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Background: Immune dysregulation is a hallmark of autoimmune diseases of the central nervous system (CNS), characterized by an excessive immune response, and primary CNS tumors (pCNS-tumors) showing a highly immunosuppressive parenchymal microenvironment., Methods: Aiming to provide novel insights into the pathogenesis of CNS autoimmunity and cerebral tumor immunity, we analyzed the peripheral blood (PB) and cerebrospinal fluid (CSF) of 81 autoimmune limbic encephalitis (ALE), 148 relapsing-remitting multiple sclerosis (RRMS), 33 IDH-wildtype glioma, 9 primary diffuse large B cell lymphoma of the CNS (CNS-DLBCL), and 110 controls by flow cytometry (FC). Additionally, an in-depth immunophenotyping of the PB from an independent cohort of 20 RRMS and 18 IDH-wildtype glioblastoma patients compared to 19 controls was performed by FC combined with unsupervised computational approaches., Results: We identified alterations in peripheral and intrathecal adaptive immunity, mainly affecting the T cell (Tc) but also the B cell (Bc) compartment in ALE, RRMS, and pCNS-tumors compared to controls. ALE, RRMS, and pCNS-tumors featured higher expression of the T cell activation marker HLA-DR, which was even more pronounced in pCNS-tumors than in ALE or RRMS. Glioblastoma patients showed signs of T cell exhaustion that were not visible in RRMS patients. In-depth characterization of the PB revealed differences mainly in the T effector and memory compartment between RRMS and glioblastoma patients and similar alterations in the Bc compartment, including atypical Bc, CD19 + CD20 - double negative Bc, and plasma cells. PB and CSF mFC together with CSF routine parameters could reliably differentiate ALE and RRMS from pCNS-tumors facilitating early diagnosis and treatment., Conclusions: ALE, RRMS, and pCNS-tumors show distinct but partially overlapping changes mainly in HLA-DR + Tc, memory Tc, exhausted Tc, and Bc subsets providing insights into disease pathogenesis. Moreover, mFC shows diagnostic potential facilitating early diagnosis and treatment., (© 2024. The Author(s).)

Anti-IgLON5 disease is a rare neurological disease, identified just ten years ago, where autoimmunity and neurodegeneration converge. The heterogeneity of symptoms, sometimes mimicking pure neurodegenerative diseases or motor neuron diseases, in addition to lack of awareness, represents a diagnostic challenge. Biomarkers of neuronal damage in combination with in vivo visualization of tau deposition using positron emission tomography (PET) scanning could represent a major advance in monitoring disease progression. Recent studies with more autopsies available have helped refine the knowledge of the pathological features of the disease and strengthen the autoimmune hypothesis of the disease. Although the pathogenesis of anti-IgLON5 disease remains unclear, the irreversible antibody-mediated decrease of IgLON5 clusters from the cell surface and alterations produced in the cytoskeleton, as well as the behavioural abnormalities and signs of neuroinflammation and neurodegeneration observed in the brains of animals infused with antibodies from patients by passive transfer, which have recently been published, support the autoimmune hypothesis of the disease. This review aims to summarize these important aspects and recent advances in the pathophysiology of anti-IgLON5 disease., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

The past two decades have seen a considerable paradigm shift in the way autoimmune CNS disorders are considered, diagnosed, and treated; largely due to the discovery of novel autoantibodies directed at neuroglial surface or intracellular targets. This approach has enabled multiple bona fide CNS autoantibody-associated diseases to thoroughly infiltrate the sphere of clinical neurology, facilitating advances in patient outcomes. This review focusses on the fundamental immunological concepts behind CNS autoantibody-associated diseases. First, we briefly review the broad phenotypic profiles of these conditions. Next, we explore concepts around immune checkpoints and the related B cell lineage. Thirdly, the sources of autoantibody production are discussed alongside triggers of tolerance failure, including neoplasms, infections and iatrogenic therapies. Penultimately, the role of T cells and leucocyte trafficking into the CNS are reviewed. Finally, biological insights from responses to targeted immunotherapies in different CNS autoantibody-associated diseases are summarised. The continued and rapid expansion of the CNS autoantibody-associated field holds promise for further improved diagnostic and therapeutic paradigms, ultimately leading to further improvements in patient outcomes., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

The concept that many neurologic and psychiatric disorders of unknown cause are immune-mediated has evolved fast during the past 20 years. The main contribution to the expansion of this field has been the discovery of antibodies that attack neuronal or glial cell-surface proteins or receptors, directly modifying their structure and function. These antibodies facilitate the diagnosis and prompt treatment of patients who often improve with immunotherapy. The identification of this group of diseases, collectively named "autoimmune encephalitides", was preceded by many years of investigations on other autoimmune CNS disorders in which the antibodies are against intracellular proteins, occur more frequently with cancer, and associate with cytotoxic T-cell responses that are less responsive to immunotherapy. Here, we first trace the recent history of the autoimmune encephalitides and address how to assess the clinical value and implement in our practice the rapid pace of autoantibody discovery. In addition, we review recent developments in the post-acute stage of the two main autoimmune encephalitides (NMDAR and LGI1) focusing on symptoms that are frequently overlooked or missed, and therefore undertreated. Because a better understanding of the pathophysiology of these diseases relies on animal models, we examine currently available studies, recognizing the existing needs for better and all-inclusive neuro-immunobiological models. Finally, we assess the status of biomarkers of disease outcome, clinical scales, current treatment strategies, and emerging therapies including CAR T-cell technology. Altogether, this overview is intended to identify gaps of knowledge and provide suggestions for improvement and insights for future research., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a rare autoimmune disease, which is characterized by the immune system attacking astrocytes in the central nervous system, resulting in inflammation and damage to the nervous system. We reported a 41-year-old female patient with only drowsiness for 3 months, who was, otherwise, healthy with no other signs of meningoencephalitis or myelitis. There were no obvious abnormalities in her neurological and ophthalmic tests. Brain magnetic resonance imaging (MRI) plain scan + enhancement with the gadolinium contrast agent revealed patchy hypointensity on T1-weighted imaging, hyperintensity on T2-weighted imaging, hyperintensity on T2-weighted fluid-attenuated inversion recovery in the left basal ganglia, corona radiata, and local septum pellucida, with no enhancement in the enhanced lesions. Cerebrospinal fluid (CSF) revealed white blood cell count of 5.00 × 10 6 /L, CSF protein of 828.53 mg/L, and glucose of 2.83 mmol/L. Aquaporin-4 (AQP4) antibody, N-methyl-D-aspartate receptor (NMDAR) antibody and GFAP antibody were all positive, whereas the remaining autoimmune encephalitis antibody tests were negative. Oncology screening [including head, chest, and whole-abdomen (involving the pelvic cavity) CT and tumor markers] did not reveal any obvious evidence of tumor presence. The patient received systemic treatment with high-dose intravenous injection of steroids combined with immunosuppressive agents, and the clinical and imaging features of the patients improved. To the best of our knowledge, reports on overlapping positivity of AQP4 antibody and NMDAR antibody in patients with GFAP astrocytopathy were still very rare. We hope to supplement the existing literature on this topic, review the relevant literature, and strive to increase the understanding toward GFAP astrocytopathy with overlapping autoimmune syndrome so as to enable early diagnosis and early treatment and to improve the clinical outcome of patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wei, Chen and Meng.)

