- Email: [email protected]
Neurobehavioral outcomes in autoimmune encephalitis
Accepted Manuscript Neurobehavioral outcomes in autoimmune encephalitis
Anusha K. Yeshokumar, Eliza Gordon-Lipkin, Ana Arenivas, Jesse Cohen, Arun Venkatesan, Deanna Saylor, John C. Probasco PII: DOI: Reference:
S0165-5728(17)30274-6 doi: 10.1016/j.jneuroim.2017.08.010 JNI 476621
To appear in:
Journal of Neuroimmunology
Received date: Revised date: Accepted date:
6 July 2017 8 August 2017 22 August 2017
Please cite this article as: Anusha K. Yeshokumar, Eliza Gordon-Lipkin, Ana Arenivas, Jesse Cohen, Arun Venkatesan, Deanna Saylor, John C. Probasco , Neurobehavioral outcomes in autoimmune encephalitis, Journal of Neuroimmunology (2017), doi: 10.1016/ j.jneuroim.2017.08.010
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ACCEPTED MANUSCRIPT Neurobehavioral Outcomes in Autoimmune Encephalitis Anusha K. Yeshokumar, MD1; Eliza Gordon-Lipkin, MD1,2; Ana Arenivas, PhD3,4; Jesse Cohen, BA1; Arun Venkatesan, MD PhD1; Deanna Saylor, MD MHS1; John C. Probasco, MD1 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
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Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore,
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1
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Maryland
Department of Neuropsychology, Kennedy Krieger Institute, Baltimore, Maryland
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Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of
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3
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Medicine, Baltimore, Maryland
Corresponding Author
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John C. Probasco, MD
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Department of Neurology, Johns Hopkins School of Medicine Meyer 6-113 - 600 N. Wolfe St. - Baltimore, MD 21287
Study Funding
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Phone: (410) 955-8174; Fax: (410) 955-0672; Email: [email protected]
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This work was supported by the Johns Hopkins Center for Refractory Status Epilepticus and Neuroinflammation.
ACCEPTED MANUSCRIPT Abstract This study evaluates long-term neurobehavioral function in patients with clinically diagnosed autoimmune encephalitis (AE) of various etiologies through retrospective chart review and a cross-sectional structured telephone interview. Of 77 patients meeting clinical diagnostic criteria
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for AE over a ten year period, 39/77 (51%) patients had known AE-associated antibodies, and
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38/77 (49%) had no detected antibody. 9/77 (12%) died, and 26/77 (34%) had “poor” neurologic
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disability score (mRS 3-5) at the last documented follow-up. 44 participants enrolled in the telephone interview, of whom 38/44 (86%) endorsed ongoing difficulties with fatigue, emotional
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lability, short-term memory, and/or concentration. On standardized assessment of adaptive
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behavior (ABAS-3), 23/44 (52%) scored “below average” (general adaptive composite: mean 86.95, standard deviation 18.45). Of the participants with “good” neurologic disability outcome
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(mRS 0-2), 12/30 (40%) scored “below average” in adaptive behavior. In summary, patients with
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AE frequently have persistent impairments in neurologic disability, neurocognitive symptomatology, and adaptive behavior, which may not be adequately captured by routine
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neurologic assessments. Comprehensively elucidating these persistent neurobehavioral
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impairments and predicting which patients are at highest risk will allow for optimal care of
Keywords
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patients and their families.
Autoimmune encephalitis; antibody-mediated; neurobehavioral function; neurologic disability; adaptive behavior; neurocognition
ACCEPTED MANUSCRIPT 1. Introduction Given the recent advances in the understanding of pathogenic mechanisms in autoimmune encephalitis (AE),1 there remains a paucity of data surrounding long-term neurologic and behavioral outcomes. Studies assessing long-term motor disability using modified rankin scale
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(mRS) report overall good outcomes, particularly in patients with anti-N-methyl-D-aspartate
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receptor (anti-NMDAR) encephalitis.2 While some studies have assessed cognition and other
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aspects of outcome in this and other forms of AE,3-7 most studies have been retrospective, limited to two-year follow-up, and/or limited to use of mRS as the primary outcome measure.8-15
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Little is known about the role of antibody presence or other patient and clinical factors on
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outcomes in AE. Furthermore, studies suggest that some forms of AE present and respond to treatment differently between children and adults,16,17 and it remains unclear whether disease
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acquisition during periods of critical neurodevelopment may in itself lead to cognitive and
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functional delays and deficits.
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This study aimed to evaluate long-term neurobehavioral function in patients with AE through a
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structured telephone interview, including a survey and a standardized rating scale of adaptive behavior.18 Adaptive behavior describes the ability to handle common demands in life and to
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maintain age-appropriate independence in everyday environments.19 It has been studied in many medical conditions, particularly learning disorders, intellectual disability, and post-cardiac arrest.19-22 We hypothesized that patients with AE will report persistent impairment in adaptive behavior, as well as neurologic disability and neurocognitive symptoms.
ACCEPTED MANUSCRIPT 2. Materials and Methods 2.1 Standard Protocol Approvals, Registrations, and Patient Consents The study was approved by the Johns Hopkins Hospital Institutional Review Board, and oral informed consent was obtained from all participants 18 years of age or older. For participants
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under the age of 18 years, oral informed consent was obtained from their guardian.
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2.2 Study Participants
Medical records of children (<18 years of age) and adults (>18 years of age) treated at the Johns
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Hopkins Hospital in Baltimore from July 1st, 2005 until June 30th, 2015 with a billing diagnosis
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of encephalitis were reviewed. Patients were included if they met clinical criteria on limited chart review for possible AE and were further sub-classified as definite limbic encephalitis or
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Hashimoto’s encephalopathy, as appropriate.23 It was also required that at least one year had
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passed from the time of diagnosis to study enrollment in order to examine patients’ long-term outcomes. Eligible patients (if under 18 years of age, patients’ legal guardians) were contacted
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by telephone and asked to consent to participation in a structured telephone interview for this
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study. Patients’ decision to participate or decline participation (along with the date contact was established) was recorded to ensure adequate documentation of informed consent. Patients were
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excluded if chart review demonstrated a diagnosis other than AE and were included but not contacted if chart review demonstrated that the patient was deceased.
2.3 Clinical Data Collection Additional information was obtained from participants’ inpatient and outpatient records regarding demographic information, presenting symptoms and signs, laboratory test results,
ACCEPTED MANUSCRIPT electroencephalogram and neuroimaging study results, treatments received, and clinical findings at discharge and follow-up.
