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Autoimmune encephalitis is a relatively novel nosological entity characterized by an immune-mediated damage of the central nervous system. While originally described as a paraneoplastic inflammatory phenomenon affecting limbic structures, numerous instances of non-paraneoplastic pathogenesis, as well as extra-limbic involvement, have been characterized. Given the wide spectrum of insidious clinical presentations ranging from cognitive impairment to psychiatric symptoms or seizures, it is crucial to raise awareness about this disease category. In fact, an early diagnosis can be dramatically beneficial for the prognosis both to achieve an early therapeutic intervention and to detect a potential underlying malignancy. In this scenario, the radiologist can be the first to pose the hypothesis of autoimmune encephalitis and refer the patient to a comprehensive diagnostic work-up - including clinical, serological, and neurophysiological assessments.In this article, we illustrate the main radiological characteristics of autoimmune encephalitis and its subtypes, including the typical limbic presentation, the features of extra-limbic involvement, and also peculiar imaging findings. In addition, we review the most relevant alternative diagnoses that should be considered, ranging from other encephalitides to neoplasms, vascular conditions, and post-seizure alterations. Finally, we discuss the most appropriate imaging diagnostic work-up, also proposing a suggested MRI protocol.

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. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. • Kappa index was >3 in half of patients with a diagnosis of autoimmune encephalitis. • It was more sensitive to detect immunoglobulin intrathecal synthesis than OCB. • In 3 patients it was the only altered CSF parameter suggestive of CNS inflammation. • Kappa index could support the diagnosis in suspected autoimmune encephalitis. [ABSTRACT FROM AUTHOR]

• Neuronal surface antibodies are relatively frequent in patients with neurodegenerative disorders. • An unclassified diagnosis and an irregular progression predicted seropositivity. • Seropositivity was associated with ataxia, reflex myoclonus and sleep disorders. • Less than a half of seropositive cases met a priori the current criteria for autoimmune encephalitis. • There may be a proportion of cases of neurodegenerative diseases who could respond to immunotherapies. Autoimmune encephalitis due to antibodies against neuronal surface antigens (NSA-Ab) frequently presents with cognitive impairment, often as the first and prevalent manifestation, but few studies have systematically assessed the frequency of NSA-Ab in consecutive patients with established neurodegenerative disorders. We studied sera of 93 patients (41F, 52 M), aged 69.2 ± 9.4 years, with neurodegenerative conditions, and of 50 population controls aged over 60 years. Specific NSA-Abs were investigated by antigen-specific cell-based assays (CBAs). After testing, we evaluated the association between the NSA-Abs and clinical, CSF and radiological features. The patients included 13/93 (13.8%) who had specific antibodies to neuronal surface antigens: 6 GlyR, 3 GABA A R (1 also positive for AMPAR), 2 LGI1, 1 CASPR2 and 1 GABA B R. One of the 50 controls (2%) was positive for NMDAR antibody and the others were negative on all tests (P = 0.020). No difference was observed in antibody frequency between patients presenting with parkinsonism and those presenting with dementia (P = 0.55); however, NSA-Ab were more frequent in those with unclassified forms of dementia (5/13, 38.5%) than in those with unclassified parkinsonism (2/9, 22.2%) or with classified forms of dementia (4/43, 9.3%) or parkinsonism (2/28, 7.1%) (P = 0.03). A logistic regression analysis demonstrated that an unclassified diagnosis (P = 0.02) and an irregular progression (P = 0.024) were predictors of seropositive status. NSA-Abs are relatively frequent in patients with neurodegenerative disorders, particularly in those with an irregular disease progression of atypical clinical features, inconsistent with a recognized diagnosis. The significance of these antibodies and their possible primary or secondary roles need to be investigated in prospective studies. [ABSTRACT FROM AUTHOR]

• New dopa-responsive phenotype expands the spectrum of GlyR antibody-associated PERM syndrome. • Appendicular rigidity with axial hypotonia and oculomotor abnormalities suggested hypodopaminergic tone. • Downstream effects GlyR antibody may interfere with the dopamine network. [ABSTRACT FROM AUTHOR]

