Clinical Radiology 70 (2015) 248e253
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Clinical Radiology journal homepage: www.clinicalradiologyonline.net
Antenatal diagnosis of agenesis of the corpus callosum I. Craven a, M.J. Bradburn b, P.D. Griffiths c, * a
Department of Neuroradiology, Leeds General Infirmary, Leeds, UK Clinical Trials Research Unit, ScHARR, Sheffield, UK c Academic Unit of Radiology, University of Sheffield, Sheffield, UK b
article in formation Article history: Received 26 August 2014 Received in revised form 29 October 2014 Accepted 6 November 2014
AIM: To estimate the diagnostic performance of ultrasound in detecting agenesis of the corpus callosum (ACC). MATERIALS AND METHODS: A retrospective review was performed of 1722 in utero MRI examinations. All cases were identified in which the fetus had been referred from ultrasonography with a diagnosis of ACC and those in which ACC was given as a diagnosis on the in utero MRI study. The MRI was assumed to provide the correct diagnosis of ACC and descriptive statistics of diagnostic accuracy for ultrasound were calculated. RESULTS: Of the 1722 ultrasound examinations performed, 121 had a diagnosis of ACC and approximately 50% were confirmed at MRI. Forty-two fetuses with ACC not suspected at ultrasonography were also identified at MRI. Ultrasonography had a positive predictive value of 47% (95% CI: 38e56%) and a negative predictive value of 97% (95% CI: 96e98%) for detecting ACC. CONCLUSION: Ultrasound is poor in diagnosing ACC and in utero MRI should be performed if there is any suspicion on antenatal ultrasonography. Ó 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction The corpus callosum is a white matter structure that contains fibres connecting homologous structures in the two cerebral hemispheres, and it is by far the largest commissure in terms of volume. The corpus callosum starts to develop at approximately 8 weeks gestational age in humans and it is complete in its cranio-caudal extent by 18e19 weeks, although further maturation and growth continues into postnatal life. Agenesis of the corpus callosum (ACC) is the commonest developmental abnormality,
* Guarantor and correspondent: P. Griffiths, Academic Unit of Radiology, Floor C, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, UK. Tel.: þ44 144 271 3207. E-mail address: p.griffiths@sheffield.ac.uk (P.D. Griffiths).
resulting from failure of commissuration and can occur for a number of reasons including genetic, metabolic, or vascular abnormalities, but in most cases the cause is not found.1 The term “ACC” implies that the entire structure has failed to form, but in other fetuses the corpus callosum may fail to form in part leading to the term “hypoplasia of the corpus callosum”.2 In the context of the detection of antenatal malformations, ACC is much more common than hypoplasia of the corpus callosum. The prognosis for an individual fetus with ACC can rarely be known with certainty, but it is influenced by the presence or absence of chromosomal, genetic, or other structural abnormalities (involving either the brain or other system). Brain abnormalities associated with ACC are common and have deleterious effects on prognosis. One recent paper using in utero MRI (iuMRI) detected other
http://dx.doi.org/10.1016/j.crad.2014.11.004 0009-9260/Ó 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
I. Craven et al. / Clinical Radiology 70 (2015) 248e253
brain abnormalities in over 60% of cases.3 Even in cases where ACC is the only abnormal antenatal finding, it is expected that 10e30% will have a poor neurodevelopmental outcome.4e8 It is, therefore, important to have a robust method of identifying ACC in utero in order to give accurate prognostic information. The imaging tool for detecting structural brain abnormalities in the fetus has historically been ultrasonography and many countries have screening programmes based on that imaging method. Several papers have questioned the accuracy of detecting ACC by ultrasound.9e11 The introduction of iuMRI of the fetal brain has raised further concern as this disease seems to be the single largest source of disagreements between antenatal ultrasound and iuMRI findings. In the present study, the assumption (and will subsequently attempt to defend the assumption) that iuMRI provides reference standard information for detecting ACC in utero. As such, we have calculated indicators of diagnostic performance for antenatal ultrasonography in detecting ACC by reviewing over 1700 iuMRI studies of the fetal brain from our institution (Academic Unit of Radiology, University of Sheffield).
Materials and methods Participants A retrospective review was conducted of all iuMRI studies of the fetal brain performed at our institution over a 7 year period between 2004 and 2011. Referrals for iuMRI were made after ultrasonography of the fetus had been performed by a consultant in foeto-maternal medicine working in one of a large number of foeto-maternal centres in Britain. In over 95% of cases, the referral was for a brain abnormality identified or suspected at ultrasonography. In the other cases, the brain was imaged because of an abnormality in another anatomical location (usually the spine) or the fetus was known to have an increased risk of brain malformation but was structurally normal at ultrasonography. The iuMRI was usually performed within 5 working days of the referral from ultrasonography and the radiologist reporting the iuMRI study was aware of the findings on the antenatal ultrasound examination. The women did not have any known or suspected contraindications to MRI and all iuMRI studies were performed at, or after, 18 weeks gestational age. Most of the women had iuMRI as part of research studies after providing informed written consent under the guidance and approval of the Institutional Research Ethics Committee. Those women were not paid for their involvement in the study but travel expenses were offered for themselves and a companion. Relevant review was sought, and approval obtained, from the Institutional Clinical Effectiveness Unit and Research Department in order to allow cases performed for clinical purposes to be reported in this paper.
