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J Neurosurg Pediatr. Author manuscript; available in PMC 2016 September 25. Published in final edited form as: J Neurosurg Pediatr. 2016 September ; 18(3): 306–319. doi:10.3171/2016.2.PEDS15628.

DTI study of Children with Congenital Hydrocephalus: 1 Year Post-Surgical Outcomes

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Francesco T. Mangano, DO1,5, Mekibib Altaye, PhD2,5, Robert C. McKinstry, MD, PhD6,9, Joshua S. Shimony, MD, PhD6,9, Stephanie K. Powell, PhD7,9,10, Jannel M. Phillips, PhD4,5, Holly Barnard, PhD4,5, David D. Limbrick Jr., MD, PhD8,9, Scott K. Holland, PhD3,5, Blaise V. Jones, MD3,5, Jonathon Dodd, PhD7,9,10, Sarah Simpson, BS3, Mercer Deanna, BS8,9, Akila Rajagopal, MS, Sarah Bidwell, MA3, and Weihong Yuan, PhD3,5 1Division

of Pediatric Neurosurgery, Cincinnati Children’s Hospital Medical Center, Cincinnati,

Ohio 2Division

of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio

3Department

of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio

4Division

of Developmental and Behavioral Pediatrics – Psychology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio

5University

of Cincinnati College of Medicine, Cincinnati, Ohio

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6Mallinckrodt

Institute of Radiology, Saint Louis, MO

7Department

of Neurology, Saint Louis, MO

8Department

of Neurological Surgery, Saint Louis, MO

9Washington

University School of Medicine, Saint Louis, MO

10Department

of Psychology, St. Louis Children’s Hospital, St. Louis, MO

Abstract

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Object—To investigate white matter structural abnormalities using diffusion tensor imaging (DTI) in children with hydrocephalus before CSF diversionary surgery (including ventriculoperitoneal shunting and endoscopic third ventriculoscopy) and the course of recovery post-surgery in association with neuropsychological and behavioral outcome. Methods—This was a prospective study that included 54 children with congenital hydrocephalus (21F/33M; age range: 0.03–194.5 months) who underwent surgery and 64 normal controls (30F/ 34M, age range: 0.30–197.75 months). DTI and neurodevelopmental outcome data were collected once in the control group and at pre-surgery, 3-month, and 12-month post-surgery in the patients.

Correspondence should be addressed to: Weihong Yuan, PhD, Pediatric Neuroimaging Research Consortium, Division of Radiology, Cincinnati Childrens Hospital Medical Center, 3333 Burnet Avenue, MLC 5033, Cincinnati, OH 45229, United States, Phone: 1-513-636-2862; Fax: (513) 636-3754; [email protected]. Authors Disclosure Statements No competing financial interest exists for any of the authors.

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DTI measures, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) values were extracted from the genu of corpus callosum (gCC) and the posterior limb of internal capsule (PLIC). Group analysis was performed first cross-sectionally to quantify DTI abnormalities at three time points by comparing the controls and the patients group at the three time points separately. Longitudinal comparisons were conducted pairwise between different time points in patients whose data were acquired at multiple time points. Neurodevelopmental data were collected and analyzed using the Adaptive Behavior Assessment System, Second Edition (ABAS-II) and the Bayley Scales of Infant Development, Third Edition (Bayley-III). Correlation analyses were performed between DTI and behavioral outcomes.

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Results—Significant DTI abnormalities were found in both the gCC (lower FA and higher MD, AD, and RD) and the PLIC (higher FA, lower AD and RD) at pre-surgery. The DTI measures in the gCC remained mostly abnormal at 3-month and 12-month post-surgery. The DTI abnormalities in the PLIC were significant in FA and AD at 3-month post-surgery but did nor persist when tested at 12-month post-surgery. Significant longitudinal DTI changes in the patients were found in the gCC between 3-month and 12-month post-surgery. In the PLIC, trend level longitudinal changes were found between pre-surgery and 3-month post-surgery as well as between 3-month and 12month post-surgery. Significant correlation between DTI and developmental outcome were found at all three time points. Notably, significant correlation was found between DTI in the PLIC at 3month post-surgery and developmental outcome at 12-month pots-surgery.

