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Abnormal cerebral MRI findings and neuroimpairments in very low birth weight (VLBW) adolescents
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Official Journal of the European Paediatric Neurology Society
Original article
Abnormal cerebral MRI findings and neuroimpairments in very low birth weight (VLBW) adolescents Jon Skranesa,d,f,, Karianne Indredavik Evensena, Gro C. Løhaugena,f, Marit Martinussene, Siri Kulsenga,d, Gunnar Myhrb, Torstein Vikc, Ann–Mari Brubakka,d a Department of Laboratory Medicine, Children’s and Women’s Health, Norwegian University of Science and Technology, Kvinne/barnsenteret, Olav Kyrres gt. 11, N-7489 Trondheim, Norway b Department of Circulation and Imaging, Norwegian University of Science and Technology, Trondheim, Norway c Department of Community Medicine and General Practice, Norwegian University of Science and Technology, Trondheim, Norway d Department of Pediatrics, St. Olav’s University Hospital, Trondheim, Norway e Department of Gynaecology, St. Olav’s University Hospital, Trondheim, Norway f Department of Pediatrics, Sørlandet Hospital, Arendal, Norway
art i cle info
ab st rac t
Article history:
Background: High prevalence of abnormal cerebral MRI findings as well as major and
Received 18 May 2007
minor motor, perceptual and cognitive impairments has been reported in very low birth
Received in revised form
weight (VLBW) children.
6 August 2007
Aim: To investigate whether cerebral MRI pathology relates to different types of
Accepted 21 August 2007
neuroimpairments in adolescents with VLBW.
Methods: At age 15, 55 adolescents with birth weight p1500 g (VLBW) were examined. Keywords:
Motor function was evaluated by Movement Assessment Battery for Children (ABC) and the
Cerebral MRI
Grooved Pegboard (GP) test, cognitive function by Wechsler Intelligence Scales, and visuo-
VLBW
motor and visual perceptual function by The Developmental Test of Visual-Motor
Adolescence
Integration (VMI) with the supplementary tests of Visual Perception (VP), and Motor
Brain
Coordination (MC). Executive functions were assessed by Wisconsin Card Sorting Test
Neuroimpairments
(WCST) and the Stroop test. Cerebral MRI was assessed semi-quantitatively for ventricular,
CP
white and grey matter pathology.
Results: There was a rather weak relationship between MRI pathology and neuroimpairments. Poor performance on the WCST was related with ventricular dilatation (VD), white matter reduction and corpus callosum thinning. There was a correlation between results on the VMI test and the Movement ABC test and MRI pathology, but the correlation became much weaker when children with cerebral palsy were excluded. There was no relationship between MRI findings and estimated intelligence quotient (IQ) scores. Normal MRI predicted normal or near normal neuropsychological functioning.
Conclusion: Cerebral MRI pathology suggestive of perinatal white matter injury was related to disadvantages in performances on executive functions, to a lesser degree to motor and visual perceptual problems, but not to cognitive impairments in VLBW adolescents. & 2007 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Corresponding author. Department of Laboratory Medicine, Children’s and Women’s Health, Norwegian University of Science and Technology, Kvinne/barnsenteret, Olav Kyrres gt. 11, N-7489 Trondheim, Norway. Tel.: +47 99 39 02 85; fax: +47 72 57 38 01. E-mail address: [email protected] (J. Skranes). 1090-3798/$ - see front matter & 2007 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpn.2007.08.008
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1.
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Introduction
Very low birth weight (VLBW: birth weight p1500 g) children are at increased risk of perinatal brain injury such as periventricular haemorrhages and leukomalacia (PVL). Deep white matter adjacent to the lateral ventricles is vulnerable to injury caused by perinatal infection, nutritional deficits and hypotension with hypoxia-ischemia.1 Correlates to PVL seen on cerebral MRI are dilated occipital horns of lateral ventricles, atrophy of the peritrigonal white matter, periventricular hyperintensity areas, and thinning of corpus callosum.2–8 Several reports have confirmed that MRI pathology persist into adolescence and adulthood.9–12 In the actual study population of VLBW children, we have already published clinical test results on mental health, executive function, motor abilities and also separate cerebral MRI findings compared with an age-matched control group.12,13–15 In addition the relationship between cerebral MRI findings and mental health has been reported.16 Although more sophisticated and quantitative MR techniques may visualize more subtle white matter changes, conventional MRI is still the major image modality used in the clinics. It is therefore of interest to use this modality in comparing with clinical outcome measurements in neonatal high risk patients like VLBW children. The aim of the present study was to compare MRI findings in early adolescence with motor and neuropsychological evaluations in VLBW survivors. We wanted to investigate whether the VLBW adolescents with specific MRI abnormalities had inferior performance on the clinical tests compared with those without such MRI findings.
2.
Materials and methods
2.1.
Study population
The present study is part of a follow-up study of a geographically based 3-year birth cohort of VLBW adolescents born in 1986–1988. The assessments were performed between November 2000 and October 2002 when the children were 14–15 years of age.
2.2.
VLBW adolescents
VLBW was defined as birth weight p1500 g. In 1986–88, 121 children were admitted to the NICU at the University Hospital in Trondheim. At follow-up 33 had died, one child with trisomy 21 was excluded, and six had moved. Of the remaining 81, 55 (67.9%, 28 boys and 27 girls) met for motor and neuropsychological assessment and cerebral MRI examination.
2.3.
Non-participants
There were no differences in mothers’ age at childbirth, duration of pregnancy, or the infants’ birth weight, body length and head circumference between those who participated and those who did not consent to participation.
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2.4.
Methods
2.4.1.
Assessment of motor functions
The Movement assessment battery for children (Movement ABC) was used for motor evaluation and consists of eight items grouped as three subscores: manual dexterity, ball skills, and static/dynamic balance.17 Each item is scored from 0 (optimal score) to 5 (lowest performance). The highest age band, designed for 11–12-year-old children, was used. According to the manual scores ofifth centile is indicative of definite motor problems, and as the study population was examined at age 14, we used the fifth centile derived from an agematched control group as a measure of motor impairment. In fact, the fifth centile of the M-ABC test score in the control group was similar to the fifth centile of the manual.14 The Grooved Pegboard (GP) test requires manual dexterity.18 The adolescent is instructed to insert, successively and as quickly as possible, 25 pegs in the keyhole-shaped holes, ordered in a 5 5 matrix and pointing in different directions. The task was performed both with the writing hand and with the non-writing hand. The scores were the times (s) used to complete each task. Adolescents with CP who did not manage to finish the task within the time limit were assigned a score three SD above the mean of an age-matched control group. Poor performance was defined as any value one SD or more above (i.e., longer than) the mean time of the controls.19
2.4.2. Assessment of visuo-motor and visual perceptual functions The Developmental Test of Visual-Motor Integration (VMI–IV) consists of 27 geometric designs in increasing order of difficulty that has to be copied. No time limit is imposed. The supplementary task Visual Perception (VP) requires the subject to identify depictions of the designs that he/she had copied earlier. The supplementary task Motor Coordination (MC) requires the subject to trace the same designs with a pencil without leaving double-lined paths in which the designs are presented for the occasion. Time limits to complete the supplementary tasks are 3 and 5 min, respectively. Correctness of the performances was judged according to the manual.20 The number of correct performances was scored. Adolescents who did not manage to complete the tests within time limit because of cerebral palsy were assigned a score (i.e., the largest number of errors) three SD from the mean of the control group. Poor performance was defined as a minor perceptual impairment if the result value was between one SD and two SD from the mean of the control group, and as a major perceptual impairment if the result value was more than two SD from the mean of the control group.19
2.4.3.
