Long-term neuropsychological outcome following pediatric anti-NMDAR encephalitis

Abstract

Objective: To provide detailed long-term outcome data of children and adolescents following pediatric anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis, to identify neuropsychological impairments, and to evaluate the influence of these factors on quality of life (QoL).

Methods: All Dutch children diagnosed with anti-NMDAR encephalitis were identified. Patients currently aged 4 years or older were included in the follow-up study, consisting of a visit to our clinic for a detailed interview and a standardized neuropsychological assessment. The following domains were included: attention, memory, language, executive functioning, QoL, and fatigue. Primary outcome measures were z scores on sustained attention, long-term verbal memory, QoL, fatigue, and working memory.

Results: Twenty-eight patients were included. Median Pediatric Cerebral Performance Category at last visit was 1 (interquartile range 1-2, range 1-4), and 64% (18/28) of patients returned consistently to their previous school level. Twenty-two patients were included in the cross-sectional part of the long-term follow-up study. Median follow-up time was 31 months (interquartile range 15-49, range 5-91). There were problems with sustained attention (z = -2.10, 95% confidence interval = -2.71 to -1.46, p < 0.0001) and fatigue (z = -0.96, 95% confidence interval = -1.64 to -0.28, p = 0.008). Cognitive deficits were not correlated with QoL, while fatigue was strongly correlated with QoL (r = 0.82, p < 0.0001).

Conclusions: Although follow-up is often reported as "good" following pediatric anti-NMDAR encephalitis, many patients have cognitive problems and fatigue, even up until adolescence, resulting in academic achievement problems and lower QoL. For physicians, it is essential to be aware of these problems, to provide valuable advice to patients and caregivers in the acute and follow-up phase, and to consider early neuropsychological counseling.

Figure 1. Flowchart of patient selection

One patient was excluded because he was younger than 4 years (transplacental transmission of anti-N-methyl-d-aspartate receptor), and one patient was untraceable. Twenty-four patients participated in the follow-up study, of whom 2 are followed prospectively. Sixteen of the 22 participants completed the full neuropsychological assessment, 6 patients only completed the questionnaires, 3 visited our clinic, and 3 were contacted by phone because of geographical distance. NPT = neuropsychological testing.

Figure 2. Patient symptoms

(A) Distribution of presenting symptoms of patients younger than 12 years and of patients aged 12–18 years. (B) Cumulative symptoms during disease course. (C) Number of core symptoms at presentation, treatment, and antibody diagnosis, and total number of symptoms.

Figure 3. Overview of correlations between primary outcome measures

Outcome measures: sustained attention (Dutch Dot Cancellation Test–attention fluctuations), long-term verbal memory (RAVLT–Delayed Recall), fatigue (PedsQL-MFS Self-Report–Total Score), QoL (PedsQL Self-Report–Total Score), and working memory (BRIEF–Working Memory). In all graphs, results of uncorrected z scores are shown, but the correlations are calculated with corrected z scores (maximum 3, minimum −3). Anti-NMDAR = anti-N-methyl-d-aspartate receptor; BRIEF = Behavior Rating Inventory of Executive Function; HSV = herpes simplex virus; LTM = long-term verbal memory; MFS = Multidimensional Fatigue Scale; PedsQL = Pediatric Quality of Life; QoL = quality of life; RAVLT = Rey Auditory Verbal Learning Test.