iuMRI protocol iuMRI was performed using a 1.5 Tesla superconducting system (before 2008: Infinion, Philips Medical Systems,
249
Best, Netherlands; 2008 and after HDx, GE Healthcare, Milwaukee, WI, USA). A range of sequences were performed but always included single-shot fast spin echo sequences (5 mm thick sections in all three orthogonal planes and 3 mm thick sections in at least two orthogonal planes). The studies were reported by a radiologist at the time of the iuMRI examination. For the purpose of the study, the Unit’s database was searched for the total number of fetal brain examinations performed in the study period. In addition, specific searches were made for reports with any positive reference to a diagnosis of “ACC” in either the referral information from antenatal ultrasonography or the report of the iuMRI examination. The referral details and iuMRI examinations of the “ACC” cases were re-reviewed by the two neuroradiologists involved in the study (I.C., P.D.G.) in order to confirm the veracity of the information obtained from the database.
Analysis Following that analysis, four groups were formed as listed below. These were created on the assumption that iuMRI was the reference standard for diagnosing ACC in utero in order to calculate descriptive statistics for the diagnostic performance of antenatal ultrasonography: (1) ACC was diagnosed on antenatal ultrasound and confirmed on iuMRI (true positives: group A); (2) ACC was diagnosed on antenatal ultrasound but not confirmed on iuMRI (false positives: group B); (3) ACC was not diagnosed on antenatal ultrasound but was diagnosed on iuMRI (false negatives: group C); (4) ACC was not considered to be a diagnosis on antenatal ultrasound or iuMRI (true negatives: group D). Specifically, positive and negative predictive rates are presented along with their 95% confidence interval, calculated by the exact binomial method. Descriptive statistics were calculated on the basis of “hypogenesis of the corpus callosum” being an incorrect ultrasound diagnosis of ACC and then re-calculated assuming that “hypogenesis of the corpus callosum” was a correct diagnosis in order to provide the range of possible positive and negative predictive rates. Table 1 Descriptive statistics for the diagnosis of agenesis of the corpus callosum (ACC) at antenatal ultrasound (US) assuming in utero MRI (iuMRI) diagnosis or exclusion of diagnosis is correct. Confirmed ACC diagnosis on iuMRI
Referred with US diagnosis of ACC Referred from US without ACC diagnosis Total a
Total
Yes
No
57
64
121
[64a] 42
[57a] 1559
[121a] 1601
99 [106a]
1623 [1616a]
1722
Positive predictive value 47% (38e56%) [53% (44e62%)a] Negative predictive value 97% (96e98%)
Assuming “hypogenesis of the corpus callosum” is equivalent to ACC.
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Table 2 Gestational age of cases with suspected or confirmed diagnosis of agenesis of the corpus callosum (ACC) at the time of in utero MRI. Method of ACC diagnosis
Median (IQR) Range
Both US and iuMRI (group A; n ¼ 57)
US only (group B; n ¼ 64)
iuMRI only (group C; n ¼ 42)
22 (20e24)
23 (21e26)
24 (22e30)
18e36
18e33
20e40
US, ultrasound, iuMRI, in utero MRI.
Results In total, 1722 iuMRI examinations of the fetal brain were performed during the study period. The level of agreement between the two imaging methods is summarized in Table 1. In 1559 cases, ACC did not feature as a diagnosis on either the antenatal ultrasound or the iuMRI examination
(true negatives: group D). In 121 cases, a diagnosis of ACC was made on the antenatal ultrasound. Of these, 57/121 were confirmed as ACC at iuMRI; 57/121 had a normal intact corpus callosum on iuMRI and an additional seven demonstrated “hypogenesis of the corpus callosum”. If the iuMRI diagnosis of “hypogenesis of the corpus callosum” is considered to be an incorrect diagnosis of ACC at ultrasound, there were 57 true positives (group A) and 64 false positives (group B). The positive predictive value was 47% (38e56%). If the iuMRI diagnosis of “hypogenesis of the corpus callosum” was interpreted as being the same as a diagnosis as ACC on ultrasound, the number of true positives (group A) became 64 and the false positives (group B) became 57. The revised positive predictive value was 53% (44e62%), the negative predictive value and specificity were unchanged, but the sensitivity increased to 60% (95% CI: 50e70%). In addition, there were 42 cases where ACC was diagnosed at iuMRI but not suspected on the antenatal
Figure 1 Ultrafast T2-weighted images of the brain of a fetus (31 weeks gestational age) with a diagnosis of ACC made at ultrasound, which was not confirmed at iuMRI. Coronal (a) and sagittal (b) imaging shows the corpus callosum is present throughout but mild ventriculomegaly is present on axial imaging (c).