Assessment of cognitive functions
An estimate of the adolescents’ intelligence quotient (IQest) was calculated using four subtests of Wechsler Intelligence Scales (WISC-III).21 The four subtests were Arithmetic, Vocabulary, Block design and Picture arrangement.22 Ageadjusted scaled scores and raw scores were used. Cognitive impairment was defined as total IQest score below one SD (IQesto79) of the mean of the controls (mean IQest ¼ 95), but
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higher than a score of 70.19 Mental retardation was defined as total IQest score of 70 or less.
2.4.4.
Assessment of executive functions
Assessment with the The Wisconsin Card Sorting Test (WCST), Research Edition, version 3 for Windows was performed to assess the problem-solving and cognitive flexibility aspects of executive functions.22–24 The subject is told to sort 128 cards with designs of geometrical figures that differ according to the categories colour, shape or number, but she/he is not told that the rules for sorting differ according to the categories colour, shape or number. The rule for sorting varies periodically. The subject has to derive the sorting rule from the feedback following every sorting. After 10 correct responses, a set is considered to be installed and the sorting rule is changed. The total number of correct responses, trials to complete the first category, errors of perseveration (a sorting response according to the previous sorting rule) and non-perseveration errors (all other errors) were counted. Executive function impairment was defined as WCST non-perseverative errors score one SD or more from the mean of the control group.19 The Stroop Colour-Word test (Stroop, 1935, modified by Das and Naglieri, 1989) was been used to assess selective attention. It requires inhibition of an automatic reaction to the advantage of a non-automatic one.25 The test consists of three tasks that have to be performed as quickly as possible. In the first the subject reads aloud four colour names written in black. In the second she/he names rectangles printed in the same colours. Finally, in the interference task, she/he names the colours of the ink in which colour names are presented (e.g., the word green printed in yellow colour). Time (s) to complete each of the three tasks was recorded and errors made in the interference task were counted. Interference times were calculated by subtracting time of both baseline tasks from the time of the interference task.
2.4.5.
Cerebral MRI assessment
Cerebral MRI was performed on a 1.5 T Siemens system, which included sagittal T1-weighted spin echo images (TR
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500 ms, TE 14 ms, 19 slices, 5 mm thickness), axial proton density weighted (TR 2800, TE 13 ms) and axial T2-weighted SE images (TR 2800, TE 117 ms) and inversion recovery T1weighted (TR 7000 ms, TI 500 ms, TE 65 ms) series. Two experienced radiologists blinded to the neonatal histories, earlier MRI results and to the results of the assessments of clinical function, studied the MRI examinations independently and thereafter in consensus if disagreement. Images were semi-quantitatively assessed; size of ventricles, degree of white matter reduction, degree of corpus callosum thinning, white matter gliosis and grey matter abnormalities were recorded and scored according to a standardized registration form with 67 items (Appendix). Complete agreement in the evaluations by the two radiologists was found in 86 cases (71.1%), in 35 cases there was minor disagreement and then a third consensus evaluation was done. The scoring was done as a modification of a classification system developed and used by Inder and colleagues for classifying perinatal MRI findings in term infants.1,26 This classification was used since MRI pathology among VLBW children has a perinatal origin.27 The MRI findings were graded into normal (modification of Inder grade 1), mild (modification of Inder grade 2), moderate and severe (modification of Inder grade 3) abnormalities (Table 1). Criteria for ventricular dilatation (VD) included focal or localized dilatation of the lateral ventricles, as well as angulations of the occipital horns as a mild abnormality. Mild diffuse dilatation was also registered as a mild abnormality. White matter reduction was graded as mild if unilateral reduction of periventricular white matter, moderate if bilateral reduction. Criteria for thinning of corpus callosum included focal thinning as mild and mild to moderate diffuse thinning as moderate abnormality. The images were compared with normal mature corpus callosum of the age group.28 Gliosis was recorded as no gliosis (normal), focal periventricular gliosis (mild), diffuse periventricular (moderate) and combined periventricular and subcortical (severe abnormality). Cortical grey matter abnormalities was graded as normal, unilateral (mild), bilateral (moderate) and extensive (severe abnormality). This grading was subsequently dichotomized between normal and abnormal (mild/moderate/severe abnormality)
Table 1 – Classification of the MRI findings in the study population
Normal Mild abnormality
Moderate abnormality Severe abnormality
Ventr. Dilat. (VD)
Wm reduct. (WMR)
Corp. call. thinning (CCT)
Gliosis
Gm abnorm. (GMA)
No VD Unilat. or bilat.focal dilatation (occipital, nonoccipital) Unilat. or bilat. mild diffuse dilatation Moderate diffuse dilatation
No WMR Unilateral reduction of periventricular wm
No CCT Focal thinning (posterior part, other parts)
No gliosis Focal periventricular gliosis
No GMA Unilateral GMA
Bilateral reduction of periventricular wm Severe loss of white matter
Mild/moderate diffuse thinning Severe diffuse thinning
Diffuse periventricular gliosis Diffuse periventricular and subcortical gliosis
Bilateral GMA Extensive GMA
Severe diffuse dilatation
Abbreviations: Ventr. Dilat. (VD): ventricular dilatation; Wm reduct. (WMR): white matter reduction; Corp. call. thinning (CCT): thinning of corpus callosum; Gm abnorm. (GMA): cortical grey matter abnormalities.
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results. Any pathology of cerebellum, basal ganglia and thalamus was also registered. A VD score was registered with the score 1 ¼ no dilatation, score 2 ¼ mild abnormality, score 3 ¼ moderate abnormality; and score 4 ¼ severe abnormality. A white matter reduction (WMR) score was registered in the same way. An abnormality score (AS) was defined as the sum of the following MRI findings: Ventricular dilatation (no: 0, yes: 1), white matter reduction (no: 0, yes: 1), corpus callosum thinning (no: 0, yes: 1) and gliosis (no: 0, yes: 1). AS ¼ 0 meant no pathology, while AS ¼ 4 indicated all four types of pathology. The AS for each child and the mean score for the separate groups were calculated.
2.4.6.
Ethics
The Regional Committee for Medical Research Ethics approved the study protocol. Written informed consent was obtained from both adolescents and parents.
2.4.7.
Statistical analysis
Data were analysed by using SPSS version 13.0 for Windows. Group differences were analysed using non-parametric tests (Kruskal–Wallis with Mann–Whitney U-test post hoc). Differences were considered statistically significant if pp0.05, two tailed. A clinical score more than 1 standard deviation (SD) from the mean score of an age-matched control group was defined as an impairment. Odds ratios (OR) with 95% confidence interval (CI) were calculated and used as an estimate of the relative risk of neuroimpairments in the adolescents with and without different MRI abnormalities. Nonparametric correlations by Spearman’s rho were calculated between different MR abnormality scores and the clinical test scores.
3.
Results
Group characteristics, number of major and minor neuroimpairments and MR pathology are listed in Table 2.
3.1.
