Autoimmune Encephalitis historical perspective
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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 developed as a disease concept through successive clinical and immunological discoveries. Early descriptions of limbic encephalitis by Brierley and colleagues in 1960 and its association with carcinoma described by Corsellis and colleagues in 1968 established important foundations.[1][2]
The discovery of neuronal surface antibodies expanded the field beyond classical paraneoplastic neurological syndromes. Dalmau and colleagues identified anti-NMDA receptor encephalitis in 2007. In 2016, Graus and colleagues introduced clinical criteria supporting earlier recognition and assessment of antibody-negative presentations.[3][4]
Discovery
Autoimmune encephalitis was recognized through overlapping developments in neuropathology, cancer-associated neurological disease, antibody testing, and experimental neuroscience. The following chronology distinguishes the early clinical syndromes from the later identification of their antigenic targets.
| Year | Investigators or discovery | Historical significance |
|---|---|---|
| 1960 | Brierley, Corsellis, Hierons, and Nevin described subacute encephalitis predominantly affecting limbic structures. | This early clinicopathological account established a foundation for subsequent descriptions of limbic encephalitis.[1] |
| 1968 | Corsellis, Goldberg, and Norton described limbic encephalitis associated with carcinoma. | Their report established the term and emphasized the relationship between the limbic syndrome and an underlying malignancy.[2] |
| 1985 | Graus, Cordon-Cardo, and Posner reported neuronal antinuclear antibodies in patients with sensory neuronopathy and small-cell lung carcinoma. | This was a milestone in the broader paraneoplastic antibody field that provided the background for later antibody-defined encephalitis research; the original report concerned sensory neuronopathy.[5] |
| 2001 | Buckley and colleagues reported two patients with reversible limbic encephalitis and antibodies detected by the voltage-gated potassium channel (VGKC) assay. | Improvement after plasma exchange in one patient supported the possibility of an immunotherapy-responsive limbic syndrome. The specific antigenic targets of many VGKC-complex antibodies were identified later.[6] |
| 2005 | Vitaliani and colleagues described four young women with ovarian teratoma, prominent psychiatric symptoms, seizures, impaired consciousness, and hypoventilation. | This clinical description preceded identification of the NMDA receptor as an antigenic target in the subsequently defined syndrome.[7] |
| 2007 | Dalmau and colleagues identified NMDA receptor antibodies in a series of 12 women with teratoma-associated encephalitis. | The report defined anti-NMDA receptor encephalitis as a recognizable antibody-associated disease and documented neurological improvement following tumor treatment and immunotherapy in several patients.[3] |
| 2008 | Dalmau and colleagues characterized 100 patients with anti-NMDA receptor encephalitis and localized the principal antibody target to the extracellular region of the NR1 subunit, now termed GluN1. | The series broadened the recognized clinical population, included patients without detected tumors, and demonstrated reversible loss of neuronal surface NMDA receptors after exposure to patients' antibodies.[8] |
| 2009–2010 | Lai and colleagues identified AMPA receptor antibodies; Lancaster and colleagues identified GABAB receptor antibodies. | These discoveries established additional antibody-defined forms of limbic encephalitis, including syndromes associated with tumors and prominent seizures. The GABAB receptor report appeared online in 2009 and in the January 2010 journal issue.[9][10] |
| 2010 | Lai and colleagues identified LGI1 as the antigen in many cases previously attributed to VGKC antibodies. Irani and colleagues characterized LGI1 and CASPR2 antibodies within the VGKC-complex group. | The findings refined disease classification and enabled antigen-specific testing for clinically distinct syndromes.[11][12] |
| 2012–2013 | Boronat and colleagues identified antibodies to dipeptidyl-peptidase-like protein-6, also known as DPPX or DPP6. | The discovery expanded the spectrum to a syndrome combining cognitive or psychiatric symptoms, central nervous system hyperexcitability, and frequent gastrointestinal symptoms. The report was published online in 2012 and in the January 2013 journal issue.[13] |
| 2014 | Armangue and colleagues demonstrated the development of neuronal antibodies after herpes simplex encephalitis. | The study linked some post-herpes neurological relapses to newly developing brain autoimmunity, including NMDA receptor antibodies, and established an important infection-associated route to autoimmune encephalitis.[14] |
| 2014 | Petit-Pedrol and colleagues described encephalitis associated with GABAA receptor antibodies. | The report expanded the recognized antibody spectrum to an encephalitic syndrome with refractory seizures and status epilepticus.[15] |
Landmark Events in the Development of Treatment Strategies
