Binks SNM(1), Saylor D(2), Easton A(3), Thakur KT(4), Irani SR(5).

# Encephalitis *The Lancet 2026* Seminar Encephalitis Sophie N M Binks, Deanna Saylor, Ava Easton, Kiran T Thakur, Sarosh R Irani Lancet 2026; 407: 1968–83 Brain inflammation secondary to encephalitis is an urgent global emergency and presents multiple opportunities to reduce current substantial morbidity and mortality. Aetiologies can be divided into infectious and autoimmune Nuffield Department of Clinical Neurosciences, University of causes. In this Seminar, we highlight pragmatic clinical approaches to recognise and distinguish the most common Oxford, Oxford, UK pathogenic viruses and emerging range of autoantibodies encountered in routine practice. These pre-test impressions (S N M Binks BMBS DPhil, are judiciously shaped by valuable, simple investigations—particularly serum and cerebrospinal fluid nucleic acid Prof S R Irani FRCP DPhil); Department of Neurology, and autoantibody testing—to identify the precise causative agent. This clinically led approach ensures early recognition John Radcliffe Hospital, Oxford, of encephalitis subtypes, facilitates the timely administration of antivirals and immunotherapies proven to improve UK (S N M Binks); Department patient outcomes, and minimises the frequent misdiagnosis of autoimmune encephalitis. Finally, we review emerging of Neurology, University of targeted therapeutic approaches, measurements of clinical encephalitis outcomes, and environmental and vaccine- North Carolina, Chapel Hill, NC, USA (D Saylor MD); Encephalitis centred strategies to improve prevention, diagnosis, and care for patients with encephalitis, cognisant of long-term International, Malton, UK patient, caregiver, and economic burdens. (A Easton PhD); Department of Clinical Infection, Microbiology Introduction groups, with an estimated 100 000 people dying annually and Immunology, University of Liverpool, Liverpool, UK Encephalitis has long been one of medicine’s most from the condition.1,3 Encephalitis imposes a substantial (A Easton PhD); Program in challenging and enigmatic syndromes, spanning the still- economic burden: hospitalisation estimates were Neuroinfectious Diseases, unexplained 20th century epidemic of encephalitis approximately US$2 billion in the USA5 and more than Department of Neurology, lethargica, the rapidly expanding spectrum of causative £23 million per year in England,6 excluding costs Columbia University Irving Medical Center–New York autoantibodies identified in the past two decades, and associated with intensive care, rehabilitation, and Presbyterian Hospital, contemporary outbreaks driven by emerging viral long-term dependence. New York, NY, USA pathogens. Characterised as brain inflammation, the Moreover, WHO describes encephalitis as an “increasing (K T Thakur MD); Department of umbrella of encephalitis represents a heterogeneous global threat” with “an urgent public health imperative”.7–9 Neurology, and Department of Neurosciences, Mayo Clinic, group of disorders with an increasingly recognised Recommended methods to avert this potential crisis Jacksonville, FL, USA number of infectious and autoimmune causes. Despite include prevention, improved recognition, and timely (Prof S R Irani) the possibility of prevention and, in some cases, potential treatment. Several forms of infectious encephalitis are Correspondence to: for reversibility with early therapeutic interventions, preventable, with improved vaccine confidence and Professor Sarosh R Irani, encephalitis has a high mortality rate with myriad vaccination programmes being key to reducing incidence, Department of Neurology, and Department of Neuroscience, sequelae, including life-changing disabilities.1,2 death, and disability.10 Furthermore, early diagnosis and Mayo Clinic, Jacksonville, Encephalitis aects men and women of all ages and timely treatments are interdependent, and equally pivotal FL 32224, USA ethnicities worldwide, although epidemiological and in improving patient outcomes and mortality. In herpes irani.sarosh@mayo.edu more precise clinical features vary by cause. Global simplex virus (HSV) encephalitis, timely acyclovir incidence data estimate 500 000–1·5 million people administration reduces mortality from approxi- develop encephalitis each year.2–4 In 2021, encephalitis mately 70% to around 20% (p=0·03).11,12 Similarly, forms of was the fourth leading cause of neurological health loss autoimmune encephalitis show the most impressive in children younger than 5 years, and 13th across all age clinical improvements after early immunot herapy administration, with some studies observing poorer out comes for each day of delayed immunotherapy.13–15 Search strategy and selection criteria Prompt treatment administration in infectious encephali- To capture key recent publications in the field, Embase and tis and autoimmune encephalitis is primarily facilitated MEDLINE databases were searched for articles published from by educating physicians to recognise the key presenting Jan 1, 2022, to June 4, 2025, using the following terms: clinical features. Improving accurate recognition of encephalitis, anti-N-methyl-D-aspartate receptor encephalitis aims to avoid two well recognised problems: encephalitis, viral encephalitis, Japanese encephalitis, West missed opportunities for earlier therapies and over- Nile Fever, varicella zoster, and limbic encephalitis diagnosis. The latter is principally secondary to the See Online for appendix (appendix p 1). Only articles published in English, human misattribution of autoimmune encephalitis in the context studies, clinical studies or trials, observational studies, of clinically irrelevant autoantibody results and multiple guidelines, multicentre studies, and practice guidelines were varied encephalopathic syndromes (figures 1–3).16,17 considered. 184 and 350 unique references were generated Over the past two decades, incidence of infectious from the two databases, respectively. We also searched encephalitis has remained stable, primarily due to selected articles for further references that we judged vaccinations and improved recognition. By contrast, relevant, in addition to landmark publications familiar to the diagnosis of autoimmune encephalitis has risen authors. Review articles are cited as referenced summaries for dramatically, driven by the discovery of pathogenic topics outside the scope of this Seminar. autoantibodies that have identified syndromes previously considered to be idiopathic.18–20 Overall, all-cause 1968 Seminar auto immune encephalitis is at least as common as toxins or metabolic disturbances (eg, liver or renal infectious encephalitis in high-income countries,21,22 failure, or Wernicke–Korsako syndrome), systemic with similar observations emerging in low-to-middle- infection, hypertension, or cerebral hypoxia.26–28 Typically, income countries (LMICs).23,24 Autoimmune and MRI and routine cerebrospinal fluid (CSF) investigations infectious encephalitis, and their subtypes, should appear unremarkable, whereas electroencephalography therefore be considered in parallel for the contemporary (EEG) shows diuse slowing of cerebral activity, management of acute encephalitis. consistent with a global brain disturbance. By contrast, In this Seminar, we use clinical observations to facilitate many forms of encephalitis (figure 1), particularly the accurate recognition of common forms of auto- infectious encephalitis, present over a similar time immune and infectious encephalitis, and highlight course but with combinations of fever, new-onset established and emerging diagnostics. We also outline seizures, focal deficits (eg, aphasia, hemiparesis, or acute therapeutic strategies alongside promising avenues brainstem signs), CSF pleocytosis, and, often, MRI for precision medicine, and discuss how these approaches hyperintensities. In addition to the causes of shape patient outcomes after encephalitis. When encephalopathies,26,28 other mimics of encephalitis distinctive, we provide brief perspectives on encephalitis include the myriad dierential diagnoses within the in LMICs, children, and immunocompromised hosts. category of rapidly progressive dementia, including Finally, we review recent developments and highlight treatable conditions such as cerebral vasculitis, outstanding research questions in encephalitis care, inflammatory cerebral amyloid angiopathy, non- spanning prevention, impacts of climate change, clinical convulsive seizures, and new onset refractory status classifications, and enhanced molecular diagnostics. epilepticus.29,30 Distinguishing these conditions from forms of infectious and autoimmune encephalitis What is encephalitis? enables accurate diagnosis and helps guide specific Within general medicine, neurology, paediatrics, treatments. psychiatry, and emergency medicine practices, regularly asked questions include: “is this encephalitis?” and, if so, A clinical approach to differentiating common “which form of encephalitis?” These questions reflect the causes of encephalitis importance of recognising syndromes that are potentially Once encephalitis is considered likely (also see the treatable or even reversible. Initially, answers can be Diagnostic investigations section and figure 4), guided by understanding core features that broadly management options dier depending on the subtype distinguish encephalopathy from encephalitis (appendix (ie, infectious vs autoimmune encephalitis). Broadly, these p 2).25 Encephalopathy typically manifests in patients subtypes share the core features of seizures, and multiple over a few days with diuse brain dysfunction, often with cognitive and psychiatric distur bances. The diagnostic coma or disorientation (or both), but without focal process for acute encephalitis should therefore involve neurological features consistent with localised disease. parallel testing for causes of both subtypes to ensure Generally, an underlying cause is identified, such as timely diagnosis (figures 1–3). However, the nature and Speed of Dominant clinical features Brain MRI CSF cells CSF PCR onset 1–3 days Delirium or reduction of consciousness, few focal features, Normal – Encephalopathy – cause often identified Infection + Plus fever, headache, seizures, delirium, movement Abnormal +++ disorder, or focal deficits MOGAD – >3 days Early, multiple psychiatric features, seizures, speech, and Normal ++ NMDAR – movement disorder Weeks Focal seizures (eg, faciobrachial dystonic seizures), Mesial temporal changes +/– LGI1 – memory, disorientation, and behaviour or normal CASPR2 Months Focal seizures, memory, mood, without delirium Normal – GAD65 – Figure 1: Pragmatic approach to distinguish common forms of encephalitis Encephalopathy, infectious encephalitis, and forms of autoimmune encephalitis can be largely differentiated based on the speed of symptom onset, dominant clinical features, and by incorporating MRI, the presence of CSF cells, and PCR results. This clinical guide is intended to provide a simple, digestible approach to capture common encephalitis syndromes, without being definitive, and should be refined with data from figures 2 and 3, and appendix pp 4–29. CSF=cerebrospinal fluid. GAD65=glutamic acid decarboxylase 65. LGI1=leucine-rich glioma-inactivated 1. MOGAD=myelin oligodendrocyte glycoprotein antibody-associated disease. NMDAR=N-methyl-D-aspartate