Group characteristics
There were no adolescent with major impairments in hearing or vision that could have interfered with task performance. Cerebral MRI was performed in 55 VLBW adolescents, while psychometric testing was done in 54 adolescents.
3.2.
Table 2 – Child characteristics, number of major and minor neuroimpairments and MRI pathology in 55 VLBW adolescents Child characteristics Birth weight (g) Gestational age (weeks) Gender (boys/girls) Age at clinical assessment (years) Age at MRI examination (years) Mothers’ education (years)
Mean (SD) 1189 (244) 29.0 (2.7) 28/27 14.2 (0.3) 15.0 (0.6) 13.2 (3.3)
Major neuroimpairment Cerebral palsy Mental retardation Visuo-motor Visual perceptual (VP)
No (%) 6 (11.0) 16 (29.6) 2 (3.7) 10 (18.5)
Minor neuroimpairment Gross motor Fine motor Visuo-motor Visual perceptual (VP) Motor coordination (MC) Cognitive Executive
No (%) 8 (14.8) 3 (5.6) 12 (22.2) 5 (9.3) 16 (29.6) 9 (16.7) 9 (16.7)
MRI pathology Dilated ventricles Corpus callosum pathology Reduced white matter tissue Gliosis Abnormality score 0 (normal MRI) Abnormality scores 1–2 Abnormality scores 3–4
No (%) 45 (81.8) 26 (47.3) 29 (52.7) 16 (29.1) 9 (16.4) 21 (38.2) 25 (45.5)
Abbreviations: SD: standard deviation, VLBW: very low birth weight. A major motor impairment was defined as cerebral palsy. A minor motor impairment was defined as Movement ABC total scoreso fifth centile derived from an age-matched control group. A major cognitive impairment was defined as mental retardation (estimated full scale IQ score of 70 or less). A minor cognitive impairment was defined as estimated full scale IQ scores one SD or more from the mean of the control group, but higher than 70. Major and minor visuo-motor impairment was defined as VMI scores two and one SD or more from the mean of the control group, respectively. Major and minor visual perceptual impairment was defined as VP scores two and one SD or more from the mean of the control group, respectively. Motor coordination impairment was defined as MC scores one SD or more from the mean of the control group in non-CP adolescents. Executive functions impairment was defined as WCST non-perseverative errors score one SD or more from the mean of the control group in non CP adolescents.
Major neuroimpairments
Cerebral palsy (CP) was diagnosed in six (11%) of the adolescents (five with diplegia, one with hemiplegia). Mental retardation was found in 16 adolescents (29.6%). Major visuomotor and visual perceptual problems were seen in two (3.7%) and 10 (18.5%) VLBW adolescents, respectively.
3.3.
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visuo-motor impairments seen on VMI and five (9.3%) had visual perceptual impairments evaluated by the VMI supplementary VP test. Impairments in MC, cognition and executive functions were seen in 16 (29.6%), nine (16.7%) and nine (16.7%) adolescents, respectively.
Minor neuroimpairments 3.4.
Among the 35 VLBW adolescents without cerebral palsy and/ or mental retardation, eight (14.8%) and three (5.6%) had gross and fine motor impairments, respectively, based on the Movement ABC test. Twelve adolescents (22.2%) had minor
Cerebral MRI findings
VD was found in 45 of VLBW (81.8%) and was mostly seen as focal dilatation of the occipital horns of the lateral ventricles (Fig. 1). Corpus callosum thinning (CCT), mainly of the
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Fig. 1 – VLBW adolescent with dilated occipital horns of lateral ventricles and reduced periventricular white matter occipitally (axial IR T1W image).
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and the abnormality score (AS) are shown in Tables 4 and 5 for all the VLBW and the non-CP VLBW adolescents, respectively. When the CP children were included, there was a correlation between the VD score and results on VMI, the performance IQ subtest picture arrangement and the WCST. The WMR score correlated with motor, visual motor and executive test results, while the abnormality score was only correlated with the WCST perseveration and non-perseveration errors count. Table 5 shows the results for the non-CP VLBW adolescents. The WMR score correlated with the motor balance test, otherwise there was only correlations between the MR scores and the WCST results.
3.6.
Major neuroimpairments and MRI findings (Table 6)
Table 6 reports the relationship between major neuroimpairments and MRI abnormalities. All the CP VLBW adolescents had extensive MRI pathology. Among the 16 mentally retarded adolescents 14, eight and nine had ventricular dilatation, corpus callosum thinning and white matter reduction, respectively. All adolescents with major visuo-motor and visual perceptual impairments also had pathology on MRI. Among the 10 with major visual perceptual impairments, all had ventricular dilatation and seven had corpus callosum thinning (odds ratio 3.4 (95%CI 0.8–14.8), p ¼ 0.09 vs. those with visual impairments without corpus callosum thinning). Fig. 2 – VLBW adolescent with thinning of posterior part of corpus callosum (sagittal T1W image).
posterior part (Fig. 2) was found in 26 of VLBW (47.3%). White matter reduction (WMR) was found in 29 of VLBW (52.7%). Gliosis was recorded in 16 of the VLBW (29.1%). Gliosis was found in the occipital and parietal lobes, mainly bilateral in the periventricular regions. None had subcortical gliosis. No abnormalities in cortical grey matter, in cerebellum, the basal ganglia and thalamus were reported. Normal MRI was found in nine VLBW (16.4%). Twenty-five VLBW (45.4%), including the six with CP, had an abnormality score of three and four.
3.5.
Clinical test scores and cerebral MRI findings (Tables 3–5)
When comparing the mean scores of the motor and perceptual tests no differences were found for those with and without MR pathology (data not shown). Table 3 shows the mean scores of the cognitive and executive tests in relation to different MRI abnormalities (ventricular dilatation, corpus callosum thinning, white matter reduction and gliosis) in the non-CP VLBW group. Estimated scores on performance, verbal and total IQ did not differ for those with and without abnormal MRI. On the WCST higher scores were reported in those with VD and with corpus callosum thinning. On the Stroop 1 test those with gliosis had higher scores while those with VD had lower scores than those without MR pathology. The significant correlations between the clinical test scores and the VD score, the white matter reduction (WMR) score
3.7.
Minor neuroimpairments and MRI findings (Table 7)
Table 7 reports the relationship between different neuroimpairments and MRI abnormalities among the 35 VLBW adolescents without cerebral palsy and mental retardation. Among the nine adolescents with executive functions impairment based on a WCST non-perseveration errors score of more than one SD from the mean of the controls, all had VD, while seven had corpus callosum thinning (odds ratio 9.5 (95%CI 1.6–57), po0.01 vs. those with neuroimpairments without thinning) and eight had white matter reduction (odds ratio 18.0 (95%CI 1.9–169), po0.01 vs. those without WMR). Five adolescents with minor visual perceptual impairments all had ventricular dilatation, while four of them also had white matter reduction (odds ratio 6.0 (95%CI 0.6–60), p ¼ 0.1 vs. those without WMR). Among those with minor visuo-motor impairments based on a score on the VMI test between one SD and two SD from the mean of the controls, 10 of 12 had VD. For the other minor neuroimpairments there were no increased odds for having MR pathology. The nine VLBW adolescents with normal MRI had none or only one neuroimpairment.
4.