2.4 Clinical, Adaptive, and Functional Outcome Assessments
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A survey (Appendix A) was administered to collect basic information about the participant’s
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premorbid education/employment status, initial presentation of AE, current medical status,
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services received, general function, and current education/employment status. Participants were also asked specifically about perceived difficulties with fatigue, emotional lability, short-term
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memory, and concentration.
The Adaptive Behavior Assessment System, Third Edition (ABAS-3),18 a standardized age-
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normalized neurobehavioral rating scale of over 200 items for individuals from early infancy to
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adulthood, was also administered. This tool assesses development, behavior, and cognitive abilities and includes subscales for communication, community use, functional academics, home
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living, health and safety, leisure, self-care, self-direction, social, motor, and work. These
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subscales are summed and normalized to the standardization sample to generate a general adaptive composite (GAC) and three major adaptive domain scores (conceptual, social, and
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practical). For participants <18 years of age, parents or other caregivers completed the ageappropriate form for children (0-5 years or 5-21 years). For participants >18 years of age, either the capable adult or other caregiver completed the form for adults (16-89 years).
Scores for mRS, a motor disability scale with scores ranging from 0 for no symptoms to 6 for death,24 were assigned independently by two raters and adjudicated to consensus in the event of
ACCEPTED MANUSCRIPT difference. Each participant was assigned a score at hospital admission and discharge based on documentation in the clinical record as well as at last neurology follow-up based on either documentation in clinical record or results of the structured telephone interview. As has been done in other studies of autoimmune encephalitis, a “good” score was defined by mRS 0-2 and a
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“poor” score by mRS 3-6.2
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2.5 Statistical Analyses
Statistical analyses were performed using STATA software version 14 (College Station, TX).
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Chi-square and Fisher exact tests for categorical variables and two-sided t-tests for continuous
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variables were used, with p-value < 0.05 considered significant. Survival analyses using Cox proportional hazards regression analysis were conducted to evaluate for factors associated with
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death. The effects of patient and clinical factors alone on each outcome measure (mRS and
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GAC) were tested with simple regression, and the individual effects of multiple patient and clinical factors, adjusting for potential confounders, were tested in multiple regression models.
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Examined patient and clinical factors included age, proportion of children, sex, white race, black
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race, anti-NMDAR seropositivity, antibody negative status, target antigen location (cell surface versus intracellular), limbic encephalitis, tumor presence, seizure presence, requirement for
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intensive care unit (ICU) admission, duration from symptom onset to treatment initiation, and treatment received. Given the cohort size, analyses for smaller subgroups of age (e.g., young adults versus older adults), race (e.g., Asian versus other), antibody neoplasm association (classically paraneoplastic antibodies versus autoimmune antibodies), and antibody status (e.g., presence of voltage-gated potassium channels antibodies versus other) could not be completed.
ACCEPTED MANUSCRIPT 3. Results 3.1. Participants Review of medical records yielded 312 participants with a diagnosis of encephalitis of which 77 met criteria for AE. Of these, 9 (12%) patients were deceased, and 9 (12%) did not have an
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active telephone number listed. Of the 59 who were contacted for neurobehavioral assessments,
3.2 Retrospective Analyses and Neurologic Disability
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44 (75%) were enrolled in the study, 9 (15%) declined, and 6 (10%) could not be reached.
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The 77 participants with AE ranged in age from 16 months to 80 years (Figure 1), and the mean
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duration of follow-up since diagnosis was 4.0 years (SD 3.0 years, Figure 2). 44 participants were female (57%), 66 were adults at the time of diagnosis (86%), and 39 (51%) had detectable
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antibodies associated with AE (Table 1). No participant had more than one antibody with titers in
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the abnormal range. 45 participants (58%) had seizures, and 16 (21%) had a detected tumor. 26 (34%) received both first- (high-dose steroids, plasma exchange, and/or IV immunoglobulin) and
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second-line treatment (rituximab and/or cyclophosphamide), and 42 (55%) were admitted to the
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neurology critical care unit during initial hospitalization.
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At last neurology follow-up, 41 (53%) of participants had a “good” neurologic disability score, defined as mRS < 2 (Figure 3). This percentage was higher than at the time of admission (17%, p<0.001) and hospital discharge (25%, p<0.001), indicating that further improvement was seen following discharge. On analysis of clinical factors associated with mRS outcomes, antiNMDAR antibody seropositivity was associated with greater proportion of “good” outcomes (mRS ≤ 2) at last neurology follow-up (92% vs 48%, p<0.01) and of improved mRS from
ACCEPTED MANUSCRIPT discharge to last neurology follow-up (83% vs 40%, p<0.05), despite no differences in mRS at admission or duration between symptom onset and treatment initiation. No other association between mRS score at last neurology follow-up and patient or clinical factors was seen
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(Appendix B).
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3.3 Death
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At the time of study enrollment, 9 participants were deceased. Disease duration and cause of death in this subgroup are depicted in Table 2. Survival analysis of the entire cohort revealed no
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association between death and age of diagnosis, gender, race, diagnosis, antibody status, tumor,
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seizures, ICU requirement, or treatment (Appendix C).
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3.4 Long Term Neuropsychiatric Symptoms and Adaptive behavior
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44 participants participated in the structured telephone interview on clinical status and adaptive behavior. Demographics of this cohort are shown in Table 1. Participants’ distribution of age and
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duration of follow-up are shown in Figure 1 and Figure 2, respectively. At the time of
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enrollment, mean duration of follow-up since diagnosis was 4.4 years (SD 3.2 years). Comparative analysis of enrolled participants (n=44) versus those who did not enroll (n=24) was
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performed, and no differences were found with respect to patient or clinical factors, mRS at admission, or mRS at discharge.
At enrollment, 38/44 (86%) participants endorsed at least one of the following persistent neuropsychiatric symptoms: fatigue (36%), emotional lability (61%), short-term memory loss (55%), and concentration difficulty (39%). Further analyses found that fewer participants with
ACCEPTED MANUSCRIPT anti-NMDAR encephalitis described difficulties with emotional lability (30% vs. 71%, p < 0.05), though no differences were seen in the other reported neuropsychiatric symptoms. No other association between neuropsychiatric symptoms and patient or clinical factors (including
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diagnosis of limbic encephalitis) was identified.
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Employment status and functional independence were examined in participants who were > 18
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years of age at the time of symptom onset and < 65 years of age at the time of study enrollment (n=26). Prior to onset of encephalitis, 22 participants (85%) were employed. However, at
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enrollment, the number of participants who were employed declined to 11 (42%, p<0.05).
