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Autoimmune encephalitis

Autoimmune encephalitis is a group of rare, immune-mediated disorders characterized by the production of autoantibodies that target neuronal cell surface or synaptic proteins, resulting in and subacute neurological dysfunction. First systematically described in 2007 with the identification of anti-NMDAR encephalitis, these conditions mimic infectious but arise from the body's misguided immune attack on healthy tissue, often leading to symptoms such as seizures, impairment, psychiatric disturbances, and altered . Unlike traditional encephalitis caused by viruses, autoimmune forms are potentially reversible with prompt , though delays can result in severe complications including or . The most common subtype, anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, accounts for a significant portion of cases and predominantly affects young women, with an estimated annual incidence of 0.1 to 0.8 per 100,000 population. It often presents with prodromal symptoms like or fever, progressing to prominent psychiatric features such as , agitation, or catatonia, followed by seizures, dyskinesias, and autonomic instability. Other variants include anti-LGI1 and anti-CASPR2 encephalitides, which may involve with memory loss and , or GABAergic receptor antibodies linked to refractory seizures. Paraneoplastic forms, associated with underlying tumors like ovarian teratomas (in up to 38% of anti-NMDAR cases), underscore the need for oncologic evaluation. Etiologically, autoimmune encephalitis can be triggered by infections (e.g., ), malignancies, or idiopathic factors, with genetic predispositions like specific HLA alleles contributing to production. relies on clinical presentation, analysis showing pleocytosis or , detection of specific autoantibodies via serum or CSF testing, revealing epileptiform activity, and that may demonstrate limbic or multifocal signal changes. Early recognition is critical, as —typically involving corticosteroids, intravenous immunoglobulin, plasma exchange, or rituximab—can lead to substantial recovery in over 80% of patients when initiated promptly. Long-term management may include tumor resection if applicable and monitoring for relapses, which occur in up to 20% of cases.

Introduction

Definition and Overview

Autoimmune encephalitis (AE) is a group of immune-mediated inflammatory disorders affecting the parenchyma, characterized by the production of autoantibodies that target neuronal surface antigens or synaptic proteins, resulting in disrupted neuronal function and clinical manifestations of . These autoantibodies, often of the IgG class, bind to extracellular epitopes on proteins such as ionotropic or metabotropic receptors, leading to receptor , crosslinking, or , which impairs synaptic without causing permanent neuronal in most cases. Unlike intracellular antigen-targeted antibodies, those against surface proteins are typically associated with a more reversible course due to their direct pathogenic role in antibody-mediated mechanisms. The core features of AE include an acute or subacute onset over days to weeks, frequently presenting with cognitive deficits, behavioral changes, or seizures, and a potential for substantial recovery with prompt such as corticosteroids, intravenous immunoglobulin, or plasma exchange. In certain subtypes, known as paraneoplastic AE, the condition arises in association with underlying tumors, such as ovarian teratomas in anti-NMDAR encephalitis, where tumor removal can enhance treatment response. This reversibility distinguishes AE from many chronic inflammatory or degenerative processes, as early intervention often halts progression and promotes neurological improvement in up to 80% of patients. AE must be differentiated from infectious encephalitides, such as encephalitis, which involve direct pathogen invasion and typically feature prominent fever, higher pleocytosis, and abnormalities, whereas AE often lacks systemic infection signs and responds to rather than antimicrobials. In contrast to neurodegenerative diseases like Alzheimer's or , AE is usually monophasic or relapsing-remitting, with yielding functional recovery rather than inexorable decline. The recognition of AE as a distinct entity emerged in the early 2000s, with the seminal description of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in 2007, marking the first well-characterized antibody-associated form and spurring identification of over 20 additional autoantibody types targeting diverse neuronal proteins. This expansion has transformed AE from a rare paraneoplastic syndrome into a broader category of treatable disorders, emphasizing the importance of antibody testing in unexplained encephalopathies.

Historical Development

The concept of autoimmune encephalitis emerged from early observations of inflammatory brain disorders linked to underlying malignancies, now recognized as paraneoplastic syndromes. In 1960, Brierley and colleagues described subacute encephalitis primarily affecting the limbic areas in adults, characterized by memory loss, seizures, and psychiatric symptoms, often in association with or other tumors, though the autoimmune basis was not yet understood. These cases were initially attributed to direct oncogenic effects or undefined toxic mechanisms rather than immune-mediated processes, with further reports in the 1970s and 1980s reinforcing the paraneoplastic connection, particularly with small cell . Breakthroughs in the and identified specific autoantibodies targeting intracellular neuronal proteins, marking the shift toward recognizing autoimmune contributions in paraneoplastic . In 1986, Graus and colleagues discovered anti-Hu antibodies in patients with sensory neuronopathy and associated with , establishing them as a serological marker for paraneoplastic syndromes. Similarly, anti-Ma antibodies were identified in the early in cases of and brainstem involvement linked to testicular or other tumors, further delineating immune-mediated neuronal damage. These intracellular antibodies primarily highlighted paraneoplastic contexts, with limited treatment responses due to their association with irreversible neuronal destruction. A occurred in 2007 when Dalmau and colleagues reported anti-N-methyl-D-aspartate receptor (NMDAR) antibodies as the first identified neuronal surface autoantibodies causing encephalitis, often in young women without tumors but sometimes paraneoplastic with ovarian teratomas. This discovery expanded the spectrum to include non-paraneoplastic autoimmune encephalitis (AE), emphasizing reversible synaptic dysfunction and immunotherapy responsiveness. In the , recognition grew with identification of additional surface antibodies (e.g., against LGI1 and CASPR2) and the establishment of diagnostic criteria; notably, Graus et al. proposed international guidelines in 2016 for possible, probable, and definite AE, integrating clinical, imaging, and CSF findings to standardize diagnosis beyond antibody specificity. Recent advances as of 2025 have addressed diagnostic challenges in seronegative AE through multi-omics approaches, including of , revealing patterns of immune dysregulation and neuronal injury that aid even without detectable . Additionally, post-infectious triggers have gained prominence, with growing evidence linking infection to AE onset via molecular mimicry or bystander activation, as evidenced by systematic reviews of cases from 2020 onward showing anti-NMDAR and other antibody-positive encephalitis following COVID-19. Ongoing clinical trials as of 2025 focus on neural surface AE, while emerging therapies such as have shown promise in cases.