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Conclusion—Our data showed significant WM abnormality based on DTI in both the gCC and the PLIC in children with congenital hydrocephalus before surgery and the abnormalities persisted in both the gCC and the PLIC at 3-month post-surgery. The DTI values remained significantly abnormal in the gCC at 12-month post-surgery. Longitudinal analysis showed signs of recovery in both WM structures between different time points. Combined with the significant correlation found between DTI and neuropsychological outcome, our study suggests that DTI can serve as a sensitive imaging biomarker for underlying neuroanatomical changes and post-surgical developmental outcome and even as a predictor for future outcomes. Keywords hydrocephalus; DTI; white matter injury; post-surgery; outcome

Introduction

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For children with hydrocephalus, CSF diversionary surgery (including ventriculoperitoneal shunting and endoscopic third ventriculoscopy) is the standard of care that can relieve clinical signs and symptoms of enlarged ventricles and increased intracranial pressure (ICP). Surgery has significantly reduced morbidity and mortality.25 However, despite advances in technology, hydrocephalus remains an incurable lifelong disorder. The rapid post-op reversal of acute clinical symptoms does not correspond to a complete reversal of structural damage in the brain. Accumulating evidence has shown that there is no significant correlation between ventricle volume and neurocognitive outcome.11,30 The neuroanatomical change sustained prior to the surgery may remain or continue to progress, leading to long term behavioral and neuropsychological deficits.32 Data from both human and animal research have suggested that extensive areas of white matter fibers connecting various functionally

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important cortical and subcortical regions are vulnerable targets of injury as the result of ventricular enlargement and increased ICP in hydrocephalus.13,14,17,20,29,33,35

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DTI is an advanced MR imaging technique that uses diffusion properties of water molecules as probes to examine tissue structure, revealing characteristics of its microscopic organization. Anisotropic diffusion properties, as measured by DTI, are strongly influenced by the micro-structural components of WM9 and provide a direct indication of the integrity of these components. Recent neuroimaging studies have shown that DTI can provide imaging biomarkers for hydrocephalus outcome.43 Cross-sectional studies have shown that DTI parameters can differentiate brain structures with hydrocephalus from normal controls in both human and animal studies.16,22,27,30,34,38,40–42,44 Initial longitudinal studies have shown that DTI parameters had variable degrees of tendency to return to a normal range after surgery.2,6,26,36 However, there is also strong evidence from both clinical and experimental studies suggesting that the damage to brain structures suffered before CSF diversion may be irreversible.5,12,13,15,19,29,31,32

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Here we report the results of a prospective, longitudinal neuroimaging study combined with neuropsychological outcome assessment in pediatric patients with hydrocephalus. Data were acquired prior to CSF diversionary surgery, and again at 3-month and 12-month postsurgery. The overall goal of this study was to establish the WM anisotropic diffusion property derived from DTI as a marker for in vivo white matter damage and its course of recovery in children with hydrocephalus. This data allows us to have a better understanding of the variability in the outcomes and provide a non-invasive and quantifiable means to predict these outcomes. The following hypotheses were tested and confirmed: (1) Children with congenital hydrocephalus have abnormal anisotropic diffusion properties in WM prior to surgery; (2) The abnormal diffusion property in WM will recover with trends toward normal range after surgery; and (3) The WM anisotropic diffusion properties correlate significantly with outcome measures. The findings in this study provide a necessary step toward establishing DTI as a significant clinical tool in the management of hydrocephalic patients.

Methods and Material Study Design and Participants

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All participants were enrolled in a federally funded multi-center, prospective, longitudinal imaging study of pediatric hydrocephalus aimed at investigating neuroimaging and neurobehavioral outcomes at baseline prior to surgical management and at 3-month and 12month post-surgery follow-up. Between Dec. 2009 and June 2014, a total of 146 children, including 74 children who were potential surgery candidates for hydrocephalus (age range 0.03–180.8 months) and 72 normal control children (age range 0.56–197.75 months) were recruited from the two participating hospitals, Cincinnati Children’s Hospital Medical Center (CCHMC) and St. Louis Children’s Hospital and Washington University (SLCH/ WashU). Participants’ legal guardians gave written consent when enrolled into the study. Children older than 11 yrs also provided oral assent. The study was conducted according to IRB guidelines at both institutions.

