Autoimmune Encephalitis classification
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Julinka Auta Fernandes
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Differentiating Autoimmune Encephalitis from Other Conditions |
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Autoimmune Encephalitis On the Web |
Overview
Autoimmune encephalitis may be classified according to antibody status and antigenic target, predominant clinical-anatomical syndrome, underlying cause, and diagnostic certainty. These classifications are complementary: a patient may simultaneously have an antibody-defined syndrome, a particular anatomical phenotype, and an associated tumor.[1]
Classification
Classification Based On Antibody Status and Antigenic Target
Autoimmune encephalitis includes antibody-associated and antibody-negative disease. Antibody-associated syndromes can be grouped by the location of the antigen and its clinical significance.
| Serological group | Representative antibodies | Classification significance |
|---|---|---|
| Antibodies against neuronal surface or extracellular synaptic antigens | NMDAR, LGI1, CASPR2, AMPAR, GABAAR, GABABR, DPPX, mGluR5, and neurexin-3α | These identify several distinct syndromes. Direct antibody-mediated neuronal dysfunction has been demonstrated for a number of these targets, including NMDAR.[2] |
| Classical cancer-associated antibodies against intracellular neuronal antigens | Hu/ANNA-1, Ma2, CRMP5/CV2, amphiphysin, and KLHL11 | These generally serve as biomarkers of predominantly T-cell-mediated neurological autoimmunity. Cancer associations and clinical phenotypes depend on the antibody.[3] |
| GAD65-associated neurological autoimmunity | Antibodies against the intracellular enzyme glutamic acid decarboxylase-65 | Manifestations include limbic encephalitis, chronic epilepsy, stiff-person syndrome, and cerebellar ataxia. The pathogenic role of the antibodies remains uncertain; a positive result alone does not establish encephalitis.[4] |
| Antibody-negative autoimmune encephalitis | No established disease-associated neural antibody identified after appropriate testing | Classification requires a compatible syndrome and fulfillment of relevant clinical and investigation-based criteria. Negative antibody testing alone does not establish autoimmune encephalitis.[5] |
Antibody-defined classification requires clinically compatible findings and appropriate assay interpretation. Isolated thyroid antibodies or VGKC-complex antibodies without LGI1 or CASPR2 specificity do not define an autoimmune encephalitis subtype. Low serum GAD65 concentrations may also be nonspecific.[1][4]
Major Antibody-Associated Syndromes
Autoimmune encephalitis includes the following important antibody-associated syndromes. The clinical features and tumor associations listed are representative; their frequencies vary with age, sex, and the population studied.
| Antibody-associated syndrome | Characteristic clinical pattern | Representative tumor association |
|---|---|---|
| Anti-NMDA receptor encephalitis: IgG against GluN1 | Psychiatric or behavioral change, speech dysfunction, seizures, dyskinesias, reduced consciousness, autonomic dysfunction, or hypoventilation.[2] | Ovarian teratoma, particularly in adolescent and adult females; many patients have no tumor. |
| LGI1-antibody encephalitis | Limbic dysfunction, memory impairment, seizures, particularly faciobrachial dystonic seizures, and frequent hyponatremia.[6] | Tumors are uncommon; no single characteristic tumor. |
| CASPR2-antibody-associated disease | Limbic encephalitis or a broader syndrome with insomnia, dysautonomia, neuropathic pain, and peripheral nerve hyperexcitability; Morvan syndrome may occur. | Thymoma, particularly in patients with Morvan syndrome or peripheral involvement.[7] |
| AMPA receptor-antibody encephalitis | Limbic encephalitis, sometimes with more widespread encephalopathy or psychiatric symptoms. | Lung cancer, thymoma, and breast cancer are important associations.[8] |
| GABAB receptor-antibody encephalitis | Limbic encephalitis with prominent seizures, sometimes status epilepticus. | Small-cell lung cancer is an important association.[9] |