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Further, only 13 participants (50%) were able to able to “rely on himself or herself to travel in the community (e.g. walking or uses public transportation, a bicycle or a car)”. 20 participants
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(77%) were able to “take medications without supervision”, and only 12 participants (46%) were
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“responsible for his or her personal finances.”
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On the ABAS-3, lower scores were seen in standard scores (SS) of the general adaptive
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composite (GAC) and across all three adaptive domains in the enrolled participants as compared to normative data (mean GAC SS 86.7 vs. 100.0, p<0.001). 23 of 44 participants (52%) scored
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“below average” on GAC (SS ≤ 89). As depicted in Figure 4, GAC decreases/worsens as expected with increasing/worsening mRS. Interestingly, of the participants with “good” neurologic disability outcomes (as defined by mRS ≤ 2, n=30), 40% (n=12) still scored “below average” on adaptive behavior (GAC SS ≤ 89). No particular domain on the ABAS-3 was selectively affected in these patients.
ACCEPTED MANUSCRIPT On analysis of clinical factors associated with ABAS-3 outcomes, mean GAC SS of participants with anti-NMDAR antibody seropositivity was higher than that of participants with other forms of AE (97.2 vs. 83.9, p<0.05). The mean score for participants with anti-NMDAR encephalitis was within the “average” range, while the mean score for those with other forms of AE was in
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the “below average” range. Additionally, participants of black race had a higher mean GAC SS
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than those of non-black race (103.8 vs. 84.2, p < 0.05). Participants who had had seizures had a
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higher mean GAC SS than those who did not (92.9 vs. 81.8, p < 0.05). These associations were independent of anti-NMDAR antibody seropositivity and other patient and clinical factors. No
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other association between ABAS-3 scores and patient or clinical factors was identified
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(Appendix D).
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4. Discussion
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This study demonstrates persistence of neurologic disability, neuropsychiatric symptoms, and neurobehavioral dysfunction in patients several years after diagnosis and treatment of AE. While
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this study included patients of a broad age range and variable follow-up duration, it is novel in its
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investigation of patient-reported impairment in neurobehavioral outcomes in clinically diagnosed
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AE of various etiologies.
In our study, while some patients with AE continue to experience improved neurologic disability outcomes after hospital discharge, nearly half had persistent “poor” outcomes, as defined by mRS > 2, at long-term follow-up. One study of 577 patients with anti-NMDAR encephalitis found that more than 80% of participants had a “good” outcome, defined as mRS of 0-2 at 24 months’ follow-up.2 A similar proportion was seen in patients with anti-NMDAR encephalitis in
ACCEPTED MANUSCRIPT our study (92%), suggesting that prognosis may differ based on the underlying antibodymediated etiology.
The modified Rankin Scale, a measure designed for stroke clinical trials, captures primarily
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motor function and does not evaluate cognitive or behavioral function, which are frequently
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affected at presentation in patients with AE. In our study, commonly reported neuropsychiatric
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deficits included fatigue, emotional lability, short-term memory, and concentration. Many of these symptoms are likely to be multifactorial in origin and should be evaluated further in future
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studies. Strikingly, only half of patients returned to employment and less than half traveled
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independently in the community. Small studies examining neurologic and behavioral outcomes
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personal and professional lives.3-7,25
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have likewise found that patients with AE are left with neurocognitive deficits that affect their
More than half of patients in our study scored “below average” in adaptive behavior across all
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domains on the ABAS-3 at the time of study enrollment. This standardized age-normalized
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neurobehavioral rating scale examines 11 skill domains of everyday activities to assess an individual’s ability to function independently and meet environmental demands. Furthermore,
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nearly half of patients with “good” neurologic disability outcomes scored “below average” in adaptive behavior. While patients with AE may appear from routine neurologic assessments and disability scores to have returned to baseline, assessment of adaptive behavior with the ABAS-3 identifies impairments in their ability to perform expected life tasks. The evaluation of adaptive behavior therefore adds a layer of quantitative clinical information that is not adequately captured by assessment of neurologic disability alone and could help monitor neurobehavioral
ACCEPTED MANUSCRIPT status longitudinally. Further study is warranted to better understand the role of various patient factors (including race) and clinical factors (including presence of seizures as well as various treatments received) on future adaptive behavior.
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Patients with anti-NMDAR encephalitis demonstrated better long-term outcomes in neurologic
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disability (by mRS), emotional lability, and neurobehavioral function (by ABAS-3) as compared
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to patients with other forms of AE. These differences were noted despite no differences in group demographics, clinical severity on presentation, or treatment received. While this finding
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certainly requires further investigation, it may be that anti-NMDAR encephalitis represents a
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distinct subset of AE with a specific prognosis. Alternatively, it may be that the clinical phenotype of anti-NMDAR encephalitis is better recognized than that of other autoimmune
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encephalitides, thereby leading to earlier diagnosis and treatment initiation, which may have
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factored into better outcomes. A difference between these groups in duration between symptom onset and treatment initiation was not seen in our study, but this may be attributed to the small
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sample size of patients with anti-NMDAR encephalitis. Until this difference in outcomes is
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better understood, clinicians must use caution in extrapolating findings and data regarding
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outcomes from this disease to other forms of AE.
Limitations of our study include its retrospective identification of the cohort, cross-sectional assessment of participants, and use of subjective outcomes measures. However, patient-reported outcome measures are a reliable and increasingly accepted method for clinical research of many neurologic diseases,26 including epilepsy,27-29 stroke,30-32 multiple sclerosis,33-35 and movement.36-38 Additionally, the heterogeneity of patients and small sample sizes of subgroups
ACCEPTED MANUSCRIPT in our study likely affected the ability to identify associations between outcome measures and some patient and clinical factors. While differences in long-term outcomes were not seen in our study between children and adults with AE, prior studies have observed differences in clinical presentation and response to treatment.16,17 It is possible that our study may have been
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underpowered to detect this and other subgroup differences, which could become evident from a
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prospective multi-center study.
In this study, we utilized patient-reported data to demonstrate persistence of neurologic
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disability, neurobehavioral dysfunction, and neuropsychiatric symptoms in patients several years
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following diagnosis of AE. These findings highlight the importance of larger prospective and multi-site studies to evaluate patients’ long-term outcomes and their trajectory of recovery with
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tools well suited to assess neurobehavioral impairments in this population. In addition to better
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characterizing the recovery from and chronic sequelae of AE, further studies may also enable a better understanding of the role of individual patient and clinical factors (including age, antibody
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presence, and various treatment modalities) on long-term outcomes. Ultimately, the adequate
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elucidation of persistent neurobehavioral deficits and ability to predict which patients are at
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highest risk will allow clinicians to optimally support and counsel patients and their families.
