Younger Age at Onset Is Associated With Worse Long-term Behavioral Outcomes in Anti-NMDA Receptor Encephalitis

Discussion

This study explores adaptive behavior outcomes after anti-NMDARE and demonstrates that although overall outcomes on this domain appear to be favorable, differences are seen by age such that younger children appear to have worse outcomes compared with adolescents and young adults. Long-term outcomes after anti-NMDARE appear to be favorable overall, as suggested by the fact that the average adaptive behavior score for participants in this study falls in the average range. Through use of a standardized age-normalized rating scale, adaptive behavior assesses an individual's ability to function independently and meet environmental demands. It has been demonstrated by our group^13,17 and others^18,19 that adaptive behavior and other outcomes following anti-NMDARE may be better than those following other forms of autoimmune encephalitis and infectious encephalitis. In this study, our findings regarding adaptive behavior are corroborated by examination of neurologic disability, for which we found that the majority of participants have good outcome (mRS score 0–2), akin to what has been found in other studies in this disease.⁴ Furthermore, less than 50% of participants reported ongoing difficulties with fatigue, emotional lability, memory difficulties, and concentration difficulties.

Despite overall favorable adaptive behavior outcomes, we demonstrate that children with anti-NMDARE had worse scores compared with those who experienced anti-NMDARE onset in adolescence or young adulthood. Of note, younger age at onset did not lead to a higher risk of neurologic disability as assessed using the mRS. This finding emphasizes the importance of evaluating aspects of daily performance beyond traditional measures of motoric and fine motor functioning. Although children's outcomes were worse than those of adults, they did not, on average, fall into the ranges of low or extremely low. However, modest impairments in adaptive functioning can still affect quality of life at home, at school, and in the community.²⁰ Our findings of worse adaptive behavior outcomes in younger children are supported by previous literature examining the effects of age at symptom onset on long-term neurologic disability, as measured by mRS scores. An early and pivotal study of treatment and prognostic factors for long-term outcomes demonstrated in analyses restricted to adolescents and children a relationship of improved odds of good outcome (defined as mRS score of 0–2) after 24 months of follow-up with increasing age.⁴ In a more recent meta-analysis of individual patient data of 1,550 cases, infants younger than 2 years (along with adults aged 65 years and older) were likewise observed to have a more than 3 times increased odds of poor outcome, defined as mRS score of 3–6 after a median follow-up of 12.0 months (range 0.5–268.0 months).²¹ Conversely, in a separate literature review and meta-analysis of 80 previously reported cases of children with anti-NMDARE, no association was found between age at onset and rates of incomplete recovery, defined as mRS score of 2–6, after a median follow-up of 12 months (range 1.3–54 months).²² Future research is required to determine whether pediatric-onset anti-NMDARE portends a higher likelihood of need for school and social supports. It will also be of value to quantify the effect of anti-NMDARE on family functioning, not just the acute effect experienced during the acute illness, but the longer-term effect.

Early-onset anti-NMDARE might have a greater effect in the context of the developing brain. It has been demonstrated that clinical recovery results from downregulation of B-cell production of anti-NMDAR antibodies, leading to restoration of NMDARs and subsequent reversal of impairment in NMDAR function.²³ However, it is not clear that such restoration of NMDARs would lead to restoration of all activity of NMDAR-related networks in a developing brain. Furthermore, profound encephalopathy can occur for months in anti-NMDARE during periods of critical neural development in children. It is possible that the prolonged loss of environmental enrichment, such as missed school and socialization, during the acute periods of anti-NMDARE may in itself lead to impairment in neural networks underlying learning and development that would otherwise be normally developing. Such phenomena have been reported in studies of pediatric traumatic brain injury.^24,25 Even subtle alterations of these developmental trajectories may lead to reductions in daily function and quality of life, which can have critical consequences in social and educational settings.