Discussion
On cerebral MRI more than half of the VLBW adolescents had VD, thinning of the corpus callosum and cerebral white matter reduction. However, MRI pathology in the VLBW group was only to a limited degree related to poor clinical performance and neuroimpairments. Those with major
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Table 3 – Cerebral MRI findings and results on the cognitive and executive tests in 48 VLBW adolescents without cerebral palsy Ventricular dilatation
Corpus callosum thinning
White matter reduction
Gliosis
Yes n ¼ 38
No n ¼ 10
Yes n ¼ 19
No n ¼ 29
Yes n ¼ 22
No n ¼ 26
Yes n ¼ 13
No n ¼ 35
Mean (SD)
Mean (SD)
Mean (SD)
Mean (SD)
Mean (SD)
Mean (SD)
Mean (SD)
Mean (SD)
80.4 (23.0) 82.2 (27.9) 82.9 (18.8)
84.8 (17.9) 90.9 (23.6) 83.0 (18.7)
84.5 (26.6) 87.4 (32.0) 84.7 (22.1)
79.2 (14.4) 81.8 (23.7) 81.8 (16.2)
80.5 (20.9) 82.0 (26.9) 82.9 (18.6)
82.0 (23.1) 85.8 (27.7) 83.0 (18.9)
82.1 (23.5) 85.0 (31.7) 82.1 (23.5)
83.3 (16.8) 83.7 (25.7) 83.3 (16.8)
79.5 (10.2) 10.2 (3.3)
73.3 (19.4) 25.7 (36.6)
77.6 (14.4) 21.1 (28.2)
76.0 (16.2) 24.1 (34.4)
75.8 (17.1) 21.9 (29.5)
73.5 (17.5) 29.1 (40.5)
76.8 (16.3) 20.6 (27.8)
11.7 (3.8)
21.2 (12.8)
14.8 (7.9)
19.0 (10.6)
16.0 (10.4)
16.9 (7.8)
17.5 (11.4)
Errors of nonperseveration
75.0 (17.8) 26.3 (34.7)a 18.8 (11.2)a 24.1 (15.1)a
12.5 (6.6)
26.3 (13.3)a
18.7 (14.7)
24.1 (13.1)
19.7 (15.6)
28.8 (17.6)
19.0 (12.5)
Stroop colour-word test Stroop 1 Stroop2 Stroop interference
18.9 (3.7)a 26.7 (5.2) 53.3 (12.5)
22.0 (3.3) 28.6 (3.8) 56.4 (13.7)
19.4 (4.1) 28.4 (5.1) 53.3 (10.0)
19.7 (3.9) 26.3 (4.8) 54.3 (14.3)
19.3 (3.8) 27.8 (5.7) 54.0 (13.8)
19.8 (4.1) 26.5 (4.2) 53.9 (12.0)
21.8 (4.6)a 28.1 (5.0) 52.7 (11.8)
18.7 (3.3) 26.7 (4.9) 54.4 (13.1)
WISC-III Total IQest Performance IQest Verbal IQest Wisconsin card sorting test Total correct Trials to complete 1st category Errors of perseveration
Abbreviations: WISC: Wechsler Intelligence Scales; IQest: estimated IQ; WCST: Wisconsin Card Sorting Test; CP: cerebral palsy; VLBW: very low birth weight. a po0.05 vs. normal (Mann–Whitney test).
Table 4 – Significant correlations between clinical test scores and MR abnormality scores in 54 VLBW adolescents (CP included)
Clinical test VMI score Motor coordination score MABC—balance score MABC—total score WCST trials 1st category WCST perseveration errors WCST non-perseveration errors
VD score
MR abnormality scores WMR score
Abnormality score
0.268a – – – 0.278a 0.330a 0.359b
0.281a 0.275a 0.408b 0.312a – 0.365b 0.420b
– – – – – 0.344a 0.470b
Abbreviations: VLBW: very low birth weight; CP: cerebral palsy; VD: ventricular dilatation; WMR: white matter reduction; VMI: Visual Motor Integration; MABC: Movement ABC test; WCST: Wisconsin Card Sorting Test. VD score: 1: normal, 2: mild abnormality; 3: moderate abnormality; 4: severe abnormality (see Table 1 for explanations). WMR score: 1: normal, 2: mild abnormality, 3: moderate abnormality; 4: severe abnormality (see Table 1 for explanations.) Abnormality score: The sum of the following findings: Ventricular dilatation (no: 0, yes: 1), white matter reduction (no: 0, yes: 1), corpus callosum thinning (no: 0, yes: 1) and gliosis (no: 0, yes: 1). AS ¼ 0 means no pathology, while AS ¼ 4 indicates all four types of pathology. a pp0.05, b po0.01 (correlations by Spearman’s rho).
neuroimpairments, i.e., cerebral palsy, mental retardation and major visuo-motor and visual perceptual impairments, all had MRI pathology except for two adolescents with mental retardation. For minor impairments only those with executive
function impairments had increased odds for having MR pathology, while those with visual perceptual impairments showed a trend towards higher odds. The strongest correlation was to the results on the WCST that reflects problem
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Table 5 – Significant correlations between clinical test scores and MR abnormality scores in 49 non-CP VLBW adolescents
Clinical test MABC—balance score WCST trials first category WCST perseveration errors WCST non perseveration errors
VD score
MR abnormality scores WMR score
Abnormality score
– 0.270c 0.330a 0.365a
0.297a – – 0.314a
– – 0.270c 0.409b
Abbreviations: VLBW: very low birth weight; CP: cerebral palsy; VD: ventricular dilatation; WMR: white matter reduction; MABC: Movement ABC test; WCST: Wisconsin Card Sorting Test. VD score: 1: normal, 2: mild abnormality; 3: moderate abnormality; 4: severe abnormality (see Table 2 for explanations). WMR score: 1: normal, 2: mild abnormality, 3: moderate abnormality; 4: severe abnormality (see Table 2 for explanations). Abnormality score: The sum of the following findings: Ventricular dilatation (no: 0, yes: 1), white matter reduction (no: 0, yes: 1), corpus callosum thinning (no: 0, yes: 1) and gliosis (no: 0, yes: 1). AS ¼ 0 means no pathology, while AS ¼ 4 indicates all four types of pathology. a pp0.05, b po0.01, c p ¼ 0.06 (correlations by Spearman’s rho).