Epidemiology

Incidence and Prevalence

Autoimmune encephalitis (AE) is a rare but increasingly recognized condition, with an estimated annual incidence of 0.8 to 1.0 cases per 100,000 person-years in adults based on population-based studies from high-income regions. In pediatric populations, the overall incidence of AE appears higher relative to specific subtypes, reaching up to 7.0 cases per million children per year, though data remain limited due to diagnostic challenges. For anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, the most prevalent subtype, the incidence is approximately 1.5 cases per million individuals annually, with a higher relative frequency in children and adolescents, where it accounts for 50-80% of pediatric AE cases and has an estimated incidence of 0.85 to 4.2 cases per million children annually in various studies. Among AE subtypes, anti-NMDAR encephalitis represents the most common form, comprising approximately 40% of diagnosed cases across age groups, particularly in younger patients including children and adolescents. In contrast, anti-leucine-rich glioma-inactivated 1 (anti-LGI1) encephalitis is more prevalent in older adults, with a peak incidence between 60 and 70 years and a marked male predominance (roughly 2:1 male-to-female ratio), occurring at an annual rate of about 0.8 to 1.0 cases per million in studied populations. These variations highlight the heterogeneous of AE, influenced by age and antibody specificity. Global reporting of AE is disproportionately higher in and , where advanced diagnostic testing for neuronal antibodies is widely available, leading to incidence estimates of 0.8-1.5 per 100,000 in these areas. In low-resource settings, underdiagnosis is substantial, potentially affecting 50-70% of cases due to limited access to analysis and assays, resulting in many instances being misattributed to infectious or psychiatric etiologies. This disparity underscores the need for improved to capture the true burden. Over the past decade, the reported incidence of has approximately doubled from 2010 to 2020, attributed to heightened clinical , broader testing panels, and inclusion in diagnostic criteria, with some tertiary centers observing a fourfold increase in case detection rates among admitted patients. This trend has continued into the 2020s, with ongoing increases attributed to enhanced testing and , as of 2025. This temporal rise reflects evolving recognition rather than a true surge in occurrence, emphasizing the role of diagnostic advancements in epidemiological trends.

Risk Factors and Demographics

Autoimmune exhibits a bimodal age distribution, with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis predominantly affecting young females aged 15 to 30 years, often associated with ovarian teratomas. In contrast, anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis typically occurs in older adults aged 50 to 70 years. Overall, autoimmune shows a female predominance at a ratio of approximately 2:1, largely driven by the high incidence in females with anti-NMDAR , where the ratio can reach 4:1. However, certain subtypes display male bias, such as anti-contactin-associated protein-like 2 (CASPR2) encephalitis, which affects males in over 90% of cases. Genetic factors play a limited role, with rare family clustering observed in less than 5% of cases, suggesting minimal hereditary transmission. Specific (HLA) associations have been identified in subtypes like anti-IgLON5 disease, where HLA-DRB110:01 and HLA-DQB105:01 haplotypes confer increased risk. Environmental triggers include post-infectious processes, such as encephalitis, which precedes up to 30% of anti-NMDAR cases, and infections in select instances. Paraneoplastic associations occur in 20% to 30% of patients, most commonly with small-cell in older adults. Comorbid autoimmune conditions are present in 10% to 15% of cases, including such as , which co-occurs in about 6% to 8% of certain subtypes like CASPR2 encephalitis. Prior exposure to for other autoimmune disorders has been noted in some seronegative cases, potentially exacerbating vulnerability.

