| Rare Neurological Diseases | Neuroimmunology  

Autoimmune encephalitis: beyond the autoantibodies

A large study on 147 patients with antibody negative autoimmune encephalitis defines long term outcome and provides important clues on treatment strategies


Autoimmune encephalitis (AE) diagnostic criteria have been defined in 2016, defining for the first time the boundaries for classifying patients with antibody-negative AE.[1]

Lee at al. tackled this issue by publishing reporting on the long-term outcome of 147 patients with antibody-negative AE.[2] Patients included fulfilled the criteria for antibody-negative probable autoimmune encephalitis (ANPRA), autoimmune limbic encephalitis and acute disseminated encephalomyelitis. Notably, patients with ANPRA had variable clinical-radiological phenotypes.  A good 2-year outcome was achieved only by 56.5% of patients, and ANPRA patients had the worst outcome. Immunotherapy was overall beneficial, and continuing immunotherapy in patients with persistent disease at 6 months was associated with more improvement. A prognostic score (RAPID) to predict disability was created, consisting of 1) refractory status epilepticus 2) age of onset ≥60 years 3) ANPRA diagnosis; 4) infratentorial involvement and 5) delay of immunotherapy ≥1 month.  Longitudinal MRI evidence of cerbellar atrophy was associate with a poor outcome.

This study raises the attention towards the classification of rare autoimmune neurological disorders revolving around a specific antibody. As in the field of AQP4 associated neuromyelitis optica spectrum disorders (NMOSD),[3] antibody-negative forms might have several explanations, such as the presence of unknown antibodies or alternative pathogenic mechanisms. A better understanding of antibody-negative AE, and ANPRA, will be crucial to define optimal treatment strategies. Importantly, despite a more frequent poor outcome especially in ANPRA patients, this study supports the use of early  immunosuppression for both antibody positive and negative AE, guiding clinicians in their therapeutic choices.[4]

Key points:

  1. Antibody negative autoimmune encephalitis improves with immunotherapy
  2. Patients with ANPRA have a poorer outcome compared to other forms of antibody-negative AE
  3. Continuing immunotherapy after 6 months in refractory forms is associated with more improvement
  4. The RAPID score can be helpful to stratify prognosis and select patients that should be treated more aggressively
  5. Early immunotherapy is beneficial in both antibody-positive and negative AE


[1] Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, Cortese I, Dale RC, Gelfand JM, Geschwind M, Glaser CA, Honnorat J, Höftberger R, Iizuka T, Irani SR, Lancaster E, Leypoldt F, Prüss H, Rae-Grant A, Reindl M, Rosenfeld MR, Rostásy K, Saiz A, Venkatesan A, Vincent A, Wandinger KP, Waters P, Dalmau J. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016 Apr;15(4):391-404. doi: 10.1016/S1474-4422(15)00401-9. Epub 2016 Feb 20. PMID: 26906964; PMCID: PMC5066574. https://pubmed.ncbi.nlm.nih.gov/26906964/

[2] Lee WJ, Lee HS, Kim DY, Lee HS, Moon J, Park KI, Lee SK, Chu K, Lee ST. Seronegative autoimmune encephalitis: clinical characteristics and factors associated with outcomes. Brain. 2022 Oct 21;145(10):3509-3521. doi: 10.1093/brain/awac166. PMID: 35512357. https://pubmed.ncbi.nlm.nih.gov/35512357/

[3] Wingerchuk DM, Banwell B, Bennett JL, Cabre P, Carroll W, Chitnis T, de Seze J, Fujihara K, Greenberg B, Jacob A, Jarius S, Lana-Peixoto M, Levy M, Simon JH, Tenembaum S, Traboulsee AL, Waters P, Wellik KE, Weinshenker BG; International Panel for NMO Diagnosis. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015 Jul 14;85(2):177-89. doi: 10.1212/WNL.0000000000001729. Epub 2015 Jun 19. PMID: 26092914; PMCID: PMC4515040. https://pubmed.ncbi.nlm.nih.gov/26092914/

[4] van Steenhoven RW, Titulaer MJ. Seronegative autoimmune encephalitis: exploring the unknown. Brain. 2022 Oct 21;145(10):3339-3340. doi: 10.1093/brain/awac338. PMID: 36111366; PMCID: PMC9586533. https://pubmed.ncbi.nlm.nih.gov/36111366/

Matteo Gastaldi, IRCCS Mondino Foundation

Publish on behalf of the Scientific Panel on Neuroimmunology