Table 6 – Odds ratios (OR) with 95% confidence intervals (CI) of different major neuroimpairments among 54 VLBW adolescents according to MRI abnormalities Ventricular dilatation (vd) n ¼ 44
Major neuroimpairment Cerebral palsy: n ¼ 6 Mental retardation: n ¼ 16 Major visuo-motor impairment: n ¼ 2 Major visual perceptual impairments: n ¼ 10
Corpus callosum thinning (cct) n ¼ 25
White matter reduction (wmr) n ¼ 28
na
OR
(95% CI)
na
OR
(95% CI)
na
OR
(95% CI)
6 14 2 10
– 1.9 – –
– (0.4–10.0) – –
6 8 1 7
– 1.2 1.2 3.4
– (0.4–4.0) (0.1–19.7) (0.8–14.8)b
6 9 2 7
– 1.3 – 2.6
– (0.4–4.2) – (0.6–11.2)
Reference is VLBW children with major neuroimpairments without MR pathology (vd, cct, and wmr, respectively). Abbreviations: VLBW: very low birth weigh; VMI: Visual Motor Integration Test; VP: Visual Perception Test. Mental retardation was defined as an estimated total IQ score of 70 or less. Major visuo-motor impairment was defined as VMI scores two SD or more from the mean of the control group. Major visual perceptual impairment was defined as VP scores two SD or more from the mean of the control group. a Number of those with neuroimpairments. b p ¼ 0.09 vs. without cct, w2-test (Fisher Exact test).
solving aspects of executive functions. Other correlations mostly disappeared when adolescent with CP were excluded. Normal MRI was related to no or only one neuroimpairment. There were no differences in background data between participants and those who did not consent to participate. Thus, it is unlikely that the results of this population based cohort study are caused by selection bias. During assessment of motor and neuropsychological functions the investigator was blinded to group assignment, and the radiologists assessing the MR images did not know the results of previous MRI findings or the clinical tests. It is thus also unlikely that the results are caused by assessment bias. The weak relation between MRI findings and clinical test results especially with regard to minor neuroimpairments is not very surprising and has been reported before. In a paper from 1999 Cooke and Abernethy found MRI abnormalities in 42.5% of VLBW adolescents at 15–17 years of age, but no
significant differences in IQ, motor clumsiness or frequency of attention deficit/hyperactivity disorder were observed between those with and without MRI abnormalities.9 Stewart et al.10 found that 55% of a cohort of 72 participants born at o33 weeks’ gestation had evidence of brain abnormalities on MRI at 14–15 years of age. They reported VD in 39 and white matter abnormalities (thinning of corpus callosum, abnormal white matter signal, or reduced white matter volume) in 36 of the preterm adolescents. There was no clear relation between brain structure and neurological outcomes, except for scores on the neurobehavioural measure (Rutter behavioural score) which showed a clear effect of abnormal brain MRI in the premature group. Other studies have found correlations between neuropsychological functioning and the size of corpus callosum. Nosarti et al.29 found that verbal IQ and verbal fluency scores were positively associated with total mid-sagittal corpus callosum size and mid-posterior surface
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Table 7 – Odds ratios (OR) with 95% confidence intervals (CI) of different minor neuroimpairments among 35 non-CP and non-MR VLBW adolescents according to MRI abnormalities Ventricular dilatation (vd) n ¼ 27
Minor neuroimpairment Gross motor/balance impairment: n ¼ 8 Fine motor impairment: n ¼ 3 Total motor impairment: n ¼ 6 Visuo-motor impairment: n ¼ 12 Visual perceptual impairments: n ¼ 5 Motor coordination impairment: n ¼ 16 Cognitive impairment: n ¼ 9 Executive functions impairment: n ¼ 9
Corpus callosum thinning (cct) n ¼ 14
White matter reduction (wmr) n ¼ 16
na
OR
(95% CI)
na
OR
(95% CI)
na
OR
(95% CI)
6 2 4 10 5 11 7 9
0.8 0.6 0.5 1.8 – 0.4 1.1 –
(0.1–4.9) (0.1–7.1) (0.1–3.2) (0.3–10.5) – (0.1–2.1) (0.2–6.5) –
1 0 1 5 2 5 1 7
0.2 – 0.3 1.1 1.0 0.5 0.1 9.5
(0.1–1.5) – (0.1–2.4) (0.3–4.6) (0.1–6.9) (0.1–2.0) (0.01–1.1) (1.6–57)b
4 2 3 6 4 8 3 8
1.3 2.6 1.3 1.3 6.0 1.4 0.5 18.0
(0.3–6.3) (0.2–31) (0.2–7.3) (0.3–5.3) (0.6–60)c (0.4–5.2) (0.1–2.4) (1.9–169)b
Reference is VLBW children with minor neuroimpairments without MRI pathology (vd, cct, and wmr, respectively). Abbreviations: CP: cerebral palsy; MR: mental retardation; VLBW: very low birth weigh; VMI: Visual Motor Integration Test; VP: Visual Perception Test; MC: Motor Coordination Test; WISC: Wechsler Intelligence Scales; WCST: Wisconsin Card Sorting Test. Motor impairment was defined as Movement ABC scores ofifth centile derived from the control group. Visuo-motor impairment was defined as VMI scores one SD or more from the mean of the control group. Visual perceptual impairment was defined as VP scores one SD or more from the mean of the control group. Motor coordination impairment was defined as MC scores one SD or more from the mean of the control group. Cognitive impairment was defined as estimated total IQ scores (WISC-III) one SD or more (IQ o79) from the mean of the control group. Executive functions impairment was defined as WCST non-perseverative errors score one SD or more from the mean of the control group. a Number of those with neuroimpairments. b po0.01 vs. without cct and wmr, respectively, c p ¼ 0.1 vs. without wmr, w2 test (Fisher Exact test).
area, while Caldu et al.30 reported a significant correlation between corpus callosum size and gestational age, Wechsler performance IQ, and memory performance. We have already reported that attention-deficit/hyperactivity disorder symptoms, assessed by ADHD-Rating Scale IV, were associated with white matter reduction and thinning of corpus callosum in the same study group.16 In the present study we find a correlation between MRI abnormalities and the results of the WCST, which measures executive functions that are crucial for normal behaviour. The WCST is specifically thought to assess executive functions mediated by the prefrontal cortex such as problem solving, strategic planning, use of environmental feedback to shift set, and inhibition of impulsive responding.31 Executive dysfunction is generally attributed to structural or functional frontal pathology.23 However, normal function of prefrontal cortex depends on the normal integrity of several white matter tracts connecting it to other brain regions. Christ et al.32 investigated a group of CP children born prematurely and found that white matter damage due to periventricular leukomalacia (PVL) most likely contributed to impairments in executive function. Another study reported more executive dysfunction in a large group of ELBW children compared with controls, but where not able to say whether this was a primary deficit in prefrontal cortex or secondary to impairments in other domains as neuroimaging was not done.33 In our study however, VLBW adolescents with cerebral MRI pathology, which was mainly located in the posterior regions of the brain, were at a disadvantage on executive functions compared with those without MRI pathology. The increased numbers of errors of both perse-
veration and non-perseveration on the Wisconsin Card Sorting Test may indicate that planning and work was less effective with unsystematic problem solving and repetition of errors in those with pathological MRI. As the majority of the frontal lobe is subcortical white matter,25 we speculate whether these higher order cognitive deficits can be explained by loss of white matter tracts connecting occipital, parietal and temporal lobe functions to prefrontal areas. Dilatation especially of the occipital horns of the lateral ventricles and thinning mainly of the posterior part of the corpus callosum in this group of VLBW adolescents may indicate loss of periventricular white matter due to perinatal PVL.12 This is consistent with the view that executive processes are mediated by networks that incorporate multiple cortical regions (posterior as well as prefrontal regions) with collaborative and overlapping functions.23 Thus although the prefrontal cortex is a vital component of the circuitry subserving executive function, posterior cortical regions and subcortical structures collaborate with prefrontal cortex to mediate successful executive processing. We speculate whether the relationship between MRI pathology in the posterior part of the brain and executive dysfunction seen in the VLBW adolescents in our study is caused by damage to or reduced function of association fibres in tracts like superior occipitofrontal fasciculus compromising executive abilities. There was a trend towards significance between MR pathology and major and minor visual perceptual impairments. All adolescents with visual perceptual impairments had ventricular dilatation and most of them had signs of
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white matter loss. Among the 35 VLBW without CP and mental retardation, 10 of 12 with low performance on the visual motor integration (VMI) test had VD. When the CP children were included, there was a negative correlation between VMI scores and the VD score and the white matter reduction (WMR) score (Table 4). There was also a relationship between the Movement ABC Balance subtest score and white matter reduction seen on MRI, also when the CP children were excluded. Olsen et al.34 reported that VLBW children with VD performed poorly on tasks requiring spatial and visual perceptual abilities. The relationship between MRI pathology and problems on visuo-motor, including balance and visual perceptual tasks may be due to damage of neuronal networks including visual fibres and association fibres between posterior visual and anterior motor areas. In our study IQ scores were not related to MRI abnormalities in the VLBW adolescents. However, only estimated IQ scores based on four subtests were used and not a full scale IQ scores. This may have influenced the absence of a correlation between cognitive function and MRI findings. We speculate that more sophisticated and quantitative MR techniques like morphometric analysis and diffusion tensor imaging may better determine the relationship between brain abnormalities and minor neuroimpairments in VLBW survivors that are reaching adolescence and early adult life. In fact, we have recently published a paper showing the relationship between subnormal neuropsychological performances and reduced fractional anisotropy values on diffusion tensor imaging in regional white matter in the same study population, supporting the findings from this MRI study and indicating more widespread involvement of white matter microstructure also in areas that look normal on conventional MRI.19
5.