Immune Mechanisms

Autoimmune encephalitis (AE) arises from dysregulated immune responses targeting (CNS) antigens, primarily involving humoral and cellular immunity that disrupts neuronal function. B cells and T cells play central roles, with autoantibodies and cytotoxic T cells mediating tissue damage, often triggered by environmental or neoplastic factors that breach . This leads to an inflammatory cascade involving complement activation, microglial priming, and dysregulation, culminating in synaptic loss and neuronal hyperexcitability. Autoantibody production in AE is driven by B-cell activation, which generates IgG antibodies—predominantly IgG1 and IgG4 subclasses—against neuronal surface antigens such as ion channels or synaptic proteins. These are produced by plasma cells that infiltrate the CNS after breaching the , facilitated by inflammation-induced upregulation of adhesion molecules like and , as well as such as and CCR5. Clonal expansion of CD138+ plasma cells within the compartment sustains intrathecal antibody synthesis, with higher autoantibody titers often detected in CSF compared to serum, underscoring local B-cell maturation in the CNS. T-cell involvement contributes to both initiation and persistence of AE, particularly in paraneoplastic forms. + cytotoxic T cells infiltrate the CNS and induce neuronal through release of and perforin, as observed in cases associated with intracellular antigens like or , where T-cell clusters surround damaged neurons. + T cells differentiate into pro-inflammatory subsets, including Th1 cells producing IFN-γ and TNF-α, and Th17 cells secreting IL-17 to promote permeability and further immune cell recruitment. Dysfunction of regulatory T cells (Tregs), which normally suppress autoreactive responses, correlates with disease severity, as reduced Treg frequencies in CSF are linked to poorer outcomes. Hypotheses for AE triggers include molecular mimicry, where post-viral infections lead to cross-reactive antibodies or T cells targeting neuronal epitopes, as exemplified by triggering anti-NMDA receptor responses. In paraneoplastic AE, tumor antigens (e.g., from ovarian teratomas or small-cell ) elicit immune responses that cross-react with CNS proteins, driving both humoral and cellular . storms, characterized by elevated IL-6 levels, amplify these triggers by enhancing BBB disruption and promoting Th17 differentiation, thereby facilitating autoantibody access to the CNS . The inflammatory cascade in AE begins with autoantibody binding to neuronal targets, activating the via the classical pathway and generating anaphylatoxins like C3a and C5a that recruit immune effectors. This complement activation, evident in anti-GAD65-associated AE, deposits fragments on neurons and exacerbates synaptic disruption. Concurrently, respond to damage-associated molecular patterns by upregulating /II and costimulatory molecules (e.g., CD80/86), amplifying T-cell responses and releasing pro-inflammatory mediators such as TNF-α and , which induce neuronal hyperexcitability and long-term synaptic loss.

Antibody Targets and Neuronal Effects

In autoimmune encephalitis, autoantibodies primarily target neuronal surface proteins, synaptic components, or intracellular antigens, leading to functional disruptions that impair synaptic transmission and neuronal excitability. These antibodies bind to specific epitopes on neuronal proteins, often inducing conformational changes or that alter receptor clustering and signaling pathways. Surface antigens, such as ionotropic glutamate receptors, are commonly affected in antibody-mediated encephalitis. For instance, anti-NMDA receptor antibodies target the GluN1 subunit, promoting crosslinking and subsequent of the receptors, which reduces synaptic density and diminishes NMDA receptor-mediated currents. This disrupts (LTP) and , contributing to cognitive and behavioral deficits. Similarly, anti-AMPA receptor antibodies induce rapid and degradation of GluA1/GluA2 subunits, decreasing AMPAR currents and synaptic AMPA receptor density, which impairs excitatory synaptic transmission and memory formation. Intracellular targets, in contrast, are associated with poorer therapeutic responses due to limited antibody access and persistent immune-mediated damage. Anti-GAD65 antibodies, for example, bind to decarboxylase 65, an critical for synthesis in inhibitory , thereby inhibiting production and reducing inhibitory . This leads to neuronal hyperexcitability and is often linked to refractory and , with showing limited efficacy compared to surface disorders. Synaptic proteins also serve as key targets, disrupting ion channel complexes and nodal structures. Anti-LGI1 antibodies interfere with leucine-rich glioma-inactivated 1 protein, which normally stabilizes presynaptic voltage-gated potassium channels, resulting in channel disassembly and reduced currents that promote neuronal hyperexcitability and faciobrachial dystonic seizures. Anti-CASPR2 antibodies target contactin-associated protein-like 2 at the juxtaparanodal region of the , disrupting potassium channel clustering and altering propagation, which can enhance presynaptic release and contribute to and autonomic instability. Overlapping effects arise from in patient sera, where antibodies may bind multiple antigens, amplifying synaptic dysfunction. This can lead to downstream through glutamate dysregulation, as reduced inhibitory tone or altered receptor trafficking exacerbates calcium influx and neuronal damage across affected circuits.

Clinical Presentation

Core Signs and Symptoms

Autoimmune encephalitis typically presents with a subacute onset of neuropsychiatric and neurological symptoms, reflecting immune-mediated disruption of function. Core manifestations include acute psychiatric features such as , , hallucinations, and behavioral changes, affecting approximately 70-80% of patients across subtypes. impairment and are also prominent, often leading to altered mental status and cognitive deficits that impair daily functioning. These symptoms arise from targeting neuronal surface antigens, resulting in a fluctuating clinical course. Neurological signs are equally central, with seizures occurring in about 70-80% of cases, frequently as focal or generalized events that may progress to . , including dyskinesias, , or , manifest in roughly 40-50% of patients, particularly in . Autonomic instability is common, featuring , blood pressure fluctuations, or in 60-70% of affected individuals, sometimes necessitating intensive care. These features often coexist, contributing to a progressive deterioration if untreated. The disease evolves over days to weeks, with a subacute progression marked by worsening symptoms and potential relapses despite initial stabilization. In adults, limbic-predominant symptoms like and temporal lobe seizures are more typical, whereas pediatric cases emphasize behavioral disturbances alongside prominent seizures and . This age-related variation influences early recognition, as children may present with less overt psychiatric involvement compared to adolescents and adults.