Autoimmune encephalitis treatment evolved from observations of recovery after tumor treatment or immunotherapy to mechanistic studies, larger observational cohorts, controlled trials in selected syndromes, and published consensus recommendations.[6][3][16]
| Year | Landmark | Contribution to the development of care |
|---|---|---|
| 2010 | Hughes and colleagues demonstrated antibody-mediated NMDA receptor internalization and reduced receptor-mediated synaptic currents. | The experimental demonstration of reversible receptor dysfunction provided a biological rationale for antibody-directed treatment and recovery after antibody removal.[17] |
| 2011 | Irani and colleagues characterized faciobrachial dystonic seizures associated with LGI1 antibodies. | Recognition that these seizures often preceded cognitive deterioration created an opportunity for earlier diagnosis and immunotherapy.[18] |
| 2013 | Titulaer and colleagues reported a multicenter observational cohort of 577 patients with anti-NMDA receptor encephalitis. | Earlier treatment was associated with better functional outcomes. Among patients who failed initial therapy, second-line immunotherapy was associated with better outcomes than its omission. The study also documented that recovery could continue over many months.[16] |
| 2016 | Graus and colleagues published a syndrome-based diagnostic approach. | The criteria supported earlier recognition using clinical features and conventional investigations, with defined levels of diagnostic confidence and consideration of alternative causes, without requiring clinicians to await antibody results in every case.[4] |
| 2018 | Thompson and colleagues reported treatment and cognitive outcomes in 103 patients with LGI1 antibodies and faciobrachial dystonic seizures. | This observational study associated expedited immunotherapy and seizure cessation with better outcomes and a lower risk of subsequent cognitive impairment, reinforcing the importance of recognizing the early seizure phenotype.[19] |
| 2019–2020 | Dubey and colleagues published a randomized, double-blind, placebo-controlled trial of intravenous immunoglobulin in LGI1/CASPR2-antibody-associated epilepsy. | The 17-patient trial provided controlled evidence of seizure reduction in a selected antibody-associated population. It was terminated early because of slow recruitment, limiting the precision and generalizability of the findings. Publication was online in 2019 and in the February 2020 journal issue.[20] |
| 2020 | Cellucci and colleagues published a pediatric diagnostic approach. | Provisional pediatric criteria and an investigation algorithm accounted for developmental differences and the clinical features of autoimmune encephalitis in children.[21] |
| 2021 | Abboud and colleagues, representing the Autoimmune Encephalitis Alliance Clinicians Network, published paired best practice papers. | These recommendations organized diagnosis, acute immunotherapy, escalation, symptomatic treatment, rehabilitation, and longer-term management, using published evidence and expert opinion where evidence was limited.[22][23] |
| 2021 | Nosadini and colleagues published international consensus recommendations for pediatric NMDA receptor antibody encephalitis. | A Delphi process involving 27 experts produced syndrome-specific guidance on initial treatment, escalation, treatment duration, relapse, and tumor investigation.[24] |
| 2024 | Hahn and colleagues published Canadian consensus guidelines for adults. | The guidelines provided a practical adult diagnostic and treatment framework developed through a modified RAND consensus process with input from autoimmune neurology, neuropsychiatry, and infectious diseases specialists.[25] |
| 2026 | Updated United Kingdom Joint Societies adult encephalitis guidelines were published online in October 2026. | The guidelines integrated suspected infectious and autoimmune encephalitis into a combined framework emphasizing parallel assessment, early management, specialist input, and rehabilitation.[26] |
Impact on Cultural History
Autoimmune encephalitis has influenced discussion between neurology and psychiatry because it can present with prominent psychosis or behavioral change. The 2016 encephalitis criteria and the 2020 autoimmune psychosis consensus formalized diagnostic approaches to selected presentations.[4][27]
Patient and family advocacy also became part of the disease's history. The Autoimmune Encephalitis Alliance was founded in 2012 following collaboration among affected families and journalist Susannah Cahalan. Its stated goals include physician education, support for patients and caregivers, and facilitation of research.[28]
Famous Cases
Autoimmune encephalitis has a well-documented public example in journalist Susannah Cahalan, who was diagnosed with anti-NMDA receptor encephalitis in 2009. She described her illness and recovery in the 2012 memoir Brain on Fire: My Month of Madness, which was later adapted into a film.[28][29]
References
- ↑ 1.0 1.1 Brierley JB, Corsellis JAN, Hierons R, Nevin S. Subacute encephalitis of later adult life. Mainly affecting the limbic areas. Brain. 1960;83(3):357–368. doi:10.1093/brain/83.3.357.
