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J Thorac Cardiovasc Surg 2009;137:146-153
© 2009 The American Association for Thoracic Surgery

Congenital Heart Disease

Impaired neuroanatomic development in infants with congenital heart disease

^a Department of Pediatrics, University of Toyama, Toyama, Japan
^b Department of Psychology, University of Toyama, Toyama, Japan
^c Department of Radiology, University of Toyama, Toyama, Japan
^d Department of Cardiothoracic Surgery, University of Toyama, Toyama, Japan
^e Division of Biostatistics, University of Toyama, Toyama, Japan
^f Department of Psychology, Chiba University, Chiba, Japan
^g Department of Cardiothoracic Surgery, Hyogo Children's Hospital, Kobe, Japan
^h Department of Cardiothoracic Surgery, National Cardiovascular Center, Osaka, Japan
ⁱ Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pa
^j Department of Psychiatry, University of Pennsylvania, Philadelphia, Pa

Received for publication March 23, 2008; revisions received May 29, 2008; accepted for publication June 24, 2008.

^_* Address for reprints: Fukiko Ichida, MD, Department of Pediatrics, University of Toyama, 2630 Sugitani, Toyama, Toyama, 930-0194 Japan. (Email: fukiko{at}med.u-toyama.ac.jp).

	Abstract

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Objectives: We performed a regional volumetric study of the brain using 3-dimensional magnetic resonance imaging in infants with congenital heart disease to search for variables in anatomic development of the brain that may be associated with functional impairment.

Methods: Forty infants with congenital heart disease—17 infants with single ventricle physiology, 5 with transposition of great arteries, and 18 with ventricular septal defect—were studied prospectively by 3-dimensional magnetic resonance imaging of the brain several months after heart surgery.

Results: The global volume of gray matter was significantly reduced in the patients with congenital heart disease compared with normal controls (P < .001), whereas no significant difference in the volume of white matter was observed. Further, the decrease in gray matter volume was more apparent in the frontal lobe than in the temporal lobe, especially in infants with single ventricle physiology or transposition of the great arteries. Multivariate analysis revealed that preoperative hypoxia is strongly associated with decreased frontal gray matter volume (P < .01), as well as a diagnosis of hypoplastic left heart syndrome (P < .05). Of note, frontal gray matter volume, which includes the motor area, correlated weakly with psychomotor developmental index scores (P < .01).

Conclusions: Brain developmental impairment occurs in many infants with congenital heart disease, especially in those who have preoperative hypoxia and critical congenital heart disease. This quantitative volumetric study encourages larger scale and longitudinal follow-up to elucidate the significance of impaired neuroanatomic development on functional outcome.

	Introduction

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Recent advances in diagnostic and surgical techniques have enabled early correction of most complex congenital heart diseases (CHD) in infancy and have dramatically reduced mortality.^1,2 However, a considerable rate of neurologic sequelae is observed after heart surgery in infants.^3-6 The etiology is multifactorial with the integrity of the developing nervous system being influenced by a complex interaction of perioperative factors in infants with CHD.^7,8 Newborns with critical CHD have widespread brain abnormalities before undergoing cardiac surgery, possibly caused by impaired cerebral oxygen delivery and impaired brain development in utero.⁹ Newborns with transposition of the great arteries (TGA) or single ventricle (SV) physiology have altered brain metabolism and microstructure shortly after birth, even in the absence of visible injury on magnetic resonance imaging (MRI).⁹ However, these subtle brain abnormalities are difficult to elucidate in infancy, and the final neurologic outcome can only be determined by developmental testing late after the operation.^10-12

Most infants with critical CHD, especially hypoplastic left heat syndrome (HLHS), have a reduced head circumference.¹³ Nevertheless, there are no data regarding exact brain volume and its relation to neurodevelopment in infants with critical CHD. We hypothesized that infants with critical CHD have impaired anatomic development of the brain, and this is associated with functional impairment. We performed a regional volumetric study of the brain using 3-dimensional magnetic resonance imaging (3D-MRI) in infants with heterogeneous CHD including SV, TGA, and ventricular septal defect (VSD) and performed neurodevelopmental assessment using the Bayley Scales of Infant Development II.

	Methods

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Patients
A prospective observational study was performed in 40 infants with CHD from May 2005 to April 2007. The patients were further classified into those who had critical CHD including TGA and SV (critical CHD group) and those who had a diagnosis of VSD (VSD group). Infants were excluded if their gestational age was less than 36 weeks or if there was a genetic malformation syndrome. A volumetric study of the brain using 3D-MRI was performed at least 2 months (8.6 ± 5.7 months) after the latest heart surgery in each patient. Neurodevelopmental assessment was performed by the Bayley Scales of Infant Development II in all patients by a pediatric psychologist (M.I.). The interval between the 3D-MRI study and the neurodevelopmental assessment was less than 2 weeks in all patients. Preoperative clinical data were prospectively collected from the medical records and reviewed by pediatric cardiologists who were blinded to the 3D-MRI findings.