| GABAA receptor-antibody encephalitis | Frequent or refractory seizures, encephalopathy, and often multifocal cortical-subcortical MRI abnormalities. | Thymoma is a recognized association, particularly in adults.[10] |
| DPPX-antibody encephalitis | Cognitive or psychiatric dysfunction and central nervous system hyperexcitability, often preceded by diarrhea or weight loss. | Occasional B-cell neoplasms have been reported.[11] |
| mGluR5-antibody encephalitis | Cognitive and psychiatric symptoms, with possible seizures, movement abnormalities, and sleep disturbance. | Hodgkin lymphoma is a characteristic association; cases without cancer also occur.[12] |
| Neurexin-3α-antibody encephalitis | Rare syndrome with confusion, seizures, and reduced consciousness. | No consistent tumor association has been established.[13][5] |
| GAD65-associated limbic encephalitis | Limbic encephalitis within the wider GAD65 neurological spectrum; chronic epilepsy can occur as a separate phenotype. | Usually nonparaneoplastic; concurrent neural antibodies or atypical features may alter cancer risk.[4][5] |
The tumor associations for NMDAR, LGI1, and other common neural antibodies are also summarized in current consensus guidance.[5]
Classification Based On the Clinical-Anatomical Syndrome
Autoimmune encephalitis may be classified by its predominant anatomical and clinical pattern. Several regions may be involved simultaneously.[14]
| Clinical-anatomical category | Predominant manifestations |
|---|---|
| Limbic encephalitis | Memory impairment, behavioral change, and temporal lobe seizures. |
| Cortical/subcortical encephalitis | Seizures, cognitive dysfunction, or focal cerebral deficits. |
| Striatal encephalitis | Movement disorders, including chorea or dystonia. |
| Diencephalic encephalitis | Sleep disturbance, autonomic dysfunction, or hypothalamic manifestations. |
| Brainstem encephalitis | Oculomotor, cranial nerve, bulbar, or related brainstem dysfunction. |
| Cerebellar involvement | Gait or limb ataxia, dysarthria, or nystagmus. |
| Encephalomyelitis | Combined brain and spinal cord involvement. |
| Meningoencephalitis | Encephalitic features with accompanying meningeal inflammation. |
| Combined or multifocal syndrome | Overlapping manifestations from several anatomical regions. |
These categories overlap and describe anatomy rather than an antibody-defined diagnosis.[14]
Classification Based On Etiology and Tumor Association
Autoimmune encephalitis may be associated with a tumor, follow an infection, occur as an immune-related treatment complication, or have no identified trigger.
| Etiological category | Description |
|---|---|
| Paraneoplastic | An immune-mediated neurological syndrome with a supported relationship to cancer. Direct tumor invasion, metastasis, and other explanations for neurological dysfunction must be considered separately.[3] |
| Postinfectious | Neuronal autoimmunity developing after an infection, particularly herpes simplex encephalitis.[15] |
| Iatrogenic or treatment-associated | Encephalitis occurring as a neurological immune-related adverse event of an immune checkpoint inhibitor. Attribution requires assessment of alternative causes and the clinical context.[16] |
| Idiopathic or without an identified trigger | No associated tumor or other trigger is identified at the current assessment. Cancer status may need reassessment according to the antibody and clinical circumstances.[1] |
For cancer-associated neurological autoimmunity, the 2021 PNS-Care framework distinguishes antibodies with high cancer risk (>70%), intermediate risk (30%–70%), and lower risk (<30%). These are cancer-association categories, not measures of encephalitis severity. PNS-Care combines phenotype, antibody, cancer findings, and follow-up; its possible/probable/definite PNS categories assess the paraneoplastic relationship.[3]
Classification Based On Diagnostic Certainty
Autoimmune encephalitis may be categorized by diagnostic certainty using syndrome-specific criteria.[17]
| Category | Meaning |
|---|---|
| Possible autoimmune encephalitis | Entry-level clinical criteria supporting suspicion and further investigation; this category does not confirm an autoimmune cause. |
| Probable autoimmune encephalitis | More specific criteria, such as probable anti-NMDAR encephalitis or probable antibody-negative autoimmune encephalitis. |