Objective: To characterize the long-term outcomes of patients with "possible only" or "probable" autoimmune encephalitis (AE)., Background: Despite comprising one-third of AE cases, antibody-negative cases lacking typical AE-defining features are understudied., Design/methods: We conducted a retrospective analysis of adult patients evaluated at a tertiary center neuroimmunology practice from 2006 to 2020, meeting diagnostic criteria for "possible only" or "probable but antibody-negative" AE, with at least one year of follow-up. All patients underwent neural antibody testing., Results: Forty-five patients (median age, 61 years [range, 20-88]; female, 21 [47%]) were included, with a median follow-up of 36 months (range, 12-174). A change in diagnosis was noted in six additional patients, who were excluded from further analysis, with only two receiving a non-autoimmune diagnosis during follow-up. The majority (41/45 [91%]) presented with significant disability (modified Rankin Scale [mRS] ≥3) at baseline. CSF was inflammatory in 20/44 (45%) and MRI was abnormal in 21/45 (47%). Unclassified neural-specific IgG staining on tissue-based assay was detected in five (11%). Two cases (4%) had a paraneoplastic cause. The median time from onset to immunotherapy initiation was two months (range, 0-21), resulting in at least partial improvement in all 44 (98%) treated cases. Clinical relapses occurred in 14/45 (31%). At last follow-up, the most common symptoms were memory dysfunction (31/45 [69%]), attention deficits (17/45 [38%]), gait instability (13/45 [29%]), and visuospatial dysfunction (10/45 [22%]). Most patients achieved independence (median mRS, 2 [range, 0-6]); however, 11 patients had poor neurological outcome (mRS ≥3). Higher mRS score and gait assistance requirement at three months were predictive of poor outcome (P ≤0.01)., Conclusions: Despite significant disability at initial stages, patients with antibody-negative but clinically presumed AE show potential for improvement with immunotherapy, highlighting the importance of early intervention. Early functional status and gait assistance requirements may assist in predicting long-term prognosis.

Background: Autoimmune encephalitis (AE) is the third most common encephalitis in children. Diagnosis can be challenging due to overlapping and diverse clinical presentations as well as various investigation results. This study aims to characterize the clinical, diagnostic features, as well as treatment and outcomes of AE in children and determine the incidence of pediatric AE in Latvia., Methods: The study was conducted at the Children's Clinical University Hospital in Riga. The study participants were patients under the age of 18 years diagnosed with AE from 2014 to 2022. Data regarding clinical characteristics, investigation findings, treatment strategy, and outcomes were retrospectively collected from the medical history data system., Results: We included 18 pediatric patients diagnosed with AE. The mean incidence of pediatric AE in Latvia was 0.56 per 100,000 children. Most patients (66.6%) had seronegative AE. In the seropositive group, the most common was anti-methyl-D-aspartate receptor AE, with two patients having other antibodies. The most prevalent clinical features were personality change, cognitive impairment, autonomic dysfunction, and movement disorders. The majority of patients (58.8%) received first-line treatment only. More than half (55.6%) of our AE patient group had long-term sequelae., Conclusions: Our study shows that the pediatric AE incidence in Latvia is similar to what has been previously reported in other studies. A relatively high proportion of seronegative AE was present in our cohort, indicating that awareness of possible misdiagnosis should be raised. Further research is needed to better understand the underlying mechanisms, characterize clinical features, and determine the treatment of choice in different situations to improve long-term outcomes., Competing Interests: None declared., (Thieme. All rights reserved.)

Aicardi-Goutières syndrome (AGS) is a rare genetic early-onset progressive encephalopathy with variable clinical manifestations. The IFIH1 mutation has been confirmed to be responsible for type I interferon production and activation of the Janus kinase signaling pathway. We herein stress neurological observations and neuroimaging findings in a severe case report of an infant with AGS type 7 due to an IFIH1 mutation who was diagnosed in the first month of life. We also review neurological characteristics of IFIH1 mutations through recent literature., Competing Interests: None declared., (Thieme. All rights reserved.)

Immune-mediated cerebellar ataxias (IMCAs) represent a group of disorders in which the immune system targets mainly the cerebellum and related structures. We address fundamental questions on the diagnosis and immunological pathogenesis of IMCAs, as illuminated by recent advances in the field. Various types of IMCAs have been identified, including post-infectious cerebellitis, Miller Fisher syndrome, gluten ataxia, paraneoplastic cerebellar degeneration (PCD), opsoclonus and myoclonus syndrome, and anti-GAD ataxia. In some cases, identification of several well-characterized autoantibodies points to a specific etiology in IMCAs and leads to a firm diagnosis. In other cases, various autoantibodies have been reported, but their interpretation requires a careful consideration. Indeed, some autoantibodies have only been documented in a limited number of cases and the causal relationship is not established. In order to facilitate an early treatment and prevent irreversible lesions, new entities have been defined in recent years, such as primary autoimmune cerebellar ataxia (PACA) and latent autoimmune cerebellar ataxia (LACA). PACA is characterized by autoimmune features which do not align with traditional etiologies, while LACA corresponds to a prodromal stage. LACA does not imply the initiation of an immunotherapy but requires a close follow-up. Concurrently, accumulation of clinical data has led to intriguing hypotheses regarding the mechanisms of autoimmunity, such as a pathogenesis of autoimmunity against synapses (synaptopathies), and the vulnerability of the entire nervous system when the immunity targets ion channels and astrocytes. The development of PCD in patients treated with immune-checkpoint inhibitors suggests that molecular mimicry specifically determines the direction of autoimmunity, and that the strength of this response is modulated by co-signaling molecules that either enhance or dampen signals from the antigen-specific T cell receptor., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

The horror autoinflammaticus derived from aberrant type I interferon secretion determines a special group of autoinflammatory diseases named interferonopathies. Diverse mechanisms involved in nucleic acids sensing, metabolizing or the lack of interferon signaling retro-control are responsible for the phenotypes associated to Aicardi-Goutières Syndrome (AGS), Proteasome-Associated Autoinflammatory Diseases (PRAAS), STING-Associated Vasculopathy with Infancy Onset (SAVI) and certain forms of monogenic Systemic lupus erythematosus (SLE). This review approaches interferonopathies from the basic immunogenetic concept to diagnosis and treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Autoimmune neuropathies are a heterogeneous group of immune-mediated disorders of the peripheral nerves. Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) are the archetypal acute and chronic forms. Over the past few decades, pathogenic antibodies targeting antigens of the peripheral nervous system and driving peripheral nerve damage in selected patients have been described. Moreover, the detection of these antibodies has diagnostic and therapeutic implications that have prompted a modification of the GBS and CIDP diagnostic algorithms. GBS diagnosis is based in clinical criteria, and systematic testing of anti-ganglioside antibodies is not required. Nonetheless, a positive anti-ganglioside antibody test may support the clinical suspicion when diagnosis of GBS (GM1 IgG), Miller Fisher (GQ1b IgG), or acute sensory-ataxic (GD1b IgG) syndromes is uncertain. Anti-myelin-associated glycoprotein (MAG) IgM and anti-disialosyl IgM antibodies are key in the diagnosis of anti-MAG neuropathy and chronic ataxic neuropathy, ophthalmoplegia, M-protein, cold agglutinins, and disialosyl antibodies spectrum neuropathies, respectively, and help differentiating these conditions from CIDP. Recently, the field has been boosted by the discovery of pathogenic antibodies targeting proteins of the node of Ranvier contactin-1, contactin-associated protein 1, and nodal and paranodal isoforms of neurofascin (NF140, NF186, or NF155). These antibodies define subgroups of patients with specific clinical (most importantly poor or partial response to conventional therapies and excellent response to anti-CD20 therapy) and pathologic (node of Ranvier disruption in the absence of inflammation) features that led to the definition of the "autoimmune nodopathy" diagnostic category and to the incorporation of nodal/paranodal antibodies to clinical routine testing. The purpose of this review was to provide a practical vision for the general neurologist of the use of antibodies in the clinical assessment of autoimmune neuropathies.

