Review articles

Current status and challenges of biomarker research in autoimmune encephalitis

  • KONG Xueying ,
  • HONG Zhen
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  • Department of Neurology, West China Hospital of Sichuan University, Sichuan Chengdu 610041, China

Received date: 2026-01-06

  Revised date: 2026-03-11

  Accepted date: 2026-03-12

  Online published: 2026-04-25

Abstract

Autoimmune encephalitis (AE) is a group of immune-mediated inflammatory diseases of the central nervous system, characterized by diverse and complex clinical manifestations, posing challenges for early diagnosis and risk assessment. Specific autoantibody testing plays a central role in the classification and diagnosis of AE. However, in clinical scenarios where antibody testing is limited or antibodies are negative (30%-50% of AE cases are antibody-negative AE), relying solely on antibody detection is often insufficient to meet the diagnostic and treatment needs of AE. In recent years, research on non-antibody biomarkers, including soluble biomarkers in blood and cerebrospinal fluid, imaging changes, and genetic susceptibility, has rapidly advanced. These studies not only deepen the understanding of AE pathobiology but also provide a potential basis for auxiliary diagnosis, treatment response evaluation, and individualized treatment in clinical practice. Nevertheless, the validation of non-antibody biomarkers remains limited, detection standards are not yet unified, and their clinical application still faces multiple challenges. Future research should leverage large-scale prospective cohorts, integrate artificial intelligence and other advanced technologies, and systematically investigate the value of dynamic changes in non-antibody biomarkers and multi-marker combined assessment in early diagnosis, treatment monito-ring, and prognosis evaluation of AE, thereby promoting the clinical translation of precision diagnosis and treatment for AE.

Cite this article

KONG Xueying , HONG Zhen . Current status and challenges of biomarker research in autoimmune encephalitis[J]. Journal of Diagnostics Concepts & Practice, 2026 , 25(02) : 218 -224 . DOI: 10.16150/j.1671-2870.2026.02.013