| Definite autoimmune encephalitis | Fulfillment of an established syndrome-specific definition. Definite autoimmune limbic encephalitis can be diagnosed without a detectable antibody when its full criteria are met. |
Probable antibody-negative autoimmune encephalitis requires rapid progression of memory deficits, altered mental status, or psychiatric symptoms over less than three months, exclusion of well-defined autoimmune encephalitis syndromes and alternative causes, absence of established serum and CSF neural antibodies, and at least two supportive findings: suggestive MRI abnormalities; inflammatory CSF findings; or inflammatory brain biopsy findings excluding another disorder. Relevant CSF findings include pleocytosis, CSF-specific oligoclonal bands, or an elevated IgG index.[17]
Classification in Children
Autoimmune encephalitis in children requires consideration of developmental stage and pediatric-specific presentations. The Cellucci framework proposes possible pediatric autoimmune encephalitis, probable antibody-negative pediatric autoimmune encephalitis, and definite antibody-positive pediatric autoimmune encephalitis. These categories incorporate neurological dysfunction, appropriate antibody interpretation, evidence of neuroinflammation where required, and exclusion of other causes.[18]
Related and Overlapping Neuroimmune Disorders
Autoimmune encephalitis can overlap with other neuroimmune disorders, whose specific disease classifications should also be recorded:
- Autoimmune GFAP astrocytopathy is associated with an intracellular astrocytic antigen and frequently presents as meningoencephalomyelitis.[19]
- MOG antibody-associated disease may present with cortical encephalitis or an ADEM phenotype. AQP4-IgG-positive neuromyelitis optica spectrum disorder is a distinct astrocytopathic disease. These retain their disease-specific diagnostic classifications.[20][21]
- Glycine receptor-antibody-associated disorders and IgLON5 disease may have overlapping brainstem, movement, autonomic, or sleep manifestations. Their predominant syndromes should be specified rather than using an encephalitis label solely because an antibody is detected.[14]
Clinical Course and Severity
Autoimmune encephalitis may follow a monophasic or relapsing course, which should be recorded alongside the antibody and clinical syndrome classification.[22] Some CASPR2-associated presentations evolve more slowly than the usual subacute encephalitis pattern.[7]
The Clinical Assessment Scale in Autoimmune Encephalitis (CASE; 0–27) assesses clinical severity, while the modified Rankin Scale records overall disability. These measures supplement disease classification and do not identify an antibody subtype.[23]
References
- ↑ 1.0 1.1 1.2 Hahn C, Budhram A, Alikhani K, et al. Canadian consensus guidelines for the diagnosis and treatment of autoimmune encephalitis in adults. Can J Neurol Sci. 2024;51(6):734–754. doi:10.1017/cjn.2024.16. PMID:38312020.
- ↑ 2.0 2.1 Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 2008;7(12):1091–1098. doi:10.1016/S1474-4422(08)70224-2. PMID:18851928.
- ↑ 3.0 3.1 3.2 Graus F, Vogrig A, Muñiz-Castrillo S, et al. Updated diagnostic criteria for paraneoplastic neurologic syndromes. Neurol Neuroimmunol Neuroinflamm. 2021;8(4):e1014. doi:10.1212/NXI.0000000000001014. PMID:34006622.
- ↑ 4.0 4.1 4.2 Muñoz-Lopetegi A, et al. Neurologic syndromes related to anti-GAD65: Clinical and serologic response to treatment. Neurol Neuroimmunol Neuroinflamm. 2020;7(3):e696. doi:10.1212/NXI.0000000000000696. PMID:32123047.
- ↑ 5.0 5.1 5.2 5.3 Michael BD, et al. Management of suspected infectious and autoimmune encephalitis in adults – National Guidelines from the United Kingdom Joint Societies. J Infect. Published online October 2026:106873. doi:10.1016/j.jinf.2026.106873. PMID:42863638.
- ↑ Irani SR, Michell AW, Lang B, et al. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann Neurol. 2011;69(5):892–900. doi:10.1002/ana.22307. PMID:21416487.
- ↑ 7.0 7.1 van Sonderen A, Ariño H, Petit-Pedrol M, et al. The clinical spectrum of Caspr2 antibody-associated disease. Neurology. 2016;87(5):521–528. doi:10.1212/WNL.0000000000002917. PMID:27371488.
