Abnormal brain development in neonates with congenital heart disease: evaluation with quantitative magnetic resonance spectroscopy

Transcription

1 Abnormal brain development in neonates with congenital heart disease: evaluation with quantitative magnetic resonance spectroscopy Poster No.: B-1079 Congress: ECR 2015 Type: Scientific Paper Authors: R. A. Elshafey, M. Awny, A. Elmashad, M. Nassar; Tanta/EG Keywords: CNS, MR-Spectroscopy, Diagnostic procedure, Congenital DOI: /ecr2015/B-1079 Any information contained in this pdf file is automatically generated from digital material submitted to EPOS by third parties in the form of scientific presentations. References to any names, marks, products, or services of third parties or hypertext links to thirdparty sites or information are provided solely as a convenience to you and do not in any way constitute or imply ECR's endorsement, sponsorship or recommendation of the third party, information, product or service. ECR is not responsible for the content of these pages and does not make any representations regarding the content or accuracy of material in this file. As per copyright regulations, any unauthorised use of the material or parts thereof as well as commercial reproduction or multiple distribution by any traditional or electronically based reproduction/publication method ist strictly prohibited. You agree to defend, indemnify, and hold ECR harmless from and against any and all claims, damages, costs, and expenses, including attorneys' fees, arising from or related to your use of these pages. Please note: Links to movies, ppt slideshows and any other multimedia files are not available in the pdf version of presentations. Page 1 of 31

2 Purpose Congenital heart disease (CHD) is a common cause of childhood morbidity, occurring in 6 to 8/1000 live births, with up to 50% of these children requiring open heart surgery to (1) correct their defects. (2) Brain injuries occur with high frequency in newborns with CHD. Neurodevelopmental impairment after surgical repair of CHD is a major problem, with global developmental delay or severe neurologic deficits occurring in 23% to 60% of (3) surviving infants. The timing of and mechanisms underlying neurodevelopmental deficits in children with CHD are multifactorial. Hypothesized aetiologies include disturbances in brain metabolic function, brain injury, and abnormal brain development in addition to associated genetic (4) conditions. Today it is necessary to wait 8 years or more to fully assess which newborns have the sequelae of acquired brain injury early in life because the full extent of neuropsychological (5) challenges do not become apparent well until into school age. Magnetic resonance imaging (MRI) is a powerful tool for detecting subacute brain injury (6) in the newborn. Advanced MRI techniques, such as proton magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI), now provide an unprecedented window into neonatal brain development in vivo. MRS provides an in vivo quantitative measure of brain biochemistry (7, 8) that can be performed sequentially Morphologic MR imaging scores combined with either proton 1 H spectroscopic measurements or apparent diffusion coefficients (ADCs) in the basal ganglia obtained during the 1st week of life showed a significantly better association between lactate/n -acetylaspartate ratio with neurodevelopmental outcome in term infants with hypoxic-ischemic encephalopathy following perinatal asphyxia (9,10, 11) The aim of this work is to assess abnormal brain development in newborns with cyanotic and acyanotic CHD using MR spectroscopy and then correlate the MRS results with neurologic and developmental status at age 12 months and thus enhance quality of care and life. Page 2 of 31

3 Page 3 of 31

4 Methods and materials The study was approved by Research Ethics Committee (REC) of our hospital and a written informed consent was obtained from all parents of the patients prior to study entry. The present study included 40 consecutive fullterm neonates (17 male and 23 female) suffered from congenital heart disease referred to the Department of radiodiagnosis from neonatologyy unit of pediatric Department prospectively, 10 healthy fullterm neonates were included as control group. Inclusion criteria: patients suffering from congenital heart diseases diagnosed by echocardiography at birth. Exclusion criteria: 1- Preterm. 2-Factors that would independently affect brain maturity and MRI findings, such as: a- Intrauterine growth retardation b-history of perinatal depression, or c-asphyxia at birth. 3- Have any contraindication for sedation OR MRI and MRS Control group:ten fullerm healthy neonates were included as control subjects. They fulfilled the following criteria: - No maternal illness. - No signs of fetal distress. - Apgar score at 5 min >7.0. All patients and control group subjected to the following: 1- Complete antenatal, natal and postnatal history. 2- Gestational age assessment. 3- Apgar score assessment. 4- Complete clinical and neurological examination. Page 4 of 31