receptor. Seminar combinations of these clinical features and their onset Most forms of infectious encephalitis present with duration can aid in distinguishing between infectious and neurological symptoms a few days after a prodrome of autoimmune encephalitis, and, in many causes, their systemic symptoms, with combinations of fever, subtypes (figure 1). headache, confusion, seizures, psychiatric changes, and A Suspectedacute encephalitis Urgent spinal tap Indications for CT before spinal tap: Focal neurological deficit, GCS <10 (or significantly impaired consciousness), and signs of increased intracranial pressure (eg, papilledema and abnormal posturing) Empirical intravenous acyclovir; consider cover for bacterial meningoencephalitis Serum and CSF routine testing Blood • Cultures • Serology for autoantibodies and infectious aetiologies CSF • Cell count, protein, and glucose • Gram stain and culture • PCRs for herpes simplex virus 1, and broader PCR panel, including bacteria • Autoantibodies • Regional-specific or exposure-specific testing • Save extra CSF: sterile screw-cap polypropylene tubes, 2–5 mL, ideally store at least in –20°C Brain MRI Additional studies • CSF: advanced diagnostic testing (ie, sequencing and multiplex PCR) • EEG: confirm slowing and exclude seizures • Brain biopsy: early consideration of tissue diagnosis B Pathogen isolated Pathogen discovered Vaccine-preventable aetiologies Vaccine discovered Measles Tick-borne Dengue Measles encephalitis virus VZV Rabies 900s Dengue T en ic c k e - p b h o a rn li e ti s JEV a M n e d a r s u le b s e , l m la umps, Dengue 1930 BCE 1700s Rabies virus Tuberculosis Tick-borne Measles JEV* JEV† Tuberculosis Japanese Tuberculosis encephalitis VZV 2400 BCE encephalitis Rabies virus BCE 1850 1900 1950 2000 2025 Nipah virus Herpes EEE Scrub typhus HSV-1 Orientia HSV-2 Human Hepatitis E virus 500 BCE Scrub typhus tsutsugamushi polyomavirus 2 300s Zika Usutu Eastern equine Chandipura encephalitis encephalitis Western equine WNV encephalitis virus Human herpes virus-6 Marburg Chikungunya and Powassan viruses Non-preventable aetiologies (Figure 2 continues on next page) 1970 Seminar focal deficits. More detailed clinical observations and C investigations can dierentiate between infectious 0% 20% 40% 60% 80% 100% encephalitis aetiologies to guide appropriate management Demo- Clinical features Investigations (figure 2B–C; appendix pp 4–16). Worldwide, the most graphics common subtype of infectious encephalitis is mediated Japanese encephalitis by herpes simplex virus (HSV)-1, with a bimodal age virus 44 53 96 48 51 83 59 31 8 0 0 90 75 0 distribution mostly aecting people younger than HSV-1 56 51 80 50 30 8 63 38 31 23 2 94 95 91 30 years, or older than 60 years. In older or immuno- suppressed patients, HSV encephalitis can present West Nile virus 60 70 81 47 35 19 51 8 20 48 19 55 100 0 non-specifically, with altered consciousness and without Enterovirus 2 55 85 33 20 44 71 3 18 37 25 48 75 0 headache or fever. Other common forms of infectious encephalitis are associated with varicella zoster virus Varicella zoster virus 57 61 57 56 56 3 38 16 20 34 61 16 94 51 (VZV), West Nile virus (WNV), Japanese encephalitis v b i e n i n a r d s c u i e e s v d p id ( h J u a E o l a V n i l t ) i p s , h l a o o e n c f n t d a e o l n e ty n e p p t p r e e e i s r d s o ( e e v fi m n i g r t u i u s o s r w l e e o s i g 2 t , h y B a , n v a 2 a d n C s c c d ) u a . n l F o m o p b r a o e e t r h d e x y i a  , m d e le p i r s a e l t d e n i , n i t n i V c a g t Z t i e v t V d o e Age Male Feve M r e H n e in a g d e a a c l h s e y mpt C o h m a s n R g e e s s p i i n ra m to e r n y tal status Seizures Focal signs Vo miting Rash MRI CSF EEG stroke; WNV can involve the anterior spinal cord, resulting in acute flaccid limb weakness; JEV is associated Figure 2: Acute and infectious encephalitis—features and approach (A) Approach to diagnostic investivations in acute encephalitis, including safe expedition of CSF sampling107,108 and with a heterogeneous range of movement disorders; and timely, parallel testing of both infectious and autoimmune aetiologies from blood and CSF. (B) Pathogen discovery enteroviral infections frequently involve the brainstem. timeline, describing vaccine-preventable (blue, above line) and currently non-preventable aetiologies (pink, below Some forms of infectious encephalitis can present more line). Black dots represent when the virus was isolated, grey dots show when the virus was discovered, and syringes chronically, often require a high index of suspicion, and indicate when the vaccine was discovered. Created with BioRender.com. (C) Key clinical features of the five most common infectious encephalitis viruses, with percentages of each feature displayed in each cell, extracted from the typically reflect host vulnerability or delayed reactivation, five largest studies of each virus. Median age of onset shown. Zeros are entered for unreported data. rather than acute pathogen invasion.31 These subtypes are CSF=cerebrospinal fluid. EEE= Eastern equine encephalitis. EEG=electroencephalogram. GCS=Glasgow Coma Score. outside the scope of this Seminar. HSV=herpes simplex virus. JEV=Japanese encephalitis virus. VZV=varicellar zoster virus. WNV=West Nile virus. In general, most forms of autoimmune encephalitis *Mouse-brain derived. †Cell-culture derived. present less abruptly than infectious encephalitis, with combinations of cognitive and psychiatric features, several weeks with frequent focal seizures, amnesia, and seizures, movement disorders, and loss of awareness.15,19,32 disorientation.13,40–42 Similar features are present in Patient demographics and clinical profiles are often contactin-associated protein-like 2 (CASPR2) antibody sucient to distinguish between the common encephalitis, which predominantly aects males older autoantigen-defined syndromes (figures 1, 3).15,19,20,33,34 In than 60 years (figure 3).40,43 However, in women aged turn, this autoantigen-based classification informs the 18–40 years, several months of frequent focal seizures expected immunotherapy response, and the likelihood with subtle cognitive deficits is indicative of glutamic acid and nature of any underlying tumour (ie, paraneoplastic decarboxylase 65 (GAD65) antibody-associated syndromes; figure 3B–C).35,36 Broadly, symptom onset encephalitis. Simple clinical observations can therefore over 3–7 days—with combinations of early and prominent aid diagnosis of autoantigen-defined encephalitis psychiatric features that rapidly progress to seizures, subtypes, which can help to direct and interpret first-line cognitive dysfunction, or movement disorders—is most investigations (figures 1, 3, 4; appendix pp 17–29). characteristic of N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis, the most common form of Clinical features in autoimmune encephalitis autoimmune encephalitis in people younger than The number of autoantibodies associated with 40 years.37 Myelin oligodendrocyte glycoprotein (MOG) autoimmune encephalitis has increased dramatically antibody-associated encephalitis has a similarly acute over the past two decades, and its current prevalence presentation, occurs mostly in childhood, and is an (ie, 10 cases per 100 000 population) is likely to rise increasingly recognised form of autoimmune further as new autoantibodies continue to be discovered encephalitis.38,39 Both of these subtypes can mimic (figure 3C).15,21,34,41,42 Many autoantibodies associated with infectious encephalitis as they often present with a viral autoimmune encephalitis are directed against prodrome of coryzal features, fever, and mild headache intracellular targets (figure 3C; appendix 1 pp 21–24). for a few days. By contrast, most other known These autoantibodies lack access to their targets in intact, autoimmune encephalitis subtypes present over weeks live neurons and glia, and are therefore considered non- (or even months) without these systemic features. For pathogenic.18,19 They represent valuable biomarkers of example, leucine-rich glioma-inactivated 1 (LGI1) conditions likely mediated by T cells,44 often indicating antibody encephalitis—the most common subtype of predictable clinical profiles and directing a search for autoimmune encephalitis in adults—typically aects specific remote tumours.35,36 For example, severe isolated people older than 40 years and usually presents over cerebellar ataxia is often associated with Yo-antibodies Seminar and uterine, fallopian, or breast cancer, whereas limbic– often occurring several times per hour at disease nadir (ie, hypothalamic encephalitis with narcolepsy is associated maximum disease severity; figure 4G). LGI1 antibodies with Ma2 antibodies and testicular cancer.36 are associated with a pathognomonic seizure appearance, By contrast, autoantibodies directed against extracellular termed faciobrachial dystonic seizures (FBDS), consisting epitopes are likely directly pathogenic (figure 3C; of short-lived posturing episodes predominantly aecting See Online for videos 1 and 2 appendix pp 17–20).15,18,20 The most common autoantigens the ipsilateral face and arm (figure 3B; video 1, video 2).13,45 (ie, LGI1, NMDAR, CASPR2, and MOG) each show FBDS are described by patients as jolts, jerks, or spasms, distinctive features (figure 3B). As autoantibody results lasting 1–3 s, and can be dramatic, often associated with often take a few weeks to return, recognition of dropping items and falls. Typically, after a few weeks of characteristic clinical features remains key to early increasing frequencies of FBDS, or other focal seizures, diagnosis. patients develop dense anterograde and retrograde LGI1 antibody encephalitis is the most common form of amnesia with disorientation and behavioural changes. adult-onset autoimmune encephalitis, with an incidence These symptoms can be mistaken for neurodegenerative of approximately 2 cases per million people per year, a conditions (eg, Alzheimer’s disease), particularly in the 2:1 male:female ratio, and a median age of onset of 50% of patients without medial temporal lobe swelling on 64 years.13,40,42 Typically, LGI1 antibody encephalitis presents MRI;46 however, most dementias present over years with over a few weeks with increasingly frequent focal seizures, few seizures.16 Less than 5% of patients with LGI1 antibody A Patient Age Gender Race and ethnicity Symptoms MRI Spinal fluid Antibody 0 years Native American or Seizures Alaska native Memory Normal Normal 16 years Asian Female Behaviour LGI1 Black or African American Hallucinations NMDAR Delusions Hispanic or Latino Movement Abnormal Male Numbness Native Hawaiian or 70 years other Pacific Islander Abormal Weakness 100 years White Sleep B 0% 20% 40% 60% 80% 100% Demographics Clinical features Investigations LGI1 64 62 79 8 86 54 87 49 19 14 5 43 36 53 60 14 51 CASPR2 65 82 80 21 57 0 62 36 54 44 5 30 50 9 35 24 46 NMDAR 24 34 19 34 71 0 63 84 0 54 48 51 34 8 23 72 84 MOG 21 59 6 5 75 0 68 37 0 5 64 32 0 8 20 83 43 Age Male White Tu mo F u ac r iobra S ch ei i z a u l d re y s stonic seizures Cognitive Psychiatr P i e c ripheral nerve Autono mi C c onsciou M sn o e v s e s ment disorder Slee H p yponatrae mia MRI CSF cells EEG (Figure 2 continues on next page) 1972 Seminar C Relative incidences High Extracellular targets Sez6L2 IgLON5 Rare GABAR A