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ACCEPTED MANUSCRIPT Figure 1: Distribution of Age This figure depicts the age distribution of participants at the time of diagnosis. Blue bars indicate participants in the total cohort (n=77), and red bars indicate participants who enrolled in the
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structured telephone interview (n=44).
ACCEPTED MANUSCRIPT Figure 2: Distribution of Duration of Follow-Up This figure depicts the distribution of participants’ duration of follow-up. Blue bars indicate participants in the total cohort (n=77), and red bars indicate participants who enrolled in the
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structured telephone interview (n=44).
ACCEPTED MANUSCRIPT Figure 3: Modified Rankin Scale (mRS) Scores This figure depicts mRS scores of participants at the time of hospital admission, hospital discharge, and last neurology follow-up. “Good” outcome is defined as mRS score of 0-2, and “poor” outcome as mRS score of 3-6. The numbers in each box denote the percentage of
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participants (of total cohort n=77) who received each score.
ACCEPTED MANUSCRIPT Figure 4: Modified Rankin Scale (mRS) Scores at Last Neurology Follow-up Compared to General Adaptive Composite (GAC) Standard Scores (SS) This figure compares mRS scores at the time of study enrollment to GAC SS of participants enrolled in the structured telephone interview (n=44). The dashed box indicates participants with
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“good” neurologic disability outcome (mRS < 2) who scored “below average” in adaptive
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behavior (ABAS-3 < 89).
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Table 1: Demographics and Clinical Profiles of the Retrospective Cohort and Enrolled Cohort Retrospective Cohort Not Enrolled (n=77) Enrolled (n=44) (n=24) SD/ Mean/Num SD/ Mean/Num SD/ Mean/Number % ber % ber %
pvalue
Female Age of Diagnosis (years)
44
57.1
23
53.5
14
58.3
0.80
43.0
22.8
42.9
22.6
41.0
20.8
0.72 0.67
48
62.3
29
67.4
15
62.5
0.80
Black
12
15.6
6
14.0
4
16.7
0.73
7.0
2
8.3
-
7.0
0
0.0
-
7.0
3
12.5
-
21
48.8
13
54.2
1.00
10
23.3
1
4.2
0.08
5
11.6
3
12.5
-
7.8
3
3
3.9
3
Other
8
10.4
3
Antibody Status
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Asian Hispanic
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White
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Race
38
49.4
12
15.6
VGKC Antibodies* Thyroid Antibodies (TPO/TG)**
9
11.7
4
5.2
2
4.7
2
8.3
-
Ca Channel Antibodies
3
3.9
1
2.3
1
4.2
-
ANNA-1/Hu Antibodies
3
3.9
0
0.0
3
8.3
-
LGI-1 Antibodies
2
2.6
2
4.7
0
0.0
-
Ma 1/2 Antibodies
Seizures Limbic Encephalitis Tumor Present #
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Immunotherapy
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Alpha3-AChR Antibodies
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2
2.6
1
2.3
0
0.0
-
2
2.6
1
2.3
1
4.2
-
1
1.3
1
2.3
0
0.0
-
1
1.3
0
0.0
1
4.2
-
45
58.4
21
48.8
15
62.5
0.31
58
75.3
35
81.4
17
70.8
0.55
16
20.8
12
27.9
2
8.3
0.11
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CASPR-2 Antibodies
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GAD-65 Antibodies
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Antibody-Negative Anti-NMDAR Antibodies
0.43
First-Line Only
51
66.2
26
60.5
17
70.8
First- and Second-Line
26
33.8
18
41.9
7
29.2
Duration from Symptom Onset to Treatment Initiation (years)
0.6
1.3
0.7
1.6
0.5
0.6
0.43
ICU Required
42
54.5
19
41.9
15
62.5
0.20
mRS at Admission
0.10
mRS <=2
12
15.6
5
11.6
7
29.2
mRS >2
56
72.7
39
90.7
17
70.8
mRS at Discharge
0.06 mRS <=2
18
23.4
8
18.6
10
41.7
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50
64.9
36
83.7
14
58.3
9
11.7
-
-
-
-
-
4.0
3.0
4.4
3.2
0.8
2.4
0.90
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p-values for Chi-square or t-test, as appropriate, between enrolled and not enrolled groups. *Further classification as LGI-1 or CASPR-2 not available. **Thyroid peroxidase (TPO) and/or thyroglobulin (TG) antibodies detected. # First-Line Treatment = steroids, plasma exchange, and/or IV immunoglobulin. Second-Line Treatment = rituximab and/or cyclophosphamide. Abbreviations: ICU = intensive care unit, mRS = modified Rankin Scale
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4
77 days
5
70 days
6
84 days
7
106 days
8
10 months 4 years, 10 months
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66 days
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11 days
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11 days
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Disease Duration
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Subj ect
Table 2: Patient and Clinical Characteristics of Deceased Subjects Age at Diagn osis Gen (years Tu Cause of Death Antibody Status der ) mor Cardiac Arrest (Acute AntibodyMal Myocarditis) Negative e 22 No Respiratory Failure (Withdrawal Ca Channel Fem of Care) Antibodies ale 76 No Cardiac Arrest (Autonomic Anti-NMDAR Fem Instability) Antibodies ale 22 No Refractory Status Epilepticus AntibodyFem (Withdrawal of Care) Negative ale 24 No Fem Lung Cancer Hu Antibodies ale 65 Yes GAD-65 Fem Lung Cancer Antibodies ale 73 Yes Cardiac Arrest (Pulmonary AntibodyFem Embolism) Negative ale 80 No AntibodyFem Encephalitis Negative ale 74 No AntibodyMal Cardiac Arrest Negative e 6 No
Seiz ures Yes Yes Yes Yes Yes Yes Yes Yes Yes
Treatm ent FirstLine FirstLine Second -Line FirstLine FirstLine FirstLine FirstLine FirstLine FirstLine
ACCEPTED MANUSCRIPT Graphical abstract
Adaptive behavior (General Adaptive Composite Standard Score) worsens with worsening neurologic disability (mRS), however, a proportion of patients who score well on neurologic
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disability measures still score below average on adaptive behavior.
ACCEPTED MANUSCRIPT Highlights
Adults and children with autoimmune encephalitis frequently have persistent impairments in neurologic disability, neurocognitive symptomatology, and adaptive behavior. These impairments may not be adequately captured by routine neurologic assessments
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Comprehensively elucidating persistent neurobehavioral impairments and predicting
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which patients are at highest risk will allow for optimal care of patients and their families.
