Autoimmune Encephalitis risk factors
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Julinka Auta Fernandes
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Overview
Autoimmune encephalitis comprises several immune-mediated brain disorders with different risk profiles. Recognized contexts include an associated tumor, previous herpes simplex encephalitis, immune checkpoint inhibitor exposure, and a background of autoimmunity. Age and sex associations depend on the antibody subtype. Many cases occur without an identified trigger.[1]
Risk factors and associations can guide clinical suspicion, but their presence does not establish autoimmune encephalitis and their absence does not exclude it.[2] Their frequency varies by subtype; the categories below do not represent a universal ranking.
Common Risk Factors
Autoimmune encephalitis is associated with the following commonly recognized clinical contexts:
- Associated neoplasm: A tumor can provide an immune trigger in paraneoplastic autoimmune encephalitis. The association depends on the neurological syndrome, antibody, age, and sex. Relevant tumors include benign ovarian teratomas as well as malignancies; tumor association is not uniform across autoimmune encephalitis subtypes.[3]
| Tumor | Associated antibody or syndrome |
|---|---|
| Ovarian teratoma | N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis.[3] |
| Small cell lung cancer | Gamma-aminobutyric acid B receptor (GABABR) or Hu (antineuronal nuclear antibody type 1; ANNA-1)-associated encephalitis.[3] |
| Thymoma, lung carcinoma, or breast carcinoma | Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antibody encephalitis.[4] |
| Thymoma | Gamma-aminobutyric acid A receptor (GABAAR) encephalitis; contactin-associated protein-like 2 (CASPR2) antibody disease, including encephalitis and Morvan phenotypes.[3][5] |
| Testicular germ-cell tumor | Ma2 (paraneoplastic antigen Ma2)- or kelch-like protein 11 (KLHL11)-associated encephalitis, particularly with brainstem involvement.[3] |
| Hodgkin lymphoma | Metabotropic glutamate receptor 5 (mGluR5) antibody encephalitis.[3] |
- Previous herpes simplex encephalitis: Autoimmune encephalitis, often associated with NMDAR antibodies, can follow herpes simplex virus encephalitis. In a prospective cohort, 14 of 51 patients (27%) developed autoimmune encephalitis during follow-up. This estimate applies to that cohort of herpes encephalitis survivors, rather than to the general population.[6] The 2026 United Kingdom (UK) joint guideline recommends investigating new deterioration after herpes encephalitis for both persistent or recurrent infection and secondary autoimmune encephalitis. Antibody detection after infection, without a compatible clinical syndrome, is insufficient for diagnosis.[7]
- Subtype-specific age and sex associations: NMDAR antibody encephalitis occurs more frequently in children and young women, whereas leucine-rich glioma-inactivated 1 (LGI1) antibody encephalitis predominates in older men.[1] CASPR2 antibody disease also predominantly affects older men.[5] These patterns are associations and should not be used to exclude a diagnosis in other demographic groups.
- Personal or family history of autoimmune disease: The Canadian consensus identifies this history as a possible predisposing factor. It does not, by itself, demonstrate autoimmune encephalitis or provide a quantified individual risk.[1]
- Factors increasing suspicion of an associated malignancy: Smoking history and advanced age can raise suspicion of paraneoplastic autoimmune encephalitis through their association with cancer. They should not be presented as established direct risk factors for every autoimmune encephalitis subtype.[2]
Less Common Risk Factors
Autoimmune encephalitis can also occur in the following less common exposure contexts; additional genetic susceptibility associations are described separately below.