Prodromal and Associated Features

Autoimmune encephalitis often begins with a prodromal characterized by nonspecific symptoms resembling a illness, occurring in approximately 70-80% of cases, particularly in anti-NMDAR encephalitis. These symptoms typically include fever, , malaise, and gastrointestinal disturbances such as , , or , with gastrointestinal symptoms noted in up to 30% of anti-NMDAR cases preceding neurological involvement. The prodromal period generally lasts 1-2 weeks before progression to core neuropsychiatric features like behavioral changes or seizures. In subtypes associated with tumors, such as anti-NMDAR encephalitis in young females, systemic features may include pelvic or abdominal pain from an underlying ovarian , present in about 50% of adult female cases and sometimes manifesting as an early warning sign. For anti-CASPR2 encephalitis, associated features often involve peripheral nerve hyperexcitability manifesting as , with muscle cramps, fasciculations, and , alongside sicca symptoms like dry mouth in cases with overlapping . Extraneural manifestations can extend to multi-organ involvement, though rare, including autonomic instability and peripheral neuropathies. , frequently linked to anti-CASPR2 antibodies, exemplifies this with combined central , severe , and peripheral , affecting up to 40% of anti-CASPR2 patients. In anti-IgLON5 , sleep disorders dominate as an early associated feature, with non-REM and REM parasomnias, , and daytime hypersomnolence occurring in over 80% of cases, often prompting initial evaluation for sleep pathology.

Diagnosis

Clinical Assessment

The clinical assessment of suspected autoimmune encephalitis begins with a detailed history-taking to identify characteristic features and exclude alternative causes. A subacute onset of symptoms, typically progressing over days to weeks (less than 3 months), is a hallmark, often involving deficits, altered mental status, or psychiatric symptoms such as or behavioral changes. Recent infections or tumors should be inquired about as potential triggers, while mimics like drug intoxication, , or metabolic derangements must be ruled out through targeted questioning and initial screening. For instance, a history of recent viral illness or ovarian in young females raises suspicion for anti-NMDAR encephalitis. The neurological examination focuses on detecting objective signs that support an encephalitic process. Altered mental status, ranging from to , is common, alongside new focal findings such as or sensory deficits. Seizures, which may be overt or subclinical, are frequently observed and warrant immediate evaluation; (EEG) is essential to identify epileptiform activity or slowing, particularly in the temporal regions suggestive of limbic involvement. In patients presenting with prominent psychiatric features, the exam may reveal subtle neurological abnormalities like orofacial dyskinesias or autonomic instability, distinguishing autoimmune etiology from primary psychiatric disorders. Diagnostic scoring tools aid in systematizing the assessment. The Graus criteria for probable autoimmune encephalitis require subacute onset of loss, altered mental status, or psychiatric symptoms, plus at least one of the following: new focal findings, seizures, pleocytosis, or abnormalities involving the limbic regions, with reasonable exclusion of alternative causes. These 2016 criteria, refined in 2023 to better address antibody-negative cases by emphasizing substantiated absence of neural antibodies in CSF and , facilitate early recognition and emphasize clinical phenomenology over antibody results initially. Additionally, the Clinical Assessment Scale in Autoimmune Encephalitis (CASE) provides a structured severity score (0-27 points) across nine domains, including seizures, memory dysfunction, psychiatric symptoms, and , helping to quantify impairment and monitor progression during initial evaluation; recent studies as of 2024 continue to validate its utility. Certain red flags in the history and exam heighten suspicion for autoimmune encephalitis, particularly in atypical psychiatric presentations. In young patients, especially females under 30, the combination of acute with like or catatonia strongly prompts consideration of autoimmune causes over primary psychiatric illness, as these features occur frequently in anti-NMDAR cases and often lead to initial psychiatric hospitalization. Other indicators include refractory seizures, autonomic dysregulation (e.g., or temperature instability), or faciobrachial dystonic seizures, which necessitate urgent neurological consultation to avoid diagnostic delays averaging months in unaware settings.