References

[1] DALMAU J, GRAUS F. Antibody-mediated encephalitis[J]. N Engl J Med, 2018, 378(9):840-851.
[2] GRAUS F, TITULAER M J, BALU R, et al. A clinical approach to diagnosis of autoimmune encephalitis[J]. Lancet Neurol, 2016, 15(4):391-404.
[3] 洪桢, 程鹏. 自身免疫性脑炎靶向治疗进展及展望[J]. 神经病学与神经康复学杂志, 2025, 21(6):433-444.
  HONG Z, CHENG P. Progress and prospects in targeted therapy for autoimmune encephalitis[J]. J Neurol Neurorehabil, 2025, 21(6):433-444.
[4] BALU R, MCCRACKEN L, LANCASTER E, et al. A score that predicts 1-year functional status in patients with anti-NMDA receptor encephalitis[J]. Neurology, 2019, 92(3):e244-e252.
[5] GRESA-ARRIBAS N, TITULAER M J, TORRENTS A, et al. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: A retrospective study[J]. Lancet Neurol, 2014, 13(2):167-177.
[6] 王红欣, 姚东陂. 首次发作的成人MOG-IgG相关疾病临床特点分析[J]. 神经病学与神经康复学杂志, 2024, 20(1):1-7.
  WANG H X, YAO D P. Analysis of the clinical characte-ristics of first-episode MOG-IgG associated disorders in adults[J]. J Neurol Neurorehabil, 2024, 20(1):1-7.
[7] DI COSMO L, MULIC-AL BUNNI S, GOH Y, et al. Systematic review and meta-analysis of the clinical features associated with seronegative autoimmune encephalitis[J]. Neurol Neuroimmunol Neuroinflamm, 2026, 13(2):e200540.
[8] MUELLER S H, F?RBER A, PRüSS H, et al. Genetic predisposition in anti-LGI1 and anti-NMDA receptor encephalitis[J]. Ann Neurol, 2018, 83(4):863-869.
[9] SHU Y, QIU W, ZHENG J, et al. HLA class II alleleDRB1*16: 02is associated with anti-NMDAR encephalitis[J]. J Neurol Neurosurg Psychiatry, 2019, 90(6):652-658.
[10] LIU X, ZHENG X, SHU Y, et al. Genome-wide association study identifies IFIH1 and HLA-DQB1*05: 02 loci associated with anti-NMDAR encephalitis[J]. Neurol Neuroimmunol Neuroinflamm, 2024, 11(3):e200221.
[11] ARMANGUE T, BAUCELLS B J, VLAGEA A, et al. Toll-like receptor 3 deficiency in autoimmune encephalitis post-herpes simplex encephalitis[J]. Neurol Neuroimmunol Neuroinflamm, 2019, 6(6):e611.
[12] VAN SONDEREN A, ROELEN D L, STOOP J A, et al. Anti-LGI1 encephalitis is strongly associated with HLA-DR7 and HLA-DRB4[J]. Ann Neurol, 2017, 81(2):193-198.
[13] LIU X, GUO K D, LIN J, et al. HLA-DRB1*03: 01 is associated with female sex and younger age of anti-LGI1 encephalitis[J]. Euro J Neurology, 2022, 29(8):2367-2375.
[14] KIM T J, LEE S T, MOON J, et al. Anti-LGI1 encephalitis is associated with unique HLA subtypes[J]. Ann Neurol, 2017, 81(2):183-192.
[15] GRüTER T, M?LLERS F E, TIETZ A, et al. Clinical, serological and genetic predictors of response to immunotherapy in anti-IgLON5 disease[J]. Brain, 2023, 146(2):600-611.
[16] GAIG C, ERCILLA G, DAURA X, et al. HLA and microtubule-associated protein tau H1 haplotype associations in anti-IgLON5 disease[J]. Neurol Neuroimmunol Neuroinflamm, 2019, 6(6):e605.
[17] YOGESHWAR S M MU? IZ-CASTRILLO S, SABATER L, et al. HLA-DQB1*05 subtypes and not DRB1*10:01 mediates risk in anti-IgLON5 disease[J]. Brain, 2024, 147(7): 2579-2592.
[18] STRIPPEL C, HERRERA-RIVERO M, WENDORFF M, et al. A genome-wide association study in autoimmune neurological syndromes with anti-GAD65 autoantibodies[J]. Brain, 2023, 146(3):977-990.
[19] MU?IZ-CASTRILLO S, AMBATI A, DUBOIS V, et al. Primary DQ effect in the association between HLA and neurological syndromes with anti-GAD65 antibodies[J]. J Neurol, 2020, 267(7):1906-1911.
[20] BECHER B, SPATH S, GOVERMAN J. Cytokine networks in neuroinflammation[J]. Nat Rev Immunol, 2017, 17(1):49-59.