Background: The presence of inflammatory changes in the cerebrospinal fluid (CSF), including immunoglobulin intrathecal synthesis (IS), can support the diagnosis of autoimmune encephalitis (AE) and allow prompt treatment. The main aim of our study was to calculate the Kappa index as a marker of IS, in patients with AE., Methods: Charts of patients undergoing a diagnostic work-up for suspected AE between 2009 and 2023 were reviewed and the Graus criteria applied. CSF and serum kappa free light chains were determined using the Freelite assay (The Binding Site Group) and the turbidimetric Optilite analyzer., Results: We identified 34 patients with "definite" AE (9 anti-NMDAR AE and 25 limbic AE) and nine patients with "possible" AE. Five patients (15%) with definite AE had pleocytosis and twelve (34%) showed CSF-restricted oligoclonal bands (OCB) at isoelectric focusing. The Kappa index was >6 in 29.4% and > 3 in 50% of the definite AE patients. It was elevated (>3) in 36.4% of patients with definite AE who resulted negative to OCB testing and was the only altered parameter suggestive of an ongoing inflammatory process in the CNS in three definite AE patients with otherwise normal CSF findings (i.e. normal cell count and protein levels, no OCBs). In the possible AE group, one patient had a Kappa index >3 in the absence of OCB., Conclusions: The Kappa index could be useful, as a more sensitive marker of IS and as a supportive marker of neuroinflammation, in the diagnostic work-up of suspected AE., Competing Interests: Declaration of competing interest DF's institution has received kappa free light chain assays (Freelite) for research purposes from Binding Site (Birmingham). GDN, MG, PN, RB, SM, AMS, MS, FV, KS, MC and SM have nothing to disclose., (Copyright © 2024. Published by Elsevier B.V.)

Objective: To analyze the clinical features of anti-neurofascin-155 (NF155) antibody positive autoimmune nodopathy in children. Methods: This was a case series study. A total of 6 children who were diagnosed accurately as anti-NF155 antibody positive autoimmune nodopathy by cell immunofluorescence assay at the Children's Hospital of Fudan University from January 2020 to December 2023 were collected. This study retrospectively analyzed 6 pediatric children's clinical manifestations, laboratory and electrophysiological examination results, and treatment outcomes. Results: Among 6 children with anti-NF155 antibody positive autoimmune nodopathy, there were 4 boys and 2 girls. The onset age of 6 children ranged from 3 years and 8 months to 12 years. All 6 children had extremity weakness (more severe in the distal and the lower extremities than in the upper extremities), 5 children had sensory deficits such as numbness or pain in the extremities, 4 children had tremors and ataxia, 3 children had cranial nerve involvement. Among the 6 children, 4 children had protein-cell separation in cerebrospinal fluid examinations. Among the 6 children, 1 child had central nervous system demyelination, the brain magnetic resonance imaging showed multiple abnormal signals in the bilateral cerebral hemispheres. Four children showed motor and sensory nerve damage in electrophysiological examination, and 2 children only showed motor nerve damage. Three children showed myelin and axonal damage, and 3 children only showed axonal damage. Among the 6 children, 5 children were treated with intravenous immunoglobulin and steroids. Among them, 2 children underwent plasma exchange due to poor efficacy, and subsequently, rituximab was added. There was 1 child changed the treatment with olfatomumab since the symptoms did not significantly improve after using rituximab. After treatment for 4-15 months, 2 children had no clinical symptoms, 1 child had improvement in clinical symptoms, 2 children had no significant improvement in clinical symptoms, and 1 child who did not receive the immunotherapy had no significant change in clinical symptoms. Conclusions: Anti-NF155 antibody positive autoimmune nodopathy in children presents with varying degrees of clinical manifestations. It is mainly characterized by extremity weakness, numbness and pain, often accompanied bytremorsand ataxia. Some pediatric patients may also have central nervous system demyelination. Cerebrospinal fluid and electrophysiological examination are important auxiliary examination methods. If steroid therapy is not effective, plasma exchange and rituximab treatment should be used as soon as possible.

Objective: The field of autoimmune neurology is rapidly evolving. This article reviews the epidemiology and pathophysiology as well as current approaches to clinical and paraclinical assessment, testing paradigms, and general principles of treatment., Latest Developments: Improved recognition of autoimmune diagnoses among patients who have phenotypically diverse, subacute onset neurologic presentations is facilitated by disease-specific antibody biomarker discovery. These antibodies have varying associations with paraneoplastic causation (from no association to greater than 70% positive predictive value), immunotherapy responses, and outcomes. To simplify assessment in an increasingly complex discipline, neurologic phenotype-specific serum and CSF antibody evaluations are recommended. Clinical trials have led to the approval of monoclonal therapies for neuromyelitis optica spectrum disorder (NMOSD) and are underway for N-methyl-d-aspartate (NMDA) receptor and leucine-rich glioma inactivated protein 1 (LGI1) encephalitides., Essential Points: Autoimmune neurology is now a mainstream subspecialty, consisting of disorders with diverse presentations detectable using antibody testing of serum and CSF. Early and sustained immunotherapy (eg, corticosteroids, intravenous immunoglobulin [IVIg], plasma exchange) is recommended and may be supplemented by immune suppressants (eg, rituximab or cyclophosphamide) to sustain responses and optimize outcomes., (Copyright © 2024 American Academy of Neurology.)

Objective: This article discusses common principles in diagnosing and managing autoimmune neurologic conditions in children., Latest Developments: The key to improving outcomes in all patients with autoimmune neurologic diseases is making an early diagnosis, promptly initiating treatment, and identifying patients who will benefit from long-term maintenance treatment. Some neuroinflammatory syndromes can be diagnosed with an antibody biomarker (eg, aquaporin-4 antibodies, N-methyl-d-aspartate [NMDA] receptor antibodies), whereas others require clinical diagnostic criteria (eg, multiple sclerosis, opsoclonus-myoclonus syndrome). A proportion of children will be labeled as seronegative, and further investigations for other inflammatory or monogenetic etiologies need to be carried out in parallel with treating the central nervous system inflammation. Time to treatment and treatment escalation were shown to correlate with outcomes in many patients with these disorders. The choice and duration of treatment should be evaluated considering side effects and risks in the short and long terms. The presence of a highly inflammatory disease process in children supports the use of highly effective disease-modifying therapies in pediatrics., Essential Points: The phenotypes of pediatric autoimmune neurologic conditions may change across different age groups, as the brain is still actively developing. In general, the presentation in children is more inflammatory, but overall disability is lower, likely because of better neuroplasticity and repair. Convincing evidence has increasingly emerged to support the biological rationale that effective immunosuppressive therapies used in adult neuroimmunology are equally effective in children., (Copyright © 2024 American Academy of Neurology.)