I. Craven et al. / Clinical Radiology 70 (2015) 248e253
ultrasound referral (42 false negatives: group C). The positive predictive value of ultrasonography was 47% (95% CI: 38e56%) and the negative predictive value in this cohort was 97% (96e98%). The sensitivity and specificity were 58% (45e67%) and 96% (95e97%) respectively. The median gestational ages for fetuses according to their diagnostic group (AeC) are presented in Table 2. Representative examples are shown in Figs 1e3.
Discussion It is important to make accurate diagnoses of brain abnormalities in the fetus in order to provide the best information to the future parents about the nature of the abnormality and the likely clinical consequences. In the UK, pregnant women are offered a screening ultrasound examination performed by a trained sonographer at approximately 20 weeks gestation and the majority of women elect to have that study. If a fetal abnormality is known or suspected on that examination, the woman is offered a detailed “anomaly” ultrasound examination performed by a medically qualified foeto-maternal expert (from an
251
obstetric or radiological background). All of the fetuses studied in this paper were referred for iuMRI on the basis of findings from that “second-level” ultrasound examination, and in most cases, the referral was from a regional foetomaternal centre. In spite of the experience of ultrasound operators using improved ultrasound equipment and techniques, the diagnosis of brain abnormalities can be difficult and this appears to be true for ACC.9e11 The introduction of iuMRI has revolutionized the diagnosis of brain pathologies in adult, paediatric, and neonatal practice (including premature babies), and appears to have similar improvements when imaging the fetal brain.12e17 Discrepancies between the ultrasound and iuMRI diagnosis of ACC in the fetus feature heavily in the published literature and appears to cause the largest single group of disagreements.17e19 Most of the reports in the literature describe cases of ACC that have not been shown on ultrasonography but have been shown on iuMRI (false negatives), the iuMRI examination being performed for ventriculomegaly in many cases. There are few reports of referrals being made from ultrasound carrying a diagnosis of ACC that was refuted on iuMRI (false positives). The
Figure 2 Ultrafast T2-weighted images of the brain of a fetus (22 weeks gestational age) with a diagnosis of ACC made at ultrasound and confirmed at iuMRI. Coronal (a) and sagittal (b) imaging shows complete failure of commissuration and selective enlargement of the trigones of the lateral ventricles (colpocephaly) on the axial imaging (c).
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I. Craven et al. / Clinical Radiology 70 (2015) 248e253
Figure 3 Ultrafast T2-weighted images of the brain of a fetus (24 weeks gestational age) with a diagnosis of a supratentorial cyst with mass effect made on ultrasound. iuMRI in the coronal plane (a) confirms the presence of a predominantly left-sided, extra-axial cyst but, in conjunction with sagittal imaging (b), ACC is confirmed as well. Axial imaging (c) shows that the cyst does not communicate with the ventricular system and there is a high suspicion of a pervasive cortical formation abnormality of the left cerebral hemisphere.
information provided by the present study refines and fills an important gap in the existing literature. Ultrasonography is poor in detecting ACC as highlighted particularly by the low positive predictive value. It is difficult to explain why ACC is such a difficult diagnosis to make at antenatal ultrasonography, but some possibilities have been discussed elsewhere.20 Various assumptions have been made in the present study, and there are other methodological flaws that need to be discussed. The group of fetuses used as the truenegative group was not a group of “normal” fetuses, as the majority had brain abnormalities other than ACC as shown on antenatal ultrasound and/or iuMRI. This does not affect the positive predictive value; around half of ACC cases diagnosed by ultrasonography appear false, irrespective of how many ultrasound-negative examinations are included. The sensitivity, specificity, and negative predictive value
calculated for this cohort will necessarily be underestimates of those that apply to the entire population. As normal fetuses are not routinely offered iuMRI, there is no clear way around this problem at the present time. Probably the most serious argument against the findings of this paper is the choice of the reference standard for the detection of fetal ACC and using iuMRI in this role requires justification. First, it is a pragmatic choice. The best reference data for fetuses that go on to delivery is postnatal MRI; for those cases resulting in termination of pregnancy, post-mortem findings provide the best reference data. Both of those have problems. One of the most important findings of the present study was the high rate of incorrectly diagnosed ACC cases at ultrasound when the rest of the brain was normal (or what we consider normal, i.e., mild ventriculomegaly). In such cases, the child is likely to be neuro-
