Assessment of Cognitive Status in Pediatric Anti-NMDA Receptor Encephalitis during Inpatient Rehabilitation: A Retrospective Cohort

Abstract

Objectives:

Anti-NMDA receptor autoimmune encephalitis (NMDARE) is a common pediatric encephalitis, resulting in neuropsychiatric symptoms. Predicting severity and course is challenging, with objective cognitive assessments lacking in NMDARE, especially in children. The CASE (Clinical Assessment Scale in Autoimmune Encephalitis) measures severity in autoimmune encephalitis. The CALS (Cognitive and Linguistic Scale) assesses cognitive-linguistic recovery in children with acquired brain injury. This study examines severity and cognitive status in pediatric NMDARE by comparing objectives measures: modified Rankin score (mRS), CASE, and CALS.

Methods:

Twenty-one patients were identified via retrospective chart review with a confirmed NMDARE diagnosis (ages of 3–18 years) who required inpatient rehabilitation. The mRS, CASE, and CALS were assessed at admission and discharge.

Results:

Scores demonstrated improvement from admission to discharge, with variability in individual recovery trajectories. CALS identified three clusters of patients with differential rates of early recovery. CALS <30 was associated with minimal improvement and poor outcomes. CALS ≥30 had a likelihood ratio score of 12.0 to predict improvement. CASE and CALS were moderately correlated, but neither correlated with mRS.

Discussion:

CALS and CASE appear to be complementary measures for assessing severity and cognitive status in pediatric NMDARE, including those with low responsiveness, with implications for treatment and outcomes.

1. Introduction

Anti-NMDA receptor encephalitis (NMDARE) is associated with neuropsychiatric symptoms and poor two-year recovery in 20% of patients^1,2. Predicting clinical severity, course and recovery is challenging, with limited pediatric studies.^3–5 Currently, objective clinical assessments do not adequately characterize cognitive sequelae in NMDARE, especially during early recovery, aside from formal neuropsychological testing.^6,7

The modified Rankin score (mRS) is used to assess outcomes in NMDARE in children and adults.⁸ However, it is limited by its emphasis on motor rather than cognitive functioning. Patients with the same mRS score can have wide variability in cognitive symptoms.

The Clinical Assessment Scale for Autoimmune Encephalitis (CASE) measures disease severity in autoimmune encephalitis, including NMDARE, predominantly with adults.⁹ Scores range from 0–27, with higher scores suggesting greater severity. One pediatric NMDARE study found patients exhibited persistent cognitive symptoms (e.g., memory, language, consciousness) despite having a “good outcome” as assessed by the mRS.¹⁰ The CASE incorporates more cognitive symptoms than mRS, although remains limited.

The Cognitive and Linguistic Scale (CALS) is used to serially track cognitive-linguistic recovery following acquired brain injury. Cognitive domains include arousal/responsiveness, attention/behavioral regulation, processing speed, new memory, language/visual-spatial processing, problem-solving, and deficit awareness. Scores range from 20–100,^11,12 with lower scores suggesting worse cognitive status. A score of 20 is suggestive of a patient who is not awake or responsive to environmental stimuli and a score < 30 is suggestive of a patient who may be awake, yet is not consistently responsive, such as with a disorder of consciousness (DOC).¹³ The CALS takes 15–30 minutes to administer and provides a more detailed cognitive assessment than either the CASE or mRS. The CALS has predominantly been used in traumatic brain injury (TBI), although widely used in other neurologic disorders.¹²

To our knowledge, no previous studies have examined the CALS to monitor cognitive-linguistic recovery in pediatric NMDARE. There is a need to identify complementary measures to assess severity and cognitive status that also inform treatment and predict outcomes. This study aims to: 1) assess disease severity and cognition in pediatric NMDARE using the CASE and CALS and 2) examine the association between the mRS, CASE and CALS during inpatient rehabilitation.

2. Methods

2.1. Standard Protocol Approvals, Registrations, and Patient Consents

Institutional Review Board (IRB) approved and waived informed consent for this study. The sample includes pediatric NMDARE patients (age <18 years), with available CALS data obtained at inpatient rehabilitation admission and discharge by a pediatric neuropsychologist. CASE scores were determined retrospectively. NMDARE diagnosis was confirmed with positive cerebrospinal fluid (CSF) anti-NMDAR antibody testing and ≥ one neuropsychiatric symptom.¹⁴ Clinical information was collected in REDCap.¹⁵ One patient was excluded for insufficient data.

1.2.2. Statistical Analyses

Statistical analyses included descriptive statistics (mean, standard deviation, median, interquartile range). CASE and CALS scores were assessed with linear regression (R² values>0.8 = high correlation, 0.5–0.8 = moderate correlation, and < 0.5 = low correlation). Paired Student’s t test or Wilcoxon rank sum tests assessed differences in admission and discharge scores for mRS, CASE and CALS as appropriate (SAS 16.0, Cary, NC).