Introduction: N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most common autoimmune encephalitis due to autoantibodies against neuronal surface antigens, can affect both children and adults, leading to neurological and neuropsychological sequelae. However, it is potentially treatable and the prompt start of immunotherapy associates with better prognosis. Conversely, misdiagnosis can be harmful. The detection of NMDAR antibodies in serum and cerebrospinal fluid plays a pivotal role in the diagnostic work-up. Reliable methods for NMDAR antibody detection are thus fundamental to assure accurate diagnosis and allow early treatments. Areas covered: This review recapitulates the pathogenic mechanisms of NMDAR encephalitis as a model of antibody mediated synaptopathy, and gives insights into the related state-of-the-art laboratory testing. The differences in clinical presentations, tumor associations and responses to treatments between adults and children are also described. Expert commentary: The relevance of NMDAR encephalitis has placed neuroimmunology laboratories in a crucial position, but methods for NMDAR antibody detection are awaiting thorough and consensus-based standardizations. In the next few years, this process, along with novel insights into the pathogenic mechanisms, could improve the disease management and clarify the still pending role of NMDAR antibodies in healthy people and in other more common neuropsychiatric disorders. [ABSTRACT FROM PUBLISHER]

Abstract We describe the case of a woman with Parkinson disease who developed an N -methyl- d -aspartate receptor antibody-mediated encephalitis. As a novelty, the encephalitis presentation mimicked a worsening of the pre-existing extrapyramidal syndrome, manifesting mainly as severe bradykinesia and, eventually, akinesia. Brain MRI was normal, whereas cerebrospinal fluid (CSF) analysis disclosed unique-to-CSF oligoclonal bands. Prompt identification and timely immunotherapy led to a complete recovery. [ABSTRACT FROM AUTHOR]

Objectives : In this retrospective multicenter study, we evaluated the safety of SARS-CoV-2 vaccination in patients harboring autoantibodies targeting neuronal surface and/or synaptic antigens. Methods : From eight Italian Neurology Units, we included patients with: a) serum and/or CSF positivity for specific neuronal autoantibodies; b) a compatible neurological syndrome; and c) available follow-up ≥6 weeks after vaccination with any of the approved SARS-CoV-2 vaccines. Demographics, clinical data, and information regarding previous SARS-CoV-2 infection and vaccination were collected. Disease relapses were considered "post-infectious" or "post-vaccination" when occurring within 6 weeks from infection/vaccination. Results : We included 66 patients; 7/66 (11%) had a previous history of SARS-CoV-2 infection and 1/7 (14%) had post-infection relapses. BNT162b2-Pfizer-BioNTec was administered in 55 cases (83.3%) and mRNA-1273-Moderna in 11 (16.7%). The median number of doses administered per patient was 2 (1–3) and >50% of patients did not experience side effects. Five patients (8%) had post-vaccination relapses (seizure 3/5); 4/5 improved after immunotherapy, while one did not receive immunotherapy and worsened. Patients with post-vaccination relapses had higher disability scores at vaccination (p = 0.025), a trend favoring Leucine-rich glioma-inactivated protein 1 LGI1 glutamic acid decarboxylase 65 (GAD65) antibodies (p = 0.054) and shorter time from last relapse (p = 0.057). Discussion : Our data support the safety of SARS-CoV-2 vaccines in patients with neurological disorders associated with antibodies to neuronal and synaptic antigens. [ABSTRACT FROM AUTHOR]

Background: Anti-N-methyl-d-aspartate receptor encephalitis is a central nervous system inflammatory autoimmune disease affecting adults and children. The use of first- and second-line immunotherapies is supported. Recent reports suggest the efficacy of bortezomib in severe anti-N-methyl-d-aspartate encephalitis in adult patients not responsive to second-line treatment; there are no data about pediatric patients.Patient Description: We describe an eight-year-old child with anti-N-methyl-d-aspartate encephalitis not responsive to first- and second-line treatments who experienced marked clinical improvement after bortezomib administration.Discussion: Bortezomib is a selective and reversible inhibitor of the 26S proteasome, which is used to treat oncologic and rare autoimmune disorders in pediatric patients. As observed in adult patients, bortezomib administration induced anti-N-methyl-d-aspartate antibody titer decline and clinical improvement with an acceptable risk profile.Conclusion: This is the first report of the use of bortezomib in children with anti-N-methyl-d-aspartate encephalitis; it could be a useful therapeutic option in children with refractory anti-N-methyl-d-aspartate encephalitis. [ABSTRACT FROM AUTHOR]