Laboratory and Imaging Methods

Laboratory diagnosis of autoimmune encephalitis relies heavily on cerebrospinal fluid (CSF) analysis, which provides supportive evidence of neuroinflammation. CSF pleocytosis, typically lymphocytic and mild to moderate (5-50 cells/μL), is observed in around 50-60% of cases across various subtypes in reported cohorts, reflecting immune cell infiltration into the central nervous system. Oligoclonal bands, indicative of intrathecal immunoglobulin production, are present in approximately 40-50% of patients in some cohorts, further supporting an autoimmune process. Additionally, intrathecal antibody synthesis, assessed via antibody-specific indices (e.g., anti-NMDAR IgG index), enhances diagnostic specificity by confirming local production of pathogenic autoantibodies rather than passive serum leakage. Detection of specific autoantibodies in serum and CSF remains the cornerstone for confirming autoimmune encephalitis, particularly for neuronal surface antigens. Cell-based assays (CBAs) are the gold for identifying IgG against targets such as the (e.g., NMDA-R IgG), offering high sensitivity of 80-90% when testing both compartments, with CSF demonstrating superior specificity (often >95%) for intrathecal synthesis. These assays involve transfected cells expressing the , allowing visualization of binding via , and are preferred over older methods like due to reduced false positives from cross-reacting . For instance, in anti-NMDAR encephalitis, CSF positivity is nearly always required for definitive , as alone may yield false negatives in up to 20% of cases. Neuroimaging modalities complement laboratory findings by visualizing structural and functional brain changes. Brain MRI, using T2/FLAIR sequences, reveals hyperintensities in limbic structures (e.g., medial temporal lobes, ) in about 60% of patients with limbic-predominant autoimmune encephalitis, though findings may be normal in up to 40% early in the disease course. Fluorodeoxyglucose (FDG-PET) is more sensitive, detecting regional hypometabolism in limbic and extralimbic areas (e.g., temporal lobes, ) in over 70% of cases where MRI is inconclusive, aiding in early and subtype differentiation. Electroencephalography (EEG) provides electrophysiological evidence of and seizures, supporting the in conjunction with clinical criteria. In anti-NMDAR , the characteristic "extreme delta brush" pattern—rhythmic delta oscillations superimposed with beta activity—is seen in approximately 30% of adults, often correlating with disease severity and requiring continuous monitoring for detection. For limbic autoimmune subtypes (e.g., anti-LGI1), focal epileptiform discharges or slowing in temporal regions occur in 50-80% of cases, highlighting irritative and dysfunctional cortical activity.

Treatment

First-Line Immunotherapies

First-line immunotherapies for autoimmune encephalitis aim to rapidly suppress the autoimmune response and prevent irreversible neuronal damage through high-dose , typically initiated soon after to confirm exclusion of infectious mimics. These treatments are standardized across antibody-mediated forms, with selection influenced by factors such as the presence of paraneoplastic tumors and patient-specific contraindications, though core regimens remain consistent regardless of specific targets. Intravenous corticosteroids, such as at 1 g/day for 5 days, represent a of initial due to their potent effects and broad accessibility. This regimen yields clinical improvement in approximately 80% of patients (65% with steroids alone), with response rates up to 75% in non-paraneoplastic cases like anti-LGI1 encephalitis. Intravenous immunoglobulin (IVIG) is administered at 0.4 g/kg/day for 5 days (totaling 2 g/kg), providing passive immunity and modulating B-cell activity to reduce autoantibody production. It is particularly useful when corticosteroids are contraindicated, such as in active infections or psychiatric comorbidities, and achieves comparable efficacy to steroids in many seropositive cases. Plasma exchange serves as an alternative or adjunct, involving 5-7 sessions to remove circulating autoantibodies, especially beneficial in patients with poor peripheral vascular access where IVIG infusion is challenging. It is often reserved for steroid-refractory cases but can be combined upfront in severe presentations for enhanced autoantibody clearance. In paraneoplastic autoimmune encephalitis, prompt tumor management is integral, with surgical resection—such as ovarian removal in anti-NMDAR cases—leading to major neurological improvement in approximately 80% of patients when performed early alongside . with corticosteroids, IVIG, and/or plasma exchange is the standard approach for most patients to maximize response, with initiation ideally within 2-4 weeks of symptom onset to optimize recovery and minimize . Delays beyond 4 weeks are associated with poorer outcomes and higher relapse risk.

Advanced and Supportive Therapies

In cases refractory to first-line immunotherapies, second-line treatments are employed to achieve deeper B-cell depletion or broader . Rituximab, a monoclonal anti-CD20 administered at 375 mg/m² weekly for four doses, is the most commonly used second-line agent, targeting CD20-positive B cells to reduce production and has been shown to improve outcomes in 80-94% of autoimmune encephalitis () patients across major subtypes. , an alkylating agent, is reserved for aggressive or rapidly progressive disease, often combined with rituximab, and functions by inhibiting in rapidly dividing immune cells to suppress ongoing . Emerging biologics target specific inflammatory pathways in refractory AE. , an antagonist, has demonstrated efficacy in cytokine-driven cases unresponsive to rituximab by blocking IL-6-mediated inflammation, with case reports indicating neurological stabilization. Bruton tyrosine kinase (BTK) inhibitors, such as evobrutinib, represent a novel class under investigation in 2020s clinical trials for autoimmune neurological disorders such as , with potential applications to AE by inhibiting B-cell and microglial activation to prevent antibody-mediated neuronal damage. Ongoing trials as of 2025 include a phase 2B study of inebilizumab for anti-NMDAR encephalitis, targeting CD19-positive B cells in refractory cases. Supportive therapies address acute complications and stabilize patients during immunotherapy escalation. Antiepileptic drugs like are first-line for seizure control in AE-associated , providing rapid suppression of hyperexcitability without exacerbating cognitive symptoms. (ICU) management is essential for autonomic instability, such as or cardiorespiratory crises, involving hemodynamic monitoring and to prevent secondary organ damage. For prominent psychiatric features like , multidisciplinary supportive care includes antipsychotics such as to manage and behavioral disturbances, alongside environmental modifications to reduce distress. Relapse prevention strategies are critical given the 20-30% rate observed across AE subtypes, often within the first two years. Long-term maintenance with low-dose corticosteroids or repeated rituximab cycles (e.g., every 6 months) significantly lowers risk by sustaining immune modulation, with rituximab reducing odds by up to 71% in anti-NMDAR encephalitis.