Another potential explanation may be a difference in clinical factors by age that may play a role in outcomes. Prior studies have demonstrated that requirement for ICU admission and longer time between diagnosis and treatment initiation^4,10 are associated with poorer long-term neurologic disability outcomes in anti-NMDARE. Although no differences were seen in this study in rates of ICU admission, delays in treatment initiation were not able to be evaluated, as it was difficult to accurately ascertain this information in many patients who had been transferred from outside hospitals. Furthermore, fewer children did receive second-line treatment (defined as rituximab and/or cyclophosphamide) compared with adults in this study. This may reflect physician discomfort with the use of these medications in children, despite several studies indicating safety and efficacy in the pediatric population, as they are not approved by the United States Food and Drug Administration for pediatric use.²⁶ Correspondingly, prior studies have demonstrated a decreased risk of relapse in individuals receiving second-line treatment as well as improved neurologic disability outcomes in those who received second-line treatment after failing first-line treatment.¹⁰

A final possibility is a difference in sociologic factors between children and adults. Although an adult's independence in activities of daily living is typically self-motivated, a child's independence occurs within the context of a family. Given the often severe and protracted course of anti-NMDARE, it is possible that parents remain guarded about the freedom and independence they afford to a child who is recovering from severe illness. Such imposed limitations would be reflected in many of the questions on the ABAS-3 (e.g., “makes simple meals that require no cooking” or “attends fun activities at another's home”). This may contribute to the observed lower scores in children in comparison to adolescents and young adults (notably, in the domains of health and safety, and self-care). Although this phenomenon may affect adaptive behavior in this patient population, it, nonetheless, may still represent an important psychosocial consequence of this disease and an important dynamic to consider when counseling families. Relatedly, because both children and adults were included in this study, respondents to the ABAS-3 included both participants themselves and their primary caregivers. Our analyses did not identify differences in ABAS-3 scores between those who responded themselves and those for which a caregiver responded. However, as seen in studies of other conditions,^27,28 it is possible that individuals with anti-NMDARE themselves may answer differently than the parents/caregivers responding on their behalf.

Adaptive behavior outcomes of older adults with anti-NMDARE were partially examined in this study. Five participants in this cohort were over the age of 30 years and, in fact, all 5 were over the age of 50 years. Given the small number of participants in this age group, they were excluded from subgroup analyses examining the role of age on outcomes. Although not specifically analyzed in this study, qualitatively, 2 participants scored in the above average range and 3 participants in the below average range on the ABAS-3. Of interest, the 2 participants who scored well both had a tumor discovered; however, there were no other apparent differences between the 2 groups in the clinical variables collected. Other comorbidities, including reasons for neurodegeneration, were not evaluated. Future studies should look at a larger cohort of older participants with anti-NMDARE with appropriate healthy controls and extraction of comprehensive medical information to determine if and how outcomes in this age group differ from those of children, adolescents, and young adults.

This study across 3 subspecialty centers demonstrates that anti-NMDARE is associated with an overall favorable outcome, although younger age at onset associates with worse long-term adaptive behavior. Limitations include the retrospective identification of patients, which may have introduced the possibility of selection bias (e.g., the inclusion of a large children's hospital as one of the 3 cohorts led to a relative abundance of children and adolescents in this study.) An additional limitation was the cross-sectional assessment of participants, which led to variabilities in factors such as time from symptom onset to study enrollment. Future work through prospective and larger studies will evaluate behavioral recovery and quality of life after anti-NMDARE and identify additional factors associated with differential recovery. This will enable the examination of the role of factors that could not be examined in this study due to inconsistent data availability such as time from symptom onset to immunotherapy initiation and MRI brain findings. Although this study included a sizeable cohort because of its multisite nature, larger studies are needed to examine other variables such as potential differences between the outcomes of very young children and older adults compared with those of adolescents and young adults. Ultimately, improved understanding of outcomes may have implications for clinical management and the design of interventional (both pharmacologic and nonpharmacologic) studies in this patient population.