Magnetic Resonance Imaging to Enhance the Diagnosis of Fetal Brain Abnormalities in utero

314 Pages·2017·10.57 MB·English

Magnetic Resonance Imaging to Enhance the Diagnosis
of Fetal Brain Abnormalities in utero
Deborah Ann Jarvis
A Thesis Submitted in Fulfilment of the Requirements for the Degree of
Doctor of Philosophy
July 2017
Faculty of Medicine Dentistry and Health
Department of Infection, Immunity and Cardiovascular Science
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Acknowledgements

I would like to express my sincere gratitude to my supervisors Professor Paul Griffiths and
Dr Paul Armitage for their exceptional guidance, support and for being so accessible
throughout my Ph.D. study. I want to thank Professor Griffiths for the many opportunities he
has given me during his supervision of this work. His patience, motivation, and the generous
amount of time he has invested to share his vast knowledge and answer my endless
questions is very much appreciated. I want to thank Dr Paul Armitage who has managed to
teach me enough of his immense knowledge of software and image processing to make this
research possible and whose calm, patient and reassuring approach has given me clarity
and motivation at significant points when I have needed it.

I am also thankful to all those in Academic Radiology for their help and words of support and
encouragement throughout. Special thanks go to my fellow Radiographers whose
camaraderie, encouraging banter and essential coffee making services have been vital for
the completion of this work. To Julia Bigley and Pam Greenwood for the time they have
given to read this manuscript, for their helpful comments and correction of grammatical
errors I am also very thankful. I would also like to thank Leanne Armstrong for her excellent
administration and organisation of study data which has made several aspects of this
research so much easier. I also wish to thank the staff at ScHARR for their guidance
regarding the systematic review, Mike Bradburn for statistical input, and in particular Cara
Mooney for her efficient management of the MERIDIAN study, her help collating study data
and the time invested being second reviewer for the systematic review for which I am
incredibly grateful.

Finally, I would like to thank my family for their support, encouragement and their
understanding when I have been busy working instead of spending time with them. Most of
all I thank my amazingly patient and understanding husband Neil whose constant
encouragement and unwavering belief in me throughout this PhD has given me the
determination to finish. Thank you.

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Abstract

Purpose
This thesis aims to determine the diagnostic performance of in utero MR (iuMR) imaging to
diagnose fetal brain abnormalities and describes the development, application and
processing of a 3D volume MR acquisition.

Methods
A systematic review and meta-analysis of existing evidence was conducted. A prospective
multicentre study of pregnant women, with a fetal brain abnormality on ultrasound (USS),
was undertaken – The MERIDIAN study. In addition, an investigation of fetuses with no brain
abnormality on USS was undertaken. Diagnostic accuracy and confidence, as well as
positive and negative predictive values, were calculated. A 3D image acquisition technique
was introduced, its ability to aid diagnosis measured and computational post-processing
applied. Fetal brain volumes were extracted from the 3D data using image segmentation
and these were assessed for reproducibility and validity. Resultant data allowed 3D models
of fetal brains to be printed. Normally developing fetal brain volumes were plotted graphically
thereby allowing comparison with abnormal fetuses.

Results
A total of 570 complete datasets were available from 903 eligible participants. Diagnostic
accuracy was 68% for USS and 93% for iuMR. 95% of diagnoses made by iuMR were
reported with high confidence compared to 82% on USS. Changes in pregnancy
management occurred in 33% of cases. Positive and negative predictive values of iuMR
were 93% and 99.5% respectively. 3D image quality was diagnostic in 89.6%, of which
91.4% gave an accurate diagnosis. Intra- and inter-observer agreement of brain volume
measurements was high. Agreement between computer based and brain model volume
measurements was also high.

Conclusions
iuMR imaging improves diagnostic accuracy and confidence for fetal brain abnormalities,
influencing pregnancy management in a high proportion of cases. 3D imaging enables
versatile visualisation of fetal brain anatomy and reliable extraction of volumes. This
additional quantitative information could improve diagnosis in relevant cases.

