of 750 patients tested, 6 were positive for Homer-3 antibodies. All manifested subacute or insidious-onset cerebellar ataxia. Furthermore, 2 patients each exhibited encephalopathy, myeloradiculopathy, REM sleep behavior disorder, and autonomic dysfunction. Brain magnetic resonance images were normal (n = 1) or revealed cerebellar atrophy (n = 1), cerebellum and pons atrophy with the hot cross bun sign (n = 2), and bilateral cerebral abnormalities (n = 2). Definite leukocytosis was identified in the CSF of 2 patients, protein concentration elevation was observed in the CSF of 1 patient, and oligoclonal bands were present in 2 patients. All patients received immunotherapy, including corticosteroid, IV immunoglobulin, plasma exchange, and mycophenolate mofetil, after which the residual disability was still severe (modified Rankin Scale score ≥3 at the last follow-up in 4 patients and final Scale for the Assessment and Rating of Ataxia scores of 12–29), although 4 patients partially improved and 1 patient stabilized. The remaining 1 patient continued to deteriorate after repeated immunotherapy. Two patients relapsed.DiscussionDisorders associated with Homer-3 antibody can mimic multiple system atrophy with cerebellar features in both clinical and radiologic aspects. Accurate identification of autoimmune-mediated cases is critical. Timely, comprehensive immunotherapy is warranted, given the possibility of long-term clinical benefit.

Antibody-Mediated Autoimmune Diseases of the CNS: Challenges and Approaches to Diagnosis and Management.

Antibody-mediated disorders of the central nervous system (CNS) are increasingly recognized as neurologic disorders that can be severe and even life-threatening but with the potential for reversibility with appropriate treatment. The expanding spectrum of newly identified autoantibodies targeting glial or neuronal (neural) antigens and associated clinical syndromes (ranging from autoimmune encephalitis to CNS demyelination) has increased diagnostic precision, and allowed critical reinterpretation of non-specific neurological syndromes historically associated with systemic disorders (e.g., Hashimoto encephalopathy). The intracellular vs. cell-surface or synaptic location of the different neural autoantibody targets often helps to predict the clinical characteristics, potential cancer association, and treatment response of the associated syndromes. In particular, autoantibodies targeting intracellular antigens (traditionally termed onconeural autoantibodies) are often associated with cancers, rarely respond well to immunosuppression and have a poor outcome, although exceptions exist. Detection of neural autoantibodies with accurate laboratory assays in patients with compatible clinical-MRI phenotypes allows a definite diagnosis of antibody-mediated CNS disorders, with important therapeutic and prognostic implications. Antibody-mediated CNS disorders are rare, and reliable autoantibody identification is highly dependent on the technique used for detection and pre-test probability. As a consequence, indiscriminate neural autoantibody testing among patients with more common neurologic disorders (e.g., epilepsy, dementia) will necessarily increase the risk of false positivity, so that recognition of high-risk clinical-MRI phenotypes is crucial. A number of emerging clinical settings have recently been recognized to favor development of CNS autoimmunity. These include antibody-mediated CNS disorders following herpes simplex virus encephalitis or occurring in a post-transplant setting, and neurological autoimmunity triggered by TNFα inhibitors or immune checkpoint inhibitors for cancer treatment. Awareness of the range of clinical and radiological manifestations associated with different neural autoantibodies, and the specific settings where autoimmune CNS disorders may occur is crucial to allow rapid diagnosis and early initiation of treatment.

Autoimmune Neurogenic Dysphagia.

Autoimmune neurogenic dysphagia refers to manifestation of dysphagia due to autoimmune diseases affecting muscle, neuromuscular junction, nerves, roots, brainstem, or cortex. Dysphagia is either part of the evolving clinical symptomatology of an underlying neurological autoimmunity or occurs as a sole manifestation, acutely or insidiously. This opinion article reviews the autoimmune neurological causes of dysphagia, highlights clinical clues and laboratory testing that facilitate early diagnosis, especially when dysphagia is the presenting symptom, and outlines the most effective immunotherapeutic approaches. Dysphagia is common in inflammatory myopathies, most prominently in inclusion body myositis, and is frequent in myasthenia gravis, occurring early in bulbar-onset disease or during the course of progressive, generalized disease. Acute-onset dysphagia is often seen in Guillain–Barre syndrome variants and slowly progressive dysphagia in paraneoplastic neuropathies highlighted by the presence of specific autoantibodies. The most common causes of CNS autoimmune dysphagia are demyelinating and inflammatory lesions in the brainstem, occurring in patients with multiple sclerosis and neuromyelitis optica spectrum disorders. Less common, but often overlooked, is dysphagia in stiff-person syndrome especially in conjunction with cerebellar ataxia and high anti-GAD autoantibodies, and in gastrointestinal dysmotility syndromes associated with autoantibodies against the ganglionic acetyl-choline receptor. In the setting of many neurological autoimmunities, acute-onset or progressive dysphagia is a potentially treatable condition, requiring increased awareness for prompt diagnosis and early immunotherapy initiation.