I. Craven et al. / Clinical Radiology 70 (2015) 248e253
developmentally normal and, as such, would be unlikely to have postnatal MRI. It is widely accepted that the fetal post-mortem rate after termination of pregnancy in the UK is low and restrictions put on pathologists in terms of time to fix and perform the post mortem frequently result in sub-optimal conditions for brain examinations. In a previous study comparing postmortem fetal MRI with post-mortem pathological findings, the brain could not be studied at all in 20% of cases.21 Both of these factors severely limit the ability to use the post mortem as a reference standard. So should iuMRI be used as a reference standard for fetal ACC? MRI is considered to be the optimal method of detecting postnatal ACC, and there is certainly no requirement for neurosurgical or post-mortem confirmation in that situation. It is true that the ultrafast imaging methods used in iuMRI have a lower anatomical resolution than postnatal MRI but the resolution is still high. The authors are not aware of a case of fetal ACC reported inaccurately at iuMRI in the published literature. However, it should be noted the same case is not being made for hypogenesis of the corpus callosum, where there are several reports of misdiagnosis of the milder forms of hypogenesis at iuMRI, including a report by the present authors.17 This explains why two groups of descriptive statistics were calculated, one assuming hypogenesis of the corpus callosum was an incorrect diagnosis and the other assuming it was correct. It should be recognized, however, that this only involved approximately 7% of cases with a commissural abnormality. Therefore, iuMRI provides the best reference standard for diagnosing fetal ACC at the present time. The prognosis for an individual fetus diagnosed with ACC is uncertain, but as an isolated finding it is expected that 10e30% will have a poor outcome.5e7,22e27 The information given to the parents about the fetus is influenced by the presence of additional brain abnormalities where seizures and neurodevelopmental delay are considerably more likely. It is now widely accepted that iuMRI is better than ultrasound in detecting associated brain malformations. This is particularly important in the context of ACC as researchers have found additional brain malformations in a high proportion of cases3,25,26 and as high as 63% in one report.4 This issue is not discussed in detail in the current paper because of the lack of reference outcome data for the associated brain abnormalities. Although iuMRI provides a reliable method for the reference diagnosis of ACC, that claim cannot be made for cortical formation abnormalities (such as polymicrogyria or heterotopia). Suffice to say that out of the 64 true positives, additional brain abnormalities were shown in 39% of fetuses at iuMRI and in only 21% at ultrasonography. Those figures do not include fetal ventriculomegaly, as this an anatomical sequelae of failed commissuration rather than an additional brain abnormality. The biggest disagreement was in cases of cortical formation abnormalities, which also provided the largest group of other brain malformations. In conclusion, the diagnosis of ACC in the fetus is challenging at ultrasonography and if any suspicion is raised, iuMRI is likely to provide extra valuable information in a high proportion of cases.
253
References 1. Dobyns WB. Absence makes the search grow longer. Am J Hum Genet 1996;58:7e16. 2. Rakic P, Yakovlev PI. Development of the corpus callosum and cavum septae in man. J Comp Neurol 1968;132:45e72. 3. Glenn OA, Goldstein RB, Li KC, et al. Fetal magnetic resonance imaging in the evaluation of fetuses referred for sonographically suspected abnormalities of the corpus callosum. J Ultrasound Med 2005;24:791e804. 4. Cignini P, D’Emidio L, Padula F, et al. The role of ultrasonography in the diagnosis of fetal isolated complete agenesis of the corpus callosum: a long-term prospective study. J Matern Fetal Neonatal Med 2010;23:1504e9. 5. Fratelli N, Papageorghiou AT, Prefumo F, et al. Outcome of prenatally diagnosed agenesis of the corpus callosum. Prenat Diagn 2007;27:512e7. 6. Ghi T, Carletti A, Contro E, et al. Prenatal diagnosis and outcome of partial agenesis and hypoplasia of the corpus callosum. Ultrasound Obstet Gynecol 2010;35:35e41. 7. Moutard ML, Kieffer V, Feingold J, et al. Agenesis of corpus callosum: prenatal diagnosis and prognosis. Childs Nerv Syst 2003;19:471e6. 8. Gupta JK, Lilford RJ. Assessment and management of fetal agenesis of the corpus callosum. Prenat Diagn 1995;15:301e12. 9. Bennett GL, Bromley B, Benacerraf BR. Agenesis of the corpus callosum: prenatal detection usually is not possible before 22 weeks of gestation. Radiology 1996;99:447e50. M, Droulle P, et al. Prenatal echographic diagnosis of 10. Blum A, Andre corpus callosum agenesis. The Nancy experience 1982e1989. Genet Couns 1990;1:115e26. 