Objective: Autoimmune neurologic disorders encompass a broad category of diseases characterized by immune system attack of the central, peripheral, or autonomic nervous systems. This article provides information on both acute and maintenance immunotherapy used to treat autoimmune neurologic disorders as well as a review of symptomatic management and special considerations when caring for patients with these diseases., Latest Developments: Over the past 20 years, more than 50 antibodies have been identified and associated with autoimmune neurologic disorders. Although advances in diagnostic testing have allowed for more rapid diagnosis, the therapeutic approach to these disorders has largely continued to rely on expert opinion, case series, and case reports. With US Food and Drug Administration (FDA) approval of biologic agents to treat neuromyelitis optica spectrum disorder (NMOSD) and myasthenia gravis as well as ongoing clinical trials for the treatment of autoimmune encephalitis, the landscape of immunotherapy options continues to expand. Consideration of the unique pathogenesis of individual autoimmune neurologic disorders as well as the mechanism of action of the diverse range of treatment options can help guide treatment decisions today while evidence from clinical trials informs new therapeutics in the future., Essential Points: Recognizing patients who have a clinical history and examination findings concerning for autoimmune neurologic disorders and conducting a thorough and directed imaging and laboratory evaluation aimed at ruling out mimics, identifying specific autoimmune syndromes, and screening for factors that may have an impact on immunotherapy choices early in the clinical course are essential to providing optimal care for these patients. Providers must consider immunotherapy, symptomatic treatment, and a multidisciplinary approach that addresses each patient's unique needs when treating patients with autoimmune neurologic disorders., (Copyright © 2024 American Academy of Neurology.)

Objective: This article reviews autoimmune neuromuscular disorders and includes an overview of the diagnostic approach, especially the role of antibody testing in a variety of neuropathies and some other neuromuscular disorders., Latest Developments: In the past few decades, multiple antibody biomarkers associated with immune-mediated neuromuscular disorders have been reported. These biomarkers are not only useful for better understanding of disease pathogenesis and allowing more timely diagnosis but may also aid in the selection of an optimal treatment strategy., Essential Points: Recognition of autoimmune neuromuscular conditions encountered in inpatient or outpatient neurologic practice is very important because many of these disorders are reversible with prompt diagnosis and early treatment. Antibodies are often helpful in making this diagnosis. However, the clinical phenotype and electrodiagnostic testing should be taken into account when ordering antibody tests or panels and interpreting the subsequent results. Similar to other laboratory investigations, understanding the potential utility and limitations of antibody testing in each clinical setting is critical for practicing neurologists., (Copyright © 2024 American Academy of Neurology.)

An 83-year-old man with hepatocellular carcinoma developed muscle weakness, ptosis, and dyspnea 3 weeks after receiving atezolizumab. Soon after, mechanical ventilation was initiated, which was followed by marked blood pressure spikes. The levels of creatine kinase and troponin-I were significantly elevated, and acetylcholine receptor antibodies were positive. The patient was diagnosed with immune checkpoint inhibitor (ICI)-induced myositis, myasthenia gravis (MG), myocarditis, and suspected autoimmune autonomic ganglionopathy (AAG). After immunotherapy, the serum markers and blood pressure normalized, and he was weaned from the ventilator after five months. To our knowledge, this is the first reported case of AAG secondary to ICI-induced myositis, MG, and myocarditis.

Objective: This article reviews the clinical and antibody spectrum of autoimmune cerebellar ataxia and other autoimmune movement disorders. It highlights characteristic phenotypes and red flags to the diagnosis and how these rare, but treatable, disorders are integrated into a differential diagnosis., Latest Developments: An increasing number of neuronal antibodies have been identified in patients with cerebellar ataxia, for example, against Kelch-like protein 11 (KLHL11), seizure-related 6 homolog-like 2, septin-3 and septin-5, or tripartite motif containing protein 9 (TRIM9), TRIM46, and TRIM67. Ig-like cell adhesion molecule 5 (IgLON5) antibody-associated syndromes have emerged as an important alternative diagnostic consideration to various neurodegenerative diseases such as Huntington disease or atypical parkinsonism. Opsoclonus-myoclonus syndrome emerged as the most relevant parainfectious movement disorder related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)., Essential Points: Autoimmune cerebellar ataxia and other autoimmune movement disorders encompass a broad spectrum of different clinical syndromes, antibodies, and immunopathophysiologic mechanisms. Clinical acumen is key to identifying the cases that should undergo testing for neuronal antibodies. Given the overlap between phenotypes and antibodies, panel testing in serum and CSF is recommended., (Copyright © 2024 American Academy of Neurology.)

Objective: This article focuses on the clinical features and diagnostic evaluations that accurately identify patients with ever-expanding forms of antibody-defined encephalitis. Forms of autoimmune encephalitis are more prevalent than infectious encephalitis and represent treatable neurologic syndromes for which early immunotherapies lead to the best outcomes., Latest Developments: A clinically driven approach to identifying many autoimmune encephalitis syndromes is feasible, given the typically distinctive features associated with each antibody. Patient demographics alongside the presence and nature of seizures, cognitive impairment, psychiatric disturbances, movement disorders, and peripheral features provide a valuable set of clinical tools to guide the detection and interpretation of highly specific antibodies. In turn, these clinical features in combination with serologic findings and selective paraclinical testing, direct the rationale for the administration of immunotherapies. Observational studies provide the mainstay of evidence guiding first- and second-line immunotherapy administration in autoimmune encephalitis and, whereas these typically result in some clinical improvements, almost all patients have residual neuropsychiatric deficits, and many experience clinical relapses. An improved pathophysiologic understanding and ongoing clinical trials can help to address these unmet medical needs., Essential Points: Antibodies against central nervous system proteins characterize various autoimmune encephalitis syndromes. The most common targets include leucine-rich glioma inactivated protein 1 (LGI1), N-methyl-d-aspartate (NMDA) receptors, contactin-associated proteinlike 2 (CASPR2), and glutamic acid decarboxylase 65 (GAD65). Each antibody-associated autoimmune encephalitis typically presents with a recognizable blend of clinical and investigation features, which help differentiate each from alternative diagnoses. The rapid expansion of recognized antibodies and some clinical overlaps support panel-based antibody testing. The clinical-serologic picture guides the immunotherapy regime and offers valuable prognostic information. Patient care should be delivered in conjunction with autoimmune encephalitis experts., (Copyright © 2024 American Academy of Neurology.)