5 including neonal illness severeity scores (12). 5- Routine laboratory investigations: - Arterial blood gases analysis. 6- Echocardiography. 7- Electroencephalography (EEG). 8- Radiological investigation: -Magnetic Resonance imaging (MRI). -MR spectroscopic imaging (MRS) MRI studies were performed as soon as the baby could be safely transported to the MRI scanner. All neonates were protected by a Perspex pod. Throughout the examination, neonates were supervised by an experienced neonatal pediatrician. Pure oxygen breathing was maintained in neonates throughout the scanning procedure to ensure the security of the neonate during MR examination. All MR imaging and 1HMRS studies were performed using a 1.5 T system (Signa; GE Medical Systems, Milwauee, WI, USA) with a quadrature head coil. Routine MRI sequences: Routine axial spin echo T2-weighted images (repetition time [TR] 2000 ms, echo time [TE] 20/ 100 ms; matrix size 256x256; field of view [FOV] 240 mm; slices thickness 5 mm), FLAIR(TR 8000 ms, TE 50/ 158 ms; matrix size 256x 256; FOV 240 mm; slice thickness 5 mm, inversion time, 2200 ms). Axial T1-weighted MR images (TR = 600 ms, TE = 10 ms, axial slices 5 mm) were obtained in the axial, coronal and sagittal planes Three-Dimensional MRS imaging: Optimal water resonance suppression was achieved. The parameters used were 2000/270, 192 acquisitions, a spectral width of 2500 Hz, and 2048 data points for all patients. In all patients, MR spectra were obtained with a TE of 144 with additional TE 35. The acquisition time for each sequence was 4 min 54 s. The areas of interest in all neonates were the basal ganglia, thalamus, frontal and occipital lobes. Basal ganglia and thalami are most sensitive to the effects of asphyxia. Metabolites of biologic importance, such as N- Acetylaspartate (NAA), Choline (Cho), Creatine (Cr), and Lactate (Lac), were detected by this technique Page 5 of 31

6 Ratios of NAA/ Ch, lactate/naa, Ch/Cr and lactate/ch were calculated bilaterally for each voxel. The data were processed at workstation (Sun workstation (Sun Microsystems, Mountain View, CA using 4.6 ready view software package) MRS staging of brain asphyxia with CHD according to Lact/Ch ratio into three groups: - Group I (mild) -> the value of Lac/Ch lesser than Group II (moderate)-> the value of Lac/Ch between 0.15 and Group III (severe)-> the value of Lac/Ch greater than 0.3. Neuroldevelopmental examination: Out of 40 cases, 26 cases followed up clinically at 1 year old, as 5 died before the examination, 9 lost to follow up. At 12 month old neurologic and developmental status was examined by pediatric neurologist who was blinded to the results of the imaging studies and to the neonatal course of the infants Using the neuromotor scoring system, In addition, neurodevelopment was assessed by administering the Mental Developmental Index (MDI) of the Bayley Scales of Infant Development II (BSID) with MRI &MRS results. (13) Then correlate the results The imaging data were reviewed by two radiologists (with more than five years of experience) blinded of the patients clinical pictures; and then they nearly reached a consensus opinion. Statistical Analysis: Statistical presentation and analysis of the present study was conducted, using the mean and standard deviation by SPSS V.16.. Analysis of variance [ANOVA] tests and Tukey's test was used to determine the significance between groups: According to the computer program SPSS for Windows. ANOVA test was used for comparison among different times in the same group in quantitative data. P value < 0.05 was considered significant. Correlations were made among MRS results and neuromotor scores by using the Spearman rank correlation test. Page 6 of 31

7 Results The present study included forty neonates with congenital heart diseases (cyanotic HD (n=20), acyanotic HD (n=20) with ten healthy neonates as control group. The 40 neonates enrolled in this study had various forms of CHD were discussed in table 1. The conventional MRI of the studied groups revealed that 29 neonates had normal MRI(CHD (n=19) and control group (n=10)), atrophy, watershed infarctions and periventricular leukomalacia (PVL) were the most observed findings (table 2). The most consistently noted abnormality on the spectra of the patients was the presence of a variably sized lactate doublet centered at 1.31 ppm especially at short TE sequence that may be inverted at a intermediate TE sequence. Evidence of direct relation with positive correlation between the amount of lactate and neuromotor scores. This is can be achieved by correlation between Lact/Ch & Lact/NAA ratios and neuromootor scores at 12 months of age (P< for each, r= and respectively). And also was significantly higher in cyanotic patients compared to acyanotic and controls (table 4, 6) The area under the NAA peaks was decreased in some patients who subsequently had neurodevelopmental impairment, and the mean ratio of NAA/Ch, was significantly lower with negative correlation in newborns with CHD. And also was significantly lower in cyanotic patients compared to acyanotic and controls (P 0.03, r ) (Table 4, 5). Significant correlation between Lact/NAA and NAA/Ch across all studied segments of the brain except for calcarine cortex revealed insignificance (P 0.09 & 0.1 respectively) (table 5,6) Insignificant positive correlation between neurodevelopmental outcome with Cho/Cr was observed (P 0.07) (table 4). Cases: Case 1 : 8 days old neonate with ASD Figure 1 : normal MRI findings (apart from small right occipital subgalial haematoma) are noted which is evident by Low SI in the perirolandic cortex (red arrow). The central WM is of slightly lower SI (blue arrow) than the more frontal and posterior WM consistent with the onset of myelination. (fig 2) Posterior limb of internal capsule has a small region of low SI (blue arrow), the globus pallidus is of intermediate to high SI (red arrow) but the posterior putamen and the ventro-lateral nucleus of the thalamus are of low SI. With small hyperintense SI in posterior periventricular WM. Page 7 of 31