Conclusion
MR pathology suggestive of perinatal PVL; that is VD especially of the posterior horns of the lateral ventricles, periventricular white matter reduction and corpus callosum thinning, was related to disadvantages in performances on executive functions based on the WCST in non-CP VLBW adolescents. We speculate whether these higher order cognitive deficits may be due to loss of projectional, association and commissural fibre networks that connect prefrontal areas with other brain regions. IQ scores were not related to MRI abnormalities in VLBW adolescents, and IQ score could not explain the reduced executive functions. The relationship between MRI findings and other minor neuroimpairments was very weak. We speculate that this is due to the insufficiency of conventional MRI to depict minor changes in white matter microstructure and to visualize the organization in the white matter tracts, and not that there are no anatomical correlate to those impairments. Conventional MRI seems not sensitive enough to be a method that can depict brain pathology that explains minor neurological impairments in VLBW adolescents. However, those with normal MRI seem to have a normal or near normal neurological functioning.
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Acknowledgement The study was funded by Department of Child and Adolescent Psychiatry, Norwegian University of Science and Technology, and Research Funds at St. Olav’s Hospital, Trondheim University Hospital. Part of the study group was recruited from a multicenter study sponsored by the US National Institute of Child Health and Human Development, NIH (NICHD Contract nos. 1-HD-4-2803 and 1-HD-1-3127).
Appendix.
MRI registration form
A) Qualitative judgement 1. Size of lateral ventricles Normal Focal enlargement (not occipital)
Enlargement of occipital horns
Unilat. diffuse enlargement—mild
Unilat. diffuse enlargem.—moderate
Unilat. diffuse enlargem.—severe
Bilat. diffuse enlargement—mild Bilat. diffuse enlargement—moderate Bilat. diffuse enlargement—severe Description of abnormalities:
right side -left side bilat right side -left side bilat right side -left side right side -left side right side -left side
——
(0) (1)
——
(2)
——
(3)
——
(4)
——
(5)
——
(6)
——
(7)
——
(8)
——
(9)
——
(10)
——
(11)
——
(12)
—— ——
(13) (14)
——
(15)
2. White matter (WM) gliosis (hyperintensity signal T2w images) Normal WM —— (0) Focal PV-WM —— (1) right side
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Diffuse PV-WM
Unilat. SC-WM
Diffuse bilat. PV-WM and bilat. SC-WM Description of abnormalities 3. Localization of gliosis Occipital region No gliosis Gliosis unilat. right side Gliosis unilat. left side Gliosis bilat Parietal region No gliosis Gliosis unilat. right side Gliosis unilat. left side Gliosis bilat Temporal region No gliosis Gliosis unilat. right side Gliosis unilat. left side Gliosis bilat Cerebellum No gliosis Gliosis unilat. right side Gliosis unilat. left side Gliosis bilat Frontal region No gliosis Gliosis unilat. right side Gliosis unilat. left side Gliosis bilat 4. White matter reduction (WMR) Not reduced Unilat. reduction of WM—right side Unilat. reduction of WM—left side Bilat. reduction of WM Severe loss of white matter Description of abnormalities: 5. Cysts in white matter No cysts Small cysts (no3) unilat. in PV regions—right side
-left side bilat right side -left side bilat right side -left side
——
(2)
——
(3)
——
(4)
——
(5)
——
(6)
——
(7)
——
(8)
——
(9)
—— —— —— ——
(0) (1) (2) (3)
—— —— —— ——
(0) (1) (2) (3)
—— —— —— ——
(0) (1) (2) (3)
—— —— —— ——
(0) (1) (2) (3)
—— —— —— ——
(0) (1) (2) (3)
—— ——
(0) (1)
—— —— ——
(2) (3) (4)
—— ——
(0) (1)
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Small cysts (no3) unilat. in PV regions—left side Small cysts (no3) bilat. in PV regions Bilat. multiple cysts in PV regions and/or deep WM Description of abnormalities: 6. Corpus callosum (CC) Normal corpus callosum Thinning involving the posterior body Mild/moderate diffuse thinning Severe diffuse thinning Description of abnormalities:
——
(2)
——
(3)
——
(4)
—— ——
(0) (1)
—— ——
(2) (3)
7. Grey matter (GM)—cortex and subcortical structures No cortical abnormalities —— (0) Unilat. abnormalities (ulegyria, —— (1) cort. dysplasia)—right side Unilat. abnormalities (ulegyria, —— (2) cort. dysplasia)—left side Bilat. cortical abnormalities —— (3) Description of abnormalities: Hippocampus—abnormalities
Cerebellum-abnormalities
Basal ganglia+thalamus—abnormalities
—— No (0) —— No (0) —— No (0)
—— Yes (1) —— Yes (1) —— Yes (1)
Description of abnormalities:
R E F E R E N C E S
1. Inder TE, Wells SJ, Mogridge NB, Spencer C, Volpe JJ. Defining the nature of the cerebral abnormalities in the premature infant: a qualitative magnetic resonance imaging study. J Pediatr 2003;143:171–9. 2. Wilson DA, Steiner RE. Periventricular leukomalacia: evaluation with MR imaging. Radiology 1986;160:507–11. 3. Yokochi K, Aiba K, Horie M, et al. Magnetic resonance imaging in children with spastic diplegia: correlation with the severity of their motor and mental abnormality. Dev Med Child Neurol 1991;33:18–25. 4. Skranes JS, Nilsen G, Smevik O, et al. Cerebral magnetic resonance imaging (MRI) of very low birth weight infants at one year of corrected age. Pediatr Radiol 1992;22:406–9. 5. Krageloh-Mann I, Hagberg B, Petersen D, et al. Bilateral spastic cerebral palsy—pathogenetic aspects from MRI. Neuropediatrics 1992;23:46–8. 6. Maalouf EF, Duggan PJ, Rutherford MA, et al. Magnetic resonance imaging of the brain in a cohort of extremely preterm infants. J Pediatr 1999;135:351–7. 7. Childs AM, Cornette L, Ramenghi LA, et al. Magnetic resonance and cranial ultrasound characteristics of periventricular white matter abnormalities in newborn infants. Clin Radiol 2001;56:647–55.