With the discovery of an expanding number of neural autoantibodies, autoimmune etiologies of seizures have been increasingly recognized. Clinical phenotypes have been identified in association with specific underlying antibodies, allowing an earlier diagnosis. These phenotypes include faciobrachial dystonic seizures with LGI1 encephalitis, neuropsychiatric presentations associated with movement disorders and seizures in NMDA-receptor encephalitis, and chronic temporal lobe epilepsy in GAD65 neurologic autoimmunity. Prompt recognition of these disorders is important, as some of them are highly responsive to immunotherapy. The response to immunotherapy is highest in patients with encephalitis secondary to antibodies targeting cell surface synaptic antigens. However, the response is less effective in conditions involving antibodies binding intracellular antigens or in Rasmussen syndrome, which are predominantly mediated by cytotoxic T-cell processes that are associated with irreversible cellular destruction. Autoimmune encephalitides also may have a paraneoplastic etiology, further emphasizing the importance of recognizing these disorders. Finally, autoimmune processes and responses to novel immunotherapies have been reported in new-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES), warranting their inclusion in any current review of autoimmune-associated seizure disorders., (© 2024 The Authors. Epileptic Disorders published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background and Objectives: Up to 46% of patients with presumed autoimmune limbic encephalitis are seronegative for all currently known central nervous system (CNS) antigens. We developed a cell-based assay (CBA) to screen for novel neural antibodies in serum and cerebrospinal fluid (CSF) using neurons and astrocytes derived from human-induced pluripotent stem cells (hiPSCs)., Methods: Human iPSC-derived astrocytes or neurons were incubated with serum/CSF from 99 patients [42 with inflammatory neurological diseases (IND) and 57 with non-IND (NIND)]. The IND group included 11 patients with previously established neural antibodies, six with seronegative neuromyelitis optica spectrum disorder (NMOSD), 12 with suspected autoimmune encephalitis/paraneoplastic syndrome (AIE/PNS), and 13 with other IND (OIND). IgG binding to fixed CNS cells was detected using fluorescently-labeled antibodies and analyzed through automated fluorescence measures. IgG neuronal/astrocyte reactivity was further analyzed by flow cytometry. Peripheral blood mononuclear cells (PBMCs) were used as CNS-irrelevant control target cells. Reactivity profile was defined as positive using a Robust regression and Outlier removal test with a false discovery rate at 10% following each individual readout., Results: Using our CBA, we detected antibodies recognizing hiPSC-derived neural cells in 19/99 subjects. Antibodies bound specifically to astrocytes in nine cases, to neurons in eight cases, and to both cell types in two cases, as confirmed by microscopy single-cell analyses. Highlighting the significance of our comprehensive 96-well CBA assay, neural-specific antibody binding was more frequent in IND (15 of 42) than in NIND patients (4 of 57) (Fisher's exact test, p = 0.0005). Two of four AQP4+ NMO and four of seven definite AIE/PNS with intracellular-reactive antibodies [1 GFAP astrocytopathy, 2 Hu+, 1 Ri+ AIE/PNS)], as identified in diagnostic laboratories, were also positive with our CBA. Most interestingly, we showed antibody-reactivity in two of six seronegative NMOSD, six of 12 probable AIE/PNS, and one of 13 OIND. Flow cytometry using hiPSC-derived CNS cells or PBMC-detected antibody binding in 13 versus zero patients, respectively, establishing the specificity of the detected antibodies for neural tissue., Conclusion: Our unique hiPSC-based CBA allows for the testing of novel neuron-/astrocyte-reactive antibodies in patients with suspected immune-mediated neurological syndromes, and negative testing in established routine laboratories, opening new perspectives in establishing a diagnosis of such complex diseases., Competing Interests: RBV received travel grants from Roche and received speaker honoraria from Novartis. None were related to this work. AH has served as an expert in advisory boards from Novocure and Bayer and received speaker honoraria from Novocure, all paid to the institution and not related to this work. AZ has patents submitted for Tensacin-R IgG, PDE10A-IgG, and DACH1-IgG as biomarkers of neurological autoimmunity, receives research funding from Roche/Genetech non-relevant to this work, and has consulted for Alexion Pharmaceutical without personal compensation. MT has served as an expert in advisory boards for Biogen, Genzyme-Sanofi, Merck, Novartis, and Roche; received travel grants from Biogen, Genzyme-Sanofi, Merck, Novartis, and Roche; and received speaker honoraria from Biogen, Novartis, and Merck. None were related to this work. CP has served as an expert in advisory boards and received travel grants from Biogen, Genzyme-Sanofi, Merck, Novartis, and Roche. None were related to this work. RDP has served on scientific advisory boards for Biogen, BMS, Merck, Novartis, Roche, and Sanofi-Genzyme and has received funding for travel or speaker honoraria from Biogen, Merck, Roche, and Sanofi-Genzyme. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Mathias, Perriot, Jones, Canales, Bernard-Valnet, Gimenez, Torcida, Oberholster, Hottinger, Zekeridou, Theaudin, Pot and Du Pasquier.)

Rationale: Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a rare autoimmune disease of the central nervous system that affects the meninges, brain, spinal cord, and optic nerves. GFAP astrocytopathy can coexist with a variety of antibodies, which is known as overlap syndrome. Anti-NMDAR-positive encephalitis overlap syndrome has been reported; however, encephalitis overlap syndrome with both anti-NMDAR and sulfatide-IgG positivity has not been reported., Patient Concerns: The patient was a 50-year-old male who was drowsy and had chills and weak limbs for 6 months. His symptoms worsened after admission to our hospital with persistent high fever, dysphoria, gibberish, and disturbance of consciousness. Positive cerebrospinal fluid NMDA, GFAP antibodies, and serum sulfatide antibody IgG were positive., Diagnoses: Autoimmune GFAP astrocytopathy with anti-NMDAR and sulfatide-IgG-positive encephalitis overlap syndrome., Interventions: In addition to ventilator support and symptomatic supportive treatment, step-down therapy with methylprednisolone (1000 mg/d, halved every 3 days) and pulse therapy with human immunoglobulin (0.4 g/(kg d) for 5 days) were used., Outcomes: After 6 days of treatment, the patient condition did not improve, and the family signed up to give up the treatment and left the hospital., Conclusions: Patients with autoimmune GFAP astrocytopathy may be positive for anti-NMDAR and sulfatide-IgG, and immunotherapy may be effective in patients with severe conditions., Lessons: Autoimmune GFAP astrocytopathy with nonspecific symptoms is rarely reported and is easy to be missed and misdiagnosed. GFAP astrocytopathy should be considered in patients with fever, headache, disturbance of consciousness, convulsions, and central infections that do not respond to antibacterial and viral agents. Autoimmune encephalopathy-related antibody testing should be performed as soon as possible, early diagnosis should be confirmed, and immunomodulatory therapy should be administered promptly., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background and Objectives: Aicardi Goutières syndrome (AGS) is type I interferonopathy characterized by severe neurologic impairment. Although many children with AGS demonstrate motor and expressive language deficits, the magnitude of receptive language impairment is uncharacterized. We sought to characterize cognitive function in AGS-affected children using assessment tools with reduced dependence on motor abilities and compare cognitive testing outcomes with overall severity and parental assessment of adaptive behavior., Methods: We performed a cross-sectional study. Children were recruited as part of the Myelin Disorders Biorepository Project at the Children's Hospital of Philadelphia. We included individuals with a confirmed diagnosis of AGS. We administered the Leiter International Performance Scale, third edition (Leiter-3), and the Vineland Adaptive Behavior Scale, third edition (VABS-3), in the context of research encounters. Motor skills were categorized by AGS Severity Scale mobility levels. Descriptive statistics and Spearman's rank correlation were used to compare assessments. Mann-Whitney and Kruskal-Wallis tests with correction with Dunn's multiple comparison test were used to compare test performance between mobility groups., Results: Cognitive and adaptive behavior performance was captured in 57 children. The mean age at encounters was 8.51 (SD 5.15) years. The median (IQR) Leiter-3 score was 51 (interquartile range [IQR] 60), with administration failure in 20 of 57 (35%) individuals. On the VABS-3, the Motor Domain (median 29, IQR 36.25) was more impacted than the Communication (median 50, IQR 52), Daily Living Skills (median 52, IQR 31), and Socialization (median 54, IQR 40) Domains ( p < 0.0001). The AGS Scale correlated with VABS-3 ( r = 0.86, p < 0.0001) and Leiter-3 ( r = 0.87, p < 0.0001). There was correlation between VABS-3 Domains and Leiter-3 ( r -range 0.83-0.97). Gross motor and fine motor categories, respectively, correlated with VABS-3 ( H = 39.37, p < 0.0001; U = 63, p < 0.0001) and Leiter-3 ( H = 40.43, p < 0.0001; U = 66, p < 0.0001). Within each gross motor and fine motor category of the AGS Scale, a subset of children scored within normal IQ range., Discussion: Parental assessment of function by the VABS-3 correlated with directly assessed performance measures. Our data underscore the potential value of VABS-3 and Leiter-3 as tools to assess psychometric function in AGS. With a deeper understanding of our patients' abilities, we can better guide clinicians and families to provide appropriate support and personalized interventions to empower children with leukodystrophies to maximize their communication and educational potential.