11. Pilu G, Sandri F, Perolo A, et al. Sonography of fetal agenesis of the corpus callosum: a survey of 35 cases. Ultrasound Obstet Gynecol 1993;3:318e29. 12. Levine D, Barnes PD, Robertson RR, et al. Fast MRI of fetal central nervous system abnormalities. Radiology 2003;229:51e61. 13. Herman-Sucharska I, Bekiesinska-Figatowska M, Urbanik A. Fetal central nervous system malformations on MRI images. Brain Dev 2009;31:185e99. 14. Benacerraf BR, Shipp TD, Bromley B, et al. What does magnetic resonance imaging add to the prenatal sonographic diagnosis of ventriculomegaly? J Ultrasound Med 2007;26:1513e22. 15. Glenn OA, Barkovich AJ. Magnetic resonance imaging of the fetal brain and spine: an increasingly important tool in prenatal diagnosis, part 1. AJNR Am J Neuroradiol 2006;27:1604e11. 16. Sonigo PC, Rypens FF, Carteret M, et al. MRI of fetal cerebral anomalies. Pediatr Radiol 1998;28:212e22. 17. Griffiths PD, Reeves MJ, Morris JE, et al. A prospective study of fetuses with isolated ventriculomegaly investigated by antenatal sonography and in utero MRI. AJNR Am J Neuroradiol 2010;31:106e11. 18. d’Ercole C, Girard N, Cravello L, et al. Prenatal diagnosis of fetal corpus callosum agenesis by ultrasonography and magnetic resonance imaging. Prenat Diagn 1998;18:247e53. 19. Manfredi R, Tognolini A, Bruno C, et al. ACC in fetuses with mild ventriculomegaly: role of MRI. Radiol Med 2010;115:301e12. 20. Griffiths PD, Batty R, Reeves MJ. Connolly DJ Imaging the corpus callosum, septum pellucidum and fornix in children: normal anatomy and variations of normality. Neuroradiology 2009;51:337e45. 21. Griffiths PD, Variend D, Evans M, et al. Postmortem MRI of the fetal and stillborn central nervous system. AJNR Am J Neuroradiol 2003;31:106e11. 22. Volpe P, Paladini D, Resta M, et al. Characteristics, associations and outcome of partial agenesis of the corpus callosum in the fetus. Ultrasound Obstet Gynecol 2006;27:509e16. 23. Vergani P, Ghidini A, Strobelt N, et al. Prognostic indicators in the prenatal diagnosis of agenesis of corpus callosum. Am J Obstet Gynecol 1994;170:753e8. 24. Shevell MI. Clinical and diagnostic profile of agenesis of the corpus callosum. J Child Neurol 2002;17:896e900. 25. Francesco P, Maria-Edgarda B, Giovanni P, et al. Prenatal diagnosis of agenesis of corpus callosum: what is the neurodevelopmental outcome? Pediatr Int 2006;48:298e304. 26. Tang PH, Bartha AI, Norton ME, et al. Agenesis of the corpus callosum: an MRI analysis of associated abnormalities in the fetus. AJNR Am J Neuroradiol 2009;30:257e63. 27. Hetts SW, Sherr EH, Chao S, et al. Anomalies of the corpus callosum: an MRI analysis of the phenotypic spectrum of associated malformations. AJR Am J Roentgenol 2006;187:1343e8.
Contents lists available at ScienceDirect
Clinical Radiology journal homepage: www.clinicalradiologyonline.net
Antenatal diagnosis of agenesis of the corpus callosum I. Craven a, M.J. Bradburn b, P.D. Griffiths c, * a
Department of Neuroradiology, Leeds General Infirmary, Leeds, UK Clinical Trials Research Unit, ScHARR, Sheffield, UK c Academic Unit of Radiology, University of Sheffield, Sheffield, UK b
article in formation Article history: Received 26 August 2014 Received in revised form 29 October 2014 Accepted 6 November 2014
AIM: To estimate the diagnostic performance of ultrasound in detecting agenesis of the corpus callosum (ACC). MATERIALS AND METHODS: A retrospective review was performed of 1722 in utero MRI examinations. All cases were identified in which the fetus had been referred from ultrasonography with a diagnosis of ACC and those in which ACC was given as a diagnosis on the in utero MRI study. The MRI was assumed to provide the correct diagnosis of ACC and descriptive statistics of diagnostic accuracy for ultrasound were calculated. RESULTS: Of the 1722 ultrasound examinations performed, 121 had a diagnosis of ACC and approximately 50% were confirmed at MRI. Forty-two fetuses with ACC not suspected at ultrasonography were also identified at MRI. Ultrasonography had a positive predictive value of 47% (95% CI: 38e56%) and a negative predictive value of 97% (95% CI: 96e98%) for detecting ACC. CONCLUSION: Ultrasound is poor in diagnosing ACC and in utero MRI should be performed if there is any suspicion on antenatal ultrasonography. Ó 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction The corpus callosum is a white matter structure that contains fibres connecting homologous structures in the two cerebral hemispheres, and it is by far the largest commissure in terms of volume. The corpus callosum starts to develop at approximately 8 weeks gestational age in humans and it is complete in its cranio-caudal extent by 18e19 weeks, although further maturation and growth continues into postnatal life. Agenesis of the corpus callosum (ACC) is the commonest developmental abnormality,
* Guarantor and correspondent: P. Griffiths, Academic Unit of Radiology, Floor C, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, UK. Tel.: þ44 144 271 3207. E-mail address: p.griffiths@sheffield.ac.uk (P.D. Griffiths).