- ↑ Höftberger R, van Sonderen A, Leypoldt F, et al. Encephalitis and AMPA receptor antibodies: Novel findings in a case series of 22 patients. Neurology. 2015;84(24):2403–2412. doi:10.1212/WNL.0000000000001682. PMID:25979696.
- ↑ Lancaster E, Lai M, Peng X, et al. Antibodies to the GABAB receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol. 2010;9(1):67–76. doi:10.1016/S1474-4422(09)70324-2. PMID:19962348.
- ↑ Spatola M, Petit-Pedrol M, Simabukuro MM, et al. Investigations in GABAA receptor antibody-associated encephalitis. Neurology. 2017;88(11):1012–1020. doi:10.1212/WNL.0000000000003713. PMID:28202703.
- ↑ Hara M, Ariño H, Petit-Pedrol M, et al. DPPX antibody-associated encephalitis: Main syndrome and antibody effects. Neurology. 2017;88(14):1340–1348. doi:10.1212/WNL.0000000000003796. PMID:28258082.
- ↑ Spatola M, Sabater L, Planagumà J, et al. Encephalitis with mGluR5 antibodies: Symptoms and antibody effects. Neurology. 2018;90(22):e1964–e1972. doi:10.1212/WNL.0000000000005614. PMID:29703767.
- ↑ Gresa-Arribas N, Planagumà J, Petit-Pedrol M, et al. Human neurexin-3α antibodies associate with encephalitis and alter synapse development. Neurology. 2016;86(24):2235–2242. doi:10.1212/WNL.0000000000002775. PMID:27170573.
- ↑ 14.0 14.1 14.2 Abboud H, Probasco JC, Irani S, et al. Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management. J Neurol Neurosurg Psychiatry. 2021;92(7):757–768. doi:10.1136/jnnp-2020-325300. PMID:33649022.
- ↑ Armangue T, Leypoldt F, Málaga I, et al. Herpes simplex virus encephalitis is a trigger of brain autoimmunity. Ann Neurol. 2014;75(2):317–323. doi:10.1002/ana.24083. PMID:24318406.
- ↑ Guidon AC, Burton LB, Chwalisz BK, et al. Consensus disease definitions for neurologic immune-related adverse events of immune checkpoint inhibitors. J Immunother Cancer. 2021;9(7):e002890. doi:10.1136/jitc-2021-002890. PMID:34281989.
- ↑ 17.0 17.1 Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391–404. doi:10.1016/S1474-4422(15)00401-9. PMID:26906964.
- ↑ Cellucci T, Van Mater H, Graus F, et al. Clinical approach to the diagnosis of autoimmune encephalitis in the pediatric patient. Neurol Neuroimmunol Neuroinflamm. 2020;7(2):e663. doi:10.1212/NXI.0000000000000663. PMID:31953309.
- ↑ Fang B, McKeon A, Hinson SR, et al. Autoimmune glial fibrillary acidic protein astrocytopathy: A novel meningoencephalomyelitis. JAMA Neurol. 2016;73(11):1297–1307. doi:10.1001/jamaneurol.2016.2549. PMID:27618707.
- ↑ Banwell B, Bennett JL, Marignier R, et al. Diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease: International MOGAD Panel proposed criteria. Lancet Neurol. 2023;22(3):268–282. doi:10.1016/S1474-4422(22)00431-8. PMID:36706773.
- ↑ Wingerchuk DM, Banwell B, Bennett JL, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015;85(2):177–189. doi:10.1212/WNL.0000000000001729. PMID:26092914.
- ↑ Abboud H, Probasco J, Irani SR, et al. Autoimmune encephalitis: proposed recommendations for symptomatic and long-term management. J Neurol Neurosurg Psychiatry. 2021;92(8):897–907. doi:10.1136/jnnp-2020-325302. PMID:33649021.
- ↑ Lim JA, Lee ST, Moon J, et al. Development of the clinical assessment scale in autoimmune encephalitis. Ann Neurol. 2019;85(3):352–358. doi:10.1002/ana.25421. PMID:30675918.