PARS2 encodes an aminoacyl-tRNA synthetase that catalyzes the ligation of proline to mitochondrial prolyl-tRNA molecules. Diseases associated with PARS2 primarily affect the central nervous system, causing early infantile developmental epileptic encephalopathies (EIDEE; DEE75; MIM #618437) with infantile-onset neurodegeneration. Dilated cardiomyopathy has also been reported in the affected individuals. About 10 individuals to date have been described with pathogenic biallelic variants in PARS2. While many of the reported individuals succumbed to the disease in the first two decades of life, autopsy findings have not yet been reported. Here, we describe neuropathological findings in a deceased male with evidence of intracranial calcifications in the basal ganglia, thalamus, cerebellum, and white matter, similar to Aicardi-Goutières syndrome. This report describes detailed autopsy findings in a child with PARS2-related mitochondrial disease and provides plausible evidence that intracranial calcifications may be a previously unrecognized feature of this disorder., (© 2024 Wiley Periodicals LLC.)

Serological tests are important to detect autoantibodies (autoAbs) in patients with autoimmune neuropathies (AN) and myasthenia gravis (MG) as they are biomarkers for diagnosis, stratification, treatment selection, and monitoring. However, tests to detect autoAbs frequently lack proper standardization and results differ across diagnostic laboratories. We compared results for tests routinely performed in Spanish diagnostic laboratories to detect AN and MG autoAbs. In the Spanish Society of Immunology Autoimmunity Group national workshop, serum samples from 13 patients with AN or MG were tested for anti-ganglioside, anti-myelin-associated glycoprotein (MAG), anti-nicotinic acetylcholine receptor (AChR), and anti-muscle-specific kinase (MuSK) autoAbs using reference methods and were distributed for analysis to 27 participating laboratories using their routine methods. Overserved were inter-laboratory variability and worryingly low sensitivity, especially for anti-ganglioside immunoglobulin G and anti-MAG autoAb detection. This pilot study reflects autoAbs detection state of the art in AN and MG testing in leading diagnostic laboratories in Spain, highlighting the need for standardization prior to clinical use., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Objective: Differentiating forms of autoimmune encephalitis (AE) from other causes of seizures helps expedite immunotherapies in AE patients and informs studies regarding their contrasting pathophysiology. We aimed to investigate whether and how Nuclear Magnetic Resonance (NMR)-based metabolomics could differentiate AE from drug-resistant epilepsy (DRE), and stratify AE subtypes., Methods: This study recruited 238 patients: 162 with DRE and 76 AE, including 27 with contactin-associated protein-like 2 (CASPR2), 29 with leucine-rich glioma inactivated 1 (LGI1) and 20 with N-methyl-d-aspartate receptor (NMDAR) antibodies. Plasma samples across the groups were analyzed using NMR spectroscopy and compared with multivariate statistical techniques, such as orthogonal partial least squares discriminant analysis (OPLS-DA)., Results: The OPLS-DA model successfully distinguished AE from DRE patients with a high predictive accuracy of 87.0 ± 3.1% (87.9 ± 3.4% sensitivity and 86.3 ± 3.6% specificity). Further, pairwise OPLS-DA models were able to stratify the three AE subtypes. Plasma metabolomic signatures of AE included decreased high-density lipoprotein (HDL, -(CH 2 ) n -, -CH 3 ), phosphatidylcholine and albumin (lysyl moiety). AE subtype-specific metabolomic signatures were also observed, with increased lactate in CASPR2, increased lactate, glucose, and decreased unsaturated fatty acids (UFA, -CH 2 CH=) in LGI1, and increased glycoprotein A (GlycA) in NMDAR-antibody patients., Interpretation: This study presents the first non-antibody-based biomarker for differentiating DRE, AE and AE subtypes. These metabolomics signatures underscore the potential relevance of lipid metabolism and glucose regulation in these neurological disorders, offering a promising adjunct to facilitate the diagnosis and therapeutics., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

IFN-signaling gene (ISG) expression scores are potential markers of inflammation with significance from cancer to genetic syndromes. In Aicardi Goutières Syndrome (AGS), a disorder of abnormal DNA and RNA metabolism, this score has potential as a diagnostic biomarker, although the approach to ISG calculation has not been standardized or validated. To optimize ISG calculation and validate ISG as a diagnostic biomarker, mRNA levels of 36 type I IFN response genes were quantified from 997 samples (including 334 AGS), and samples were randomized into training and test data sets. An independent validation cohort (n = 122) was also collected. ISGs were calculated using all potential combinations up to 6 genes. A 4-gene approach (IFI44L, IFI27, USP18, IFI6) was the best-performing model (AUC of 0.8872 [training data set], 0.9245 [test data set]). The majority of top-performing gene combinations included IFI44L. Performance of IFI44L alone was 0.8762 (training data set) and 0.9580 (test data set) by AUC. The top approaches were able to discriminate individuals with genetic interferonopathy from control samples. This study validates the context of use for the ISG score as a diagnostic biomarker and underscores the importance of IFI44L in diagnosis of genetic interferonopathies.

Autoimmune conditions underlie some cases of psychosis. Scientists are expanding their search for patients, who often benefit from treatment.

Autoimmune encephalitis due to glial fibrillar acidic protein (GFAP) astrocytopathy is a rare cause of subacute neuropsychiatric changes. In this case, a young patient presented with a viral prodrome and meningismus, followed by progressive encephalopathy and movement disorders over the span of 2 weeks. Due to his clinical trajectory, inflammatory cerebrospinal fluid (CSF) analysis, initial normal brain imaging and negative serum autoimmune encephalopathy panel, his initial diagnosis was presumed viral meningoencephalitis. The recurrence and progression of neuropsychiatric symptoms and myoclonus despite antiviral treatment prompted further investigation, inclusive of testing for CSF autoimmune encephalopathy autoantibodies, yielding a clinically meaningful, positive GFAP autoantibody. This case highlights the importance of appropriately testing both serum and CSF autoantibodies when an autoimmune encephalitic process is considered. Through this case, we review the clinical and radiographic manifestations of GFAP astrocytopathy, alongside notable pearls pertaining to this autoantibody syndrome and its management., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

A Caucasian male in his 60s presented with acute onset of dizziness, dysarthria, and gait ataxia. Upon extensive workup, positive findings were cerebrospinal fluid (CSF) showing lymphocytic pleocytosis with oligoclonal bands, positive celiac disease autoantibodies in blood, a duodenal biopsy indicating lymphocytic infiltration, and positive anti-mGluR1 antibody titers in CSF. The patient was started on a strict gluten-free diet and intravenous immunoglobulin therapy for 5 days and showed mild consecutive improvements each day of treatment. He was discharged after 22 days, and was encouraged to continue gluten adherence, physical and speech therapy, and follow up with neuroimmunology. This report demonstrates that autoimmune encephalitis due to anti-mGluR1antibodies and gluten ataxia are both immune-mediated disorders that should be considered in acute cerebellar ataxia cases. By broadening the differential diagnosis and a comprehensive CSF analysis, identification of gluten ataxia and autoimmune encephalitis were beneficial in the management of this particular patient., (Copyright© South Dakota State Medical Association.)