resulting from failure of commissuration and can occur for a number of reasons including genetic, metabolic, or vascular abnormalities, but in most cases the cause is not found.1 The term “ACC” implies that the entire structure has failed to form, but in other fetuses the corpus callosum may fail to form in part leading to the term “hypoplasia of the corpus callosum”.2 In the context of the detection of antenatal malformations, ACC is much more common than hypoplasia of the corpus callosum. The prognosis for an individual fetus with ACC can rarely be known with certainty, but it is influenced by the presence or absence of chromosomal, genetic, or other structural abnormalities (involving either the brain or other system). Brain abnormalities associated with ACC are common and have deleterious effects on prognosis. One recent paper using in utero MRI (iuMRI) detected other
http://dx.doi.org/10.1016/j.crad.2014.11.004 0009-9260/Ó 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
I. Craven et al. / Clinical Radiology 70 (2015) 248e253
brain abnormalities in over 60% of cases.3 Even in cases where ACC is the only abnormal antenatal finding, it is expected that 10e30% will have a poor neurodevelopmental outcome.4e8 It is, therefore, important to have a robust method of identifying ACC in utero in order to give accurate prognostic information. The imaging tool for detecting structural brain abnormalities in the fetus has historically been ultrasonography and many countries have screening programmes based on that imaging method. Several papers have questioned the accuracy of detecting ACC by ultrasound.9e11 The introduction of iuMRI of the fetal brain has raised further concern as this disease seems to be the single largest source of disagreements between antenatal ultrasound and iuMRI findings. In the present study, the assumption (and will subsequently attempt to defend the assumption) that iuMRI provides reference standard information for detecting ACC in utero. As such, we have calculated indicators of diagnostic performance for antenatal ultrasonography in detecting ACC by reviewing over 1700 iuMRI studies of the fetal brain from our institution (Academic Unit of Radiology, University of Sheffield).
Materials and methods Participants A retrospective review was conducted of all iuMRI studies of the fetal brain performed at our institution over a 7 year period between 2004 and 2011. Referrals for iuMRI were made after ultrasonography of the fetus had been performed by a consultant in foeto-maternal medicine working in one of a large number of foeto-maternal centres in Britain. In over 95% of cases, the referral was for a brain abnormality identified or suspected at ultrasonography. In the other cases, the brain was imaged because of an abnormality in another anatomical location (usually the spine) or the fetus was known to have an increased risk of brain malformation but was structurally normal at ultrasonography. The iuMRI was usually performed within 5 working days of the referral from ultrasonography and the radiologist reporting the iuMRI study was aware of the findings on the antenatal ultrasound examination. The women did not have any known or suspected contraindications to MRI and all iuMRI studies were performed at, or after, 18 weeks gestational age. Most of the women had iuMRI as part of research studies after providing informed written consent under the guidance and approval of the Institutional Research Ethics Committee. Those women were not paid for their involvement in the study but travel expenses were offered for themselves and a companion. Relevant review was sought, and approval obtained, from the Institutional Clinical Effectiveness Unit and Research Department in order to allow cases performed for clinical purposes to be reported in this paper.
iuMRI protocol iuMRI was performed using a 1.5 Tesla superconducting system (before 2008: Infinion, Philips Medical Systems,
249
Best, Netherlands; 2008 and after HDx, GE Healthcare, Milwaukee, WI, USA). A range of sequences were performed but always included single-shot fast spin echo sequences (5 mm thick sections in all three orthogonal planes and 3 mm thick sections in at least two orthogonal planes). The studies were reported by a radiologist at the time of the iuMRI examination. For the purpose of the study, the Unit’s database was searched for the total number of fetal brain examinations performed in the study period. In addition, specific searches were made for reports with any positive reference to a diagnosis of “ACC” in either the referral information from antenatal ultrasonography or the report of the iuMRI examination. The referral details and iuMRI examinations of the “ACC” cases were re-reviewed by the two neuroradiologists involved in the study (I.C., P.D.G.) in order to confirm the veracity of the information obtained from the database.
Analysis Following that analysis, four groups were formed as listed below. These were created on the assumption that iuMRI was the reference standard for diagnosing ACC in utero in order to calculate descriptive statistics for the diagnostic performance of antenatal ultrasonography: (1) ACC was diagnosed on antenatal ultrasound and confirmed on iuMRI (true positives: group A); (2) ACC was diagnosed on antenatal ultrasound but not confirmed on iuMRI (false positives: group B); (3) ACC was not diagnosed on antenatal ultrasound but was diagnosed on iuMRI (false negatives: group C); (4) ACC was not considered to be a diagnosis on antenatal ultrasound or iuMRI (true negatives: group D). Specifically, positive and negative predictive rates are presented along with their 95% confidence interval, calculated by the exact binomial method. Descriptive statistics were calculated on the basis of “hypogenesis of the corpus callosum” being an incorrect ultrasound diagnosis of ACC and then re-calculated assuming that “hypogenesis of the corpus callosum” was a correct diagnosis in order to provide the range of possible positive and negative predictive rates. Table 1 Descriptive statistics for the diagnosis of agenesis of the corpus callosum (ACC) at antenatal ultrasound (US) assuming in utero MRI (iuMRI) diagnosis or exclusion of diagnosis is correct. Confirmed ACC diagnosis on iuMRI
Referred with US diagnosis of ACC Referred from US without ACC diagnosis Total a
Total
Yes
No
57
64
121
[64a] 42
[57a] 1559
[121a] 1601
99 [106a]
1623 [1616a]
1722
Positive predictive value 47% (38e56%) [53% (44e62%)a] Negative predictive value 97% (96e98%)
Assuming “hypogenesis of the corpus callosum” is equivalent to ACC.
