Brain Magnetic Resonance Imaging and Electroencephalography predictors of outcomes in children with anti-NMDA receptor encephalitis Pubblico

Abstract

Objective: 

Anti-NMDA receptor encephalitis (NMDARE) is a neuroinflammatory disorder characterized by neuropsychiatric symptoms. NMDARE can result in up to 10% mortality and up to 25% with poor neuropsychiatric outcomes. Currently, few biomarkers can predict poor outcomes in NMDARE. In this thesis, I examine features from common ancillary tests performed in children with NMDARE, including brain magnetic resonance imaging (MRI) and electroencephalography (EEG) and their associations with outcomes. 

Methods: 

Retrospective data was collected for this study, including multicenter data for MRI T2 hyperintense lesions and a single center for MRI volumetric data and EEG features. Odds ratios with 95% confidence intervals were used to calculate odds of persistent disability based on neuroimaging abnormalities. Multivariable logistic or linear regression modeling was performed to assess the relationship of T2-hyperintense MRI lesions, MRI volumes, or EEG features with outcomes. Initially complete case analyses were performed, and then for sensitivity analysis, multiple imputation was performed for missing data (SAS 16.0, Cary, NC).

Results:

An abnormal brain MRI correlated with poor one-year outcomes (OR 2.9; 95% CI: 1.2-7.0), particularly lesions located in the frontal (OR 4.2; 95% CI: 1.5-11.6) and occipital lobe (OR 6.8; 95% CI: 1.1-43.3). Even after adjusting for potential confounders including age of onset, improvement in less than four weeks and time-to-treatment, abnormal MRI was a significant factor in predicting poor one-year outcomes as defined by mRS (OR 3.0, 95% CI 1.0-8.8), along with frontal (OR 3.3, 95% CI 1.1-10.5), and occipital lobe lesions (OR 14.5, 95% CI 1.9-113.4). I then performed two pilot studies: for brain volumetric studies, higher brain volumes correlated with poor functional outcomes, including total brain (p<0.001), whole brain gray matter (p=0.004) and whole brain white matter (p=0.05). For EEG characteristics, loss of PDR (p = 0.013), loss of sleep architecture (p = 0.041), and epileptiform discharges (p = 0.041) correlated with mRS at one year.

Conclusions:

T2 hyperintense brain MRI lesions on brain MRI, brain volumes, and certain EEG parameters may predict poor outcomes in NMDARE. Further larger studies are needed to corroborate these findings.

Table of Contents

TABLE OF CONTENTS

Acknowledgements………….…………………………………………………….............. iii

List of Tables…………………………………………………………………………………. xi

List of Figures…………………………..…………………………………………………… xii

Chapter 1: Introduction …………………………………..…………………..……………..1

1.1.                 Background ……………………………………………………………………..1

1.2.                 Limited data exists on the natural history, optimal management, or long-term outcomes in pediatric NMDARE…………………………………………………1

1.3.                 Barriers to treating NMDARE ………………………………………………….2

1.4.                 Biomarkers to predict clinical course and treatment response in NMDARE…………………………………………………………………………………3 

1.5.                 Chapter Preview…………………………………………………………………4

Chapter 2: Magnetic Resonance Imaging Lesions and their Association with Outcomes in Pediatric NMDARE …….……………………………………………………..7 

2.1. Background and prior work by others……………………………………………7

            2.2 Approach……………………………………………………………………… ….…8

2.3 Results …………………………………………………………………………….13

2.4 Discussion …………………………………………………………………………19

Chapter 3: Brain MRI volumes and their associations with outcomes in NMDARE

……………………………………….………………………………………………………….22

3.1. Background and prior work ……….…………………………………………….22

3.2 Approach……………………………………………………………………… …...23

3.3 Results ……………………………………………………………………………..25

3.4 Discussion …………………………………………………………………………29

Chapter 4: Electroencephalography predictors for outcomes in pediatric NMDARE …………………………………………………………………….……………………………..32

4.1. Background and prior work by others…………………………………………..32

4.2 Study Design and Methods………………………………………………………36

4.3 Results ……………………………………………………………………………..38

4.4 Discussion …………………………………………………………………………43

Chapter 5: Future Work……………………………………………………………………..45

5.1. The CONNECT registry…………………………………………………...……..45

5.2. Magnetic resonance imaging (MRI) brain lesions and their association with outcomes………………………………………………………………………...……..45

5.3. Brain volumetric changes in NMDARE and their association with outcomes…………………………………………………………………………...…46

5.4. Future work for EEG characteristics and their associations with outcomes in pediatric NMDARE………………………………………………………………...…47

5.5. Blood and cerebrospinal fluid biomarkers to predict outcomes in pediatric NMDARE………………………………………………………………………...……48

Chapter 6: Conclusions …………………………………………………………………..49 

References…………………………………………………………………………………..50

About this Master's Thesis

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School	Laney Graduate School
Department	Clinical Research
Degree	M.S.
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, General
Parola chiave	NMDA receptor encephalitis
Committee Chair / Thesis Advisor	Amita Manatunga, Emory University
Committee Members	Timothy Gershon, Emory University William Tyor, Emory University

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