Autoimmune nodopathy (AN), a newly established category of autoimmune disease, refers to an immune-mediated neuropathy associated with development of autoantibodies against membrane proteins, including neurofascin 186, neurofascin 155, contactin-1, and contactin-associated protein 1 located in the nodes of Ranvier or paranodes. Subclass analysis of these autoantibodies reveals predominant elevation of immunoglobulin (G4. Patients with AN show clinical and laboratory characteristics such as distal-predominant sensorimotor disturbance, sensory ataxia, poor response to intravenous immunoglobulin, and highly elevated cerebrospinal fluid protein levels. B cell-depletion therapy using an anti-CD20 monoclonal antibody is effective for patients with AN. Autoantibody measurement is beneficial not only for diagnosis but also for deciding treatment strategies for AN.

Objective: The differential diagnosis between autoimmune glial fibrillary acidic protein astrocytopathy (AGFAPA) mimicking tuberculous meningitis and tuberculous meningitis (TBM) remains challenging in clinical practice. This study aims to identify the clinical, laboratory parameters, and clinical score systems that may be helpful in differentiating AGFAPA from TBM., Method: Overall 22 AGFAPA patients who were initially misdiagnosed as TBM (AGFAPA-TBM) and 30 confirmed TBM patients were included. The clinical, laboratory, imaging parameters, Thwaites systems, and Lancet consensus scoring systems (LCSS) of all patients were reviewed. Logistic regression was employed to establish a diagnostic formula to differentiate AGFAPA-TBM from TBM. The receiver operating characteristic (ROC) curve was applied to determine the best diagnostic critical point of the formula., Results: Urinary retention was more frequent in AGFAPA-TBM patients (72.7% vs 33.3%, p = 0.012). A significantly lower ratio of T-SPOT. TB was noted in AGFAPA-TBM patients (9.1% vs 82.1%, p < 0.001). We found the LCSS was able to differentiate AGFAPA-TBM from TBM (AUC value 0.918, 95% CI=0.897-0.924). Furthermore, we set up a new scoring system with three variables: urinary retention, T-SPOT. TB, and cerebral imaging criteria in LCSS. The proposed diagnostic score ranges from -8 to 2, and a score of ≥ 0 was suggestive of AGFAPA-TBM (AUC value 0.938, 95% CI=0.878-0.951)., Conclusions: This study is the first to evaluate the Thwaites system and LCSS in AGFAPA-TBM and TBM. We provide an alternative diagnostic formula to differentiate AGFAPA-TBM from TBM and suggest testing for GFAP antibodies to avoid misdiagnosis when this scoring system meets AGFAPA-TBM., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Autoimmune autonomic ganglionopathy (AAG) and acute autonomic sensory neuropathy (AASN) are immune-mediated neuropathies that affect the autonomic and/or dorsal root ganglia. Autoantibodies against the nicotinic ganglionic acetylcholine receptor (gAChR) detected in the sera of patients with AAG play a key role in the pathogenesis of this condition. Notably, gAChR antibodies are not detected in the sera of patients with AASN. Currently, AAG and AASN are not considered to be on the same spectrum with regard to disease concept based on clinical symptoms and laboratory findings. However, extra-autonomic brain symptoms (including psychiatric symptoms and personality changes) and endocrine disorders occur in both diseases, which suggests shared pathophysiology between the two conditions.

Objective: To delineate the clinical characteristics of antibody-negative autoimmune encephalitis (AE) and to investigate factors associated with long-term outcomes among antibody-negative AE., Methods: Patients diagnosed with antibody-negative AE were recruited from January 2016 to December 2022 at the Second Xiangya Hospital of Central South University. The study assessed the long-term outcomes of antibody-negative AE using the modified Rankin scale (mRS) and the Clinical Assessment Scale in Autoimmune Encephalitis (CASE). Predictors influencing long-term outcomes were subsequently analyzed. External validation of RAPID scores (refractory status epilepticus [RSE], age of onset ≥60 years, ANPRA [antibody-negative probable autoimmune encephalitis], infratentorial involvement, and delay of immunotherapy ≥1 month) was performed., Results: In total, 100 (47 females and 53 males) antibody-negative AE patients were enrolled in this study, with approximately 49 (49%) experiencing unfavorable long-term outcomes (mRS scores ≥3). Antibody-negative AE was subcategorized into ANPRA, autoimmune limbic encephalitis (LE), and acute disseminated encephalomyelitis (ADEM). Psychiatric symptoms were prevalent in LE and ANPRA subtypes, while weakness and gait instability/dystonia were predominant in the ADEM subtype. Higher peak CASE scores (odds ratio [OR] 1.846, 95% confidence interval [CI]: 1.163-2.930, p = 0.009) and initiating immunotherapy within 30 days (OR 0.210, 95% CI: 0.046-0.948, p = 0.042) were correlated with long-term outcomes. Receiver operating characteristic (ROC) analysis returned that the RAPID scores cutoff of 1.5 best discriminated the group with poor long-term outcomes (sensitivity 85.7%, specificity 56.9%)., Interpretation: The ANPRA subtype exhibited poorer long-term outcomes compared to LE and ADEM subtypes, and early immunotherapy was crucial for improving long-term outcomes in antibody-negative AE. The use of RAPID scoring could aid in guiding clinical decision making., (© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Purpose of Review: The present review summarizes the diagnostic approach to autoimmune encephalitis (AE) in the intensive care unit (ICU) and provides practical guidance on therapeutic management., Recent Findings: Autoimmune encephalitis represents a group of immune-mediated brain diseases associated with antibodies that are pathogenic against central nervous system proteins. Recent findings suggests that the diagnosis of AE requires a multidisciplinary approach including appropriate recognition of common clinical syndromes, brain imaging and electroencephalography to confirm focal pathology, and cerebrospinal fluid and serum tests to rule out common brain infections, and to detect autoantibodies. ICU admission may be necessary at AE onset because of altered mental status, refractory seizures, and/or dysautonomia. Early management in ICU includes prompt initiation of immunotherapy, detection and treatment of seizures, and supportive care with neuromonitoring. In parallel, screening for neoplasm should be systematically performed. Despite severe presentation, epidemiological studies suggest that functional recovery is likely under appropriate therapy, even after prolonged ICU stays., Conclusion: AE and related disorders are increasingly recognized in the ICU population. Critical care physicians should be aware of these conditions and consider them early in the differential diagnosis of patients presenting with unexplained encephalopathy. A multidisciplinary approach is mandatory for diagnosis, ICU management, specific therapy, and prognostication., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