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Contents

Abstract ............................................................................................................................... 3
Abbreviations ...................................................................................................................... 9
List of Figures ................................................................................................................... 11
List of Tables ..................................................................................................................... 16
Thesis Aims and Overview ............................................................................................... 18
Peer Reviewed Publications Arising From the Thesis ................................................... 22
Chapter 1 Introduction and Background ............................................................................. 24
1.1 Summary ................................................................................................................... 25
1.2 Normal and Abnormal Development of the Brain ....................................................... 25
1.2.1 Primary Neurulation ............................................................................................ 27
1.2.2 Ventral Induction ................................................................................................. 28
1.2.3 Commissuration .................................................................................................. 30
1.2.4 Cortical Formation Abnormalities ........................................................................ 31
1.2.5 Developmental Abnormalities of the Infratentorial Brain. ..................................... 37
1.3. Acquired Abnormalities of the Fetal Brain ................................................................. 42
1.3.1 Infections of the Fetal Brain ................................................................................. 42
1.3.2 Fetal Stroke ......................................................................................................... 45
1.4 Ventriculomegaly ....................................................................................................... 50
1.5 Fetal Imaging Techniques ......................................................................................... 52
1.5.1 In Utero Ultrasound ............................................................................................. 52
1.5.2 In Utero MR Imaging ........................................................................................... 53
1.5.3 MR Safety ........................................................................................................... 63
1.6 Measures of Diagnostic Performance ........................................................................ 65

Chapter 2 A Systematic Literature Review and Meta-Analysis to Determine the Contribution
of MR Imaging to the Diagnosis of Fetal Brain Abnormalities In Utero ................................ 69
2.1 Summary ................................................................................................................... 70
2.2 Background ............................................................................................................... 71
2.3 Study Aims ................................................................................................................ 72
2.4 Methods .................................................................................................................... 73
2.4.1 Protocol ............................................................................................................... 73
2.4.2 Eligibility Criteria.................................................................................................. 73
2.4.3 Search Methods .................................................................................................. 74
2.4.4 Data Collection .................................................................................................... 75
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2.4.5 Assessment of Methodological Quality of Included Studies ................................. 77
2.4.6 Data Items and Analysis ...................................................................................... 79
2.5 Results ...................................................................................................................... 81
2.5.1 Study Characteristics .......................................................................................... 82
2.5.2 Methodological Quality ........................................................................................ 83
2.5.3 Diagnostic Accuracy of USS and MRI ................................................................. 84
2.6 Discussion ................................................................................................................. 93
2.7 Conclusion ................................................................................................................. 96

Chapter 3 MERIDIAN: A Study to Investigate the Additional Value of iuMR Imaging for the
Diagnosis of Fetal Brain Abnormalities ................................................................................ 97
3.1 Summary ................................................................................................................... 98
3.2 Background ............................................................................................................... 99
3.3 Primary Aims ........................................................................................................... 100
3.4 Methods .................................................................................................................. 101
3.4.1 Study Design and Ethics Approval .................................................................... 101
3.4.2 Calculation of Sample size ................................................................................ 102
3.4.3 Participants ....................................................................................................... 103
3.4.4 Recruitment ....................................................................................................... 104
3.4.5 Pregnancy Outcome Reference Diagnosis ........................................................ 105
3.4.6 Diagnostic Accuracy Data Analysis ................................................................... 106
3.4.7 Assessment of Diagnostic Confidence .............................................................. 107
3.5 Results .................................................................................................................... 113
3.5.1 Diagnostic Accuracy .......................................................................................... 116
3.5.2 Diagnostic Confidence ...................................................................................... 117
3.5.3 Clinical Management ......................................................................................... 120
3.6 Discussion ............................................................................................................... 122
3.7 Conclusion ............................................................................................................... 126

Chapter 4 The MERIDIAN Add-On Study. ........................................................................ 127
4.1 Summary ................................................................................................................. 128
4.2 Introduction .............................................................................................................. 129
4.3 Methods .................................................................................................................. 129
4.3.1 Participants and Recruitment ............................................................................ 130
4.3.2 Outcome Measures and Statistical Analysis ...................................................... 132
4.4 Results .................................................................................................................... 133
4.5 Discussion ............................................................................................................... 138
4.6 Conclusion ............................................................................................................... 142
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Chapter 5 Three Dimensional (3D) MR imaging of the Fetal Brain in utero ...................... 143
5.1 Summary ................................................................................................................. 144
5.2 Background ............................................................................................................. 145
5.3 Study Aim ................................................................................................................ 150
5.4 Methods .................................................................................................................. 151
5.5 Results .................................................................................................................... 153
5.5.1 Image Quality .................................................................................................... 153
5.5.2 Diagnostic Accuracy .......................................................................................... 155
5.5.3 Diagnostic Confidence ...................................................................................... 157
5.6. Discussion .............................................................................................................. 160
5.7. Conclusion .............................................................................................................. 163