Antibody Testing for Neurological Autoimmune Disorders: Evaluation of Best Practices at a Tertiary Referral Center.

Background: Autoimmune neurology is a rapidly evolving field of study, where best practices for neurological antibody testing have yet to be determined. The growing number of options for antibody panel testing can create confusion amongst ordering clinicians and lead to ordering several concurrent panels (i.e., overlapping evaluations) or repeat panel evaluations. This study determined the frequency of these evaluations for autoimmune and paraneoplastic disorders and investigated how these practices informed clinical decision making and management.Methods: This was a retrospective observational study of adult patients presenting to University of Texas Southwestern (UTSW) in 2017 with requests for antibody panels for autoimmune encephalitis and paraneoplastic disorders. Individuals with more than one panel requested were defined as either an overlapping evaluation (more than one panel requested within 14 days) or repeat evaluation (more than one panel requested 14 or more days apart). For those individuals with repeat panel testing, the proportion of panels with a change in antibody status or subsequent changes in clinical diagnosis and decision making were recorded.Results: There was a total of 813 panels sent on 626 individuals. Twenty percent (126 individuals) had more than one panel requested. Only 10% of individuals had a matched serum and CSF evaluation. Forty-seven overlapping evaluations were performed in 46 (7.3%) of the individuals studied. Fifty-four (8.6%) individuals underwent 70 repeat evaluations encompassing 79 panels (9.7% of total panels ordered). Ten repeat evaluations showed a change in antibody status, of which only two were clinically significant. There was a single case where clinical management was affected by repeat autoantibody evaluation.Conclusions: Ordering practices for suspected autoimmune encephalitis and paraneoplastic disorders are suboptimal with frequent overlapping antibody panel evaluations and non-paired serum/CSF samples at our center. Repeat autoantibody testing is a commonplace practice yet yielded novel information in only a minority of cases. These new results were, as a rule, clinically irrelevant and changed clinical decision making in <1% of cases. There is limited utility in these practice patterns. Future efforts should be directed at the development and standardization of neurological autoimmune and paraneoplastic autoantibody testing practice standards.

Short- and Long-Lived Autoantibody-Secreting Cells in Autoimmune Neurological Disorders.

As B cells differentiate into antibody-secreting cells (ASCs), short-lived plasmablasts (SLPBs) are produced by a primary extrafollicular response, followed by the generation of memory B cells and long-lived plasma cells (LLPCs) in germinal centers (GCs). Generation of IgG4 antibodies is T helper type 2 (Th2) and IL-4, -13, and -10-driven and can occur parallel to IgE, in response to chronic stimulation by allergens and helminths. Although IgG4 antibodies are non-crosslinking and have limited ability to mobilize complement and cellular cytotoxicity, when self-tolerance is lost, they can disrupt ligand-receptor binding and cause a wide range of autoimmune disorders including neurological autoimmunity. In myasthenia gravis with predominantly IgG4 autoantibodies against muscle-specific kinase (MuSK), it has been observed that one-time CD20+ B cell depletion with rituximab commonly leads to long-term remission and a marked reduction in autoantibody titer, pointing to a short-lived nature of autoantibody-secreting cells. This is also observed in other predominantly IgG4 autoantibody-mediated neurological disorders, such as chronic inflammatory demyelinating polyneuropathy and autoimmune encephalitis with autoantibodies against the Ranvier paranode and juxtaparanode, respectively, and extends beyond neurological autoimmunity as well. Although IgG1 autoantibody-mediated neurological disorders can also respond well to rituximab induction therapy in combination with an autoantibody titer drop, remission tends to be less long-lasting and cases where titers are refractory tend to occur more often than in IgG4 autoimmunity. Moreover, presence of GC-like structures in the thymus of myasthenic patients with predominantly IgG1 autoantibodies against the acetylcholine receptor and in ovarian teratomas of autoimmune encephalitis patients with predominantly IgG1 autoantibodies against the N‐methyl‐d‐aspartate receptor (NMDAR) confers increased the ability to generate LLPCs. Here, we review available information on the short-and long-lived nature of ASCs in IgG1 and IgG4 autoantibody-mediated neurological disorders and highlight common mechanisms as well as differences, all of which can inform therapeutic strategies and personalized medical approaches.

The Role of Sphingolipids in Allergic Disorders.