A rapidly expanding repertoire of neural antibody biomarkers exists for autoimmune central nervous system (CNS) disorders. Following clinical recognition of an autoimmune CNS disorder, the detection of a neural antibody facilitates diagnosis and informs prognosis and management. This review considers the phenotypes, diagnostic assay methodologies, and clinical utility of neural antibodies in autoimmune CNS disorders. Autoimmune CNS disorders may present with a diverse range of clinical features. Clinical phenotype should inform the neural antibodies selected for testing via the use of phenotype-specific panels. Both serum and cerebrospinal fluid (CSF) are preferred in the vast majority of cases but for some analytes either CSF (e.g. N-methyl-D-aspartate receptor [NMDA-R] IgG) or serum (e.g. aquaporin-4 [AQP4] IgG) specimens may be preferred. Screening using 2 methods is recommended for most analytes, particularly paraneoplastic antibodies. We utilize murine tissue-based indirect immunofluorescence assay (TIFA) with subsequent confirmatory protein-specific testing. The cellular location of the target antigen informs choice of confirmatory diagnostic assay (e.g. blot for intracellular antigens such as Hu; cell-based assay for cell surface targets such as leucine-rich glioma inactivated 1 [LGI1]). Titers of positive results have limited diagnostic utility with the exception of glutamic acid decarboxylase (GAD) 65 IgG autoimmunity, which is associated with neurological disease at higher values. While novel antibodies are typically discovered using established techniques such as TIFA and immunoprecipitation-mass spectrometry, more recent high-throughput molecular technologies (such as protein microarray and phage-display immunoprecipitation sequencing) may expedite the process of antibody discovery. Individual neural antibodies inform the clinician regarding the clinical associations, oncological risk stratification and tumor histology, the likely prognosis, and immunotherapy choice. In the era of neural antibody biomarkers for autoimmune CNS disorders, access to appropriate laboratory assays for neural antibodies is of critical importance in the diagnosis and management of these disorders., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr Gilligan is funded by the Irish Clinical Academic Training (ICAT) Programme, supported by the Wellcome Trust and the Health Research Board (Grant Number 203930/B/16/Z), the Health Service Executive National Doctors Training and Planning and the Health and Social Care, Research and Development Division, Northern Ireland. Dr Gilligan has a patent pending for CAMKV-IgG. Dr. McGuigan reports no disclosures. Dr. McKeon is funded by grants from NIH (RO1NS126227, U01NS120901), and has consulted for Janssen and Roche Pharmaceuticals without personal compensation. Dr. McKeon has patents for Septin-5-IgG and Septin-7-IgG licensed to Euroimmun, a patent for GFAP-IgG issued, a patent for MAP1B-IgG with royalties paid to himself and licensed to Ravo Diagnostika, and patents for CAMKV-IgG, KLCHL11-IgG and PDE10A-IgG pending., (Copyright © 2024. Published by Elsevier Inc.)

Detection of neuronal antibodies for autoimmune encephalitis and paraneoplastic neurological syndromes relies on commercially available cell-based assays and lineblots. However, lineblots may reveal the presence of neuronal antibodies in patients with various non-autoimmune etiologies. Herein we describe patients with non-autoimmune etiologies (cohort B) and detectable neuronal antibodies and compare them to definite cases of autoimmune encephalitis (cohort A) for differences in clinical data. All patients positive for at least one neuronal antibody were retrospectively evaluated for autoimmune encephalitis and/or paraneoplastic neurological syndrome between 2016 and 2022. 39 cases in cohort B and 23 in cohort A were identified. In cohort B, most common diagnoses were neurodegenerative disorders in 9/39 (23.1%), brain tumors in 6/39 (15.4%) while most common detected antibodies were anti-titin (N10), anti-recoverin (N11), anti-Yo (N8) and all were detected in serum only. Differential aspects between cohort A and B were CSF pleocytosis (14/23 (60.8%) vs 11/35 (31.4%), p = 0.042, respectively), MRI features suggestive of encephalitis (6/23 (26.1%) vs 0 (0%), p = 0.002, respectively) and epilepsy restricted to temporal lobes (14/23 (60.9%) vs 2/30 (6.7%), p = 0.0003, respectively). A large proportion of lineblot results were non-specific when only serum was tested and were frequently found in non-autoimmune neurological conditions., (© 2024. The Author(s).)

Competing Interests: Dr. Dutra received a grant from Laboratório Fleury for the Brazilian Autoimmune Encephalitis Network and for the Brain Registry study (Brazilian Registry on Autoimmune Encephalitis).

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy was described for the first time in 2016. The most common clinical manifestation is meningoencephalomyelitis associated with a characteristic imaging pattern that allows diagnostic suspicion and its confirmation through determination of antibodies in serum and cerebrospinal fluid (CSF). We present a case of a 35-year-old patient with involvement of the central and peripheral nervous system and a recent diagnosis of thyroid cancer, which compared to the compatible clinical picture of meningoencephalomyelitis, characteristic findings on MRI and after the exclusion of alternative pathologies, we finally arrived at the diagnosis by the positive determination of anti-GFAP in CSF. The patient underwent surgical treatment and radioactive iodine for the diagnosed thyroid tumor and she subsequently received treatment with corticosteroids with partial improvement of the neurological symptomatology. We emphasize that in this pathology the MRI images usually depict a characteristic pattern, although not pathognomonic, it is necessary to consider other causes. Before a high suspicion of this entity due to the clinical and imaging picture, it is convenient to measure the antibody in CSF, given the greater sensitivity and specificity compared to its serum screening, in order to arrive to the definitive etiological diagnosis as it was done in the clinical case that is presented.

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., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

A 6-year-old female with a history of Aicardi-Goutières syndrome (AGS) presented to dermatology clinic with hypopigmented and hyperpigmented macules and patches consistent with dyschromatosis symmetrica hereditaria (DSH). Previous genetic workup demonstrated a de novo, heterozygous mutation in the adenosine deaminase acting on RNA 1 (ADAR) gene. While the co-occurrence of AGS and DSH has previously been described in mutations of the ADAR gene, our case highlights the potential association between these disorders that may aid in earlier future diagnosis of AGS., (© 2023 Wiley Periodicals LLC.)

Autoimmune encephalitis (AE) is a group of inflammatory conditions that can associate with the presence of antibodies directed to neuronal intracellular, or cell surface antigens. These disorders are increasingly recognized as an important differential diagnosis of infectious encephalitis and of other common neuropsychiatric conditions. Autoantibody diagnostics plays a pivotal role for accurate diagnosis of AE, which is of utmost importance for the prompt recognition and early treatment. Several AE subgroups can be identified, either according to the prominent clinical phenotype, presence of a concomitant tumor, or type of neuronal autoantibody, and recent diagnostic criteria have provided important insights into AE classification. Antibodies to neuronal intracellular antigens typically associate with paraneoplastic neurological syndromes and poor prognosis, whereas antibodies to synaptic/neuronal cell surface antigens characterize many AE subtypes that associate with tumors less frequently, and that are often immunotherapy-responsive. In addition to the general features of AE, we review current knowledge on the pathogenic mechanisms underlying these disorders, focusing mainly on the potential role of neuronal antibodies in the most frequent conditions, and highlight current theories and controversies. Then, we dissect the crucial aspects of the laboratory diagnostics of neuronal antibodies, which represents an actual challenge for both pathologists and neurologists. Indeed, this diagnostics entails technical difficulties, along with particularly interesting novel features and pitfalls. The novelties especially apply to the wide range of assays used, including specific tissue-based and cell-based assays. These assays can be developed in-house, usually in specialized laboratories, or are commercially available. They are widely used in clinical immunology and in clinical chemistry laboratories, with relevant differences in analytic performance. Indeed, several data indicate that in-house assays could perform better than commercial kits, notwithstanding that the former are based on non-standardized protocols. Moreover, they need expertise and laboratory facilities usually unavailable in clinical chemistry laboratories. Together with the data of the literature, we critically evaluate the analytical performance of the in-house vs commercial kit-based approach. Finally, we propose an algorithm aimed at integrating the present strategies of the laboratory diagnostics in AE for the best clinical management of patients with these disorders.