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alone.
Anusha K. Yeshokumar, Eliza Gordon-Lipkin, Ana Arenivas, Jesse Cohen, Arun Venkatesan, Deanna Saylor, John C. Probasco PII: DOI: Reference:
S0165-5728(17)30274-6 doi: 10.1016/j.jneuroim.2017.08.010 JNI 476621
To appear in:
Journal of Neuroimmunology
Received date: Revised date: Accepted date:
6 July 2017 8 August 2017 22 August 2017
Please cite this article as: Anusha K. Yeshokumar, Eliza Gordon-Lipkin, Ana Arenivas, Jesse Cohen, Arun Venkatesan, Deanna Saylor, John C. Probasco , Neurobehavioral outcomes in autoimmune encephalitis, Journal of Neuroimmunology (2017), doi: 10.1016/ j.jneuroim.2017.08.010
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Neurobehavioral Outcomes in Autoimmune Encephalitis Anusha K. Yeshokumar, MD1; Eliza Gordon-Lipkin, MD1,2; Ana Arenivas, PhD3,4; Jesse Cohen, BA1; Arun Venkatesan, MD PhD1; Deanna Saylor, MD MHS1; John C. Probasco, MD1 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
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Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore,
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Maryland
Department of Neuropsychology, Kennedy Krieger Institute, Baltimore, Maryland
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Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of
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Medicine, Baltimore, Maryland
Corresponding Author
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John C. Probasco, MD
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Department of Neurology, Johns Hopkins School of Medicine Meyer 6-113 - 600 N. Wolfe St. - Baltimore, MD 21287
Study Funding
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Phone: (410) 955-8174; Fax: (410) 955-0672; Email: [email protected]
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This work was supported by the Johns Hopkins Center for Refractory Status Epilepticus and Neuroinflammation.
ACCEPTED MANUSCRIPT Abstract This study evaluates long-term neurobehavioral function in patients with clinically diagnosed autoimmune encephalitis (AE) of various etiologies through retrospective chart review and a cross-sectional structured telephone interview. Of 77 patients meeting clinical diagnostic criteria
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for AE over a ten year period, 39/77 (51%) patients had known AE-associated antibodies, and
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38/77 (49%) had no detected antibody. 9/77 (12%) died, and 26/77 (34%) had “poor” neurologic
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disability score (mRS 3-5) at the last documented follow-up. 44 participants enrolled in the telephone interview, of whom 38/44 (86%) endorsed ongoing difficulties with fatigue, emotional
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lability, short-term memory, and/or concentration. On standardized assessment of adaptive
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behavior (ABAS-3), 23/44 (52%) scored “below average” (general adaptive composite: mean 86.95, standard deviation 18.45). Of the participants with “good” neurologic disability outcome
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(mRS 0-2), 12/30 (40%) scored “below average” in adaptive behavior. In summary, patients with
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AE frequently have persistent impairments in neurologic disability, neurocognitive symptomatology, and adaptive behavior, which may not be adequately captured by routine
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neurologic assessments. Comprehensively elucidating these persistent neurobehavioral
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impairments and predicting which patients are at highest risk will allow for optimal care of
Keywords
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patients and their families.
Autoimmune encephalitis; antibody-mediated; neurobehavioral function; neurologic disability; adaptive behavior; neurocognition
ACCEPTED MANUSCRIPT 1. Introduction Given the recent advances in the understanding of pathogenic mechanisms in autoimmune encephalitis (AE),1 there remains a paucity of data surrounding long-term neurologic and behavioral outcomes. Studies assessing long-term motor disability using modified rankin scale
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(mRS) report overall good outcomes, particularly in patients with anti-N-methyl-D-aspartate
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receptor (anti-NMDAR) encephalitis.2 While some studies have assessed cognition and other
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aspects of outcome in this and other forms of AE,3-7 most studies have been retrospective, limited to two-year follow-up, and/or limited to use of mRS as the primary outcome measure.8-15
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Little is known about the role of antibody presence or other patient and clinical factors on
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outcomes in AE. Furthermore, studies suggest that some forms of AE present and respond to treatment differently between children and adults,16,17 and it remains unclear whether disease
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acquisition during periods of critical neurodevelopment may in itself lead to cognitive and
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functional delays and deficits.
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This study aimed to evaluate long-term neurobehavioral function in patients with AE through a
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structured telephone interview, including a survey and a standardized rating scale of adaptive behavior.18 Adaptive behavior describes the ability to handle common demands in life and to
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maintain age-appropriate independence in everyday environments.19 It has been studied in many medical conditions, particularly learning disorders, intellectual disability, and post-cardiac arrest.19-22 We hypothesized that patients with AE will report persistent impairment in adaptive behavior, as well as neurologic disability and neurocognitive symptoms.
ACCEPTED MANUSCRIPT 2. Materials and Methods 2.1 Standard Protocol Approvals, Registrations, and Patient Consents The study was approved by the Johns Hopkins Hospital Institutional Review Board, and oral informed consent was obtained from all participants 18 years of age or older. For participants
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under the age of 18 years, oral informed consent was obtained from their guardian.
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2.2 Study Participants
Medical records of children (<18 years of age) and adults (>18 years of age) treated at the Johns
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Hopkins Hospital in Baltimore from July 1st, 2005 until June 30th, 2015 with a billing diagnosis
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of encephalitis were reviewed. Patients were included if they met clinical criteria on limited chart review for possible AE and were further sub-classified as definite limbic encephalitis or
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Hashimoto’s encephalopathy, as appropriate.23 It was also required that at least one year had
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passed from the time of diagnosis to study enrollment in order to examine patients’ long-term outcomes. Eligible patients (if under 18 years of age, patients’ legal guardians) were contacted
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by telephone and asked to consent to participation in a structured telephone interview for this
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study. Patients’ decision to participate or decline participation (along with the date contact was established) was recorded to ensure adequate documentation of informed consent. Patients were
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excluded if chart review demonstrated a diagnosis other than AE and were included but not contacted if chart review demonstrated that the patient was deceased.
2.3 Clinical Data Collection Additional information was obtained from participants’ inpatient and outpatient records regarding demographic information, presenting symptoms and signs, laboratory test results,
ACCEPTED MANUSCRIPT electroencephalogram and neuroimaging study results, treatments received, and clinical findings at discharge and follow-up.
2.4 Clinical, Adaptive, and Functional Outcome Assessments
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A survey (Appendix A) was administered to collect basic information about the participant’s
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premorbid education/employment status, initial presentation of AE, current medical status,
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services received, general function, and current education/employment status. Participants were also asked specifically about perceived difficulties with fatigue, emotional lability, short-term
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memory, and concentration.