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8. Counsell SJ, Rutherford MA, Cowan FM, Edwards AD. Magnetic resonance imaging of preterm brain injury. Arch Dis Child Fetal Neonatal Ed 2003;88:F269–74. 9. Cooke RW, Abernethy LJ. Cranial magnetic resonance imaging and school performance in very low birth weight infants in adolescence. Arch Dis Child Fetal Neonatal Ed 1999;81:F116–21. 10. Stewart AL, Rifkin L, Amess PN, et al. Brain structure and neurocognitive and behavioural function in adolescents who were born very preterm. Lancet 1999;353:1653–7. 11. Allin M, Matsumoto H, Santhouse AM, et al. Cognitive and motor function and the size of the cerebellum in adolescents born very pre-term. Brain 2001;124:60–6. 12. Skranes J, Martinussen M, Smevik O, et al. Cerebral MRI findings in very-low-birth-weight and small-for-gestationalage children at 15 years of age. Pediatr Radiol 2005;35:758–65. 13. Indredavik MS, Vik T, Heyerdahl S, et al. Psychiatric symptoms and disorders in adolescents with low birth weight. Arch Dis Child Fetal Neonatal Ed 2004;89:F451–5. 14. Evensen KA, Vik T, Helbostad J, et al. Motor skills in adolescents with low birth weight. Arch Dis Child Fetal Neonatal Ed 2004;89:F451–5. 15. Kulseng S, Jennekens-Schinkel A, Naess P, et al. Very-lowbirthweight and term small-for-gestational-age adolescents: attention revisited. Acta Paediatr 2006;95:224–30. 16. Indredavik MS, Skranes J, Vik T, et al. Low-birth-weight adolescents: psychiatric symptoms and cerebral MRI abnormalities. Pediatr Neurol 2005;33:260–6. 17. Henderson SE, Sugden D. Movement assessment battery for children. London: The Psychological Corporation; 1992. 18. Kløve H, Matthews CG. Manual of neuropsychological test battery. Battery II, Youth (9–15). Halstead battery. Lafayette Instrument Company. 19. Skranes J, Vangberg T, Kulseng S, et al. Clinical findings and white matter abnormalities seen on diffusion tensor imaging in adolescents with very low birth weight. Brain 2007; 130(Part 3):654–66. 20. Beery KE. The Beery– Buktencia developmental test of visual-motor integration. Administration, scoring and teaching manual, 4th ed. Modern Curriculum Press; 1997.
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283
21. Wechsler Intelligence Scale for Children. 3rd ed. Swedish version. Psykologifo¨rlaget AB; 1999. 22. Spreen O, Strauss E. A compendium of neuropsychological tests: administration, norms, and commentary, 2nd ed. New York: Oxford University Press; 1998. 23. Elliott R. Executive functions and their disorders. Br Med Bull 2003;65:49–59. 24. Heaton RK, Thompson JA, Gomez E. Wisconsin card sorting test computer version 3 for windows. Odessa, FL: PAR Psychological assessment resources, Inc.; 1999. 25. Kipps CM, Hodges JR. Cognitive assessment for clinicians. J Neurol Neurosurg Psychiat 2005;76:i22–30. 26. Woodward LJ, Anderson PJ, Austin NC, Howard K, Inder TE. Neonatal MRI to predict neurodevelopmental outcome in preterm infants. N Engl J Med 2006;355(7):685–94. 27. Volpe JJ. Brain injury in the premature infant. Neuropathology, clinical aspects, pathogenesis, and prevention. Clin Perinatol 1997;24:567–87. 28. Barkowich AJ, Truwit CL. Normal postnatal development of the corpus callosum. Practical MRI atlas of neonatal brain development. New York: Raven Press; 1990. 29. Nosarti C, Rushe TM, Woodruff PWR, et al. Corpus callosum size and very preterm birth: relationship to neuropsychological outcome. Brain 2004;127:2080–9. 30. Caldu X, Narberhaus A, Junque C, et al. Corpus callosum size and neuropsychologic impairments in adolescents who were born preterm. J Child Neurol 2006;21:406–10. 31. Demakis GJ. A meta-analytic review of the sensitivity of the Wisconsin Card Sorting Test to frontal and lateralized frontal brain damage. Neuropsychology 2003;15:255–64. 32. Christ SE, White DA, Brunstrom JE, Abrams RA. Inhibitory control following perinatal brain injury. Neuropsychology 2003;17:171–8. 33. Anderson PJ, Doyle LW. Executive functioning in school-aged children who were born very preterm or with extremely low birth weight in the 1990s. Pediatrics 2004;114:50–7. 34. Olsen P, Vainionpaa L, Paakko E, et al. Psychological findings in preterm children related to neurologic status and magnetic resonance imaging. Pediatrics 1998;102:329–36.
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Official Journal of the European Paediatric Neurology Society
Original article
Abnormal cerebral MRI findings and neuroimpairments in very low birth weight (VLBW) adolescents Jon Skranesa,d,f,, Karianne Indredavik Evensena, Gro C. Løhaugena,f, Marit Martinussene, Siri Kulsenga,d, Gunnar Myhrb, Torstein Vikc, Ann–Mari Brubakka,d a Department of Laboratory Medicine, Children’s and Women’s Health, Norwegian University of Science and Technology, Kvinne/barnsenteret, Olav Kyrres gt. 11, N-7489 Trondheim, Norway b Department of Circulation and Imaging, Norwegian University of Science and Technology, Trondheim, Norway c Department of Community Medicine and General Practice, Norwegian University of Science and Technology, Trondheim, Norway d Department of Pediatrics, St. Olav’s University Hospital, Trondheim, Norway e Department of Gynaecology, St. Olav’s University Hospital, Trondheim, Norway f Department of Pediatrics, Sørlandet Hospital, Arendal, Norway
art i cle info
ab st rac t
Article history:
Background: High prevalence of abnormal cerebral MRI findings as well as major and
Received 18 May 2007
minor motor, perceptual and cognitive impairments has been reported in very low birth
Received in revised form
weight (VLBW) children.
6 August 2007
Aim: To investigate whether cerebral MRI pathology relates to different types of
Accepted 21 August 2007
neuroimpairments in adolescents with VLBW.
Methods: At age 15, 55 adolescents with birth weight p1500 g (VLBW) were examined. Keywords:
Motor function was evaluated by Movement Assessment Battery for Children (ABC) and the
Cerebral MRI
Grooved Pegboard (GP) test, cognitive function by Wechsler Intelligence Scales, and visuo-
VLBW
motor and visual perceptual function by The Developmental Test of Visual-Motor
Adolescence
Integration (VMI) with the supplementary tests of Visual Perception (VP), and Motor
Brain
Coordination (MC). Executive functions were assessed by Wisconsin Card Sorting Test
Neuroimpairments
(WCST) and the Stroop test. Cerebral MRI was assessed semi-quantitatively for ventricular,
CP
white and grey matter pathology.