Encephlitis D2R DPPX Implicated in other CNS disorders GABABR (often paraneoplastic) LGI1 CASPR2 AMPAR GlyR mGluR2 NMDAR DNER Neurexin-3a MOG mGluR1 AQP4 mGluR5 GLUK2 1985 1990 1990 1995 1995 2000 2005 2010 2015 2020 2025 Hu Yo Amphiphysin CV2 SO P X C 1 Kγ ITPR G N F e A u P rochondrin GAD65 Recoverin AK5 TRIM 46 Ma2 Homer3 Septin 5 Ma1 KLH11 MAP1B TRIM 9/67 ANNA-3 PDE10a Zic4 Drebrin Ri LUZP4 Intracellular targets Figure 3: Autoimmune encephalitis features and discovery timeline (A) Fundamental clinical features across demographics, symptoms, and simple investigations direct the detection of autoantigen-reactive antibodies. Examples shown with LGI1 and NMDAR antibodies, which are somewhat skewed towards White and non-White populations, respectively. Used with permission of Mayo Foundation for Medical Education and Research, all rights reserved. (B) Demographics, clinical features, and investigations in autoimmune encephalitis. The percentages of each feature are extracted from the five largest studies of each of the five most common autoantibodies. Median age of onset shown. Zeros are entered for unreported data. (C) Timeline of discovery for autoantibodies targeting extracellular (above line) and intracellular (below line) epitopes. Many are implicated in autoimmune encephalitis. Created with BioRender.com. CSF=cerebrospinal fluid. EEG=electroencephalogram. GAD65=glutamic acid decarboxylase 65. LGI1=leucine-rich glioma-inactivated 1. MOG=myelin oligodendrocyte glycoprotein. NMDAR=N-methyl-D-aspartate receptor. encephalitis have a tumour, and 50% have serum with ovarian teratomas, partly accounting for the observed hyponatraemia, a potential early—albeit non-specific— 3:1 female bias. The teratoma contains germinal centre- diagnostic clue.13 like structures and B cells that can secrete NMDAR CASPR2 antibody encephalitis has several similarities antibodies, likely explaining the clinical benefits observed with LGI1 antibody encephalitis (figure 3B) as a late- after early tumour removal.37,49 More rarely, NMDAR onset, male-dominant disease (ie, an 8:1 male:female antibody encephalitis aects people older than 50 years, ratio), and both share strong yet distinct HLA-DRB1 with a low rate of teratomas but a high rate of myriad allele associations.47 However, patients with CASPR2 malignancies, and a poor overall prognosis.37,50 Adults antibody encephalitis have fewer seizures than those typically present over a few days with florid, multidomain with LGI1 antibody encephalitis, with more sleep psychiatric manifestations spanning aective, psychotic, disturbances, dysautonomia, and cerebellar involvement, behavioural, and sleep features, often resulting in early and 50% show peripheral nerve involvement with encounters with mental health services.14,37,48 However, hyperexcitability or neuropathic pain. For these patients, within just a few days, almost all patients develop especially those diagnosed with Morvan’s syndrome, a cognitive disturbances, seizures, or a complex movement thymoma should be excluded.36,40,43 disorder characterised by dystonia, chorea, stereotypies, NMDAR antibodies cause the most common form and catatonia (video 3, video 4, video 5). This rapid onset See Online for videos 3, 4, and 5 of autoimmune encephalitis in children and young and progression to neurological deficits typically adults,14,37,48 and show an approximate 30% association distinguishes NMDAR antibody encephalitis from Seminar autoimmune comorbidities, who have a few months of A B C G progressive frequent focal seizures, with mild memory and aective disturbances but without prominent disorientation.41,60 This dominant phenotype of temporal lobe seizures and neuropsychiatric involvement without delirium is typically accompanied by unremarkable CSF and MRI findings. Serologically, very high concentrations of GAD65 antibodies are required to confirm neurological relevance, compared with the far lower concentrations D E F found in people with type 1 diabetes and healthy individuals.60,61 Other less common forms of autoimmune encephalitis are associated with antibodies against multiple neuronal and glial proteins, including γ-aminobutyric-acid (GABA) and , glycine, and α-amino-3-hydroxy-5- A B methyl-4-isoxazole-propionic acid receptors (figure 3C; Figure 4: Brain imaging and patient diary in infectious and autoimmune encephalitis appendix pp 17–24).15 However, approximately 10–20% of (A) CT head scan showing haemorrhage (arrows) and oedema (hypodense) in right temporal lobe secondary to herpes simplex virus-1 encephalitis. (B) Left and right basal ganglia involvement (arrows) with Japanese encephalitis patients with autoimmune encephalitis will lack a known virus. (C) Limbic encephalitis associated with autoantibodies against the GABA receptor, with high signal intensity autoantibody target; this subtype is known as seronegative B in the hippocampus and amygdala on FLAIR imaging (arrows). (D) FLAIR imaging showing multifocal bilateral autoimmune encephalitis.62 To avoid over-diagnosis of a subcortical and right thalamic hyperintensities (arrows) associated with myelin oligodendrocyte glycoprotein syndrome with absent serological biomarkers, we antibodies. (E) Multifocal fluffy cortical and juxtacortical FLAIR hyperintensities (arrows) seen with GABA-receptor antibody encephalitis. (F) Left hilar lymph nodes (arrows) associated with small cell lung cancer and GABA A receptor encourage health-care practitioners to seek strict B antibodies. (G) Diary of a patient with leucine-rich glioma-inactivated 1 antibody encephalitis recording 1 day of coherence between clinical, imaging, and CSF findings focal seizures per column. Daily totals are circled. typical for autoimmune encephalitis.16 Patients with cancer who are treated with immune checkpoint primary psychiatric diagnoses.51–54 Childhood presen- inhibitors and CAR T cells can also develop autoimmune tations usually show less florid psychiatry and, rather, a encephalitis as an immune-related adverse eect.63,64 For rapidly evolving encephalopathy with more prominent these individuals, management focuses on balancing the seizures and movement disorders.55,56 After a few more pressing need to treat the underlying cancer against risks days, both adults and children frequently require of inducing neurological worsening or relapse. intensive care for depressed consciousness or central Recent observations have temporally linked aetiologically hypoventilation (or both), and approximately 30% of distinct forms of autoimmune and infectious encephalitis patients develop a multi-organ dysautonomia associated with the recognition that acyclovir-treated HSV-1 with potentially lethal cardiac dysrhythmias.14,37,48 Early encephalitis can precede—typically by 6–12 weeks—a screening for these typical sequelae, alongside appropriate form of autoimmune encephalitis most closely resembling monitoring measures, aims to reduce the consistently NMDAR antibody encephalitis, and without detectable reported mortality rate of 5–10%.14,37,48,57 Despite the HSV-1 DNA in the CSF.65,66 This example of post-infectious marked severity of this encephalitis, routine MRI is autoimmunity occurs in approximately 25% of children typically unremarkable.58 Biomarkers of recovery in and adolescents with HSV-1 encephalitis, with lower rates NMDAR antibody encephalitis, and other forms of in adults, and is successfully treated with immunotherapy autoimmune encephalitis, are still required to help titrate without further antimicrobials. immunotherapy regimens. In MOG antibody encephalitis—the next most Clinical features in infectious encephalitis common autoimmune encephalitis in children, which Infectious encephalitis remains a substantial neurological can also aect adults—patients show a short history of burden worldwide, and is highly heterogeneous, varying delirium, focal deficits, and seizures, often with a by geography, season, and year.3 Five pathogens (ie, HSV, meningoencephalitis that can cause headache and neck VZV, WNV, JEV, and enteroviruses) contribute a stiness.39,59 MRI is usually abnormal and can be highly substantial proportion of cases globally, and their clinical characteristic, revealing cortical and subcortical swelling, (figure 2) and radiological features (appendix p 35) will be with both parenchymal and meningeal enhancement our focus herein. Previous reviews have compre hensively (figure 4D).39 Patients can also manifest synchronous or summarised more extensive ranges of infectious old optic neuritis and transverse myelitis, which are both encephalitis.67,68 well recognised associations of MOG-antibody associated JEV remains the leading cause of epidemic encephalitis disease. Tumours are rare, but the CSF will typically in Asia, accounting for approximately 25 000 deaths contain leukocytes with a high opening pressure.38 annually.69 Although most human JEV infections are GAD65 antibody-associated encephalitis predominantly asymptomatic, particularly in vaccinated individuals, a aects young adult females with accom panying systemic minority develop clinically apparent disease with an acute 1974 Seminar encephalitis.70 Historically, this severe disease occurred typically exceeding 50 cells per µL.87,88 Neuroinvasive predominantly in children; however, in regions with disease is confirmed by detection of WNV-specific IgM in sustained paediatric vaccination programmes, adults are the CSF. Currently, no vaccine or targeted antiviral increasingly aected.71 The incubation period of JEV therapy exists; management is supportive. Prevention ranges from 5 to 15 days following an infective mosquito relies on mosquito control, personal protective strategies, bite. Aected individuals typically experience a non- and surveillance of avian reservoirs to mitigate outbreak specific febrile prodrome of fever, headache, and vomiting, risks. which can progress to delirium and seizures within Enteroviruses, especially enterovirus-A71, are a major several days.70,72–74 JEV shows marked neurotropism for global cause of paediatric encephalitis, particularly in deep grey matter structures, with lesions in the thalamus east Asia and southeast Asia.89–91 Outbreaks are seasonal and basal ganglia frequently seen on both neuroimaging in temperate climates but can occur year-round in and neuropathology (figure 4B). Consequently, individuals tropical regions, with the geographical distribution with JEV often develop movement disorders, ranging varying by strain.92 Clinically, enterovirus encephalitis from parkinsonism to hyperkinetic movements usually presents with fever, headache, altered mental (eg, chorea and athetosis).74,75 These movements can status, and, in severe cases, coma. Specific strains are resemble those seen in NMDAR antibody encephalitis associated with distinct clinical phenotypes. For example, (video 3, video 4, video 5), which can occasionally occur enterovirus-A71 has been linked to severe—and after JEV.24,76 Vaccination remains the most eective sometimes fatal—brainstem inflammation, whereas preventive measure for JEV, recommended by WHO for enterovirus-D68 has been implicated in acute flaccid those living in or travelling to endemic areas, and can paralysis.93,94 Diagnosis relies on the detection of CSF provide long-lasting protection.77 enteroviral RNA by PCR; serological testing is generally HSV-1 is the leading cause of sporadic