- Immune checkpoint inhibitor treatment: Encephalitis is a recognized neurological immune-related adverse event of cancer therapies targeting programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Treatment can precipitate new neurological autoimmunity or exacerbate pre-existing disease, including paraneoplastic syndromes.[8] A 2024 retrospective cohort characterized both focal encephalitis and meningoencephalitis after checkpoint inhibitor exposure. Such case cohorts describe affected patients and do not establish the incidence among all treated patients.[9]
- Other immune-modulating therapies: The 2021 best practice recommendations identify tumor necrosis factor alpha (TNF-alpha) inhibitors as potential triggers. This does not establish a quantified risk for individual patients.[2]
- Other preceding infectious encephalitides: The Canadian consensus recognizes other infectious encephalitides as possible antecedents. The evidence varies by pathogen; these reports should not be assumed to confer the same risk as herpes simplex encephalitis.[1]
Genetic susceptibility
Autoimmune encephalitis has subtype-specific genetic susceptibility associations:
- LGI1 and CASPR2 antibody disease: A case-control study in predominantly White populations identified associations with human leukocyte antigen (HLA) allele HLA-DRB1*07:01 for LGI1 antibody disease and HLA-DRB1*11:01 for CASPR2 antibody disease. These are susceptibility associations, rather than deterministic predictors of disease.[10]
- NMDAR antibody encephalitis: A 2024 genome-wide association study involving 413 Chinese Han patients and 7,127 controls identified associations involving interferon induced with helicase C domain 1 (IFIH1) and HLA-DQB1*05:02, among other HLA findings. These population-specific findings require further validation and should not be interpreted as a diagnosis or a prediction that an individual will develop encephalitis.[11]
References
- ↑ 1.0 1.1 1.2 1.3 Hahn C, Budhram A, Alikhani K; et al. (2024). "Canadian Consensus Guidelines for the Diagnosis and Treatment of Autoimmune Encephalitis in Adults". Canadian Journal of Neurological Sciences. 51 (6): 734–754. doi:10.1017/cjn.2024.16. PMID 38312020 Check
|pmid=value (help). - ↑ 2.0 2.1 2.2 Abboud H, Probasco JC, Irani S; et al. (2021). "Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management". Journal of Neurology, Neurosurgery & Psychiatry. 92 (7): 757–768. doi:10.1136/jnnp-2020-325300. PMID 33649022 Check
|pmid=value (help). - ↑ 3.0 3.1 3.2 3.3 3.4 3.5 Graus F, Vogrig A, Muñiz-Castrillo S; et al. (2021). "Updated Diagnostic Criteria for Paraneoplastic Neurologic Syndromes". Neurology: Neuroimmunology & Neuroinflammation. 8 (4): e1014. doi:10.1212/NXI.0000000000001014. PMID 34006622 Check
|pmid=value (help). - ↑ Milano C, Saylam E, Papi C; et al. (2025). "Clinical Characterization and Long-Term Outcome in Children and Adults With Anti-AMPA Receptor Encephalitis". Neurology: Neuroimmunology & Neuroinflammation. 12 (5): e200453. doi:10.1212/NXI.0000000000200453. PMID 40680249 Check
|pmid=value (help). - ↑ 5.0 5.1 van Sonderen A, Ariño H, Petit-Pedrol M; et al. (2016). "The clinical spectrum of Caspr2 antibody-associated disease". Neurology. 87 (5): 521–528. doi:10.1212/WNL.0000000000002917. PMID 27371488.
- ↑ Armangue T, Spatola M, Vlagea A; et al. (2018). "Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis". The Lancet Neurology. 17 (9): 760–772. doi:10.1016/S1474-4422(18)30244-8. PMID 30049614.
- ↑ Michael BD, Huang Y, McKeever S; et al. (2026). "Management of suspected infectious and autoimmune encephalitis in adults – National Guidelines from the United Kingdom Joint Societies". Journal of Infection: 106873. doi:10.1016/j.jinf.2026.106873. PMID 42863638 Check
|pmid=value (help). - ↑ Guidon AC, Burton LB, Chwalisz BK; et al. (2021). "Consensus disease definitions for neurologic immune-related adverse events of immune checkpoint inhibitors". Journal for ImmunoTherapy of Cancer. 9 (7): e002890. doi:10.1136/jitc-2021-002890. PMID 34281989 Check
|pmid=value (help). - ↑ Farina A, Villagrán-García M, Fourier A; et al. (2024). "Diagnostic and prognostic biomarkers in immune checkpoint inhibitor-related encephalitis: a retrospective cohort study". The Lancet Regional Health – Europe. 44: 101011. doi:10.1016/j.lanepe.2024.101011. PMID 39170102 Check
|pmid=value (help). - ↑ Binks S, Varley J, Lee W; et al. (2018). "Distinct HLA associations of LGI1 and CASPR2-antibody diseases". Brain. 141 (8): 2263–2271. doi:10.1093/brain/awy109. PMID 29788256.
- ↑ Liu X, Zheng X, Shu Y; et al. (2024). "Genome-Wide Association Study Identifies IFIH1 and HLA-DQB1*05:02 Loci Associated With Anti-NMDAR Encephalitis". Neurology: Neuroimmunology & Neuroinflammation. 11 (3): e200221. doi:10.1212/NXI.0000000000200221. PMID 38579189 Check
|pmid=value (help).