Differential diagnosis and comparison of diagnostic algorithms in children and adolescents with autoimmune encephalitis in Spain: a prospective cohort study and retrospective analysis.

The usefulness of current diagnostic approaches in children with suspected autoimmune encephalitis is unknown. We aimed to assess the diagnosis of autoimmune encephalitis in clinical practice and to compare the performance of two international diagnostic algorithms (one intended for patients of any age [general], the other intended for paediatric patients), with particular emphasis on the evaluation of patients with probable antibody-negative autoimmune encephalitis because this diagnosis suggests that immunotherapy should be continued or escalated but is difficult to establish. We did a prospective cohort study that included all patients (<18 years of age) with suspected autoimmune encephalitis recruited at 40 hospitals in Spain whose physicians provided clinical information every 6 months for 2 years or more. Neural antibody testing to confirm diagnosis of antibody-positive autoimmune encephalitis was done at Institut d'Investigacions Biomèdiques August Pi i Sunyer-Hospital Clínic, Barcelona. Patients were classified according to the most probable diagnosis at last follow-up into four prespecified categories. We used multivariable logistic analysis to assess a potential association between immunotherapy and outcome in individuals with probable antibody-negative autoimmune encephalitis. We also did a retrospective analysis of agreement, assessed with the kappa index, between diagnoses made according to the general and paediatric diagnostic algorithms. Between June 1, 2013, and May 31, 2021, 729 children (mean age 7·1 years [SD 4·9]; 383 boys [53%], 346 girls [47%]) with suspected autoimmune encephalitis were recruited. After a median follow-up of 36 months (IQR 26-60), patients were classified according to their most probable diagnosis: definite autoimmune encephalitis or well defined inflammatory or autoimmune disorders (n=230 [32%]); CNS infections (n=112 [15%]); inflammatory CNS disorders of unknown cause (n=81 [11%], including three (4%) with a novel Klüver-Bucy-like syndrome; and non-inflammatory disorders (n=306 [42%]), which were predominantly epileptic or psychiatric disorders (177 [58%] of 306). Neural antibodies were detected in 150 (65%) of 230 patients who had definite autoimmune encephalitis; 127 (85%) of these 150 individuals had antibodies to the NMDA receptor or myelin oligodendrocyte glycoprotein (MOG). Agreement between algorithms was excellent (kappa index 0·99, 95% CI 0·97-1·00) for the diagnosis of children with antibody-positive autoimmune encephalitis, good (0·59, 0·54-0·65) for recommendations of empiric immunotherapy, and poor (0·29, 0·21-0·37) for the diagnosis of probable antibody-negative autoimmune encephalitis. Compared with the general algorithm, the paediatric algorithm included more patients in the probable antibody-negative autoimmune encephalitis category (173 vs 41). These patients included some of those who had a diagnosis of CNS inflammatory disorder of unknown cause at the last follow-up (80 of 81 with the paediatric algorithm vs 31 of 81 with the general algorithm), who might have benefitted from immunotherapy, and some of those diagnosed with a non-inflammatory disorder at the last follow-up (47 of 306 with the paediatric algorithm vs six of 306 with the general algorithm), who did not need immunotherapy. About a third of children with suspected autoimmune encephalitis eventually had confirmation of this diagnosis, or diagnosis of another well defined inflammatory disorder. Frequent mimics of autoimmune encephalitis were infectious, epileptic, and psychiatric disorders. Both algorithms performed well in the diagnosis of antibody-positive autoimmune encephalitis, but the paediatric algorithm under-recognised definite autoimmune encephalitis that can occur without autoantibodies and might have overdiagnosed patients with probable antibody-negative autoimmune encephalitis. By contrast, the general algorithm might have underdiagnosed patients with probable antibody-negative autoimmune encephalitis. Given that the diagnosis of probable antibody-negative autoimmune encephalitis has treatment implications, inaccuracies on this diagnostic category leads to overuse or underuse of immunotherapy. Instituto de Salud Carlos III, Fundació Clínic per la Recerca Biomèdica, The Edmond J Safra Foundation, and la Caixa Foundation. For the Spanish translation of the abstract see Supplementary Materials section.

被引量：- 发表：2025

Comparative effectiveness of cognitive behavioural therapy, modafinil, and their combination for treating fatigue in multiple sclerosis (COMBO-MS): a randomised, statistician-blinded, parallel-arm trial.

Fatigue is one of the most disabling symptoms reported by people with multiple sclerosis. Although behavioural and pharmacological interventions might be partly beneficial, their combined effects have not been evaluated for multiple sclerosis fatigue, or examined with sufficient consideration of characteristics that might affect treatment response. In this comparative effectiveness research trial, we compared the effectiveness of cognitive behavioural therapy (CBT), modafinil, and their combination for treating multiple sclerosis fatigue. This randomised, analyst-blinded, parallel-arm, comparative effectiveness trial was done at two universities in the USA. Adults (aged ≥18 years) with multiple sclerosis and problematic fatigue (Fatigue Severity Scale [FSS] score ≥4) were randomly assigned (1:1:1), using a web-based treatment assignment system with minimisation, to receive CBT, modafinil, or both for 12 weeks. Statisticians were masked to group assignment, but participants, study neurologists, CBT interventionalists, and coordinators were not masked to treatment assignment. The primary outcome was the change in Modified Fatigue Impact Scale (MFIS) from baseline to 12 weeks, assessed using multiple linear regression, adjusted for age, sex, study site, anxiety, pain, baselines MFIS score, and physical activity. Analyses were done by intent to treat. The trial was registered with clinicaltrials.gov, NCT03621761, and is completed. Between Nov 15, 2018, and June 2, 2021, 336 participants were randomly assigned treatment (114 assigned to CBT, 114 assigned to modafinil, and 108 assigned to combination therapy). At 12 weeks, CBT (n=103), modafinil (n=107), and combination therapy (n=102) were associated with clinically meaningful within-group MFIS reductions of 15·20 (SD 11·90), 16·90 (15·90), and 17·30 (16·20) points, respectively. Change in MFIS scores from baseline to 12 weeks did not differ between groups: relative to combination therapy, the adjusted total mean difference in MFIS change score was 1·88 (95% CI -2·21 to 5·96) for CBT and 1·20 (-2·83 to 5·23) for modafinil. Most common adverse events for modafinil-containing treatment groups included insomnia (eight [7%] for modafinil and eight [7%] for combination therapy) and anxiety (three [3%] for modafinil and nine [8%] for combination therapy). Modafinil, CBT, and combination therapy were associated with similar reductions in the effects of multiple sclerosis fatigue at 12 weeks. Combination therapy was not associated with augmented improvement compared with the individual interventions. Further research is needed to determine whether effects of these interventions on multiple sclerosis-related fatigue is influenced by sleep hygiene and sleepiness. No serious adverse events related to the study drug were encountered. Patient-Centered Outcomes Research Institute and National Multiple Sclerosis Society.

被引量：- 发表：2024

Safety and efficacy of memantine and trazodone versus placebo for motor neuron disease (MND SMART): stage two interim analysis from the first cycle of a phase 3, multiarm, multistage, randomised, adaptive platform trial.

被引量：- 发表：1970

Evobrutinib in multiple sclerosis: challenges and unmet goals.

被引量：- 发表：1970

Trial designs for motor neuron disease in the 21st century.

被引量：- 发表：1970