encephalitis in less sensitive. Because no specific therapies exist for high-income countries, accounting for the majority of enteroviruses, current management is primarily identified aetiologies.3 Unlike JEV, no eective HSV-1 supportive, with ongoing research exploring antiviral vaccine exists, and long-term morbidity persists in and immunomodulatory strategies for people with severe approximately 70% of survivors despite acyclovir infection. therapy.78,79 However, prompt intravenous acyclovir VZV can cause both meningitis and encephalitis, with dramatically decreases mortality, making its empirical encephalitis occurring more frequently in older adults administration the standard of care. The optimal and immunocompromised individuals—demographics duration of acyclovir therapy remains uncertain; however, associated with poor outcomes.95–97 A vesicular rash can a minimum of 14 days of intravenous treatment is occasionally accompany VZV encephalitis.79,96 The generally recommended, with longer courses (eg, 21 days) condition commonly results in a vasculopathy aecting often used in severe cases or when clinical or virological large or small vessels, leading to ischaemic or concerns persist.79–81 Multiplex testing platforms can haemorrhagic strokes.98 Neuroimaging can reveal frontal shorten the detection time for HSV-1, thereby reducing and temporal lobe oedema (which can mimic HSV-1 unnecessary empirical acyclovir use, improving cost- encephalitis; figure 4A),99 and vascular imaging can show eectiveness, and decreasing the length of hospital vessel wall irregularities or stenosis, consistent with a stay.82,83 vasculopathy.100 PCR of the CSF has suboptimal WNV is the most common mosquito-borne cause of diagnostic sensitivity for VZV, whereas detection of VZV- encephalitis in North America, with outbreaks also specific IgG in the CSF is more sensitive; however, tests reported in parts of Europe, the Middle East, and Africa.84 can be negative early in the disease course.101,102 In the USA, neuroinvasive disease occurs with a 5% case fatality rate and 59% hospitalisation rate;85 in Europe, Diagnostic investigations 1340 locally acquired cases and 104 deaths were reported The four most important first-line investigations—blood in 2022.86 Approximately 80% of infections are tests, CSF studies, brain imaging, and EEG—show false asymptomatic. Although the majority of symptomatic positive and negative results in subtypes of autoimmune cases are self-limiting febrile illnesses,84 neuroinvasive and infectious encephalitis; as such, they should be disease occurs in less than 1% of individuals, primarily in interpreted alongside well formed clinical impressions. adults older than 65 years and immunocompromised Other than the previously highlighted hyponatraemia patients. These individuals present with fever, headache, associated with LGI1-antibodies, results of routine blood vomiting, rash, altered mental status, and systemic tests are typically normal in patients with autoimmune laboratory abnormalities, including hypona traemia, acute or infectious encephalitis, which helps to exclude renal failure, and lymphopenia.84,87 Acute flaccid paralysis systemic causes of encephalopathy, such as metabolic can be a characteristic feature of WNV, causing acute, disturbances or sepsis (appendix p 2). An important asymmetric muscle weakness and subsequent wasting of exception is the presence of autoantibodies associated the aected limbs. EEG, MRI, and CSF are frequently with autoimmune encephalitis, which, wherever abnormal, with the white blood cell count in the CSF possible, should be tested for in both the blood and CSF.41 Seminar CSF can provide direct insights into the brain; testing of encephalitis,112 but in some subtypes (eg, LGI1 antibody CSF is indicated in all suspected cases of encephalitis, encephalitis), serum autoantibody testing is more with the exception of cases that display the few sensitive.41 CSF protein and glucose concentrations are contraindications to CSF sampling (eg, those with focal typically unremarkable in most forms of autoimmune deficits, impaired consciousness, and signs of increased and infectious encephalitis. intracranial pressure; figure 2A). Spinal taps are usually CT scans of the head are needed to facilitate CSF well tolerated, only require local anaesthetic, take sampling in a minority of cases; however, their findings approximately 15 min with an experienced operator, and only guide diagnosis in very few forms of infectious necessitate minimal post-procedure bedrest. Low- encephalitis (ie, HSV-1 encephalitis-associated fronto- diameter blunt needles induce post-procedure headaches temporal intracranial haemorrhage and cerebral oedema; in fewer than 5% of patients.103,104 However, CSF is too figure 4A) and very rarely in autoimmune encephalitis. often obtained late, principally due to concerns around Brain MRI is more useful than CT, as a normal MRI can headache and the rare complication of cerebral herniation. usually exclude infectious encephalitis and abnormal Simple recommendations indicate that rapid exclusion of patterns can substantially narrow down the specific absolute contraindications to CSF sampling (figure 2A) causative pathogen (appendix p 35). Additionally, in are proven to expedite the time taken to initiate antibiotic several forms of autoimmune encephalitis, swelling therapy, and hence reduce mortality and improve patient predominantly aects the limbic regions (figure 4C), outcomes.105,106 Taken together, clinicians suspecting acute particularly the medial temporal lobes on T2-weighted encephalitis should exclude the few features strongly fluid-attenuated inversion recovery sequences. When this suggestive of markedly raised intracranial pressure,107,108 swelling extends outside the hippocampal–amygdala urgently obtain CSF samples, and immediately thereafter regions, or is accompanied by diusion restriction or administer intravenous acyclovir, plus consider empirical contrast enhancement, infectious encephalitis is more antibiotics to cover possible bacterial meningoencephalitis likely than autoimmune encephal itis.46 MRI can also show (figure 2A). In cases where CSF collection must be multifocal white matter lesions aecting subcortical delayed until CT can be conducted, or in very agitated regions and deep nuclei, such as those associated with patients who might need sedation, acyclovir can be MOG and GABA receptor antibodies (figure 4D, E). A administered empirically. However, MRI results are unremarkable in more than An elevated CSF leukocyte count (ie, >5 cells/µL) often 50% of common autoimmune encephalitis subtypes confirms the syndromic diagnosis of encephalitis. A (eg, LGI1, CASPR2, and NMDAR antibody encephalitis; normal CSF leukocyte count is useful to exclude figure 1), which commonly prompts under-diagnosis.16 infectious encephalitis; however, approximately 20% of Upon suspicion of a paraneoplastic condition, CT or PET patients with the condition can lack leukocytes, body imaging can aid the detection of a systemic tumour particularly those sampled early in their illness, or those (figure 4F). who are older or immunocompromised.109 To identify the EEG is another valuable early investigation used to rule specific cause of infectious encephalitis, CSF testing with out treatable subclinical seizures and, in patients with both multiplex and targeted (monoplex) PCR assays is autoimmune encephalitis who have normal MRI scans, essential: multiplex panels enable rapid screening for a to observe focal or diuse slowing that support the range of prespecified viral, bacterial, and fungal diagnosis.32,113 EEGs are unremarkable in 20–60% of pathogens, whereas monoplex PCRs can provide higher patients with autoimmune encephalitis, but abnormal in sensitivity for specific pathogens when clinical suspicion 50–90% of those with infectious encephalitis. Specific remains high and panel results are negative. When features, such as temporal lobe period lateralised unsuccessful, metagenomic next-generation sequencing epileptiform discharges in HSV-1 encephalitis, can be can theoretically detect any DNA or RNA within the CSF, observed.113,114 including from novel organisms.68 However, false negatives can occur in patients with low nucleic acid Management burden in the CSF. Adjunctive serological, respiratory, or A common theme in both autoimmune and infectious stool evaluations might still be required to identify some encephalitis is the time-dependent potential for recovery infectious pathogens, such as WNV, JEV, and eastern and the need to prioritise prompt administration of equine encephalitis. immunotherapies and antimicrobials. Supportive care Elevated CSF leukocyte counts by routine microscopy can also involve strategic use of antipsychotics, mood are only detected in some subtypes of autoimmune stabilisers, benzodiazepines, and anti-seizure medica- encephalitis (eg, NMDAR and MOG antibody tions, to control the varied psychiatric, behavioural, sleep, encephalitis; figure 1). Flow cytometry is more sensitive movement, and seizure manifestations.115 In people with and detects immune cells in many patients with acute autoimmune encephalitis, the risk of an enduring autoimmune encephalitis; however, this technique is not ten dency for seizures (ie, autoantibody-associated widely available outside of research laboratories.110,111 CSF epilepsy) is generally less than 10%, typically mitigating autoantibodies are a highly specific result in autoimmune the need for long-term anti-seizure medications.116,117 1976 Seminar Howe ver, epilepsy is more common after infectious immunotherapy requirements. For example, most encephalitis, and these patients often benefit from anti- patients with LGI1 antibody disease show seizure seizure medications.118 Additionally, dierential cessation and improvem ents in both cognition and frequencies of tumours associated with subtypes of quality of life within a few weeks of first-line therapies, autoimmune encephalitis oer stratified approaches to corticosteroids, plasma exchange, or intravenous IgG (or prompt tumour identification and removal (figure 3).36 combinations thereof).13,40,126 However, in NMDAR Acyclovir (10 mg/kg three times daily for at least antibody encephalitis, approximately 50% of patients 14 days) remains the foundation for HSV-1 encephalitis show insucient responses to these agents and benefit treatment,12 with the greatest benefit proven to occur from the addition of second-line therapies, such as when administered within 24–48 h of symptom onset.119 rituximab, cyclophosphamide, and ofatumumab, which Acyclovir can safely be administered concurrently with reduce rates of disability, mortality, and relapse, and dexamethasone (10 mg/kg four times daily for 4 days), corticosteroid-induced side-eects.14,37,57,127,128 By contrast, albeit with minimal clinical benefits.120 Other antiviral benefits of immunotherapy appear minimal in GAD65 therapies indicated for specific pathogens include antibody encephalitis.60 Across all autoimmune ganciclovir for cytomegalovirus encephalitis, and encephalitis subtypes, the optimal time to escalate or acyclovir or valacyclovir for VZV.5 For certain RNA withdraw immunotherapies is not yet known.115 viruses, including enteroviruses or flaviviruses, agents Multiple alternative immunotherapies for autoimmune under