Differential Diagnosis and Comparison of Diagnostic Algorithms in Children and Adolescents with Autoimmune Encephalitis
Gemma Olivé-Cirera1, Elianet Fonseca1, Li-Wen Chen2, Anna Fetta3, Eugenia Martínez-Hernández1, Mar Guasp1, Veronica González-Álvarez4, Verónica Delgadillo4, Verónica Cantarín-Extremera5, María Jiménez-Legido5, Lorena Monge-Galindo6, Ana Felipe7, Beatriz Beseler8, Eulàlia Turón-Viñas9, Joaquín Fernández-Ramos10, Maria-Jesús Martínez-González11, Maria Vázquez-López12, Luisa Arrabal Fernandez13, Mireia Alvarez-Molinero14, Beatriz Muñoz-Cabello15, Ana Camacho16, Noemí Nuñez-Enamorado16, Marianna Spatola1, Lídia Sabater1, Yolanda Blanco1, Albert Saiz1, Francesc Graus1, Josep Dalmau1, Thais Armangué1
1Neuroimmunology Program, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) / CaixaResearch Institute, Hospital Clínic de Barcelona, Barcelona, Spain, 2National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, 3Università di Bologna, IRCCS Instituto delle Scienze Neurologiche di Bologna, 4Sant Joan de Déu Children's Hospital of Barcelona, Spain, 5Hospital Infantil Universitario Niño Jesús (Madrid), Spain., 6Hospital Miguel Servet (Zaragoza), Spain, 7Hospital Vall d'Hebrón, Barcelona, Spain, 8Hospital de la Fe, Valencia, Spain., 9Hospital Sant Pau (Barcelona), Spain., 10Hospital Universitario Reina Sofía, Córdoba, Spain, 11Hospital Universitario de Cruces, Barakaldo, Bizkaia, Spain, 12Hospital Gregorio Marañon, Madrid, Spain, 13Hospital Virgen de las Nieves de Granada; Granada, Spain., 14Hospital Joan XIII, Tarragona, Spain., 15Hospital Virgen del Rocío, Sevilla, Spain, 16Hospital 12 de Octubre, Madrid, Spain.
Objective:
To assess the diagnosis of pediatric AE in clinical practice, and to compare the performance of two international diagnostic algorithms (one for patients of any age [general], the other for pediatric patients).
Background:
The accuracy of current diagnostic approaches in children with suspected autoimmune encephalitis (AE), particularly when evaluating probable antibody-negative AE (ANAE), is unknown.
Design/Methods:
Prospective multicenter nationwide cohort study including children (<18 years) with suspected AE recruited at 40 hospitals and ≥2 year follow-up. Neural antibody testing was centrally performed. Retrospective analysis of agreement between both diagnostic algorithms was performed through the kappa index.
Results:
Between June 1, 2013, and May 31st, 2021, 729 children (mean age 7.1[+/-4.9] years; 346 [48%] girls) with suspected AE were recruited. After a median follow-up of 36 (26-60) months, four diagnostic categories were identified: definite AE or well-defined inflammatory/autoimmune disorders (230/729[32%] patients); encephalitis of unknown cause (81/729 [11%]: 47[58%] non-localizable, 17 [21%] brainstem-cerebellar, 14 [17%] basal ganglia, and 3 [4%] other); infectious CNS disorders (112/729 [15%]); and non-inflammatory disorders (306/729 [42%]) predominantly epileptic or psychiatric (177/306 [58%]). Neural antibodies (>85% NMDAR or MOG) were only detected within the first diagnostic category (150/230 [65%] patients). Agreement between algorithms was excellent (0.99 95% CI [0.98-1.00]) for the diagnosis of antibody-positive AE, but poor (0.29 95%CI [0.21-0.37]) for the diagnosis of probable ANAE. Compared with the general algorithm, the pediatric algorithm included 4 times (173 vs 41) more patients in the ANAE category including both, more patients with encephalitis of unknown cause (80/81 vs 31/81) and more patients with non-inflammatory disorders (47/306 vs 6/306).
Conclusions:
About one-third of children with suspected AE eventually had this or other confirmed well-defined inflammatory disorders. Frequent mimickers were infectious, epileptic, and psychiatric disorders. Both algorithms showed limitations in the diagnosis of ANAE, with implications for immunotherapy usage.
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