The Adaptive Behavior Assessment System, Third Edition (ABAS-3),18 a standardized age-
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normalized neurobehavioral rating scale of over 200 items for individuals from early infancy to
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adulthood, was also administered. This tool assesses development, behavior, and cognitive abilities and includes subscales for communication, community use, functional academics, home
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living, health and safety, leisure, self-care, self-direction, social, motor, and work. These
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subscales are summed and normalized to the standardization sample to generate a general adaptive composite (GAC) and three major adaptive domain scores (conceptual, social, and
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practical). For participants <18 years of age, parents or other caregivers completed the ageappropriate form for children (0-5 years or 5-21 years). For participants >18 years of age, either the capable adult or other caregiver completed the form for adults (16-89 years).
Scores for mRS, a motor disability scale with scores ranging from 0 for no symptoms to 6 for death,24 were assigned independently by two raters and adjudicated to consensus in the event of
ACCEPTED MANUSCRIPT difference. Each participant was assigned a score at hospital admission and discharge based on documentation in the clinical record as well as at last neurology follow-up based on either documentation in clinical record or results of the structured telephone interview. As has been done in other studies of autoimmune encephalitis, a “good” score was defined by mRS 0-2 and a
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“poor” score by mRS 3-6.2
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2.5 Statistical Analyses
Statistical analyses were performed using STATA software version 14 (College Station, TX).
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Chi-square and Fisher exact tests for categorical variables and two-sided t-tests for continuous
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variables were used, with p-value < 0.05 considered significant. Survival analyses using Cox proportional hazards regression analysis were conducted to evaluate for factors associated with
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death. The effects of patient and clinical factors alone on each outcome measure (mRS and
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GAC) were tested with simple regression, and the individual effects of multiple patient and clinical factors, adjusting for potential confounders, were tested in multiple regression models.
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Examined patient and clinical factors included age, proportion of children, sex, white race, black
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race, anti-NMDAR seropositivity, antibody negative status, target antigen location (cell surface versus intracellular), limbic encephalitis, tumor presence, seizure presence, requirement for
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intensive care unit (ICU) admission, duration from symptom onset to treatment initiation, and treatment received. Given the cohort size, analyses for smaller subgroups of age (e.g., young adults versus older adults), race (e.g., Asian versus other), antibody neoplasm association (classically paraneoplastic antibodies versus autoimmune antibodies), and antibody status (e.g., presence of voltage-gated potassium channels antibodies versus other) could not be completed.
ACCEPTED MANUSCRIPT 3. Results 3.1. Participants Review of medical records yielded 312 participants with a diagnosis of encephalitis of which 77 met criteria for AE. Of these, 9 (12%) patients were deceased, and 9 (12%) did not have an
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active telephone number listed. Of the 59 who were contacted for neurobehavioral assessments,
3.2 Retrospective Analyses and Neurologic Disability
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44 (75%) were enrolled in the study, 9 (15%) declined, and 6 (10%) could not be reached.
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The 77 participants with AE ranged in age from 16 months to 80 years (Figure 1), and the mean
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duration of follow-up since diagnosis was 4.0 years (SD 3.0 years, Figure 2). 44 participants were female (57%), 66 were adults at the time of diagnosis (86%), and 39 (51%) had detectable
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antibodies associated with AE (Table 1). No participant had more than one antibody with titers in
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the abnormal range. 45 participants (58%) had seizures, and 16 (21%) had a detected tumor. 26 (34%) received both first- (high-dose steroids, plasma exchange, and/or IV immunoglobulin) and
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second-line treatment (rituximab and/or cyclophosphamide), and 42 (55%) were admitted to the
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neurology critical care unit during initial hospitalization.
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At last neurology follow-up, 41 (53%) of participants had a “good” neurologic disability score, defined as mRS < 2 (Figure 3). This percentage was higher than at the time of admission (17%, p<0.001) and hospital discharge (25%, p<0.001), indicating that further improvement was seen following discharge. On analysis of clinical factors associated with mRS outcomes, antiNMDAR antibody seropositivity was associated with greater proportion of “good” outcomes (mRS ≤ 2) at last neurology follow-up (92% vs 48%, p<0.01) and of improved mRS from
ACCEPTED MANUSCRIPT discharge to last neurology follow-up (83% vs 40%, p<0.05), despite no differences in mRS at admission or duration between symptom onset and treatment initiation. No other association between mRS score at last neurology follow-up and patient or clinical factors was seen
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(Appendix B).
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3.3 Death
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At the time of study enrollment, 9 participants were deceased. Disease duration and cause of death in this subgroup are depicted in Table 2. Survival analysis of the entire cohort revealed no
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association between death and age of diagnosis, gender, race, diagnosis, antibody status, tumor,
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seizures, ICU requirement, or treatment (Appendix C).
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3.4 Long Term Neuropsychiatric Symptoms and Adaptive behavior
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44 participants participated in the structured telephone interview on clinical status and adaptive behavior. Demographics of this cohort are shown in Table 1. Participants’ distribution of age and
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duration of follow-up are shown in Figure 1 and Figure 2, respectively. At the time of
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enrollment, mean duration of follow-up since diagnosis was 4.4 years (SD 3.2 years). Comparative analysis of enrolled participants (n=44) versus those who did not enroll (n=24) was
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performed, and no differences were found with respect to patient or clinical factors, mRS at admission, or mRS at discharge.
At enrollment, 38/44 (86%) participants endorsed at least one of the following persistent neuropsychiatric symptoms: fatigue (36%), emotional lability (61%), short-term memory loss (55%), and concentration difficulty (39%). Further analyses found that fewer participants with
ACCEPTED MANUSCRIPT anti-NMDAR encephalitis described difficulties with emotional lability (30% vs. 71%, p < 0.05), though no differences were seen in the other reported neuropsychiatric symptoms. No other association between neuropsychiatric symptoms and patient or clinical factors (including
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diagnosis of limbic encephalitis) was identified.
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Employment status and functional independence were examined in participants who were > 18
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years of age at the time of symptom onset and < 65 years of age at the time of study enrollment (n=26). Prior to onset of encephalitis, 22 participants (85%) were employed. However, at
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enrollment, the number of participants who were employed declined to 11 (42%, p<0.05).
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Further, only 13 participants (50%) were able to able to “rely on himself or herself to travel in the community (e.g. walking or uses public transportation, a bicycle or a car)”. 20 participants
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(77%) were able to “take medications without supervision”, and only 12 participants (46%) were
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“responsible for his or her personal finances.”