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For children in the hydrocephalus group, the inclusion criteria were as follows: age 0–18 yrs; referral to radiology for brain MRI for evaluation of hydrocephalus and later referral for CSF diversion surgery; hydrocephalus with ventriculomegaly; and no evidence of other medical diagnoses that would be a predisposition to him/her for adverse neurological outcomes (e.g., preterm birth with severe intraventricular hemorrhage, Dandy-Walker Syndrome, stroke, or spina bifida). Among the 74 patients with hydrocephalus, 20 were excluded from the study. Among these 20 patients, 11 were excluded because they did not receive surgical treatment for hydrocephalus, and 7 were excluded for failure to meet inclusion criteria. One family withdrew their consent to participate in the study. One additional child was excluded after being diagnosed with neurofibromatosis type 1. This resulted in a study population of 54 children (21F/33M; age range: 0.03–194.5 month) with congenital hydrocephalus for the final data analysis. Detailed demographic information and etiology are included in Table S1.

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The children in the control group were recruited to match the hydrocephalus group in age and gender as closely as possible. They came from two sources: (1). Pediatric patients who were referred for clinical MRI which was evaluated as normal by clinical neuroradiologists. The inclusion criteria for the children in the control group from this source were: age 0–18 yrs; referral to radiology for non-specific symptoms not clearly related to a neurological disorder (e.g. headaches); diagnosed as having normal MRI; no clinical or radiographic history of neurological or psychological disorders prior to the scan; no evidence of any neurological disorders (e.g., epilepsy, stroke) or suggestion of white matter related brain pathology within three month follow up after the initial MRI, as reviewed with the patient’s medical record. (2). Healthy normal children recruited from the general healthy population. The inclusion criterion for children in the control group from this latter source was similar to those in the former “patient normal” subgroup. The MRI images from these healthy normal controls were acquired under research protocol on the same MRI scanners without sedation. Among the 72 normal participants initially enrolled, 1 child was excluded after the diagnosis of epilepsy. Four children were excluded because of the presence of abnormal MRI findings. Two children were disqualified for having standard scores below 70 in either ABAS-II and/or Bayley-III. One additional child was excluded for poor image quality. This left a normal control population 64 children (30F/34M, age range: 0.30 – 197.75 month) for further analysis.

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Neuroimaging (MRI/DTI) and neuropsychological outcome data were acquired in children with hydrocephalus prior to the CSF diversionary surgery, 3-months post-surgery, and 12month post-surgery. Neuroimaging data and neuropsychological data were acquired only once in children in the control group. Not all participants had data at all the time points, most often due to due to the short window between diagnosis and surgery. In addition, depending on the severity of hydrocephalus, some children’s ventricle enlargement was too severe to allow for reliable delineation of region of interest. The total number of children that generated useful neuroimaging and neuropsychological outcome data are listed in Table 1.

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MRI Acquisition and Preprocessing

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MRI data were all acquired on 1.5 Tesla scanners at either CCHMC (GE Signa, GE Healthcare, Milwaukee, Wisconsin) or SLCH/WashU (Siemens Avanto, Erlangen, Germany). A 15 direction diffusion-weighted spin-echo DTI sequence with single-shot EPI was used with the following specifications: FOV = 240 mm × 240 mm, matrix = 96 × 96, resolution = 2.5 mm × 2.5 mm × 2.5 mm, number of slices =76, TR/TE = 9400/93.2 msec; ASSET or IPAT factor = 2, number of averages = 2, b=1000 s/mm2. One additional image with no diffusion weighting (b=0) was also acquired. The MR compatibility across the two sites (two 1.5T GE Signa scanners from CCHMC and one 1.5T Siemens Avanto from SLCH) was established using both MR phantom (fBIRN phantom) and a traveling human phantom prior to the start of the subject enrollment. The compatibility was tested annually with the same MR phantom and human phantom on all scanners used in the study. In addition, ACR phantoms were also used for quality assurance within a week of subject scan to assure the stability of scanner performance.34,44,45

