The Urgent Need for Evidence Over Anecdote: Equipoise in the ExTINGUISH Clinical Trial in Anti-NMDAR Encephalitis
Yoji Hoshina1, Tammy Smith1, Ka-Ho Wong1, Lisa Peterson2, Anastasia Zekeridou3, Albert Aboseif4, Christopher Coffey5, Melissa Wright1, Brenda Banwell6, Annalisa Dialino-Felix7, SUSAN FLAVIN7, Lisa Dill7, Hyun Cho8, Josep Dalmau9, Maarten Titulaer10, Gregory Day11, Stacey Clardy1
1University of Utah, 2ARUP Laboratories, 3Neuroimmunology Laboratory, Mayo Clinic, 4Mayo Clinic Rochester, 5University of Iowa, 6Childrens Hospital of Philadelphia, 7Amgen Inc., 8NIH, 9University of Barcelona, 10Erasmus Medical Center, 11Mayo Clinic
Objective:
Assess whether treatment strategies and patient outcomes in anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) have evolved since the last comprehensive review of the literature in January 2019.
Background:
There are no FDA-approved treatments for NMDARE, and no placebo-controlled clinical trials have been completed to provide evidence for management of this disease. Treatment continues to be based on expert opinion and consensus.
Design/Methods:
A systematic literature review was conducted in PubMed from January 2019 through April 2024. Detailed demographic and clinical information were extracted from English-language articles containing individual data from patients with NMDARE and were compared to previously published studies. Larger studies with ≥10 cases, follow-up duration ≥6 months, and outcomes reported as favorable (mRS 0-2) and poor (mRS 3-5 or 3-6), were grouped and analyzed by diagnosis period: pre-2013 and post-2013.
Results:
649 unique patients from 321 articles met the inclusion criteria. Since 2019, both first-line (91.3% vs. 98.3%, p<0.001) and second-line (31.8% vs. 45.3%, p<0.001) immunotherapy use has increased. The proportion of patients receiving initial immunotherapy within 30 days increased from 50.1% to 73.2% (p<0.001). Despite these changes, outcomes showed only slight improvement (mRS 0-2: 71.5% vs. 76.7%, p=0.024) with no significant change in mortality (6.3% vs. 6.9%, p=0.78). Larger cohort studies reported a broad range of favorable outcomes at final follow-up, varying from 66.7–90.9% before 2019 and 56.3–93.3% afterward, reflecting institutional and demographic variability.
Conclusions:
Since the last systematic literature review on treatment and outcomes in anti-NMDAR encephalitis was conducted in 2019, significantly more patients are treated early, and receive first- and second-line immunotherapy. Despite these changes in clinical practice, functional outcomes (measured by mRS) have only slightly improved in this time. Marked uncertainty remains regarding the optimal treatment of patients with anti-NMDAR encephalitis; the ExTINGUISH Trial in anti-NMDAR encephalitis will provide much-needed evidence to guide treatment in the future.
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