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On the ABAS-3, lower scores were seen in standard scores (SS) of the general adaptive
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composite (GAC) and across all three adaptive domains in the enrolled participants as compared to normative data (mean GAC SS 86.7 vs. 100.0, p<0.001). 23 of 44 participants (52%) scored
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“below average” on GAC (SS ≤ 89). As depicted in Figure 4, GAC decreases/worsens as expected with increasing/worsening mRS. Interestingly, of the participants with “good” neurologic disability outcomes (as defined by mRS ≤ 2, n=30), 40% (n=12) still scored “below average” on adaptive behavior (GAC SS ≤ 89). No particular domain on the ABAS-3 was selectively affected in these patients.
ACCEPTED MANUSCRIPT On analysis of clinical factors associated with ABAS-3 outcomes, mean GAC SS of participants with anti-NMDAR antibody seropositivity was higher than that of participants with other forms of AE (97.2 vs. 83.9, p<0.05). The mean score for participants with anti-NMDAR encephalitis was within the “average” range, while the mean score for those with other forms of AE was in
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the “below average” range. Additionally, participants of black race had a higher mean GAC SS
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than those of non-black race (103.8 vs. 84.2, p < 0.05). Participants who had had seizures had a
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higher mean GAC SS than those who did not (92.9 vs. 81.8, p < 0.05). These associations were independent of anti-NMDAR antibody seropositivity and other patient and clinical factors. No
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other association between ABAS-3 scores and patient or clinical factors was identified
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(Appendix D).
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4. Discussion
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This study demonstrates persistence of neurologic disability, neuropsychiatric symptoms, and neurobehavioral dysfunction in patients several years after diagnosis and treatment of AE. While
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this study included patients of a broad age range and variable follow-up duration, it is novel in its
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investigation of patient-reported impairment in neurobehavioral outcomes in clinically diagnosed
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AE of various etiologies.
In our study, while some patients with AE continue to experience improved neurologic disability outcomes after hospital discharge, nearly half had persistent “poor” outcomes, as defined by mRS > 2, at long-term follow-up. One study of 577 patients with anti-NMDAR encephalitis found that more than 80% of participants had a “good” outcome, defined as mRS of 0-2 at 24 months’ follow-up.2 A similar proportion was seen in patients with anti-NMDAR encephalitis in
ACCEPTED MANUSCRIPT our study (92%), suggesting that prognosis may differ based on the underlying antibodymediated etiology.
The modified Rankin Scale, a measure designed for stroke clinical trials, captures primarily
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motor function and does not evaluate cognitive or behavioral function, which are frequently
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affected at presentation in patients with AE. In our study, commonly reported neuropsychiatric
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deficits included fatigue, emotional lability, short-term memory, and concentration. Many of these symptoms are likely to be multifactorial in origin and should be evaluated further in future
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studies. Strikingly, only half of patients returned to employment and less than half traveled
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independently in the community. Small studies examining neurologic and behavioral outcomes
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personal and professional lives.3-7,25
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have likewise found that patients with AE are left with neurocognitive deficits that affect their
More than half of patients in our study scored “below average” in adaptive behavior across all
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domains on the ABAS-3 at the time of study enrollment. This standardized age-normalized
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neurobehavioral rating scale examines 11 skill domains of everyday activities to assess an individual’s ability to function independently and meet environmental demands. Furthermore,
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nearly half of patients with “good” neurologic disability outcomes scored “below average” in adaptive behavior. While patients with AE may appear from routine neurologic assessments and disability scores to have returned to baseline, assessment of adaptive behavior with the ABAS-3 identifies impairments in their ability to perform expected life tasks. The evaluation of adaptive behavior therefore adds a layer of quantitative clinical information that is not adequately captured by assessment of neurologic disability alone and could help monitor neurobehavioral
ACCEPTED MANUSCRIPT status longitudinally. Further study is warranted to better understand the role of various patient factors (including race) and clinical factors (including presence of seizures as well as various treatments received) on future adaptive behavior.
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Patients with anti-NMDAR encephalitis demonstrated better long-term outcomes in neurologic
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disability (by mRS), emotional lability, and neurobehavioral function (by ABAS-3) as compared
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to patients with other forms of AE. These differences were noted despite no differences in group demographics, clinical severity on presentation, or treatment received. While this finding
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certainly requires further investigation, it may be that anti-NMDAR encephalitis represents a
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distinct subset of AE with a specific prognosis. Alternatively, it may be that the clinical phenotype of anti-NMDAR encephalitis is better recognized than that of other autoimmune
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encephalitides, thereby leading to earlier diagnosis and treatment initiation, which may have
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factored into better outcomes. A difference between these groups in duration between symptom onset and treatment initiation was not seen in our study, but this may be attributed to the small
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sample size of patients with anti-NMDAR encephalitis. Until this difference in outcomes is
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better understood, clinicians must use caution in extrapolating findings and data regarding
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outcomes from this disease to other forms of AE.
Limitations of our study include its retrospective identification of the cohort, cross-sectional assessment of participants, and use of subjective outcomes measures. However, patient-reported outcome measures are a reliable and increasingly accepted method for clinical research of many neurologic diseases,26 including epilepsy,27-29 stroke,30-32 multiple sclerosis,33-35 and movement.36-38 Additionally, the heterogeneity of patients and small sample sizes of subgroups
ACCEPTED MANUSCRIPT in our study likely affected the ability to identify associations between outcome measures and some patient and clinical factors. While differences in long-term outcomes were not seen in our study between children and adults with AE, prior studies have observed differences in clinical presentation and response to treatment.16,17 It is possible that our study may have been
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underpowered to detect this and other subgroup differences, which could become evident from a
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prospective multi-center study.
In this study, we utilized patient-reported data to demonstrate persistence of neurologic
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disability, neurobehavioral dysfunction, and neuropsychiatric symptoms in patients several years
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following diagnosis of AE. These findings highlight the importance of larger prospective and multi-site studies to evaluate patients’ long-term outcomes and their trajectory of recovery with
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tools well suited to assess neurobehavioral impairments in this population. In addition to better
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characterizing the recovery from and chronic sequelae of AE, further studies may also enable a better understanding of the role of individual patient and clinical factors (including age, antibody
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presence, and various treatment modalities) on long-term outcomes. Ultimately, the adequate
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elucidation of persistent neurobehavioral deficits and ability to predict which patients are at
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highest risk will allow clinicians to optimally support and counsel patients and their families.