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I. Craven et al. / Clinical Radiology 70 (2015) 248e253
Table 2 Gestational age of cases with suspected or confirmed diagnosis of agenesis of the corpus callosum (ACC) at the time of in utero MRI. Method of ACC diagnosis
Median (IQR) Range
Both US and iuMRI (group A; n ¼ 57)
US only (group B; n ¼ 64)
iuMRI only (group C; n ¼ 42)
22 (20e24)
23 (21e26)
24 (22e30)
18e36
18e33
20e40
US, ultrasound, iuMRI, in utero MRI.
Results In total, 1722 iuMRI examinations of the fetal brain were performed during the study period. The level of agreement between the two imaging methods is summarized in Table 1. In 1559 cases, ACC did not feature as a diagnosis on either the antenatal ultrasound or the iuMRI examination
(true negatives: group D). In 121 cases, a diagnosis of ACC was made on the antenatal ultrasound. Of these, 57/121 were confirmed as ACC at iuMRI; 57/121 had a normal intact corpus callosum on iuMRI and an additional seven demonstrated “hypogenesis of the corpus callosum”. If the iuMRI diagnosis of “hypogenesis of the corpus callosum” is considered to be an incorrect diagnosis of ACC at ultrasound, there were 57 true positives (group A) and 64 false positives (group B). The positive predictive value was 47% (38e56%). If the iuMRI diagnosis of “hypogenesis of the corpus callosum” was interpreted as being the same as a diagnosis as ACC on ultrasound, the number of true positives (group A) became 64 and the false positives (group B) became 57. The revised positive predictive value was 53% (44e62%), the negative predictive value and specificity were unchanged, but the sensitivity increased to 60% (95% CI: 50e70%). In addition, there were 42 cases where ACC was diagnosed at iuMRI but not suspected on the antenatal
Figure 1 Ultrafast T2-weighted images of the brain of a fetus (31 weeks gestational age) with a diagnosis of ACC made at ultrasound, which was not confirmed at iuMRI. Coronal (a) and sagittal (b) imaging shows the corpus callosum is present throughout but mild ventriculomegaly is present on axial imaging (c).
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ultrasound referral (42 false negatives: group C). The positive predictive value of ultrasonography was 47% (95% CI: 38e56%) and the negative predictive value in this cohort was 97% (96e98%). The sensitivity and specificity were 58% (45e67%) and 96% (95e97%) respectively. The median gestational ages for fetuses according to their diagnostic group (AeC) are presented in Table 2. Representative examples are shown in Figs 1e3.
Discussion It is important to make accurate diagnoses of brain abnormalities in the fetus in order to provide the best information to the future parents about the nature of the abnormality and the likely clinical consequences. In the UK, pregnant women are offered a screening ultrasound examination performed by a trained sonographer at approximately 20 weeks gestation and the majority of women elect to have that study. If a fetal abnormality is known or suspected on that examination, the woman is offered a detailed “anomaly” ultrasound examination performed by a medically qualified foeto-maternal expert (from an
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obstetric or radiological background). All of the fetuses studied in this paper were referred for iuMRI on the basis of findings from that “second-level” ultrasound examination, and in most cases, the referral was from a regional foetomaternal centre. In spite of the experience of ultrasound operators using improved ultrasound equipment and techniques, the diagnosis of brain abnormalities can be difficult and this appears to be true for ACC.9e11 The introduction of iuMRI has revolutionized the diagnosis of brain pathologies in adult, paediatric, and neonatal practice (including premature babies), and appears to have similar improvements when imaging the fetal brain.12e17 Discrepancies between the ultrasound and iuMRI diagnosis of ACC in the fetus feature heavily in the published literature and appears to cause the largest single group of disagreements.17e19 Most of the reports in the literature describe cases of ACC that have not been shown on ultrasonography but have been shown on iuMRI (false negatives), the iuMRI examination being performed for ventriculomegaly in many cases. There are few reports of referrals being made from ultrasound carrying a diagnosis of ACC that was refuted on iuMRI (false positives). The
Figure 2 Ultrafast T2-weighted images of the brain of a fetus (22 weeks gestational age) with a diagnosis of ACC made at ultrasound and confirmed at iuMRI. Coronal (a) and sagittal (b) imaging shows complete failure of commissuration and selective enlargement of the trigones of the lateral ventricles (colpocephaly) on the axial imaging (c).