evaluation include ribavirin and favipiravir.121 encephalitis are either in development or in clinical Immunotherapies are the mainstay of treatment for trials (figure 5; appendix pp 30–34). Examples include autoimmune encephalitis, and their early administration monoclonal antibodies (eg, inebilizumab) or CAR is consistently associated with improved outcomes across T cells, which target CD19 (and are hence likely to delete subtypes.13,14,122,123 The only completed randomised broader B-cell lineages than anti-CD20 agents), CD38- controlled trial confirmed a small, statistically significant directed daratumumab, which targets many B cells and benefit of intravenous immunoglobulins over placebo in plasma cells; proteosome inhibition (eg, bortezomib), both achieving seizure control and cognitive which more selectively targets plasma cells compared improvements in LGI1 and CASPR2 antibody encephalitis with CD38-directed drugs; blockade of the pleotropic (p=0·044, odds ratio 10·5, 95% CI 1·1–98·9).124 Therefore, IL-6 receptor with tociluzimab or satralizumab; and although several trials are actively recruiting (appendix accelerated IgG degradation via FcRn blockade (eg, with pp 30–34),125 current evidence comes largely from efgartigimod).129,130 More precision experimental retrospective observational data and expert consensus.115,122 therapies include monovalent non-functional Broadly speaking, this evidence has highlighted that each recombinant NMDAR antibodies, which block antigen-defined syndrome has relatively distinct endogenous pathogenic autoantibody binding; direct First-line Second-line and next-generation therapies therapies Steroids B-cell CD19 (eg, inebilizumab and CAR-T cells) Plasma cell CNS entry Endogenous depletion CD20 (eg, rituximab) (eg, daratumumab (eg, natalizumab) autoantibody Plasma and bortezomib) blockade exchange Cytokines IL-6R (eg, tocilizumab) Intravenous immuno- globulin B cell CNS T cell autoantigen CAR T cell CAART cell Autoantigen modulation Depletion or FcRN inhibition Anti-CD19 Autoantigen tolerisation (eg, efgartigimod) Figure 5: Established and emerging immunotherapies for treating autoimmune encephalitis After first-line therapies, second-line immunotherapies should be considered, including B-cell depletion with CD19 or CD20-targeting medications, CAR T cells, IL-6R blockade with tocilizumab or satralizumab (ie, cytokine modulation), and drugs that delete plasma cells, including daratumumab (targeting CD38, which is also expressed on some B cells) and the proteosome inhibitor bortezomib. Emerging options include inhibition of leukocyte entry to the CNS (eg, natalizumab), blockade of FcRN IgG uptake to prolong the half-life of IgG (eg, with efgartigimod), blockade of endogenous antibody binding (eg, with monovalent antibody decoy therapy), direct pharmacological autoantigen binding to overcome autoantibody effects (eg, allosteric modulators), CAART cells (which express the autoantigen to induce selective deletion of autoantigen-reactive B cells), and various T-cell tolerisation or modulation approaches, to deny help to B cells. Depicted key neuroimmune compartments involved in the generation of pathogenic autoantibodies include bone marrow (the source of B cells and early T cells) and lymph nodes (a key site of crosstalk between B cells and T cells). CAR T=chimeric antigen receptor T cells. CAART=chimeric autoantibody receptor T cells. FcRN=Fc receptor neonatal. IL-6R=interleukin-6 receptor. Seminar modulators of autoantigen function;131,132 and chimeric autoantibody receptor T-cell therapies, which express the autoantigen and therefore aim to selectively deplete autoantigen-reactive B cells.133 Activities of daily living Cognitive Driving Memory Outcomes Return to work or education Attention Homekeeping Reasoning After acute (or, in some cases, long-term) immunotherapy Social skills within community Problem solving treatment, the overall function of patients with auto- Family life and planning Learning Rebuilding autonomy Critical thinking and decision making immune encephalitis improves for several years.13,14,43,134 and independence Lack of insight For those with infectious encephalitis, improvem ents are more modest following treatment with antiviral agents, which is likely due to the less reversible nature of the original lesion. Regardless, most people with autoimmune and infectious encephalitis develop persistent—and Physical Fatigue often substantial—sequelae across cognitive, physical, Carer burden Depression Sleep problems psychosocial, and functional domains (figure 6A).135–137 Sensory changes Anxiety Motor dysfunction and Major residual neurocognitive problems involve memory, Distress coordination problems mood, personality changes, emotional regulation, Anger Seizures or epilepsy Occupation changes attention, sleep, and fatigue, with varied relative prepon- Pain Relationship dynamics Paralysis derances across specific syndromes.134–140 Such deficits are Psychosocial C or h v a i n s g io e n s in taste, smell, likely under-recognised due to inadequate patient follow- Isolation Sexual dysfunction up, encephalitis-induced communication and cognitive Mental health Speech and language diculties, and minimal exposure of patients to research, Anxiety Depression collectively downplaying the multifaceted and protracted Mood changes experience of encephalitis survivors. Emotional and behavioural problems Changes in personality and sense of self Relapses are a concern in autoimmune encephalitis, Irritability with rates of 10–50% depending on the subtype. Relapses can be challenging to identify, particularly in people re-presenting incomplete manifestations of the sentinel syndrome, such as seizures or psychiatric features alone. For these individuals, clinical decisions should be made alongside repeat investigations to distinguish between 100 post-encephalitis manifestations and a genuine relapse, which would prompt immunotherapy to prevent deterioration. In both adults and children, long-term functional consequences of encephalitis include failure to return to work or school, delayed education, and poor social reintegration, and are often only apparent after detailed neuropsychological testing, occupational health assess- ments, or caregiver interviews.136,138,141 The resultant delays 50 in engaging with multiple relevant services can burden both patients and caregivers. Additional challenges include poor public awareness of encephalitis, under-recognised post-traumatic stress disorder after prolonged admission to intensive care units, and, for people with autoi mmune encephalitis, pervasive anxiety around potential relapses.142 Despite these observations, comprehensive patient journeys remain poorly described in both autoimmune and infectious encephalitis, but can identify important 0 features not captured by routine clinical assessments (see 0 25 50 75 100 videos 7 and 8 in appendix p 3). In autoimmune encephalitis, accurate outcome Figure 6: Patient outcomes after encephalitis measurements are confounded by scores being imported (A) Multiple functional domains are affected by infectious and autoimmune encephalitis. (B) In LGI1-antibody from other disciplines.136 The modified Rankin score encephalitis, the patient-rated quality of life score (EQ-5D–VAS) correlates most closely with the patient-reported (mRS), which is extensively reported in autoimmune outcome measure (PROM), rather than the clinician-assessed modified Rankin score (mRS) or clinical assessment scale in autoimmune encephalitis (CASE).135 encephalitis, was originally a clinician-assessed stroke 1978 SAV–D5-QE A B PROM correlations mRS 1 3 CASE 1 3 5 LANTERN (PROM) Seminar outcome tool used to capture physical and functional infectious encephalitis in previously unaected activities of daily living. The Clinical Assessment Scale for regions.149,150 Deforestation has increased human contact Autoimmune Encephalitis represents a more specific with wildlife reservoirs, facilitating spillover events such clinician-reporting tool and includes relevant domains as high-mortality sporadic outbreaks secondary to Nipah such as seizures, conscious level, psychiatric features, and virus, with high pandemic potential.151 Availability and movement disorders, making it particularly well suited to uptake of vaccinations remains challenging, but NMDAR antibody encephalitis.143 Only one dedicated vaccination programmes for pathogens such as JEV and patient-reported outcome measure has been reported tick-borne encephalitis markedly reduce the disease in autoimmune encephalitis:135 the LGI1-Antibody burden. Declines in vaccine coverage correspond to Encephalitis Rating scale correlates more closely with increased cases of measles encephalitis and subacute patient-rated quality-of-life than either clinician-rated or sclerosing panencephalitis, illustrating the severe imported patient-rated scales (figure 6B). Global disability consequences of vaccine hesitancy.152 Continued scales, such as the mRS, Glasgow Outcome Scale, Barthel investment in vaccine deployment and vector control Index, and generic health-related quality-of-life measures strategies are essential to mitigate these emerging threats. (eg, the EQ-5D), are commonly used in infectious Reassuringly, vaccines have not been associated with new encephalitis but are not validated in this setting.137 To cases of neurological autoimmune diseases.153,154 better incorporate cognitive and psychosocial sequelae, A diagnosis of autoimmune encephalitis is frequently the Liverpool Outcome Score was developed specifically conflated with several other clinical entities, including for paediatric encephalitis, and appears sensitive to seronegative autoimmune encephalitis, Hashimoto’s detection of early recovery.144 Patient-reported outcome encephalopathy, paediatric autoimmune neuropsychiatric measures specific to infectious encephalitis are awaited to disorders associated with streptococcal infections, enhance patient-centred clinical relevance. and subacute neurodevelopmental or regression syndromes.16,112,155–158 Additionally, isolated psychiatric Controversies and outstanding research features, brain fog, and subjective disorientation are questions highly unusual presentations of autoimmune The past 25 years have witnessed major strides towards encephalitis.15,53 Reports associating these syndromes and delineating causes of previously idiopathic forms of presentations with autoimmune encephalitis are usually autoimmune and infectious encephalitis, establishing a result of poor-quality autoantibody testing, including large cohorts to retrospectively analyse their manage- the use of non-native autoantigens, testing of CSF or ment, and evaluate outcomes. However, multiple serum in isolation, appreciable rates of low-specificity unresolved questions demand focused attention to guide autoantibodies in healthy individuals and multiple future clinical and scientific directions and decrease the disease control groups, a lack of objective inflammatory current substantial morbidity and mortality. findings on CSF or MRI testing, and diagnostic constructs First, the aetiology of a large proportion of cases remains that are largely consensus-based and subject to undetermined even with current molecular and serological change.16,53,112,159 Robust biomarkers and improved techniques, highlighting the need for