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Leypoldt F, Armangue T, Dalmau J. Autoimmune encephalopathies. Ann N Y Acad Sci.
2014;1338(1):94-114. 2.
Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-
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Finke C, Prüss H, Heine J, et al. Evaluation of Cognitive Deficits and Structural
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JAMA Neurol. 2017;74(1):50-59.
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ACCEPTED MANUSCRIPT Figure 1: Distribution of Age This figure depicts the age distribution of participants at the time of diagnosis. Blue bars indicate participants in the total cohort (n=77), and red bars indicate participants who enrolled in the
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structured telephone interview (n=44).
ACCEPTED MANUSCRIPT Figure 2: Distribution of Duration of Follow-Up This figure depicts the distribution of participants’ duration of follow-up. Blue bars indicate participants in the total cohort (n=77), and red bars indicate participants who enrolled in the
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structured telephone interview (n=44).
ACCEPTED MANUSCRIPT Figure 3: Modified Rankin Scale (mRS) Scores This figure depicts mRS scores of participants at the time of hospital admission, hospital discharge, and last neurology follow-up. “Good” outcome is defined as mRS score of 0-2, and “poor” outcome as mRS score of 3-6. The numbers in each box denote the percentage of
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participants (of total cohort n=77) who received each score.
ACCEPTED MANUSCRIPT Figure 4: Modified Rankin Scale (mRS) Scores at Last Neurology Follow-up Compared to General Adaptive Composite (GAC) Standard Scores (SS) This figure compares mRS scores at the time of study enrollment to GAC SS of participants enrolled in the structured telephone interview (n=44). The dashed box indicates participants with
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“good” neurologic disability outcome (mRS < 2) who scored “below average” in adaptive
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behavior (ABAS-3 < 89).
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Table 1: Demographics and Clinical Profiles of the Retrospective Cohort and Enrolled Cohort Retrospective Cohort Not Enrolled (n=77) Enrolled (n=44) (n=24) SD/ Mean/Num SD/ Mean/Num SD/ Mean/Number % ber % ber %
pvalue
Female Age of Diagnosis (years)
44
57.1
23
53.5
14
58.3
0.80
43.0
22.8
42.9
22.6
41.0
20.8
0.72 0.67
48
62.3
29
67.4
15
62.5
0.80
Black
12
15.6
6
14.0
4
16.7
0.73
7.0
2
8.3
-
7.0
0
0.0
-
7.0
3
12.5
-
21
48.8
13
54.2
1.00
10
23.3
1
4.2
0.08
5
11.6
3
12.5
-
7.8
3
3
3.9
3
Other
8
10.4
3
Antibody Status
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Asian Hispanic
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Race
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49.4
12
15.6
VGKC Antibodies* Thyroid Antibodies (TPO/TG)**
9
11.7
4
5.2
2
4.7
2
8.3
-
Ca Channel Antibodies
3
3.9
1
2.3
1
4.2
-
ANNA-1/Hu Antibodies
3
3.9
0
0.0
3
8.3
-
LGI-1 Antibodies
2
2.6
2
4.7
0
0.0
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Ma 1/2 Antibodies
Seizures Limbic Encephalitis Tumor Present #
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Alpha3-AChR Antibodies
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2
2.6
1
2.3
0
0.0
-
2
2.6
1
2.3
1
4.2
-
1
1.3
1
2.3
0
0.0
-
1
1.3
0
0.0
1
4.2
-
45
58.4
21
48.8
15
62.5
0.31
58
75.3
35
81.4
17
70.8
0.55
16
20.8
12
27.9
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CASPR-2 Antibodies
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Antibody-Negative Anti-NMDAR Antibodies
0.43
First-Line Only
51
66.2
26
60.5
17
70.8
First- and Second-Line
26
33.8
18
41.9
7
29.2
Duration from Symptom Onset to Treatment Initiation (years)
0.6
1.3
0.7
1.6
0.5
0.6
0.43
ICU Required
42
54.5
19
41.9
15
62.5
0.20
mRS at Admission
0.10
mRS <=2
12
15.6
5
11.6
7
29.2
mRS >2
56
72.7
39
90.7
17
70.8
mRS at Discharge
0.06 mRS <=2
18
23.4
8
18.6
10
41.7
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50
64.9
36
83.7
14
58.3
9
11.7
-
-
-
-
-
4.0
3.0
4.4
3.2
0.8
2.4
0.90
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p-values for Chi-square or t-test, as appropriate, between enrolled and not enrolled groups. *Further classification as LGI-1 or CASPR-2 not available. **Thyroid peroxidase (TPO) and/or thyroglobulin (TG) antibodies detected. # First-Line Treatment = steroids, plasma exchange, and/or IV immunoglobulin. Second-Line Treatment = rituximab and/or cyclophosphamide. Abbreviations: ICU = intensive care unit, mRS = modified Rankin Scale
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77 days
5
70 days
6
84 days
7
106 days
8
10 months 4 years, 10 months
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Table 2: Patient and Clinical Characteristics of Deceased Subjects Age at Diagn osis Gen (years Tu Cause of Death Antibody Status der ) mor Cardiac Arrest (Acute AntibodyMal Myocarditis) Negative e 22 No Respiratory Failure (Withdrawal Ca Channel Fem of Care) Antibodies ale 76 No Cardiac Arrest (Autonomic Anti-NMDAR Fem Instability) Antibodies ale 22 No Refractory Status Epilepticus AntibodyFem (Withdrawal of Care) Negative ale 24 No Fem Lung Cancer Hu Antibodies ale 65 Yes GAD-65 Fem Lung Cancer Antibodies ale 73 Yes Cardiac Arrest (Pulmonary AntibodyFem Embolism) Negative ale 80 No AntibodyFem Encephalitis Negative ale 74 No AntibodyMal Cardiac Arrest Negative e 6 No
Seiz ures Yes Yes Yes Yes Yes Yes Yes Yes Yes
Treatm ent FirstLine FirstLine Second -Line FirstLine FirstLine FirstLine FirstLine FirstLine FirstLine
ACCEPTED MANUSCRIPT Graphical abstract
Adaptive behavior (General Adaptive Composite Standard Score) worsens with worsening neurologic disability (mRS), however, a proportion of patients who score well on neurologic
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disability measures still score below average on adaptive behavior.
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Adults and children with autoimmune encephalitis frequently have persistent impairments in neurologic disability, neurocognitive symptomatology, and adaptive behavior. These impairments may not be adequately captured by routine neurologic assessments
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Comprehensively elucidating persistent neurobehavioral impairments and predicting
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which patients are at highest risk will allow for optimal care of patients and their families.
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alone.