Prognosis

Short-Term Outcomes

In autoimmune encephalitis, first-line immunotherapies such as corticosteroids, intravenous immunoglobulin, or plasma exchange lead to clinical improvement in 70-80% of patients within 1-2 months of initiation, with approximately 50% achieving full recovery during this acute phase. Early response is often marked by resolution of acute symptoms like seizures and behavioral changes, though the pace varies based on disease severity and promptness of intervention. Common early complications include , occurring in about 20-35% of cases and frequently requiring intensive care management, and necessitating , seen in approximately 57% of severe (ICU-admitted) presentations. These complications contribute to prolonged hospital stays but are often reversible with timely supportive care alongside . Factors influencing short-term outcomes are critically tied to treatment timing and underlying etiology; early immunotherapy can reduce mortality, resulting in overall rates of 6%–19% in treated cases, with lower rates in non-paraneoplastic forms (e.g., <10% in anti-NMDAR encephalitis), whereas paraneoplastic forms carry a higher mortality risk of around 20% due to associated tumor progression. Prognosis is routinely monitored using the (mRS), with 60% of patients achieving a good outcome (mRS score 0-2, indicating minimal ) at the 3-month mark.

Long-Term Complications

Autoimmune encephalitis survivors frequently experience enduring cognitive deficits, with and persisting in a substantial proportion of cases. Approximately 40% of patients demonstrate impairments one year after onset, while deficits affect 20% to 60% depending on the specific antibody subtype, such as anti-NMDAR or anti-LGI1 encephalitis. These deficits are often linked to structural changes, including visible on follow-up MRI, which correlates with long-term particularly in limbic-predominant forms like anti-LGI1 encephalitis. Psychiatric sequelae represent another significant long-term burden, with affecting 10% to 40% of patients and (PTSD) reported in up to 21% of survivors across various etiologies. Incomplete or delayed elevates relapse risk by 20% to 30%, potentially worsening these psychiatric outcomes and necessitating ongoing support. Neurological residuals further complicate recovery, including chronic in 15% to 20% of cases—higher among those with intracellular antibodies—and persistent in approximately 10%, such as in anti-DPPX-associated . These issues, including ongoing seizures, can impair and even years post-acute phase. remains diminished for many, with 50% to 70% of patients returning to work or prior activities, though rates tend to be higher in non-paraneoplastic cases due to tumor-related factors. Comprehensive multidisciplinary follow-up is essential to mitigate these impacts and optimize functional recovery.

Classification

Anti-NMDAR Encephalitis

Anti-NMDAR encephalitis is an antibody-mediated form of autoimmune encephalitis defined by the presence of (IgG) autoantibodies targeting the GluN1 subunit of the N-methyl-D-aspartate receptor (NMDAR), which bind to the receptor's extracellular domain and induce its internalization, thereby reducing synaptic NMDAR function. This condition was first systematically described in a series of 100 patients, highlighting its association with ovarian teratomas expressing NMDARs. The disease predominantly affects young females, with 81% of cases occurring in women and a age at onset of 21 years (range 1–85 years), including 37% of patients under 18 years. In a large of 577 patients, 38% had an underlying tumor, most commonly ovarian (94% of tumors), with reaching 54% in females over 18 years but only 4% in children. The classic clinical presentation unfolds in stages: a prodromal with fever, , or flu-like symptoms in 81% of cases, followed by acute onset of psychiatric symptoms such as delusions, hallucinations, , or catatonia in 77%, and then progressive neurological involvement including seizures (80%), orofacial or limb dyskinesias (approximately 60%), memory impairment, language dysfunction, autonomic instability (e.g., , blood pressure lability), and decreased level of consciousness leading to in up to 50%. In severe cases, patients require intensive care, with needed in about 70%. Diagnostic hallmarks include (CSF) analysis showing in 80–90% of patients (often 5–50 cells/μL) with normal-to-mildly elevated protein, and intrathecal synthesis confirmed by cell-based assays, where CSF testing is more sensitive than (detecting 4% CSF-only positives). (EEG) reveals abnormalities in over 80% of cases, typically diffuse slow-wave activity, with the "extreme brush" pattern—rhythmic oscillations superimposed with activity—present in up to 30% of adults, correlating with prolonged illness and dyskinesias but aiding early recognition. Relapses occur in 12–24% of patients within 2 years, more frequently if a persists without removal, often presenting with milder psychiatric or cognitive symptoms. Treatment involves tumor resection when applicable, combined with first-line (corticosteroids, intravenous immunoglobulin, or plasma exchange), leading to improvement in 80% of responsive cases within weeks to months. Second-line agents like rituximab or are used for disease, reducing risk and improving long-term outcomes. In the 577-patient cohort, 81% achieved a good outcome ( score 0–2, indicating no or mild disability) at 24 months, with early tumor removal and initiation associated with better recovery ( 5.38 for response). Pediatric cases show particularly favorable , with over 90% achieving full or near-full recovery due to earlier and lower tumor rates, while overall mortality is 6% from complications like or infections.