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Image processing and analysis were all performed using the DTIStudio 3.02 software.28 Head motion and eddy current artifact were corrected using the automatic image registration method39 embedded in the DTIStudio software.28 An automatic bad slice detection method followed by additional visual inspection was performed to identify signal dropout on DWI images. DTI metrics including FA, MD, AD, and RD were calculated using the standard technique.7 Two region of interest (ROI) were examined in this study: genu of corpus callosum (gCC) and posterior limb of internal capsule (PLIC). The two ROIs were delineated based on the approach of Hermoye et al’s work in 200623 as well as in our previous work.2,40,44 It should be noted that, because shunt artifact was seen in post-surgery DTI images from many patients who were treated with adjustable valves (almost always on the right side), a bilateral DTI measurement in PLIC was not always feasible at all three time points. Therefore, DTI data from PLIC were extracted only from left hemisphere in the present study. Ventricle Size Assessment Ventricle size was quantified using the frontal and occipital horn ratio (FOHR)46 in the controls and the participants with hydrocephalus at all three time points. Neuropsychological Outcomes

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The Adaptive Behavior Assessment System, Second Edition (ABAS-II)21 and the Bayley Scales of Infant Development, Third Edition (Bayley-III)8 were included in the present study. Both tests were completed by pediatric neuropsychologists or by psychometrists supervised by pediatric neuropsychologists at either the Division of Developmental and Behavioral Pediatrics at CCHMC or the Department of Psychology at SLCH/WashU. The ABAS-II is a caregiver report form of adaptive skills comprised of an overall adaptive score, the General Adaptive Composite (GAC), and three subscales assessing Conceptual, Social, and Practical skills. It also includes a subtest assessing motor skills. The Bayley-III is a direct assessment tool that measures early developmental skills assessing Cognitive, Language, and Motor skills for patients between 0.5 to 42 months of age. The Bayley-III also includes a caregiver report measure of early social-emotional behavior. J Neurosurg Pediatr. Author manuscript; available in PMC 2016 September 25.

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Statistical Analysis

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The developmental change in WM and DTI measures could significantly confound the results in the present study. Therefore, all the statistical analyses of DTI measures were corrected for age in the present study. We performed a regression analysis at each ROI for every DTI measure to remove the potential confounding effect of age. The residual values of the regression, defined as the difference between the actual DTI value from individual participant and the simulated normal DTI value at the corresponding age based on the regression, were then used to substitute for the raw DTI values in the subsequent analysis. The group differences of DTI between patients and controls were first tested crosssectionally before surgery, 3-month post-surgery, and 12-month post-surgery separately using independent two-tailed unpaired t-test. The false discovery rate (FDR) method was applied at each time point to correct for potential false positive findings resulted from multiple comparisons of DTI measures and ROIs. Longitudinal comparisons of DTI abnormalities were tested between each pair of the three time points using paired t-test in children with hydrocephalus who had longitudinal data at the corresponding time points. Pearson correlation analysis was performed to test the association between DTI and neuropsychological outcome assessed at the same time and between DTI at 3-month postsurgery and neuropsychological outcome assessed at 12-month post-surgery. Due to the limitation in sample size in the longitudinal comparisons and correlation analyses, the statistical significance was reported without correction for multiple comparisons in these analyses.

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Ventricle size and Correlation with DTI measures and Neuropsychologial Outcomes at Presurgery, 3-month and 12-month Post-surgery The ventricle size based on FOHR in the control group ranged from 0.197 to 0.375 (Mean ±SD = 0.310±0.036). Compared to the controls, patients with hydrocephalus had significantly larger FOHR at pre-surgery (range = 0.331–0.777, Mean±SD = 0.555±0.102, p

Diffusion tensor imaging study of pediatric patients with congenital hydrocephalus: 1-year postsurgical outcomes.

OBJECTIVE The purpose of this study was to investigate white matter (WM) structural abnormalities using diffusion tensor imaging (DTI) in children wit...
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