Autoimmune encephalitis (AE) diagnostic criteria have been defined in 2016, defining for the first time the boundaries for classifying patients with antibody-negative AE.
Lee at al. tackled this issue by publishing reporting on the long-term outcome of 147 patients with antibody-negative AE. 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), 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.
- Antibody negative autoimmune encephalitis improves with immunotherapy
- Patients with ANPRA have a poorer outcome compared to other forms of antibody-negative AE
- Continuing immunotherapy after 6 months in refractory forms is associated with more improvement
- The RAPID score can be helpful to stratify prognosis and select patients that should be treated more aggressively
- Early immunotherapy is beneficial in both antibody-positive and negative AE
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 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/
 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/
 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