Anti-LGI1 and Anti-CASPR2 Encephalitis

Autoimmune encephalitis associated with antibodies against leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) targets components of the voltage-gated potassium channel (VGKC) complex at neuronal synapses, leading to limbic-predominant or mixed central and peripheral neurological syndromes, respectively. These conditions typically affect older adults and respond well to immunotherapy, though relapses and residual deficits can occur. Anti-LGI1 encephalitis primarily involves the limbic system and manifests in approximately 67% of cases in males with a median age of onset around 60 years. Key features include faciobrachial dystonic seizures (FBDS), brief dystonic movements affecting the face and arm, occurring in about 50% of patients often preceding full limbic involvement. Amnesia and cognitive impairment are prominent, with hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion (SIADH) present in roughly 60% of cases. Paraneoplastic associations are uncommon, affecting fewer than 10% of patients, typically without thymoma. In contrast, anti-CASPR2 encephalitis often combines (CNS) and peripheral features, such as (muscle stiffness and twitching) and , characterized by severe insomnia, autonomic dysfunction, hallucinations, and pain. It similarly affects older adults (median age 60 years) with a slight male predominance. is associated in about 10% of cases, higher than in anti-LGI1 disease, though overall paraneoplastic rates remain low at under 20%. Both forms show excellent with early ; approximately 80% of anti-LGI1 patients achieve substantial remission with steroids, though cognitive , particularly , may lag, leaving mild residual issues in about 20% long-term. Anti-CASPR2 cases also respond robustly to first-line treatments like corticosteroids, with rituximab aiding refractory peripheral symptoms, but relapses occur in up to 20%.

Anti-GABA Receptor Encephalitides

Anti-GABA receptor encephalitides encompass two distinct subtypes: anti-GABA-A receptor (GABA-AR) encephalitis and anti-GABA-B receptor (GABA-BR) encephalitis, both characterized by autoantibodies targeting inhibitory receptors in the , leading to prominent epileptic phenotypes. GABA-AR encephalitis often presents as a cytotoxic form with multifocal involvement, particularly affecting children and young adults, while GABA-BR encephalitis typically manifests as in middle-aged or older individuals, with a high paraneoplastic association. These conditions highlight the role of dysfunction in generating refractory seizures and . GABA-AR encephalitis is more common in pediatric patients, comprising about 36% of cases in reviewed series, and features refractory status epilepticus in approximately 80% of affected individuals, often accompanied by , , or . (MRI) typically reveals multifocal T2/FLAIR hyperintense lesions in cortical and subcortical regions without enhancement, indicative of cytotoxic . In contrast, GABA-BR encephalitis predominantly occurs in adults with a age of 52 years, presenting with limbic symptoms such as impairment, behavioral changes, and frequent seizures in nearly all cases (100%), including in up to 35%. Approximately 50% of GABA-BR cases are paraneoplastic, most commonly associated with small cell (SCLC), and MRI shows unilateral or bilateral medial hyperintensities. Both subtypes exhibit poor initial response to antiepileptic drugs (AEDs), underscoring the autoimmune over primary . Diagnosis relies on detecting high-titer antibodies in (CSF), which are more specific than , often with pleocytosis or supporting intrathecal . For GABA-AR encephalitis, CSF antibodies confirm the diagnosis in the context of multifocal MRI abnormalities and refractory seizures unresponsive to standard AEDs. In GABA-BR encephalitis, CSF positivity reaches 100% in reported cohorts, with tumor screening essential given the paraneoplastic link. Early antibody testing is critical, as can exacerbate neurological damage. Treatment begins with first-line immunotherapies such as corticosteroids, intravenous immunoglobulin, or plasma exchange, but many patients require escalation to second-line agents like rituximab due to incomplete responses. In GABA-AR encephalitis, about 31% of cases necessitate second-line , with combination approaches achieving recovery in over 50%. For GABA-BR encephalitis, yields good outcomes in approximately 60% of non-paraneoplastic cases, though tumor-directed is vital when applicable. Delayed treatment increases mortality to 10-15% in both subtypes, primarily from or tumor progression, emphasizing prompt intervention.