3. Results

Twenty-one patients were included (Table 1). A majority of patients were female (67%) and non-White (76%). Average age at symptom onset was 11.7 years (SD=3.8). Most common initial symptoms: behavior changes (62%), flu-like symptoms (48%), or psychosis (43%). About half (48%) had an abnormal MRI, 76% had an abnormal EEG, and 10% had an identified tumor. All patients received first line and 95% received second-line immunotherapies.

Table 1.

Demographic and Clinical Characteristics of pediatric NMDARE patients (N=21).

Gender, N (%)
Female	14 (67)
Male	7 (33)
Race/Ethnicity
White/Caucasian	5 (24)
Black/African American	12 (57)
Latino/Hispanic	4 (19)
EEG abnormal	16 (76)
MRI abnormal	10 (48)
Tumor present	2 (10)
Initial symptoms
Flu-like	10 (48)
Psychosis	9 (43)
Other psych (personality/behavior change)	13 (62_
Clinical seizure-like events	7 (33)
Autonomic instability	0 (0)
Movement disorder	5 (24)
Catatonia	4 (19)
Insomnia	3 (14)
Mutism	1 (5)
Agitation	5 (24)
First line treatments	21 (100)
Second line treatments	20 (95)
Age at onset, years, mean (SD)	11.6 (3.8)
Time to treatment from symptom onset, days mean (SD)	19.7 (12.4)
Clinical assessments
mRS: Admission, mean (SD)	3.9 (0.9)
mRS: Discharge, mean (SD)	3.0 (1.2)
CASE: Admission, mean (SD)	12.2 (4.0)
CASE: Discharge, mean (SD)	8.6 (4.3)
CALS: Admission, median (IQR)	35.0 (28.5, 64.5)
CALS: Discharge, median (IQR)	79.0 (35.0, 87.0)
LOS: hospitalization, days, median (IQR)	42.0 (21.5, 63)
LOS: inpatient rehabilitation, days, median (IQR)	26.0 (15.5, 35.5)

EEG: electroencephalography, MRI: magnetic resonance imaging, IQR: interquartile range, LOS: length of stay, mRS: modified Rankin score, CASE: Clinical Assessment Scale in Autoimmune Encephalitis, CALS: Cognitive and Linguistic Scale

At the group level, mRS and CASE scores demonstrated clinical improvement from admission to discharge (Table 1; Figure 1). For CASE scores, the most severe symptoms (moderate-severe) at admission included memory (20/21=95%), psychiatric (18/21=86%), language (18/21=86%), and gait problems (18/21=86%). At discharge, moderate-severe symptoms included memory (18/21=86%) and psychiatric (15/21=81%). When examined individually, CASE scores remained stable to improved across admission (Figure 1D).

Figure 1.

Disease severity and cognitive status at admission and discharge from inpatient rehabilitation in pediatric NMDARE patients (N=21). Total scores at admission and discharge for A) CASE, B) CALS, and C) mRS. Individual scores from admission to discharge for D) CASE, E) CALS, and F) mRS. For D, E, and F, the dotted lines represent good responders by CALS, the solid lines are the intermediate group by CALS and the dash-dot line are the minimal responders by CALS. The one patient who had a decline in CALS but improved CASE and mRS is designated by the squares and dashed lines; the patient with improved CALS despite initial CALS < 30 is depicted by the triangle.

CALS scores demonstrated cognitive improvements from admission to discharge (Table 1; Figure 1B). More than 60% of patients presented with low responsiveness, consistent with DOC (CALS ≤40). Three clusters of patients emerged across admission (Figure 1E): (1) low responsiveness at admission (CALS <30) who remained low at discharge (CALS <37), (2) low responsiveness at admission (CALS 30–40) and high at discharge (CALS >70), and (3) high responsiveness at admission (CALS ≥57) and high at discharge (CALS >70). This differentiation allowed the admission CALS score to predict recovery at discharge. We then examined additional predictors of high discharge CALS scores (>60), including sex, race/ethnicity, hospital length of stay, time to treatment from symptom onset, days from onset to rehabilitation admission, time from treatment to rehabilitation admission, or rates of abnormal EEG, abnormal MRI, and PICU admission. No associations with CALS discharge scores were found among these variables.

Inpatient rehabilitation length of stay did not correlate with change in CALS from admission to discharge (p = 0.478, Figure 2). Moreover, we performed a multivariable linear regression model examining the change in CALS from inpatient rehabilitation admission to discharge using the following variables: sex, race, ethnicity, age, time to treatment, hospital length of stay, abnormal EEG, abnormal MRI, and PICU admission. With backwards elimination, PICU admission (p = 0.0448) and age (0.011) correlated with change in CALS; however, this did not remain significant when adjusted for inpatient rehabilitation length of stay.