more sensitive and understanding of the pathobiology and disease multiplex platforms for testing and diagnosing boundaries of autoimmune encephalitis are therefore key encephalitis, including low-cost point-of-care testing to areas for future study. Standardised autoantibody better serve LMICs.145,146 Second, understanding of detection methods are also an important future aim; potentially modifiable host factors is inadequate, these methods should strive to retain conformationally particularly for genetic and immunological susceptibilities native formats of autoantigens to mimic those recognised in autoimmune and infectious encephalitis, despite these by IgG in vivo.16,20,34 In parallel, characterising the B-cell factors likely being paramount to understanding the and T-cell biology underlying autoantibody production pathogenesis of the conditions.47,147 Third, epidemio logical could improve understanding of the disease and guide data remain incomplete, especially in many LMICs, where novel diagnostics and therapeutics towards patient- under-diagnosis is prevalent given the insucient centric care pathways.111,133,160,161 contemporary diagnostic facilities and reporting systems (video 6).148 Finally, rehabilitation and supportive Conclusion See Online for video 6 interventions are under-explored, despite being beneficial The past few years have reclassified many enigmatic and for patients with encephalitis. idiopathic forms of encephalitis with molecularly In infectious encephalitis, emerging and re-emerging precise, aetiology-based definitions. However, improved aetiologies represent a major global health challenge, physician education regarding clinical presentations, driven by viral evolution, environmental changes, and targeted research agendas and funding to improve globalisation. Climate change has expanded the diagnostic capacities, and global public health initiatives geographical range and activity of mosquito and tick are essential to meet the WHO-designated, urgent public vectors, increasing cases of WNV and JEV, and introducing health aim of reducing the overall encephalitis burden Zika, Chikungunya, and Powassan viruses as causes of for survivors and their caregivers. Seminar Contributors 8 Jesudason T. WHO launches Technical Brief for encephalitis. SNMB, DS, AE, and KTT: conceptualisation, data curation, formal Lancet Microbe 2025; 6: 101129. analysis, methodology, visualisation, writing (original draft), and writing 9 WHO. Encephalitis: global threats, trends and public health (review and editing). SRI: conceptualisation, data curation, formal implications. Geneva, 2025. analysis, methodology, project administration, resource acquisition, 10 Piamonte BLC, Easton A, Wood GK, et al. Addressing vaccine- supervision, visualisation, writing (original draft), and writing (review and preventable encephalitis in vulnerable populations. editing). The authors confirm that the paper has not been submitted to Curr Opin Neurol 2023; 36: 185–97. another journal and has not been published in whole or part elsewhere. 11 Aboelezz A, Mahmoud SH. Acyclovir dosing in herpes encephalitis: a scoping review. J Am Pharm Assoc (2003) 2024; Declaration of interests 64(3): 102040. SNMB reports honoraria from Vetmeduni Wien and travel/hospitality 12 Whitley RJ, Soong S-J, Dolin R, Galasso GJ, Ch’ien LT, Alford CA. support from the American Neurological Association, Association of Ch’Ien LT, Alford CA. Adenine arabinoside therapy of biopsy-proved British Neurologists, Danish Neurological Society, European Committee herpes simplex encephalitis. N Engl J Med 1977; 297: 289–94. on Treatment and Research in Multiple Sclerosis (ECTRIMS), European 13 Thompson J, Bi M, Murchison AG, et al, and the Faciobrachial Academy of Neurology, and Wenner Gren Society. SNMB is a member of Dystonic Seizures Study Group. The importance of early Encephalitis International Scientific Advisory Panel. DS has received immunotherapy in patients with faciobrachial dystonic seizures. travel support from ECTRIMS and the National Multiple Sclerosis Brain 2018; 141: 348–56. Society. AE is the chief executive of the non-profit organisation 14 Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and Encephalitis International. AE personally receives no honoraria or grant prognostic factors for long-term outcome in patients with anti- support from Encephalitis International, which receives grants, NMDA receptor encephalitis: an observational cohort study. honoraria, speaker fees, and expenses from various sources, including Lancet Neurol 2013; 12: 157–65. pharmaceutical and diagnostic companies. KTT has received consulting 15 Irani SR. Autoimmune encephalitis. Continuum (Minneap Minn) fees from Delvie Bio, the Pan American Health Organization, and 2024; 30: 995–1020. WHO. KTT is a member of the Encephalitis International Scientific 16 Flanagan EP, Geschwind MD, Lopez-Chiriboga AS, et al. Advisory Panel. SRI has received honoraria/research support from UCB, Autoimmune encephalitis misdiagnosis in adults. JAMA Neurol Immunovant, MedImmun, Roche, Janssen, Cerebral therapeutics, ADC 2023; 80: 30–39. Therapeutics, Brain, CSL Behring, and ONO Pharma; licensed royalties 17 Bastiaansen AEM, van Steenhoven RW, Te Vaarwerk ES, et al. on patent application WO/2010/046716 entitled “neurological Antibodies associated with autoimmune encephalitis in patients autoimmune disorders”; has filed two other patents entitled “diagnostic with presumed neurodegenerative dementia. Neurol Neuroimmunol Neuroinflamm 2023; 10: e200137. method and therapy” (WO2019211633 and US-2021-0071249-A1; patent cooperation treaty [PCT] application WO202189788A1) and “biomarkers” 18 Segal Y, Soltys J, Clarkson BDS, Howe CL, Irani SR, Pittock SJ. Toward curing neurological autoimmune disorders: biomarkers, (PCT/GB2022/050614 and WO202189788A1); and is a member of immunological mechanisms, and therapeutic targets. Neuron 2025; scientific advisory panels for Encephalitis International, the Sumaira 113: 345–79. Foundation, and the Autoimmune Encephalitis Alliance. 19 Dalmau J, Graus F. Antibody-mediated encephalitis. N Engl J Med Acknowledgments 2018; 378: 840–51. SNMB is supported by a National Institute for Health and Care Research 20 Varley JA, Strippel C, Handel A, Irani SR. Autoimmune (NIHR) clinical lectureship and has received funding from the encephalitis: recent clinical and biological advances. J Neurol 2023; Oxfordshire Health Services Research Committee, PetSavers, and the 270: 4118–31. Morris Animal Foundation. DS has received funding from the National 21 Dubey D, Pittock SJ, Kelly CR, et al. Autoimmune encephalitis Institutes of Health (K01TW011771). KTT has received grants from the epidemiology and a comparison to infectious encephalitis. US Centers for Disease Control and Prevention and Delve Bio. SRI is Ann Neurol 2018; 83: 166–77. supported by the Wellcome (104079/Z/14/Z), the Medical Research 22 Gable MS, Sheri H, Dalmau J, Tilley DH, Glaser CA. Council (MRC; MR/V007173/1), the NIHR Oxford Biomedical Research The frequency of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses that of individual viral etiologies in young Centre, and the Mayo Clinic Robert and Arlene Kogod Center on Aging individuals enrolled in the California Encephalitis Project. (Aging Nervous System, 2024). The views expressed are those of the Clin Infect Dis 2012; 54: 899–904. authors and not necessarily those of the National Health Service, the 23 Huong NHT, Toan ND, Thien TB, et al. In children, NIHR, or the UK Government Department of Health. The funders had N-methyl-D-aspartate receptor antibody encephalitis incidence no role in the study. We acknowledge the input of Bryan Ceronie, exceeds that of Japanese encephalitis in Vietnam. Robyn Williams, Emma Collins, Praveen Prathapan, Sidharth Suresh, Open Forum Infect Dis 2024; 11: ofae710. Zoaib Tharwani, Mohsen Farazdaghi, Carla Kim, and Neal Thurley. 24 Nibber A, Wills B, Pettingill P, et al. Evolution and significance of References neuronal surface autoantibodies after Japanese encephalitis. 1 GBD 2021 Nervous System Disorders Collaborators. Global, J Neuroimmunol 2025; 406: 578671. regional, and national burden of disorders aecting the nervous 25 Ellul M, Solomon T. Acute encephalitis—diagnosis and system, 1990–2021: a systematic analysis for the Global Burden of management. Clin Med (Lond) 2018; 18: 155–59. Disease Study 2021. Lancet Neurol 2024; 23: 344–81. 26 Ropper AH, Samuels MA, Klein J, Prasad S. Adams and Victor’s 2 Granerod J, Huang Y, Davies NWS, et al. Global landscape of principles of neurology, 12th edn. McGraw Hill, 2023. encephalitis: key priorities to reduce future disease burden. 27 Slooter AJC, Otte WM, Devlin JW, et al. Updated nomenclature of Clin Infect Dis 2023; 77: 1552–60. delirium and acute encephalopathy: statement of ten societies. 3 Wang H, Zhao S, Wang S, et al. Global magnitude of encephalitis Intensive Care Med 2020; 46: 1020–22. burden and its evolving pattern over the past 30 years. J Infect 2022; 28 Erkkinen MG, Berkowitz AL. A clinical approach to diagnosing 84: 777–87. encephalopathy. Am J Med 2019; 132: 1142–47. 4 Jmor F, Emsley HC, Fischer M, Solomon T, Lewthwaite P. 29 Day GS. Rapidly progressive dementia. Continuum (Minneap Minn) The incidence of acute encephalitis syndrome in western 2022; 28: 901–36. industrialised and tropical countries. Virol J 2008; 5: 134. 30 Hermann P, Zerr I. Rapidly progressive dementias—aetiologies, 5 Vora NM, Holman RC, Mehal JM, Steiner CA, Blanton J, Sejvar J. diagnosis and management. Nat Rev Neurol 2022; 18: 363–76. Burden of encephalitis-associated hospitalizations in the 31 Pandya D, Johnson TP. Chronic and delayed neurological United States, 1998–2010. Neurology 2014; 82: 443–51. manifestations of persistent infections. Curr Opin Neurol 2023; 6 Granerod J, Cousens S, Davies NW, Crowcroft NS, Thomas SL. New 36: 198–206. estimates of incidence of encephalitis in England. Emerg Infect Dis 32 Graus F, Titulaer MJ, Balu R, et al. A clinical approach to 2013; 19: 1455–62. diagnosis of autoimmune encephalitis. Lancet Neurol 2016; 7 The Lancet Neurology. A pivotal recognition of the burden of 15: 391–404. encephalitis. Lancet Neurol 2025; 24: 179. 1980 Seminar 33 Ramanathan S, Brilot F, Irani SR, Dale RC. Origins and 55 Mazowiecki M, Flet-Berliac L, Roux J, et al. Long-term clinical and immunopathogenesis of autoimmune central nervous system biological prognostic factors of anti-NMDA receptor encephalitis in disorders. Nat Rev Neurol 2023; 19: 172–90. children. Neurol Neuroimmunol Neuroinflamm 2025; 12: e200346. 34 de Bruijn MAAM, Leypoldt F, Dalmau J, et al. Autoimmune 56 Cellucci T, Van Mater H, Graus F, et al. Clinical approach to the encephalitis. Nat Rev Dis Primers 2025; 11: 65. diagnosis of autoimmune encephalitis in the pediatric patient. 35 Zekeridou A. Paraneoplastic neurologic disorders. Neurol Neuroimmunol Neuroinflamm 2020; 7: e663. Continuum (Minneap Minn) 2024; 30: 1021–51. 57 Ciano-Petersen NL, Robert M, Muñiz-Castrillo S, et al. Prognostic 36 Graus F, Vogrig A, Muñiz-Castrillo S, et al. Updated diagnostic value of persistent CSF antibodies at 12 months in anti-NMDAR criteria for paraneoplastic neurologic syndromes. encephalitis. Neurol Neuroimmunol Neuroinflamm 2023; Neurol Neuroimmunol Neuroinflamm 2021; 8: e1014. 10: e200108. 