8 1 (fig 3)Multivoxel 3 D HMRS picture, (fig 4) intermediate TE MRS spectrum, (fig 5) short TE MRS spectrum at the basal ganglia and thalami reveal mild decreased peaks of NAA and increased Cho, lactate peaks with mild elevation of Lact/NAA and Lact/Ch ratios and decreased NAA/Ch ratio. The overall pictures are consistent with mild brain asphyxia. Case 2 : 6 days old neonate with TGA with RV hypoplasia Figue 6,7:axial and sag. T2 WI reveal variable hypointense SI in cortex, basal ganglia and thalami (fig 8,9): axial T1 WI reveal curvilinear hyperintense SI in cortical gray matter and deep gray matter nuclei (effect of accumulation of denaturated protein from dying cells) with poor myelination evident by decreased hyperintense SI signal intensity of the posterior limb of internal capsule. Diffuse white matter displaying T1 hypointensity and T2 hyperintensity due to ischaemiainduced edema. (fig 10): diffusion WI reveal restricted diffusion of white matter cytotoxic oedema. 1 (fig 11,12,13): Multivoxel 3 D HMRS picture, intermediate TE MRS spectrum, short TE MRS spectrum at the basal ganglia and thalami reveal marked decreased peaks of NAA and increased Cho, lactate peaks with marked elevation of Lact/NAA and Lact/Ch ratios and decreased NAA/Ch ratio. The overall pictures are consistent with marked brain asphyxia. Page 8 of 31

9 Images for this section: Fig. 1: axial T2 MRI Page 9 of 31

10 Fig. 7: MRI sag. T2 WI Page 10 of 31

11 Fig. 8: MRI axial T1 WI Page 11 of 31

12 Fig. 9: MRI axial T1 WI Page 12 of 31

13 Fig. 10: MRI diffusion WI Page 13 of 31

14 Fig. 11: Multivoxel 3D 1HMRS picture Page 14 of 31

15 Fig. 2: MRI axial T2 WI Page 15 of 31

16 Fig. 3: Multivoxel 3D 1HMRS picture Page 16 of 31

17 Fig. 4: intermediate TE 1HMRS sepectrum Page 17 of 31

18 Fig. 5: short TE 1HMRS sepectrum Page 18 of 31

19 Fig. 12: intermediate TE MRS spectrum Page 19 of 31

20 Fig. 13: short TE MRS spectrum Page 20 of 31

21 Table 1: clinical diagnosis of 40 neonates with CHD Page 21 of 31

22 Table 2: MRI results of the studied cases Page 22 of 31

23 Table 3: neurodevelopmental outcome at 1 year of age Table 4: Correlation of MRS ratios with neuromotor scores at 1 year of age Page 23 of 31

24 Table 5: NAA/Ch metabolite ratio across various brain regions for the studied groups Table 6: Lact/NAA metabolite ratio across various brain regions for the studied groups Page 24 of 31

25 Table 7: Lact/Ch metabolite ratio across various brain regions for the studied groups Fig. 6: MRI axial T2 WI Page 25 of 31

26 Page 26 of 31

27 Conclusion Patients with congenital heart disease (CHD) are at high risk for adverse neurodevelopmental outcomes (1, 3). The majority of children with CHD today will survive, many will have impaired neurodevelopmental outcome across a wide spectrum of domains. They suffer widespread deficits in cognition, including memory, attention, and higher-order language skills, and fine-motor skills (1, 3, 14). The recent application of pre- and post-operative MRI in newborns with CHD, a number of preventable mechanisms for strokes in these high-risk newborns have been identified (5). Given that the timing and mechanism of brain injury in newborns with CHD can now be identified, these infants can be studied to evaluate emerging strategies of brain protection (15). So we aimed in this study to assess abnormal brain development in newborns with CHD using MR spectroscopy and then correlate the MRS results with neurologic and developmental status at age 12 months. This study reveal strong significant correlation between MRS criteria and neurodevelopmental outcome at age 1 year, this is consistent with the result (2) of Dimitropoulos et al who aimed to determine the relationship between radiologically identifiable brain injuries and delayed brain development as reflected by brain metabolic and microstructural integrity. Our findings result that the presence of lactate with increase Lact/Ch and Lact/NAA ratios in the fullterm neonate has strong positive significant correlation with brain asphyxia and indicate poor diagnostic sign, and this support those of Abdel Raheem and Mohamed & Shedeed and Elfaytouri (6) (15). The mean ratio of NAA/Ch, was significantly lower with negative correlation in newborns with CHD. And also was significantly lower in cyanotic patients compared to acyanotic and controls (P 0.03, r ) while Ch/Cr ratio reveal insignificant results (P 0.07) this is concurs with the results of Shedeed, Elfaytouri (15). conclusion Proton MRS is a valuable tool in the assessment of neonates with congenital heart disease. Page 27 of 31