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Figure 3 Ultrafast T2-weighted images of the brain of a fetus (24 weeks gestational age) with a diagnosis of a supratentorial cyst with mass effect made on ultrasound. iuMRI in the coronal plane (a) confirms the presence of a predominantly left-sided, extra-axial cyst but, in conjunction with sagittal imaging (b), ACC is confirmed as well. Axial imaging (c) shows that the cyst does not communicate with the ventricular system and there is a high suspicion of a pervasive cortical formation abnormality of the left cerebral hemisphere.
information provided by the present study refines and fills an important gap in the existing literature. Ultrasonography is poor in detecting ACC as highlighted particularly by the low positive predictive value. It is difficult to explain why ACC is such a difficult diagnosis to make at antenatal ultrasonography, but some possibilities have been discussed elsewhere.20 Various assumptions have been made in the present study, and there are other methodological flaws that need to be discussed. The group of fetuses used as the truenegative group was not a group of “normal” fetuses, as the majority had brain abnormalities other than ACC as shown on antenatal ultrasound and/or iuMRI. This does not affect the positive predictive value; around half of ACC cases diagnosed by ultrasonography appear false, irrespective of how many ultrasound-negative examinations are included. The sensitivity, specificity, and negative predictive value
calculated for this cohort will necessarily be underestimates of those that apply to the entire population. As normal fetuses are not routinely offered iuMRI, there is no clear way around this problem at the present time. Probably the most serious argument against the findings of this paper is the choice of the reference standard for the detection of fetal ACC and using iuMRI in this role requires justification. First, it is a pragmatic choice. The best reference data for fetuses that go on to delivery is postnatal MRI; for those cases resulting in termination of pregnancy, post-mortem findings provide the best reference data. Both of those have problems. One of the most important findings of the present study was the high rate of incorrectly diagnosed ACC cases at ultrasound when the rest of the brain was normal (or what we consider normal, i.e., mild ventriculomegaly). In such cases, the child is likely to be neuro-
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developmentally normal and, as such, would be unlikely to have postnatal MRI. It is widely accepted that the fetal post-mortem rate after termination of pregnancy in the UK is low and restrictions put on pathologists in terms of time to fix and perform the post mortem frequently result in sub-optimal conditions for brain examinations. In a previous study comparing postmortem fetal MRI with post-mortem pathological findings, the brain could not be studied at all in 20% of cases.21 Both of these factors severely limit the ability to use the post mortem as a reference standard. So should iuMRI be used as a reference standard for fetal ACC? MRI is considered to be the optimal method of detecting postnatal ACC, and there is certainly no requirement for neurosurgical or post-mortem confirmation in that situation. It is true that the ultrafast imaging methods used in iuMRI have a lower anatomical resolution than postnatal MRI but the resolution is still high. The authors are not aware of a case of fetal ACC reported inaccurately at iuMRI in the published literature. However, it should be noted the same case is not being made for hypogenesis of the corpus callosum, where there are several reports of misdiagnosis of the milder forms of hypogenesis at iuMRI, including a report by the present authors.17 This explains why two groups of descriptive statistics were calculated, one assuming hypogenesis of the corpus callosum was an incorrect diagnosis and the other assuming it was correct. It should be recognized, however, that this only involved approximately 7% of cases with a commissural abnormality. Therefore, iuMRI provides the best reference standard for diagnosing fetal ACC at the present time. The prognosis for an individual fetus diagnosed with ACC is uncertain, but as an isolated finding it is expected that 10e30% will have a poor outcome.5e7,22e27 The information given to the parents about the fetus is influenced by the presence of additional brain abnormalities where seizures and neurodevelopmental delay are considerably more likely. It is now widely accepted that iuMRI is better than ultrasound in detecting associated brain malformations. This is particularly important in the context of ACC as researchers have found additional brain malformations in a high proportion of cases3,25,26 and as high as 63% in one report.4 This issue is not discussed in detail in the current paper because of the lack of reference outcome data for the associated brain abnormalities. Although iuMRI provides a reliable method for the reference diagnosis of ACC, that claim cannot be made for cortical formation abnormalities (such as polymicrogyria or heterotopia). Suffice to say that out of the 64 true positives, additional brain abnormalities were shown in 39% of fetuses at iuMRI and in only 21% at ultrasonography. Those figures do not include fetal ventriculomegaly, as this an anatomical sequelae of failed commissuration rather than an additional brain abnormality. The biggest disagreement was in cases of cortical formation abnormalities, which also provided the largest group of other brain malformations. In conclusion, the diagnosis of ACC in the fetus is challenging at ultrasonography and if any suspicion is raised, iuMRI is likely to provide extra valuable information in a high proportion of cases.
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