37 Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor 58 Peer M, Prüss H, Ben-Dayan I, Paul F, Arzy S, Finke C. Functional encephalitis: case series and analysis of the eects of antibodies. connectivity of large-scale brain networks in patients with anti- Lancet Neurol 2008; 7: 1091–98. NMDA receptor encephalitis: an observational study. 38 Banwell B, Bennett JL, Marignier R, et al. Diagnosis of myelin Lancet Psychiatry 2017; 4: 768–74. oligodendrocyte glycoprotein antibody-associated disease: 59 Hamid SHM, Whittam D, Saviour M, et al. Seizures and International MOGAD Panel proposed criteria. Lancet Neurol 2023; encephalitis in myelin oligodendrocyte glycoprotein IgG disease vs 22: 268–82. aquaporin 4 IgG disease. JAMA Neurol 2018; 75: 65–71. 39 Valencia-Sanchez C, Guo Y, Krecke KN, et al. Cerebral cortical 60 Rada A, Reisch LM, Hagemann A, Woermann FG, Bien CG. encephalitis in myelin oligodendrocyte glycoprotein antibody- Temporal lobe epilepsy associated with glutamic acid decarboxylase associated disease. Ann Neurol 2023; 93: 297–302. antibodies. Neurology Neuroimmunol Neuroinflamm 2025; 12: e200422. 40 Irani SR, Alexander S, Waters P, et al. Antibodies to Kv1 potassium 61 Graus F, Saiz A, Dalmau J. GAD antibodies in neurological channel-complex proteins leucine-rich, glioma inactivated 1 disorders—insights and challenges. Nat Rev Neurol 2020; 16: 353–65. protein and contactin-associated protein-2 in limbic encephalitis, 62 Lee WJ, Lee HS, Kim DY, et al. Seronegative autoimmune Morvan’s syndrome and acquired neuromyotonia. Brain 2010; encephalitis: clinical characteristics and factors associated with 133: 2734–48. outcomes. Brain 2022; 145: 3509–21. 41 Kerstens J, Schreurs MWJ, de Vries JM, et al. Autoimmune 63 Farina A, Villagrán-García M, Vogrig A, et al. Neurological adverse encephalitis and paraneoplastic neurologic syndromes: a nationwide events of immune checkpoint inhibitors and the development of study on epidemiology and antibody testing performance. paraneoplastic neurological syndromes. Lancet Neurol 2024; 23: 81–94. Neurol Neuroimmunol Neuroinflamm 2024; 11: e200318. 64 Graham CE, Velasco R, Alarcon Tomas A, et al. Non-ICANS 42 Orozco E, Valencia-Sanchez C, Britton J, et al. Autoimmune neurological complications after CAR T-cell therapies: encephalitis criteria in clinical practice. Neurol Clin Pract 2023; recommendations from the EBMT Practice Harmonisation and 13: e200151. Guidelines Committee. Lancet Oncol 2025; 26: e203–13. 43 Ceronie B, Strippel C, Uy C, et al. Immunotherapy-resistant 65 Armangué T, Olivé-Cirera G, Martínez-Hernandez E, et al. neuropathic pain and fatigue predict quality-of-life in contactin- Neurologic complications in herpes simplex encephalitis: clinical, associated protein-like 2 antibody disease. Ann Neurol 2025; immunological and genetic studies. Brain 2023; 146: 4306–19. 97: 521–28. 66 Cleaver J, Jeery K, Klenerman P, et al. The immunobiology of 44 Dubey D, Wilson MR, Clarkson B, et al. Expanded clinical herpes simplex virus encephalitis and post-viral autoimmunity. phenotype, oncological associations, and immunopathologic Brain 2024; 147: 1130–48. insights of paraneoplastic Kelch-like protein-11 encephalitis. 67 Venkatesan A, Michael BD, Probasco JC, Geocadin RG, Solomon T. JAMA Neurol 2020; 77: 1420–29. Acute encephalitis in immunocompetent adults. Lancet 2019; 45 Irani SR, Michell AW, Lang B, et al. Faciobrachial dystonic seizures 393: 702–16. precede LGI1 antibody limbic encephalitis. Ann Neurol 2011; 68 Olie SE, Staal SL, van de Beek D, Brouwer MC. Diagnosing 69: 892–900. infectious encephalitis: a narrative review. Clin Microbiol Infect 2025; 46 Kelly MJ, Grant E, Murchison AG, et al. Magnetic resonance 31: 522–28. imaging characteristics of LGI1-antibody and CASPR2-antibody 69 Quan TM, Thao TTN, Duy NM, Nhat TM, Clapham H. Estimates of encephalitis. JAMA Neurol 2024; 81: 525–33. the global burden of Japanese encephalitis and the impact of 47 Binks S, Varley J, Lee W, et al. Distinct HLA associations of LGI1 vaccination from 2000–2015. eLife 2020; 9: e51027. and CASPR2-antibody diseases. Brain 2018; 141: 2263–71. 70 Lin FH, Chou YC, Hsieh CJ, Yu CP. Epidemiological features, 48 Irani SR, Bera K, Waters P, et al. N-methyl-D-aspartate antibody clinical symptoms, and environmental risk factors for notifiable encephalitis: temporal progression of clinical and paraclinical Japanese encephalitis in Taiwan from 2008 to 2020: retrospective observations in a predominantly non-paraneoplastic disorder of study. JMIR Public Health Surveill 2025; 11: e63053. both sexes. Brain 2010; 133: 1655–67. 71 Hills SL, Netravathi M, Solomon T. Japanese encephalitis among 49 Al-Diwani A, Theorell J, Damato V, et al. Cervical lymph nodes and adults: a review. Am J Trop Med Hyg 2023; 108: 860–64. ovarian teratomas as germinal centres in NMDA receptor-antibody 72 Hills SL, Griggs AC, Fischer M. Japanese encephalitis in travelers encephalitis. Brain 2022; 145: 2742–54. from non-endemic countries, 1973–2008. Am J Trop Med Hyg 2010; 50 Bastiaansen AEM, de Bruijn MAAM, Schuller SL, et al. Anti- 82: 930–36. NMDAR encephalitis in the Netherlands, focusing on late-onset 73 Zheng P, Wen Z, Liu Y, Wang Q. The spatiotemporal distribution patients and antibody test accuracy. and prognostic factors of Japanese encephalitis in Shanxi Province, Neurol Neuroimmunol Neuroinflamm 2021; 9: e1127. China, 2005–2022. Front Cell Infect Microbiol 2023; 13: 1291816. 51 Al-Diwani A, Handel A, Townsend L, et al. The psychopathology of 74 Guo H, Sun L, Shen X, Hu W. A retrospective study of the clinical NMDAR-antibody encephalitis in adults: a systematic review and characteristics of Japanese encephalitis in adults. J Integr Neurosci phenotypic analysis of individual patient data. Lancet Psychiatry 2022; 21: 125. 2019; 6: 235–46. 75 Dale RC, Mohammad SS. Movement disorders associated with 52 Dalmau J, Armangué T, Planagumà J, et al. An update on anti- pediatric encephalitis. Handb Clin Neurol 2024; 200: 229–38. NMDA receptor encephalitis for neurologists and psychiatrists: 76 Luo H, Ding X, Li Y, et al. Clinical characteristics of children with mechanisms and models. Lancet Neurol 2019; 18: 1045–57. anti-N-methyl-D-aspartate receptor encephalitis after Japanese 53 Theorell J, Ramberger M, Harrison R, et al. Screening for encephalitis. Pediatr Neurol 2022; 130: 46–52. pathogenic neuronal autoantibodies in serum and CSF of patients 77 WHO. Japanese encephalitis vaccines: WHO position paper. with first-episode psychosis. Transl Psychiatry 2021; 11: 566. World Health Organization, 2015. 54 Al-Diwani A, Theorell J, Zghoul T, et al. The distinctive 78 Bradshaw MJ, Venkatesan A. Herpes simplex virus-1 encephalitis in psychopathology of NMDAR-antibody encephalitis compared with adults: pathophysiology, diagnosis, and management. primary psychoses: an international, multicentre, retrospective Neurotherapeutics 2016; 13: 493–508. phenotypic analysis. Lancet Psychiatry 2026; 13: 47–61. Seminar 79 Poussier L, Mailles A, Tattevin P, et al. Characteristics, management 100 Cheng-Ching E, Jones S, Hui FK, et al. High-resolution MRI vessel and outcome of herpes simplex and varicella-zoster virus wall imaging in varicella zoster virus vasculopathy. J Neurol Sci encephalitis: a multicentre prospective cohort study. 2015; 351: 168–73. Clin Microbiol Infect 2024; 30: 917–23. 101 Nagel MA, Forghani B, Mahalingam R, et al. The value of detecting 80 Aboelezz A, Kharouba M, Mahmoud SH. Acyclovir dosing anti-VZV IgG antibody in CSF to diagnose VZV vasculopathy. strategies in herpes encephalitis: a retrospective charts review. Neurology 2007; 68: 1069–73. J Clin Neurosci 2025; 136: 111230. 102 Arumugam I, Rajasekaran SS, Gopalakrishnan K, et al. Diagnostic 81 de Montmollin E, Dupuis C, Jaquet P, et al, and the value of anti-VZV IgG in neurological diseases among varicella ENCEPHALITICA Study Group. Herpes simplex virus encephalitis unvaccinated individuals. J Neurovirol 2024; 30: 327–35. with initial negative polymerase chain reaction in the cerebrospinal 103 Arevalo-Rodriguez I, Ciapponi A, Roqué i Figuls M, Muñoz L, fluid: prevalence, associated factors, and clinical impact. Bonfill Cosp X. Posture and fluids for preventing post-dural Crit Care Med 2022; 50: e643–48. puncture headache. Cochrane Database Syst Rev 2016; 3: CD009199. 82 Sunnerhagen T, Widén J, Handhal S, Özkaya Şahin G. A retrospective 104 Engelborghs S, Niemantsverdriet E, Struyfs H, et al. Consensus observational study of 1000 consecutive patients tested with the guidelines for lumbar puncture in patients with neurological FilmArray® Meningitis/Encephalitis panel: clinical diagnosis at diseases. Alzheimers Dement (Amst) 2017; 8: 111–26. discharge and microbiological findings. Sci Rep 2024; 14: 4015. 105 Glimåker M, Sjölin J, Åkesson S, Naucler P. Lumbar puncture 83 Boers SA, van Houdt R, van Sorge NM, et al. A multicenter performed promptly or after neuroimaging in acute bacterial evaluation of the QIAstat-Dx meningitis-encephalitis syndromic test meningitis in adults: a prospective national cohort study evaluating kit as compared to the conventional diagnostic microbiology dierent guidelines. Clin Infect Dis 2018; 66: 321–28. workflow. Eur J Clin Microbiol Infect Dis 2024; 43: 511–16. 106 Park N, Nigo M, Hasbun R. Comparison of four international 84 Poran I, Basharim B, Leibovici-Weisman Y, Michaelis M, guidelines on the utility of cranial imaging before lumbar puncture in Ghantous N, Eliakim-Raz N. Characteristics and clinical outcomes adults with bacterial meningitis. Clin Neuroradiol 2022; 32: 857–62. of the West Nile virus outbreak in Israel 2024: a retrospective cohort 107 Salazar L, Hasbun R. Cranial imaging before lumbar puncture in study. Diagn Microbiol Infect Dis 2025; 113: 116936. adults with community-acquired meningitis: clinical utility and 85 McDonald E, Mathis S, Martin SW, Staples JE, Fischer M, adherence to the Infectious Diseases Society of America guidelines. Lindsey NP. Surveillance for West Nile virus disease— Clin Infect Dis 2017; 64: 1657–62. United States, 2009–2018. MMWR Surveill Summ 2021; 70: 1–15. 108 Glimåker M, Johansson B, Grindborg Ö, Bottai M, Lindquist L, 86 European Centre for Disease Prevention and Control. Sjölin J. Adult bacterial meningitis: earlier treatment and improved Epidemiological update: West Nile virus transmission season in outcome following guideline revision promoting prompt lumbar Europe, 2022. European Centre for Disease Prevention and Control, puncture. Clin Infect Dis 2015; 60: 1162–69. 2023. 109 Habis R, Kolchinski A, Heck AN, et al. Absence of cerebrospinal 87 Maayan Eshed G, Levinson T, Mina Y, et al. West Nile virus fluid pleocytosis in encephalitis. Clin Infect Dis 2025; 81: 179–87. encephalitis: clinical characteristics and a comparison to other 110 Räuber S, Schulte-Mecklenbeck A, Willison A, et al. Flow cytometry infectious encephalitides. J Neurol Sci 2024; 467: 123286. identifies changes in peripheral and intrathecal lymphocyte patterns 88 Sabadi D, Bodulić K, Savić V, et al. Clinical characteristics, in CNS autoimmune disorders and primary CNS malignancies. laboratory parameters, and molecular epidemiology of J Neuroinflammation 2024; 21: 286. neuroinvasive flavivirus infections in a hotspot region of eastern 111 Theorell J, Harrison R, Williams R, et al. Ultrahigh frequencies of Croatia. Pathogens 2025; 14: 69. peripherally matured LGI1- and CASPR2-reactive B cells 89 Rhoades RE, Tabor-Godwin JM, Tsueng G, Feuer R. Enterovirus characterize the cerebrospinal fluid in autoimmune encephalitis. infections of the central nervous system. Virology 2011; 411: 288–305. Proc Natl Acad Sci USA 2024; 121: e2311049121. 