Nineteen healthy control infants (aged 1 month to 24 months) were recruited from University Hospital staff and siblings of ambulatory child patients for volumetric study of the brain. They were born at term without any complicated perinatal courses. Their heights and weights were all in the normal range. All controls had normal neurologic development and had no abnormal findings on routine MRI.

The Research Ethics Committee of the University Hospital of Toyama approved the study. Written informed consent was obtained from parents after the purpose and all procedures of the study were fully explained. All patients and controls were sedated with monosodium trichorethyl phosphate syrup (0.5–1.0 mL/kg) before MRI.

MRI Scan Acquisition
MRI scans were performed as previously described with a 1.5-T Magnetom Vision scanner (Siemens, Erlangen, Germany).¹⁴ In brief, axial images were obtained with a fast low-angle shot gradient refocused 3-dimensional sequence with the following parameters: flip angle = 35°, repetition time = 35 ms, echo time = 6 ms, nex = 1. The image obtained was T1-weighted with a field of view of 256 mm and a matrix size of 256 x 256, and the entire scan was obtained in 15 minutes. The slice thickness was 1.0 mm, and between 140 and 170 contiguous slices were obtained in each case.

Image Processing
Each acquisition was transferred to an online UNIX workstation (SPARC20; Sun Microsystems, Santa Clara, Calif). All image processing was performed with a semi-automated software package.¹⁵ Manual delineation of cerebral hemispheres and cerebrospinal fluid (CSF) was based on standard guidelines¹⁶ and frontal and temporal lobar volumes were calculated by previously described procedures.¹⁷

Cerebral Hemispheres and CSF
Collection of data in the axial plane required neuroanatomic knowledge to separate the supratentorial from infratentorial compartments. All supratentorial slices were analyzed and the infratentorial CSF and tissue were excluded by placing a boundary around the posterior fossa on each slice.

Frontal and Temporal Lobes
As described previously,¹⁴ we have added a new method of delineation to include more frontal lobar regions, such as the motor area. We measured the global volume of gray matter (GM), white matter (WM), CSF, and regional brain volume of the frontal lobe and temporal lobe in the patients and normal controls.

Reliability of Regional Volumetric Measurements
Inter-reader reliability was examined in a sample of 10 normal controls analyzed by two raters (K.W. and J.M.). The intraclass correlation for total cerebral volumes ranged from 0.93 to 1.02 and those of frontal and temporal lobar volumes from 0.95 to 0.99. The intra-reader reliability was also examined in the same 10 scans analyzed by one of these readers (K.W.), and the correlation for total cerebral, frontal, and temporal lobar volumes ranged from 0.93 to 0.98. The reader (K.W.) then completed the analysis on the remaining scans.

Statistical Analyses
In normal controls, the relationship between the whole brain volume compartment of GM, WM, CSF, and age was modeled by linear regression with fractional polynomials of age as the covariates.¹⁸ This approach finds the combination of fractional powers of age that best describe each of the relationships. Models with up to three fractional powers were explored. For all three models (GM, WM, and CSF), one fractional power of age was sufficient. In addition, the curve-fitting approach to examine age effects on the frontal and temporal subregions, including examination of tissue types, was done simultaneously by linear regression with fractional polynomials. In infants with CHD, the difference from a normal population over age was evaluated by the Wilcoxon signed rank test. Correlation between regional brain volume and neurodevelopmental score by Bayley II scale was assessed by t test concerning the slope. Independent risk factors for the reduced regional brain volume were analyzed by multiple regression analysis after the standardization by age. Statistical computations were performed with STATA (STATA Corp, College Station, Tex) and SAS software (SAS Institute Inc, Cary, NC).

	Results

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Patient Clinical Characteristics
Clinical characteristics of the patients are described in Table 1 . Of the infants with critical CHD, 17 had SV physiology including 4 with HLHS and 5 with TGA, whereas the VSD group included 15 infants with simple VSD and 3 with associated VSD and coarctation of the aorta. Preoperative oxygen saturation was significantly lower in the group with critical CHD. No significant differences were found in patient-related variables including age, body weight, height, and head circumference. Periventricular leukomalacia was diagnosed by ultrasonography in 2 patients in the critical CHD group during the neonatal period. Age at operation was significantly younger in the critical CHD group. Other perioperative variables, including duration of intubation were not significantly different between the two groups. Perioperative seizure was observed in only 1 patient in the critical CHD group. All of the VSD patients underwent total correction, whereas 17 of the patients with critical CHD underwent palliative operation and 5 underwent total correction (Table 1). Neuroexaminations, performed by a neuropediatrician (K.H.), revealed no significant abnormalities in any of the patients except for 1 floppy infant in the critical CHD group. Clinical review of the anatomic MRI scans by a neuroradiologist (K.N.) resulted in normal findings in all patients, except for 2 patients with slight subdural hematoma.