Other Antibody-Associated Forms

Autoimmune encephalitis associated with antibodies against less common neuronal targets encompasses a heterogeneous group of disorders, including those targeting the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), (GlyR), dipeptidyl-peptidase-like protein-6 (DPPX), IgLON5, and metabotropic glutamate receptors (mGluR1 or mGluR5). These conditions often present with subacute onset of neurological symptoms involving specific regions or systemic features, and they exhibit variable paraneoplastic associations ranging from 10% to 70% across subtypes, with yielding moderate to good responses in 50% to 80% of cases depending on early intervention and tumor management. Anti-AMPAR encephalitis primarily manifests as characterized by psychiatric disturbances, memory impairment, and confusion, with additional features such as seizures or in some patients. It is paraneoplastic in approximately 70% of cases, most frequently linked to ovarian or breast tumors, though associations with and are also reported. First-line , often combined with tumor removal, results in partial neurological improvement in the majority of patients, but long-term outcomes are guarded, with up to 40% mortality due to relapses or comorbidities. Anti-GlyR encephalitis is typified by progressive with rigidity and (PERM), featuring muscle stiffness, spasms, and (exaggerated startle responses), alongside involvement leading to or respiratory issues. Paraneoplastic associations are uncommon, occurring in fewer than 20% of cases and occasionally tied to or . Patients generally show substantial improvement with prompt , including corticosteroids and intravenous immunoglobulin, achieving remission in over 70% of treated individuals, though relapses can occur. Anti-DPPX encephalitis is distinguished by a prodromal of gastrointestinal , including and prominent (often >10% body weight), followed by multifocal with cognitive decline, tremors, and . Paraneoplastic links are rare, affecting about 10% of patients and primarily involving lymphomas or . induces significant recovery in 60-80% of cases, with reduced scores post-treatment, but up to 20% experience relapses requiring second-line agents like rituximab. Anti-IgLON5 disease presents with a unique combination of sleep disorders (such as non-REM parasomnias, , and ) and bulbar symptoms (, ), often progressing to gait instability, , or , with histopathological overlap to in chronic cases. It is rarely paraneoplastic, with tumors (e.g., or ) identified in only 10-15% of patients, typically post-onset. is poor, with 30-40% mortality and limited response (partial improvement in ~50%), particularly if initiated after the first year of symptoms, due to its neurodegenerative features. Antibodies against mGluR1 or mGluR5 cause with predominant (e.g., , , gait imbalance) in mGluR1 cases, often combined with limbic involvement (, seizures) in mGluR5 variants, and post-infectious triggers (e.g., viral ) reported in up to 25% of patients. Paraneoplastic associations vary, with ~20-50% tumor incidence, including for mGluR5 and for mGluR1. Response to is favorable in 60-80% of cases, with complete recovery in about 20-40%, especially when combined with oncologic therapy, though residual may persist.

Seronegative and Overlapping Syndromes

Seronegative autoimmune encephalitis (AE) encompasses cases that meet established diagnostic criteria for AE but show no detectable neuronal autoantibodies in or (CSF), despite comprehensive testing. These cases are diagnosed as probable seronegative AE under the 2016 Graus criteria, which require subacute onset of deficits, altered mental status, or psychiatric symptoms; speech dysfunction; seizures, faciobrachial dystonic seizures, or hyperexcitability; and supportive findings such as CSF pleocytosis or electroencephalographic abnormalities, with reasonable exclusion of alternative causes. The prevalence of seronegative AE among definite AE diagnoses varies by cohort and testing methodology, ranging from 12% in some hospital-based series to up to 50% in specialized referral centers, reflecting challenges in antibody detection and potential underrecognition of subtle or intracellular targets. Patients often present with features, including memory impairment, confusion, and seizures, but may exhibit heterogeneous syndromes such as or , complicating initial classification. Overlapping syndromes highlight the spectrum of seronegative or partially antibody-associated AE, where additional autoimmune markers or clinical features suggest immune-mediated overlap without classic neuronal antibodies. , for instance, features encephalopathy with high anti-thyroid peroxidase or anti-thyroglobulin antibodies, often mimicking seronegative AE through cognitive decline, seizures, and , and is responsive to steroids despite lacking neuronal autoantibodies. Similarly, involves anti-GQ1b antibodies targeting gangliosides, presenting with acute ophthalmoplegia, , and altered consciousness that overlap with AE features like hypersomnolence and involvement, distinguishing it from pure peripheral variants like Guillain-Barré syndrome. These overlaps underscore the role of non-neuronal antibodies or post-infectious in driving encephalitic presentations. Diagnosis of seronegative AE relies on clinical acumen and ancillary tests due to absent biomarkers. CSF analysis frequently reveals inflammatory markers, including mild pleocytosis (typically 5-50 cells/μL), elevated protein, or , supporting an immune in up to 60% of cases. Brain fluorodeoxyglucose positron emission tomography (FDG-PET) aids in detection, showing characteristic hypometabolism in limbic or multifocal regions even when is normal, with sensitivity exceeding 80% for probable AE. For probable cases, an empiric trial of high-dose corticosteroids (e.g., intravenous 1 g/day for 5 days) is recommended to assess response, often followed by plasma exchange or intravenous immunoglobulin if improvement occurs, as delays in worsen outcomes. Prognosis in seronegative AE mirrors that of seropositive forms when is initiated early, with approximately 57-92% of patients showing clinical improvement and achieving a score of 0-2 at 2-year follow-up, though relapses occur in 10-20% of cases. Early within 3 months of symptom onset is associated with better recovery, but seronegative cases carry a higher risk of initial misdiagnosis as primary psychiatric disorders, such as , leading to delayed care in up to 20% of instances and potential iatrogenic harm from antipsychotics. Long-term sequelae, including cognitive deficits or , affect 30-40% of survivors, emphasizing the need for vigilant monitoring.