Figure 2:

Linear regression of change in CALS scores as compared to inpatient rehabilitation length of stay (LOS).

A CALS admission score <30 was associated with worse cognitive status whereas CALS admission score ≥ 30 predicted improved cognitive status at discharge (sensitivity=86% [95%CI: 42–99.6%], specificity=93% [95%CI: 66–99.8%]). Therefore, a CALS admission score ≥30 predicted clinical improvement with a positive likelihood ratio of 12.0 (1.8–81.0) and negative likelihood ratio of 0.15 (0.02–0.95). For logistic regression with backward selection, this same cutoff predicted discharge score (Odds Ratio 36, 95%CI 1.8–731.6, p=0.0197) even after other variables were removed (time to treatment, ICU admission, age, length of stay).

3.1. Associations between Disease Severity and Cognitive Status

Linear regressions revealed overall CASE and CALS scores moderately correlated at admission and discharge (R² =0.56 and 0.54, respectively, p<0.0001) (Figure 3). Given an inverse relationship, lower CASE and milder severity were associated with higher CALS and better cognitive performance, despite differences with individual recovery trajectories. One patient had an admission CALS score of <30, with improved cognition (29 to 82) and reduced severity during inpatient rehabilitation (CASE: 13 to 9; Figure 1C/D). Another patient had declining CALS scores (72 to 39), which preceded clinical worsening not reflected in CASE scores (4 to 5) (Figure 1D–F).

Figure 3.

Associations between disease severity and cognitive status in CALS versus CASE at admission (A) and discharge (B). Comparisons of mRS versus CASE at admission (C) and discharge (D). Comparisons of mRS versus CALS at admission (E) and discharge (F).

Associations between the CASE cognitive symptoms (memory, language, consciousness), mRS and CALS total score were also examined. CASE cognitive symptoms and CALS total scores were moderately correlated at admission (R²=0.56, when R² between 0.5–0.8 is moderate correlation, p<0.0001) yet not correlated at discharge (R²=0.46 which is < 0.5, p=0.0007). No correlations were found between CALS or CASE scores with mRS (Figure 3C–F).

4. Discussion

There is a lack of complementary assessment measures to track disease status in pediatric NMDARE. Thus, the current study examined the utility of the mRS, CASE and CALS in assessing disease severity and cognitive status during inpatient rehabilitation in this population. Overall, lower CASE scores (milder severity) were moderately associated with higher CALS scores, with some variability at the individual level. The CASE cognitive scores were also moderately correlated with CALS total scores, suggesting cognitive improvement is better reflected with the CALS. mRS did not correlate with either the CASE or CALS. Interestingly, the CALS identified three distinct groups of patients with differing rates of early recovery. While the significance of these groups is unclear and no clinical variables were identified to predict group membership, it suggests that children may experience varying rates of early recovery during inpatient rehabilitation and reiterates the importance of examining additional factors (e.g., biomarkers) that may underlie vulnerability for response to treatment. We show that the CALS was more sensitive to changes in cognition and uniquely characterized cognitive status. Given the ease of administration and validation for serial monitoring, the CALS could be used at different times during recovery and in a variety of settings (e.g., inpatient, outpatient, clinical trials).

The CALS adequately captured the >60% who presented with DOC. A CALS admission score <30 was associated with low responsiveness in NMDARE, consistent with prior research in pediatric TBI.¹³ While the pathophysiology is different, the CALS appears sensitive to adequately measuring cognitive status in NMDARE, including those in a low responsiveness state.

4.1. Limitation of study and improvements or future directions

Limitations include the small sample size from a single center. Moreover, we may be capturing a more severe population due to including those in inpatient rehabilitation, but at our institution, 96% (53/55) of pediatric NMDARE patients have been admitted to inpatient rehabilitation. While consistent with previous studies, CASE scores were calculated retrospectively from the notes of multiple medical specialists (e.g., Physiatry, Neurology, Psychiatry). The mRS was also calculated retrospectively. We did not identify other predictors for high discharge CALS scores at discharge from inpatient rehabilitation, but our sample size was small and additional contributing factors may be identified in a larger cohort. We did not capture outpatient CALS scores in this cohort but will do so in future studies.

5. Conclusions

To our knowledge, this is the first study to systematically assess cognitive status in pediatric NMDARE. CALS and CASE may be complementary measures for assessing severity and cognitive status in NMDARE. While larger studies are needed, the CALS appears to efficiently and objectively assess the cognitive-linguistic deficits during NMDARE clinical course/recovery and predict acute outcomes.

Data Access Statement:

The authors have full access to the all the data, and have the right to publish any and all data, separate and apart from the guidance of any sponsor.