- ↑ 2.0 2.1 Corsellis JAN, Goldberg GJ, Norton AR. “Limbic encephalitis” and its association with carcinoma. Brain. 1968;91(3):481–496. doi:10.1093/brain/91.3.481. PMID:5723018.
- ↑ 3.0 3.1 3.2 Dalmau J, Tüzün E, Wu HY, et al. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol. 2007;61(1):25–36. doi:10.1002/ana.21050. PMID:17262855.
- ↑ 4.0 4.1 4.2 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.
- ↑ Graus F, Cordon-Cardo C, Posner JB. Neuronal antinuclear antibody in sensory neuronopathy from lung cancer. Neurology. 1985;35(4):538–543. doi:10.1212/WNL.35.4.538. PMID:2984600.
- ↑ 6.0 6.1 Buckley C, Oger J, Clover L, et al. Potassium channel antibodies in two patients with reversible limbic encephalitis. Ann Neurol. 2001;50(1):73–78. doi:10.1002/ana.1097. PMID:11456313.
- ↑ Vitaliani R, Mason W, Ances B, et al. Paraneoplastic encephalitis, psychiatric symptoms, and hypoventilation in ovarian teratoma. Ann Neurol. 2005;58(4):594–604. doi:10.1002/ana.20614. PMID:16178029.
- ↑ 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.
- ↑ Lai M, Hughes EG, Peng X, et al. AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location. Ann Neurol. 2009;65(4):424–434. doi:10.1002/ana.21589. PMID:19338055.
- ↑ 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.
- ↑ Lai M, Huijbers MGM, Lancaster E, et al. Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series. Lancet Neurol. 2010;9(8):776–785. doi:10.1016/S1474-4422(10)70137-X. PMID:20580615.
- ↑ Irani SR, Alexander S, Waters P, et al. Antibodies to LGI1 and CASPR2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia. Brain. 2010;133(9):2734–2748. doi:10.1093/brain/awq213. PMID:20663977. Article title abbreviated.
- ↑ Boronat A, Gelfand JM, Gresa-Arribas N, et al. Encephalitis and antibodies to dipeptidyl-peptidase-like protein-6, a subunit of Kv4.2 potassium channels. Ann Neurol. 2013;73(1):120–128. doi:10.1002/ana.23756. PMID:23225603.
- ↑ 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.
- ↑ Petit-Pedrol M, Armangue T, Peng X, et al. Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor. Lancet Neurol. 2014;13(3):276–286. doi:10.1016/S1474-4422(13)70299-0. PMID:24462240. Article title abbreviated.
- ↑ 16.0 16.1 Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013;12(2):157–165. doi:10.1016/S1474-4422(12)70310-1. PMID:23290630.
- ↑ Hughes EG, Peng X, Gleichman AJ, et al. Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J Neurosci. 2010;30(17):5866–5875. doi:10.1523/JNEUROSCI.0167-10.2010. PMID:20427647.
- ↑ 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.
- ↑ Thompson J, Bi M, Murchison AG, et al. The importance of early immunotherapy in patients with faciobrachial dystonic seizures. Brain. 2018;141(2):348–356. doi:10.1093/brain/awx323. PMID:29272336.
- ↑ Dubey D, Britton J, McKeon A, et al. Randomized placebo-controlled trial of intravenous immunoglobulin in autoimmune LGI1/CASPR2 epilepsy. Ann Neurol. 2020;87(2):313–323. doi:10.1002/ana.25655. PMID:31782181.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Nosadini M, Thomas T, Eyre M, et al. International consensus recommendations for the treatment of pediatric NMDAR antibody encephalitis. Neurol Neuroimmunol Neuroinflamm. 2021;8(5):e1052. doi:10.1212/NXI.0000000000001052. PMID:34301820.
- ↑ 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.
- ↑ 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.
- ↑ Pollak TA, Lennox BR, Müller S, et al. Autoimmune psychosis: an international consensus on an approach to the diagnosis and management of psychosis of suspected autoimmune origin. Lancet Psychiatry. 2020;7(1):93–108. doi:10.1016/S2215-0366(19)30290-1. PMID:31669058.
- ↑ 28.0 28.1 Autoimmune Encephalitis Alliance. AE Alliance: Our history and mission. Accessed October 31, 2026.
- ↑ Cahalan S. Brain on Fire: My Month of Madness. New York: Free Press; 2012. Published November 13, 2012. ISBN:9781451621396.