[21] LEYPOLDT F, H?FTBERGER R, TITULAER M J, et al. Investigations on CXCL13 in anti-N-methyl-D-aspartate receptor encephalitis: A potential biomarker of treatment response[J]. JAMA Neurol, 2015, 72(2):180.
[22] DENG B, LIU X N, LI X, et al. Raised cerebrospinal fluid BAFF and APRIL levels in anti-N-methyl-d-aspartate receptor encephalitis: Correlation with clinical outcome[J]. J Neuroimmunol, 2017,305:84-91.
[23] LIBA Z, KAYSEROVA J, ELISAK M, et al. Anti-N-methyl-D-aspartate receptor encephalitis: The clinical course in light of the chemokine and cytokine levels in cerebrospinal fluid[J]. J Neuroinflammation, 2016, 13(1):55.
[24] ZENG C, CHEN L, CHEN B, et al. Th17 cells were recruited and accumulated in the cerebrospinal fluid and correlated with the poor prognosis of anti-NMDAR encephalitis[J]. Acta Biochim Biophys Sin, 2018, 50(12):1266-1273.
[25] PENG Y, LIU B, PEI S, et al. Higher CSF levels of NLRP3 inflammasome is associated with poor prognosis of anti-N-methyl-D-aspartate receptor encephalitis[J]. Front Immunol, 2019,10:905.
[26] KOTHUR K, WIENHOLT L, MOHAMMAD S S, et al. Utility of CSF cytokine/chemokines as markers of active intrathecal inflammation: Comparison of demyelinating, anti-NMDAR and enteroviral encephalitis[J]. PLoS One, 2016, 11(8):e0161656.
[27] K?RTVELYESSY P, GOIHL A, GUTTEK K, et al. Serum and CSF cytokine levels mirror different neuroimmunological mechanisms in patients with LGI1 and Caspr2 encephalitis[J]. Cytokine, 2020,135:155226.
[28] LEVRAUT M, BOURG V, CAPET N, et al. Cerebrospinal fluid IL-17A could predict acute disease severity in non-NMDA-receptor autoimmune encephalitis[J]. Front Immunol, 2021,12:673021.
[29] MU?OZ-SáNCHEZ G, GUASP M, MU?OZ-LOPETEGI A, et al. Cytokine and chemokine profiles in anti-LGI1 encephalitis: Markers of severity and outcome[J]. Neurol Neuroimmunol Neuroinflamm, 2025, 12(6):e200492.
[30] YANG X, HUANG Q, YANG H, et al. Astrocytic damage in glial fibrillary acidic protein astrocytopathy during initial attack[J]. Mult Scler Relat Disord, 2019,29:94-99.
[31] FARINA A, VILLAGRáN-GARCíA M, ABICHOU-KLICH A, et al. Serum neurofilament light chain correlates with clinical severity and predicts mortality in anti-IgLON5 disease[J]. Neurol Neuroimmunol Neuroinflamm, 2025, 12(6):e200498.
[32] BRENNER J, MARIOTTO S, BASTIAANSEN A E M, et al. Predictive value of serum neurofilament light chain levels in anti-NMDA receptor encephalitis[J]. Neurology, 2023, 100(21):e2204-e2213.
[33] BUSINARO P, MASCIOCCHI S, BARNABEI R, et al. Serum autoantibody titers and neurofilament light chain levels in CASPR2/LGI1 encephalitis: A longitudinal study[J]. Neurol Neuroimmunol Neuroinflamm, 2025, 12(5):e200431.
[34] WESSELINGH R, GRIFFITH S, KO K, et al. Biomarkers of neuroaxonal and astrocytic pathology in autoimmune encephalitis[J]. Brain Behav Immun, 2026,132:106206.
[35] CONSTANTINESCU R, KRYSL D, BERGQUIST F, et al. Cerebrospinal fluid markers of neuronal and glial cell damage to monitor disease activity and predict long-term outcome in patients with autoimmune encephalitis[J]. Euro J Neurology, 2016, 23(4):796-806.
[36] LIU B, XIE Z, LIU G, et al. Elevated neuron-specific enolase and S100 calcium-binding protein B concentrations in cerebrospinal fluid of patients with anti-N-methyl- d-aspartate receptor encephalitis[J]. Clin Chim Acta, 2018,480:79-83.
[37] DAY G S, YARBROUGH M Y, K?RTVELYESSY P, et al. Prospective quantification of CSF biomarkers in antibody-mediated encephalitis[J]. Neurology, 2021, 96(20):e2546-e2557.
