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 | N-methyl-D-aspartate (NMDA) receptor (NMDAR), leucine-rich glioma-inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR), gamma-aminobutyric acid type A receptor (GABAAR), gamma-aminobutyric acid type B receptor (GABABR), dipeptidyl-peptidase-like protein 6 (DPPX), metabotropic glutamate receptor 5 (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 (antineuronal nuclear antibody type 1; ANNA-1), Ma2 (paraneoplastic antigen Ma2), collapsin response-mediator protein 5 (CRMP5; also known as CV2), amphiphysin, and kelch-like protein 11 (KLHL11) | These generally serve as biomarkers of predominantly T-cell-mediated neurological autoimmunity. Cancer associations and clinical phenotypes depend on the antibody.[3] |
| Glutamic acid decarboxylase-65 (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 voltage-gated potassium channel (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: immunoglobulin G (IgG) against NMDA receptor subunit 1 (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 magnetic resonance imaging (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 paraneoplastic neurological syndromes (PNS) diagnostic framework (PNS-Care) 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 cerebrospinal fluid (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 glial fibrillary acidic protein (GFAP) astrocytopathy is associated with an intracellular astrocytic antigen and frequently presents as meningoencephalomyelitis.[19]
- Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease may present with cortical encephalitis or an acute disseminated encephalomyelitis (ADEM) phenotype. Aquaporin-4 (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 IgLON family member 5 (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.