Allergy is defined as a complex chronic inflammatory condition in which genetic and environmental factors are implicated. Sphingolipids are involved in multiple biological functions, from cell membrane components to critical signaling molecules. To date, sphingolipids have been studied in different human pathologies such as neurological disorders, cancer, autoimmunity, and infections. Sphingolipid metabolites, in particular, ceramide and sphingosine-1-phosphate (S1P), regulate a diverse range of cellular processes that are important in immunity and inflammation. Moreover, variations in the sphingolipid concentrations have been strongly associated with allergic diseases. This review will focus on the role of sphingolipids in the development of allergic sensitization and allergic inflammation through the activation of immune cells resident in tissues, as well as their role in barrier remodeling and anaphylaxis. The knowledge gained in this emerging field will help to develop new therapeutic options for allergic disorders.

Focused Workshops

The initial trigger leading to the immune tolerance breakdown is still unknown in most autoimmune encephalitites associated with antibodies targeting neuronal surface antigens. Nevertheless, prodromal symptoms compatible with mild infections are not infrequent, suggesting that some common and benign microbiological agents could act as triggers of the autoimmune reaction. Conversely, herpes simplex virus (HSV) encephalitis is now a well-characterized trigger of autoimmune encephalitis, and is particularly related to the development of anti- NMDAR antibodies, though other specificities have also been reported. Serological studies as well as an animal model further support the association between HSV and anti-NMDAR encephalitis, but the underlying pathogenesis is still obscure. However, a genetic predisposition involving the Toll-like receptor 3-pathway might exist at least in a subset of patients. In addition to HSV, anti-NMDAR and other autoimmune encephalitis have also been associated with other infections, chiefly Japanese encephalitis and HIV, but new epidemic and pandemic diseases such as COVID-19 are raising concern as potential triggers of autoimmune encephalitis. On the contrary, despite the recent description of anti-neural antibodies against different targets in some patients, solid evidence regarding the autoimmune pathogenesis is still lacking for several historically reported post-infectious neurological diseases, such as Sydenham chorea and von Economo's encephalitis lethargica. Interestingly, type 1 narcolepsy constitutes a good example of neurological autoimmunity triggered by infection in genetic susceptible subjects that might provide some clues for future research in autoimmune encephalitis.

Immune Checkpoint Inhibitor use in Patients with Pre-existing Neurological Autoimmune Diseases: A Case Series (4428)

Immune Checkpoint Inhibitor use in Patients with Pre-existing Neurological Autoimmune Diseases: A Case Series (4428)

Clinical spectrum of high-titre GAD65 antibodies

ObjectiveTo determine clinical manifestations, immunotherapy responsiveness and outcomes of glutamic acid decarboxylase-65 (GAD65) neurological autoimmunity.MethodsWe identified 323 Mayo Clinic patients with high-titre (>20 nmol/L in serum) GAD65 antibodies out of...

Sleep Disturbances Associated with Neurological Autoimmunity.

Associations between sleep disorders and neurological autoimmunity have been notably expanding recently. Potential immune-mediated etiopathogenesis has been proposed for various sleep disorders including narcolepsy, Kleine-Levin syndrome, and Morvan syndrome. Sleep manifestations are also common in various autoimmune neurological syndromes, but may be underestimated as overriding presenting (and potentially dangerous) neurological symptoms often require more urgent attention. Even so, sleep dysfunction has been described with various neural-specific antibody biomarkers, including IgLON5; leucine-rich, glioma-inactivated protein 1 (LGI1); contactin-associated protein 2 (CASPR2); N-methyl-D-aspartate (NMDA)-receptor; Ma2; dipeptidyl-peptidase-like protein-6 (DPPX); alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R); anti-neuronal nuclear antibody type-1 (ANNA-1, i.e., Hu); anti-neuronal nuclear antibody type-2 (ANNA-2, i.e., Ri); gamma-aminobutyric acid (GABA)-B-receptor (GABA-B-R); metabotropic glutamate receptor 5 (mGluR5); and aquaporin-4 (AQP-4). Given potentially distinctive findings, it is possible that sleep testing could potentially provide objective biomarkers (polysomnography, quantitative muscle activity during REM sleep, cerebrospinal fluid hypocretin-1) to support an autoimmune diagnosis, monitor therapeutic response, or disease progression/relapse. However, more comprehensive characterization of sleep manifestations is needed to better understand the underlying sleep disruption with neurological autoimmunity.

What's happening in Neurology®

In the August 20, 2019 podcast interview, Dr. Stacey Clardy talks with Dr. Anastasia Zekeridou about her article on phosphodiesterase 10A-IgG, a novel biomarker of paraneoplastic neurologic autoimmunity.