[38] DING Y W, PAN S Y, XIE W, et al. Elevated soluble fas and FasL in cerebrospinal fluid and serum of patients with anti-N-methyl-D-aspartate receptor encephalitis[J]. Front Neurol, 2018,9:904.
[39] BORIONI M S, MORANO A, DE MATTEIS A L, et al. Neuroglial biomarkers in autoimmune encephalitis: Advances in diagnosis, prognosis, and pathophysiological insights[J]. Neurol Sci, 2025, 46(10):4925-4941.
[40] SANVITO F, PICHIECCHIO A, PAOLETTI M, et al. Autoimmune encephalitis: What the radiologist needs to know[J]. Neuroradiology, 2024, 66(5):653-675.
[41] FINKE C, KOPP U A, PAJKERT A, et al. Structural hippocampal damage following anti-N-methyl-D-aspartate receptor encephalitis[J]. Biol Psychiatry, 2016, 79(9):727-734.
[42] FINKE C, PRüSS H, HEINE J, et al. Evaluation of cognitive deficits and structural hippocampal damage in encephalitis with leucine-rich, glioma-inactivated 1 antibodies[J]. JAMA Neurol, 2017, 74(1):50.
[43] PEER M, PRüSS H, BEN-DAYAN I, et al. Functional connectivity of large-scale brain networks in patients with anti-NMDA receptor encephalitis: An observational study[J]. Lancet Psychiatry, 2017, 4(10):768-774.
[44] PHILLIPS O R, JOSHI S H, NARR K L, et al. Superficial white matter damage in anti-NMDA receptor encephalitis[J]. J Neurol Neurosurg Psychiatry, 2018, 89(5):518-525.
[45] KOSEK S, KILSVED E, DANFORS T, et al. Regional metabolic abnormalities in autoimmune encephalitis: A meta-analysis of 498 cases with brain FDG PET[J]. Clin Nucl Med, 2025, 50(3):208-213.
[46] LEYPOLDT F, BUCHERT R, KLEITER I, et al. Fluorodeoxyglucose positron emission tomography in anti-N-methyl-D-aspartate receptor encephalitis: Distinct pattern of disease[J]. J Neurol Neurosurg Psychiatry, 2012, 83(7):681-686.
[47] YUAN J, GUAN H, ZHOU X, et al. Changing brain metabolism patterns in patients with ANMDARE: Serial 18F-FDG PET/CT findings[J]. Clin Nucl Med, 2016, 41(5):366-370.
[48] GE J, DENG B, GUAN Y, et al. Distinct cerebral 18F-FDG PET metabolic patterns in anti-N-methyl-D-aspartate receptor encephalitis patients with different trigger factors[J]. Ther Adv Neurol Disord, 2021,14:1756286421995635.
[49] NIE B, XU X, DONG W, et al. 18F- FDG PET reveals a nucleus accumbens-centered metabolic network correla-ting with clinical severity in anti-LGI1 encephalitis[J]. MedComm, 2025, 6(12):e70544.
[50] LLORENS V, GABILONDO I, GóMEZ-ESTEBAN J C, et al. Abnormal multifocal cerebral blood flow on Tc-99m HMPAO SPECT in a patient with anti-NMDA-receptor encephalitis[J]. J Neurol, 2010, 257(9):1568-1569.
[51] IIZUKA T, YOSHII S, KAN S, et al. Reversible brain atrophy in anti-NMDA receptor encephalitis: A long-term observational study[J]. J Neurol, 2010, 257(10):1686-1691.
[52] DALMAU J, GLEICHMAN A J, HUGHES E G, et al. Anti-NMDA-receptor encephalitis: Case series and analysis of the effects of antibodies[J]. Lancet Neurol, 2008, 7(12):1091-1098.
[53] BAYKAN B, GUNGOR TUNCER O, VANLI-YAVUZ E N, et al. Delta brush pattern is not unique to NMDAR encephalitis: Evaluation of two independent long-term EEG cohorts[J]. Clin EEG Neurosci, 2018, 49(4):278-284.
[54] BLACKMAN G, KUMAR K, HANRAHAN J G, et al. Quantitative EEG as a prognostic tool in suspected anti-N-methyl-d-aspartate receptor antibody encephalitis[J]. J Clin Neurophysiol, 2023, 40(2):160-164.
[55] DAVID CANCINO C A, TRENADO C, KAPLAN P W, et al. Quantitative electroencephalography biomarkers in patients with anti-N-methyl-D-aspartate receptor encephalitis: A case-control study[J]. J Clin Neurophysiol, 2025, 42(4):314-322.
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