View larger version (133K): [in this window] [in a new window]   Figure 1. Examples of tissue classification (left) and original T1-weighted images (right) from 4-month-old (A) and 1-year- old (C) normal controls (A, axial image, C, axial, coronal, and sagittal images), and representative slices from patients with hypoplastic left heart syndrome (HLHS) at the same ages (B, axial image, D, axial, coronal, and sagittal images). Decrease of the gray matter volume, especially frontal lobe (white arrows), is appreciated in the HLHS patients compared with the age-matched controls. In the tissue classification images, the gray matter appears white, the white matter is gray and the cerebrospinal fluid is black.

View larger version (17K): [in this window] [in a new window]   Figure 2. The distribution by age of the global volumes of gray matter (GM, A), white matter (WM, B), and cerebrospinal fluid (CSF, C). The line shows best fitting models for normal controls. For global volume of GM, WM, and CSF, the best fitting models for normal controls were as follows: GM = 718.84 + 89.12 x Z, where Z = In(age/100) + 0.76; WM = 320.49 + 88.59 x Z, where Z = In(age/100) + 0.76; CSF = 122.99 + 8.32 x Z, where Z = In(age/100) + 0.76. Closed circles represent each of the patients with congenital heart diseae.

View larger version (23K): [in this window] [in a new window]   Figure 3. Regional brain volumes in patients with CHD compared with normal control values. The GM and WM volumes are significantly decreased in the frontal lobe (A and C) but not in the temporal lobes (B and D) in the patients with CHD. For GM and WM in the frontal lobe, the best fitting models for normal controls were as follows: GM = 230.60 + 34.85 x Z, where Z = In (age/100) + 0.76; WM, = 93.48 + 26.68 x Z, where Z = In (age/100) + 0.76. For GM and WM in the temporal lobe, the best fitting models for normal controls were as follows: GM = 146.14 + 23.94 x Z, where Z = In (age/100) + 0.76; WM= 46.80 + 13.37 x Z, where Z = In (age/100) + 0.76.

Decreased GM Volume and Multivariate Risk Factor Analysis
Among the variables shown in Table 2 , preoperative oxygen saturation was strongly associated with decreased frontal GM volume in this cohort (P < .01). HLHS and body weight were also associated with decreased frontal GM volume (P < .05). Other variables, such as Apgar score, birth head circumference, age at latest operation, body height, head circumference at study, duration of aortic crossclamp, duration of extracorporeal circulation, duration of intubation, and duration of intensive care unit stay did not correlate with decreased GM volume.

View larger version (10K): [in this window] [in a new window]   Figure 4. Correlation between neurodevelopmental score by Bayley II scale and frontal GM volume in patients with CHD. Frontal GM volume was weakly associated with PDI (P < .01) (B) but not with MDI (A). Frontal GM volume is expressed as ratios to age-matched normal volumes. PDI, Psychomotor developmental index; MDI, mental developmental index.

	Discussion

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Preoperative Hypoxia and Brain Growth
After birth, cerebral blood flow and oxygen delivery are low in infants with complex CHD²¹ and correlate with WM injury. Low diastolic blood pressure is seen in such patients, especially in infants receiving prostaglandin E₁, as well as after systemic–pulmonary shunt operation, and may predispose to WM injury as well as global cerebral ischemia.¹⁹ In our study, the majority of the infants in the critical CHD group were receiving prostaglandin E₁ preoperatively, and the majority of the infants underwent systemic–pulmonary shunt operations. Low diastolic blood pressure coupled with hypoxia may partly affect brain growth in patients with critical CHD in our study. In addition to preoperative hypoxia and hypotension, perioperative factors including cardiac arrest, hyperglycemia or hypoglycemia, and hyperthermia may cause brain damage, but were not evident in our study, in agreement with previous reports.^22,23

In addition, multivariate risk factor analysis showed the age at latest operation did not correlate with decreased GM volume (Table 2). However, the majority of the patients in the critical CHD group had neonatal surgery such as the Norwood operation, and this operation might influence the brain development greatly. Further, although we could not analyze this in the present study because of the small number of patients, the overall length of exposure to lower oxygen saturations might have had an impact on the findings of the MRI study, as well as the developmental testing.