Chapter 6 Quantification of Total Fetal Brain Volume Using 3D MR Imaging Data Acquired
in utero .............................................................................................................................. 164
6.1 Summary ................................................................................................................. 165
6.2 Introduction .............................................................................................................. 166
6.2.1 Study Aims ........................................................................................................ 169
6.3 Methods .................................................................................................................. 170
6.3.1 Participants ....................................................................................................... 170
6.3.2 Exclusions ......................................................................................................... 170
6.3.3 Data Acquisition and Image processing ............................................................ 170
6.3.4 Calculation and validation of brain volumes ....................................................... 172
6.3.5 Statistical Analysis ............................................................................................ 175
6.4 Results .................................................................................................................... 175
6.4.1 Brain volumes ................................................................................................... 175
6.4.2 Ventricular System Volumes ............................................................................. 180
6.4.3 Reliability and Reproducibility............................................................................ 181
6.5 Discussion ............................................................................................................... 188
6.6 Conclusions ............................................................................................................. 191

Chapter 7 Clinical Applications of 3D fetal brain MR imaging and post processing. .......... 192
7.1 Chapter Summary ................................................................................................... 193
7.2 Introduction .............................................................................................................. 194
7.3 3D Printing ............................................................................................................... 195
7.4 Visual and Quantitative Applications of 3D post-processing .................................... 198
7.4.1 Normal Brain Development ............................................................................... 198
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7.5 A Review of Fetal Brain Abnormalities ..................................................................... 202
7.5.1 Holoprosencephaly ........................................................................................... 202
7.5.2 Agenesis of the Corpus Callosum (ACC) .......................................................... 205
7.5.3 Lissencephaly ................................................................................................... 209
7.5.4 Schizencephaly ................................................................................................. 213
7.5.5 Polymicrogyria. ................................................................................................. 216
7.5.6 Posterior Fossa Abnormalities ........................................................................... 218
7.5.7 Abnormalities of the Ventricular System ............................................................ 222
7.5.8 Megalencephaly/ Hemimegalencphaly .............................................................. 225
7.6 Discussion ............................................................................................................... 229

Chapter 8 Conclusions and Future Work .......................................................................... 232
8.1 The Systematic Review and Meta-analysis .............................................................. 234
8.2 The MERIDIAN Study .............................................................................................. 236
8.3 The MERIDIAN Add-on Study ................................................................................. 239
8.4 3D Volume Imaging of the Fetal Brain ..................................................................... 241
8.5 Summary ................................................................................................................. 247
8.6 Future Work ............................................................................................................. 248
8.6.1 Future directions of research ............................................................................. 251

References ....................................................................................................................... 253
Appendix 1 ........................................................................................................................ 276
Appendix 2 ........................................................................................................................ 282
Appendix 3 ........................................................................................................................ 283
Appendix 4 ........................................................................................................................ 286
Appendix 5 ........................................................................................................................ 288
Appendix 6 ........................................................................................................................ 290
Appendix 7 ........................................................................................................................ 292
Appendix 8 ........................................................................................................................ 297
Appendix 9 ........................................................................................................................ 299
Appendix 10 ..................................................................................................................... 302
Appendix 11 ...................................................................................................................... 303
Appendix 12 ...................................................................................................................... 305

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Abbreviations

2D Two dimensional
3D Three dimensional
ADC Apparent diffusion coefficient
ACC Agenesis of the corpus callosum
AUR Academic unit of radiology
BPD Biparietal diameter
CC Corpus callosum
CNS Central nervous system
CMV Cytomegalovirus
CNR Contrast to noise ratio
CSF Cerebrospinal fluid
CT Computed tomography
DAMR Diagnostic accuracy MR
DAUS Diagnostic accuracy USS
DWM Dandy walker malformation
DWI Diffusion weighted imaging
FIESTA Fast imaging employing Steady sTate acquisition
FLAIR Fluid attenuated inversion recovery
HPE Holoprosencephaly
HTA Health technology assessment
ICC Intraclass correlation coefficient
IuMR In utero magnetic resonance
MR Magnetic resonance
NICE National institute of health and care excellence
NIHR National institute of health and research
NPV Negative predictive value
OFD Occipital frontal diameter
ORD Outcome reference diagnosis
PF Posterior fossa
PPV Positive predictive value
PRISMA Preferred reporting items for systematic reviews and meta-analyses
PROM Premature rupture of the membranes
PROSPERO International prospective register of systematic reviews
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PVL Periventicular leukomalacia
QALY Quality adjusted life years
QUADAS Quality assessment of diagnostic accuracy studies
RF Radiofrequency
SAR Specific absorption rate
ScHARR School of Health and Related Research, University of Sheffield
SNR Signal to noise ratio
ssFSE Single shot fast spin echo
SWA Score based weighted analysis
T1W T1 weighted images
T2W T2 weighted images
TBV Total brain volume
TE Time to echo
TI Time interval
TICV Total intracranial volume
TR Recovery time
TTTS Twin to twin transfusion syndrome
USS Ultrasound scan(ing)
VM Ventriculomegaly
VV Ventricular system volumes
ZIP Zero filling of k-space

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