28 Neurodevelopmental monitoring is highly recommended for infants and children with congenital heart disease and suggested brain asphyxia by MRS, to provide more information about the risk factors, will clarify the degree to which they can compensate for their deficits, increase the knowledge base upon which treatment decisions are made, about when to begin preventive measures, when to start early intervention programmes which improve children's development and whether our findings have clinical importance for later academic achievement. limitation: One important limitation in our study is the lack of respecting follow up by the parents, Other limitation was the short time study and relative low number of the patients among subgroups of CHD diagnoses. The last limitation is that data from the current study were used to obtain thresholds for abnormality. This could have led to an overestimation of performance of the reported measures. Recommendation: We recommend to do brain MRI &MRS to all neonates with CHD to improve their care and quality of life. We also recommend other Longstanding study using diffusion tensor imaging and MRS as double cohort study. Page 28 of 31

29 Personal information Dr/ Rasha Ahmed Elshafey,MD assisstant professor of radiodiagnosis, Tanta university hospital, Egypt Page 29 of 31

30 References 1- Miller SP, McQuillen PS, Hamrick S, et al. Abnormal brain development in newborns with congenital heart disease. N Engl J Med. 2007; 357: Dimitropoulos A, McQuillen PS, Sethi V, et al. Brain injury and development in newborns with critical congenital heart disease. Neurology 2013;81(3): Michael JH, Scallan FRCA. Brain injury in children with congenital heart disease. Pediatr Anaesth. 2010; 13: Ransom J, Srivastava D. The genetics of cardiac birth defects. Semin Cell Dev Biol. 2007; 18: McQuillen PS, Hamrick SE, Perez MJ, et al. Balloon atrial septostomy is associated with preoperative stroke in neonates with transposition of thegreat arteries. circulation. 2006; 113: Abdel Raheem MM, Mohamed WA. Impact of congenital heart disease on brain development in newborn infants. Annals of Pediatric Cardiology 2012;5(1): Barkovich, A.J, Hajnal, B.L, Vigneron, D et al. Prediction of neuromotor outcome in perinatal asphyxia (evaluation of MR scoring systems). AJNR Am J Neuroradiol. 1998;19: Barkovich, A.J, Westmark, K.D, Bedi, H.S, et al. Proton spectroscopy and diffusion imaging on the first day of life after perinatal asphyxia (preliminary report). AJNR Am J Neuroradiol. 2001; 22: Thomas Alderliesten, Linda S. de Vries, Manon J. N. L. Benders, et al. MR Imaging and Outcome of Term Neonates with Perinatal Asphyxia: Value of Diffusion-weighted MR Imaging and H MR Spectroscopy Radiology :1, Kreis R, Hofmann L, Kuhlmann B, et al. Brain metabolite composition during early human brain development as measured by quantitative in vivo 1H magnetic resonance spectroscopy. Magn Reson Med 2002;48: von Rhein M, Scheer I, Loenneker T, et al. Structural brain lesions in adolescents with congenital heart disease. J Pediatr 2011;158: Dorling JS, Field DJ, Manktelow B. Neonatal disease severity scoring systems. Arch Dis Child Fetal Neonatal Ed. 2005;90:F Bayley N. The Bayley Scales of Infant Development II. New York: New York Psychological Corporation 1993; Page 30 of 31

31 14- Dittrich H, Bührer C, Grimmer I, et al. Neurodevelopment at 1 year of age in infants with congenital heart disease.heart 2003;89(4): Shedeed SA, Elfaytouri E. Brain maturity and brain injury in newborns with cyanotic congenital heart disease. Pediatr Cardiol 2011;32: Scherlock RL, McQuillen PS, Miller SP. Preventing brain injury in newborns with congenital heart disease. Brain imaging and innovative trial designs. Stroke. 2009; 40: Page 31 of 31