90 Fowler A, Stödberg T, Eriksson M, Wickström R. Childhood 112 Dalmau J, Graus F. Diagnostic criteria for autoimmune encephalitis in Sweden: etiology, clinical presentation and outcome. encephalitis: utility and pitfalls for antibody-negative disease. Eur J Paediatr Neurol 2008; 12: 484–90. Lancet Neurol 2023; 22: 529–40. 91 Huang CC, Liu CC, Chang YC, Chen CY, Wang ST, Yeh TF. 113 Morris H, Kaplan PW, Kane N. Electroencephalography in Neurologic complications in children with enterovirus 71 infection. encephalopathy and encephalitis. Pract Neurol 2024; 24: 2–10. N Engl J Med 1999; 341: 936–42. 114 Binaghi E, Schwab N, Capecchi F, et al. EEG variability in 92 Misra UK, Tan CT, Kalita J. Viral encephalitis and epilepsy. Epilepsia inflammatory encephalopathy: Dissemination in time and space. 2008; 49 (suppl 6): 13–18. Clin Neurophysiol 2025; 180: 2111402. 93 Lin CY, Huang SY, Jiang CB, Peng CC, Chi H, Chiu NC. 115 Abboud H, Probasco J, Irani SR, et al, and the Autoimmune Enteroviral rhombencephalitis with abducens nerve palsy and Encephalitis Alliance Clinicians Network. Autoimmune cardio-pulmonary failure in a 2-year-old boy. Children (Basel) 2022; encephalitis: proposed recommendations for symptomatic and long- 9: 643. term management. J Neurol Neurosurg Psychiatry 2021; 92: 897–907. 94 Greninger AL, Naccache SN, Messacar K, et al. A novel outbreak 116 Rada A, Hagemann A, Aaberg Poulsen C, et al. Risk of seizure enterovirus D68 strain associated with acute flaccid myelitis cases recurrence due to autoimmune encephalitis with NMDAR, LGI1, in the USA (2012–14): a retrospective cohort study. Lancet Infect Dis CASPR2, and GABAR antibodies: implications for return to 2015; 15: 671–82. driving. Neurol Neuro B immunol Neuroinflamm 2024; 11: e200225. 95 Lam C, Chen E, Thevathasan A, et al. Clinical characteristics and 117 Steriade C, Britton J, Dale RC, et al. Acute symptomatic seizures treatment of varicella zoster virus central nervous system secondary to autoimmune encephalitis and autoimmune-associated infection in an Australian tertiary hospital. Intern Med J 2025; epilepsy: conceptual definitions. Epilepsia 2020; 61: 1341–51. 55: 1152–60. 118 Wood GK, Babar R, Ellul MA, et al. Acute seizure risk in patients 96 Lenfant T, L’Honneur AS, Ranque B, et al. Neurological with encephalitis: development and validation of clinical prediction complications of varicella zoster virus reactivation: prognosis, models from two independent prospective multicentre cohorts. diagnosis, and treatment of 72 patients with positive PCR in the BMJ Neurol Open 2022; 4: e000323. cerebrospinal fluid. Brain Behav 2022; 12: e2455. 119 Singh TD, Fugate JE, Hocker S, Wijdicks EFM, Aksamit AJ Jr, 97 Landré S, Ader F, Epaulard O, Tattevin P, Stahl JP, Mailles A. Rabinstein AA. Predictors of outcome in HSV encephalitis. J Neurol Encephalitis in HIV-negative immunodeficient patients: 2016; 263: 277–89. a prospective multicentre study, France, 2016 to 2019. Euro Surveill 120 Solomon T, Hooper C, Easton A, et al, and the DexEnceph Study 2024; 29: 2300046. Group. Safety and ecacy of adjunct dexamethasone in adults with 98 Maher MD, Douglas VP, Douglas KAA, et al. Clinical and herpes simplex virus encephalitis in the UK (DexEnceph): neuroradiologic characteristics in varicella zoster virus reactivation a multicentre, observer-blind, randomised, phase 3, controlled trial. with central nervous system involvement. J Neurol Sci 2022; Lancet Neurol 2026; 25: 136–46. 437: 120262. 121 Karim M, Lo CW, Einav S. Preparing for the next viral threat with 99 Lizzi J, Hill T, Jakubowski J. Varicella zoster virus encephalitis. broad-spectrum antivirals. J Clin Invest 2023; 133: e170236. Clin Pract Cases Emerg Med 2019; 3: 380–82. 1982 Seminar 122 Abboud H, Probasco JC, Irani S, et al, and the Autoimmune 142 Easton A. A call for awareness in encephalitis. Lancet Neurol 2024; Encephalitis Alliance Clinicians Network. Autoimmune 23: 337–38. encephalitis: proposed best practice recommendations for diagnosis 143 Lim JA, Lee ST, Moon J, et al. Development of the clinical and acute management. J Neurol Neurosurg Psychiatry 2021; assessment scale in autoimmune encephalitis. Ann Neurol 2019; 92: 757–68. 85: 352–58. 123 Grüter T, Möllers FE, Tietz A, et al, and the German Network for 144 Lewthwaite P, Begum A, Ooi MH, et al. Disability after encephalitis: Research on Autoimmune Encephalitis (GENERATE). Clinical, development and validation of a new outcome score. serological and genetic predictors of response to immunotherapy in Bull World Health Organ 2010; 88: 584–92. anti-IgLON5 disease. Brain 2023; 146: 600–11. 145 Benoit P, Brazer N, de Lorenzi-Tognon M, et al. Seven-year 124 Dubey D, Britton J, McKeon A, et al. Randomized placebo- performance of a clinical metagenomic next-generation sequencing controlled trial of intravenous immunoglobulin in autoimmune test for diagnosis of central nervous system infections. Nat Med LGI1/CASPR2 epilepsy. Ann Neurol 2020; 87: 313–23. 2024; 30: 3522–33. 125 Abboud H, Clardy SL, Dubey D, et al. The clinical trial landscape in 146 Fu Y, Bi J, Yan Y, et al. Rapid Immunodot AQP4 assay for autoimmune encephalitis: challenges and opportunities. Neurology neuromyelitis optica spectrum disorder. JAMA Neurol 2023; 2025; 104: e213487. 80: 1105–12. 126 van Sonderen A, Thijs RD, Coenders EC, et al. Anti-LGI1 147 Zhang S-Y, Casanova J-L. Genetic defects of brain immunity in encephalitis: clinical syndrome and long-term follow-up. Neurology childhood herpes simplex encephalitis. Nature 2024; 635: 563–73. 2016; 87: 1449–56. 148 Saylor D, Elafros M, Bearden D, et al. Patient, provider, and health 127 Guo K, Peng F, Liu J, et al. Ecacy and safety of ofatumumab systems factors leading to lumbar puncture non-performance in treatment for anti-NMDA receptor autoimmune encephalitis Zambia: a qualitative investigation of the “tap gap”. (OFF-AE): a prospective, multicenter cohort study. Ann Neurol 2025; Am J Trop Med Hyg 2023; 108: 1052–62. 98: 80–92. 149 Mordecai EA, Ryan SJ, Caldwell JM, Shah MM, LaBeaud AD. 128 Thaler FS, Zimmermann L, Kammermeier S, et al, and the German Climate change could shift disease burden from malaria to Network for Research on Autoimmune Encephalitis (GENERATE). arboviruses in Africa. Lancet Planet Health 2020; 4: e416–23. Rituximab treatment and long-term outcome of patients with 150 Kocabiyik DZ, Álvarez LF, Durigon EL, Wrenger C. West Nile autoimmune encephalitis: real-world evidence from the virus—a re-emerging global threat: recent advances in vaccines and GENERATE registry. Neurol Neuroimmunol Neuroinflamm 2021; drug discovery. Front Cell Infect Microbiol 2025; 15: 1568031. 8: e1088. 151 Madhukalya R, Yadav U, Parray HA, et al. Nipah virus: 129 Xu J, Guo Z, Zhao J, Chen Y, Liu Z, Wu Y. Efgartigimod treatment pathogenesis, genome, diagnosis, and treatment. for therapy-refractory autoimmune encephalitis with coexistent Appl Microbiol Biotechnol 2025; 109: 158. NMDAR and LGI1 antibodies: a case report and literature review. 152 Do LAH, Mulholland K. Measles 2025. N Engl J Med 2025; Neurol Sci 2025; 46: 1995–2005. 393: 2447–58. 130 Trewin BP, Freeman I, Ramanathan S, Irani SR. Immunotherapy in 153 Willison AG, Pawlitzki M, Lunn MP, Willison HJ, Hartung H-P, autoimmune encephalitis. Curr Opin Neurol 2022; 35: 399–414. Meuth SG. SARS-CoV-2 vaccination and neuroimmunological 131 Kanno A, Kito T, Maeda M, et al. Monoclonal humanized disease: a review. JAMA Neurol 2024; 81: 179–86. monovalent antibody blocking therapy for anti-NMDA receptor 154 Handel AE, Palace J, Bateman E, Waters P, Irani SR. Changes in encephalitis. Nat Commun 2025; 16: 5292. the rate of leucine-rich glioma-inactivated 1 seropositivity during 132 Maudes E, Planaguma J, Marmolejo L, et al. Neuro-immunobiology the COVID-19 lockdown. JAMA Neurol 2023; 80: 419–20. and treatment assessment in a mouse model of anti-NMDAR 155 Mattozzi S, Sabater L, Escudero D, et al. Hashimoto encephalopathy encephalitis. Brain 2025; 148: 2023–37. in the 21st century. Neurology 2020; 94: e217–24. 133 Reincke SM, von Wardenburg N, Homeyer MA, et al. Chimeric 156 Gilbert DL, Mink JW, Singer HS. A pediatric neurology perspective autoantibody receptor T cells deplete NMDA receptor-specific on pediatric autoimmune neuropsychiatric disorder associated with B cells. Cell 2023; 186: 5084–5097. streptococcal infection and pediatric acute-onset neuropsychiatric 134 Thakolwiboon S, Gilligan M, Orozco E, et al. Autoimmune syndrome. J Pediatr 2018; 199: 243–51. encephalitis: recovery, residual symptoms and predictors of long- 157 Board of D. Pediatric acute-onset neuropsychiatric syndrome term sequelae. J Neurol Neurosurg Psychiatry 2025; 96: 736–43. (PANS). Pediatrics 2025; 155. 135 Kelly MJ, Wagner B, Ceronie B, et al. Capturing what matters: 158 Santoro JD, Jafarpour S, Keehan L, et al. Diagnostic patient-reported LGI1-ANTibody encephalitis outcome RatiNg scale abnormalities, disease severity and immunotherapy (LANTERN). Ann Clin Transl Neurol 2025; 12: 821–31. responsiveness in individuals with Down syndrome regression 136 Brenner J, Olijslagers SHC, Crijnen YS, de Vries JM, disorder. Sci Rep 2024; 14: 30865. Mandarakas MR, Titulaer MJ. Clinical outcome assessments in 159 Dalmau J, Graus F. Autoimmune encephalitis-misdiagnosis, encephalitis: a systematic review. misconceptions, and how to avoid them. JAMA Neurol 2023; Neurol Neuroimmunol Neuroinflamm 2024; 11: e200168. 80: 12–14. 137 Tooren HVD, Easton A, Hooper C, et al. How should we define a 160 Damato V, Theorell J, Al-Diwani A, et al. Rituximab abrogates “good” outcome from encephalitis? A systematic review of the range aquaporin-4-specific germinal center activity in patients with of outcome measures used in the long-term follow-up of patients neuromyelitis optica spectrum disorders. Proc Natl Acad Sci USA with encephalitis. Clin Med (Lond) 2022; 22: 145–48. 2022; 119: e2121804119. 138 Binks SNM, Veldsman M, Handel AE, et al. Fatigue predicts quality 161 Sun B, Fernandes D, Soltys J, et al. Permissive central tolerance of life after leucine-rich glioma-inactivated 1-antibody encephalitis. plus defective peripheral checkpoints license pathogenic memory Ann Clin Transl Neurol 2024; 11: 1053–58. B cells in CASPR2-antibody encephalitis. Sci Adv 2025; 139 Krohn S, Müller-Jensen L, Kuchling J, et al. Cognitive deficits in 11: eadr9986. anti-LGI1 encephalitis are linked to immunotherapy-resistant white matter network changes. Neurol Neuroimmunol Neuroinflamm 2025; 12: e200360. Copyright © 2026 Elsevier Ltd. All rights reserved, including those for 140 von Schwanenflug N, Ramirez-Mahaluf JP, Krohn S, et al. Reduced text and data mining, AI training, and similar technologies. resilience of brain state transitions in anti-N-methyl-D-aspartate receptor encephalitis. Eur J Neurosci 2023; 57: 568–79. 141 Pöyhönen H, Setänen S, Isaksson N, et al. Neurological and cognitive performance after childhood encephalitis. Front Pediatr 2021; 9: 646684. --- [PDF原文](https://sci-net.xyz/storage/7932541/5ca57d3104e83b173a5b18691130d99fb31dc59c1f388310abb2d325bf51eac0/Encephalitis.pdf) DOI: 10.1016/S0140-6736(26)00363-6