Decreased GM Volume in Infants with CHD
A high incidence of WM injury, including periventricular leukomalacia occurs in neonates with CHD preoperatively and postoperatively^24-27 and is thought to be related to hypoxia/ischemia to immature oligodendroglia in the process of myelination, which are most vulnerable to injury.²⁷ On the contrary, little attention has been paid to GM injury and brain development in infants with CHD until now. This study documents for the first time a reduction in GM volume in infants with CHD, despite no significant reduction in WM volume. During the first 2 years after birth, brain volumes, especially GM, increase rapidly.²⁸ This early growth spurt of the brain is the most prominent growth of any organs in the human body during this period. Further, the increase in GM is greater than in WM and reaches a maximum around 16 to 24 months of age, whereas the WM has a slower growth process throughout childhood. Therefore, if long-lasting hypoxia/ischemia occurs in early infancy, GM would be more affected than WM and would result in a prominent reduction in the GM volume, as our study shows. Inder and associates²⁹ also reported that periventricular WM injury in the premature infant is followed by reduced cerebral cortical GM volume at term.

Underdevelopment of Frontal GM and Delayed Psychomotor Development
Of note, frontal GM volume, which includes the motor area, was positively but weakly associated with PDI score by Bayley II scale in our study. The correlation between the neuroanatomic changes and the neurodevelopmental function could be influenced by a number of factors, including the type of initial surgical intervention, the use of cardiopulmonary bypass, and the perfusion techniques, as well as events related to hemodynamic instability and tendency to hypoxemia in the perioperative period. A neuropathologic study demonstrated that cerebral WM damage was the most significant lesion in 38 infants dying after cardiac surgery, followed by a spectrum of GM lesions,²⁷ predominantly involving the cerebral cortex and hypocampus acutely, and the thalamus and brain stem (including the inferior oliva and basis pontis) more chronically. The common occurrence of injury in the inferior oliva and basis pontis suggests the possibility that dysfunction of cerebellar pathways contributes to the motor disturbances of survivors of cardiac surgery in early infancy. Similarly, underdevelopment of frontal GM, which includes the motor area, may be positively associated with psychomotor developmental delay in infants with critical CHD. Therefore, longer functional assessment should be undertaken, especially in infants with SV physiology, including HLHS, who have long-lasting hypoxia and staged reconstruction until ultimate conversion to Fontan circulation. Another association of structural underdevelopment of the brain, "open operculum," and developmental disabilities of feeding and language are also reported with high incidence in children with complex heart disease.^21,24 Further research is needed to prove whether infants with developmental disabilities may have a structural underdevelopment of the brain as the etiology.

Study Limitations
In infants between 1 and 6 months of age, GM and unmyelinated WM have signal values that are isointense and are indistinguishable from one another. Therefore, when interpreting the results, we need to consider that GM in children under 6 months of age might include both GM and unmyelinated WM. However, in this study, only 2 infants under 6 months of age were enrolled, and they are unlikely to affect the conclusion.

The present study analyzed the volumes of the whole brain, fontal and temporal lobes, and did not analyze regional volumes of cortical subdivisions, such as premotor and sensorimotor regions. Quantitative information on regionally segmented brain volumes can be correlated with neurodevelopmental and behavioral measures to document the association between neuroanatomic development and the behavior repertoire and functional development.³⁰

Our data were also limited by a lack of comparison with 3D-MRI data before surgery, because it was not possible to perform MRIs in most of the infants with critical CHD owing to their unstable general condition. Another limitation to this study is that longer functional assessments and follow-up 3D-MRI studies are not available. A relatively small patient population and variety of diagnostic categories also limit our study.

	Conclusion

Top Abstract Introduction Methods Results Discussion Conclusion References

 
Brain developmental impairments occur in a number of infants with CHD, especially in those who have preoperative hypoxia and critical CHD. In addition, the impact of repeated procedures on patients undergoing staged palliation, as well as the age of initial intervention, could have an important role. A decrease in frontal GM volume, which includes the motor area, was weakly associated with psychomotor developmental delay in infants with critical CHD. This quantitative volumetric study encourages larger scale and longitudinal follow-up to elucidate the significance of impaired neuroanatomic development on functional outcome.

	Acknowledgments

 
We acknowledge Professors Hikaru Seto, Takuro Misaki, Hisao Nishijo, Masayoshi Kurachi, Michio Suzuki, Makoto Nakazawa, and all members of the Japanese Study of Cognitive Function after Open Heart Surgery in Pediatric Patients for their pertinent suggestions and cooperation. We appreciate professors Makiko Osawa and Rumiko Matsuoka for their encouragement. We also thank Neil Bowles, Hiroki Michizu, and Yukimi Hirose for their excellent assistance.

	Footnotes

 
This study was supported by grants from Core Research for Evolutional Science and Technology (Japan Science and Technology Agency) and Japanese Study of Cognitive Function after Open Heart Surgery in Pediatric Patients (Ministry of Health, Labour and Welfare).

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Naoki Yoshimura Yoshihiro Oshima Toshikatsu Yagihara Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Watanabe, K. Articles by Gur, R. C. Search for Related Content PubMed Articles by Watanabe, K. Articles by Gur, R. C. Related Collections Congenital - acyanotic Congenital - cyanotic