Results: There was a rather weak relationship between MRI pathology and neuroimpairments. Poor performance on the WCST was related with ventricular dilatation (VD), white matter reduction and corpus callosum thinning. There was a correlation between results on the VMI test and the Movement ABC test and MRI pathology, but the correlation became much weaker when children with cerebral palsy were excluded. There was no relationship between MRI findings and estimated intelligence quotient (IQ) scores. Normal MRI predicted normal or near normal neuropsychological functioning.
Conclusion: Cerebral MRI pathology suggestive of perinatal white matter injury was related to disadvantages in performances on executive functions, to a lesser degree to motor and visual perceptual problems, but not to cognitive impairments in VLBW adolescents. & 2007 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Corresponding author. Department of Laboratory Medicine, Children’s and Women’s Health, Norwegian University of Science and Technology, Kvinne/barnsenteret, Olav Kyrres gt. 11, N-7489 Trondheim, Norway. Tel.: +47 99 39 02 85; fax: +47 72 57 38 01. E-mail address: [email protected] (J. Skranes). 1090-3798/$ - see front matter & 2007 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpn.2007.08.008
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1.
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Introduction
Very low birth weight (VLBW: birth weight p1500 g) children are at increased risk of perinatal brain injury such as periventricular haemorrhages and leukomalacia (PVL). Deep white matter adjacent to the lateral ventricles is vulnerable to injury caused by perinatal infection, nutritional deficits and hypotension with hypoxia-ischemia.1 Correlates to PVL seen on cerebral MRI are dilated occipital horns of lateral ventricles, atrophy of the peritrigonal white matter, periventricular hyperintensity areas, and thinning of corpus callosum.2–8 Several reports have confirmed that MRI pathology persist into adolescence and adulthood.9–12 In the actual study population of VLBW children, we have already published clinical test results on mental health, executive function, motor abilities and also separate cerebral MRI findings compared with an age-matched control group.12,13–15 In addition the relationship between cerebral MRI findings and mental health has been reported.16 Although more sophisticated and quantitative MR techniques may visualize more subtle white matter changes, conventional MRI is still the major image modality used in the clinics. It is therefore of interest to use this modality in comparing with clinical outcome measurements in neonatal high risk patients like VLBW children. The aim of the present study was to compare MRI findings in early adolescence with motor and neuropsychological evaluations in VLBW survivors. We wanted to investigate whether the VLBW adolescents with specific MRI abnormalities had inferior performance on the clinical tests compared with those without such MRI findings.
2.
Materials and methods
2.1.
Study population
The present study is part of a follow-up study of a geographically based 3-year birth cohort of VLBW adolescents born in 1986–1988. The assessments were performed between November 2000 and October 2002 when the children were 14–15 years of age.
2.2.
VLBW adolescents
VLBW was defined as birth weight p1500 g. In 1986–88, 121 children were admitted to the NICU at the University Hospital in Trondheim. At follow-up 33 had died, one child with trisomy 21 was excluded, and six had moved. Of the remaining 81, 55 (67.9%, 28 boys and 27 girls) met for motor and neuropsychological assessment and cerebral MRI examination.
2.3.
Non-participants
There were no differences in mothers’ age at childbirth, duration of pregnancy, or the infants’ birth weight, body length and head circumference between those who participated and those who did not consent to participation.
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2.4.
Methods
2.4.1.
Assessment of motor functions
The Movement assessment battery for children (Movement ABC) was used for motor evaluation and consists of eight items grouped as three subscores: manual dexterity, ball skills, and static/dynamic balance.17 Each item is scored from 0 (optimal score) to 5 (lowest performance). The highest age band, designed for 11–12-year-old children, was used. According to the manual scores ofifth centile is indicative of definite motor problems, and as the study population was examined at age 14, we used the fifth centile derived from an agematched control group as a measure of motor impairment. In fact, the fifth centile of the M-ABC test score in the control group was similar to the fifth centile of the manual.14 The Grooved Pegboard (GP) test requires manual dexterity.18 The adolescent is instructed to insert, successively and as quickly as possible, 25 pegs in the keyhole-shaped holes, ordered in a 5 5 matrix and pointing in different directions. The task was performed both with the writing hand and with the non-writing hand. The scores were the times (s) used to complete each task. Adolescents with CP who did not manage to finish the task within the time limit were assigned a score three SD above the mean of an age-matched control group. Poor performance was defined as any value one SD or more above (i.e., longer than) the mean time of the controls.19
2.4.2. Assessment of visuo-motor and visual perceptual functions The Developmental Test of Visual-Motor Integration (VMI–IV) consists of 27 geometric designs in increasing order of difficulty that has to be copied. No time limit is imposed. The supplementary task Visual Perception (VP) requires the subject to identify depictions of the designs that he/she had copied earlier. The supplementary task Motor Coordination (MC) requires the subject to trace the same designs with a pencil without leaving double-lined paths in which the designs are presented for the occasion. Time limits to complete the supplementary tasks are 3 and 5 min, respectively. Correctness of the performances was judged according to the manual.20 The number of correct performances was scored. Adolescents who did not manage to complete the tests within time limit because of cerebral palsy were assigned a score (i.e., the largest number of errors) three SD from the mean of the control group. Poor performance was defined as a minor perceptual impairment if the result value was between one SD and two SD from the mean of the control group, and as a major perceptual impairment if the result value was more than two SD from the mean of the control group.19
2.4.3.
Assessment of cognitive functions
An estimate of the adolescents’ intelligence quotient (IQest) was calculated using four subtests of Wechsler Intelligence Scales (WISC-III).21 The four subtests were Arithmetic, Vocabulary, Block design and Picture arrangement.22 Ageadjusted scaled scores and raw scores were used. Cognitive impairment was defined as total IQest score below one SD (IQesto79) of the mean of the controls (mean IQest ¼ 95), but
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higher than a score of 70.19 Mental retardation was defined as total IQest score of 70 or less.
2.4.4.
Assessment of executive functions
Assessment with the The Wisconsin Card Sorting Test (WCST), Research Edition, version 3 for Windows was performed to assess the problem-solving and cognitive flexibility aspects of executive functions.22–24 The subject is told to sort 128 cards with designs of geometrical figures that differ according to the categories colour, shape or number, but she/he is not told that the rules for sorting differ according to the categories colour, shape or number. The rule for sorting varies periodically. The subject has to derive the sorting rule from the feedback following every sorting. After 10 correct responses, a set is considered to be installed and the sorting rule is changed. The total number of correct responses, trials to complete the first category, errors of perseveration (a sorting response according to the previous sorting rule) and non-perseveration errors (all other errors) were counted. Executive function impairment was defined as WCST non-perseverative errors score one SD or more from the mean of the control group.19 The Stroop Colour-Word test (Stroop, 1935, modified by Das and Naglieri, 1989) was been used to assess selective attention. It requires inhibition of an automatic reaction to the advantage of a non-automatic one.25 The test consists of three tasks that have to be performed as quickly as possible. In the first the subject reads aloud four colour names written in black. In the second she/he names rectangles printed in the same colours. Finally, in the interference task, she/he names the colours of the ink in which colour names are presented (e.g., the word green printed in yellow colour). Time (s) to complete each of the three tasks was recorded and errors made in the interference task were counted. Interference times were calculated by subtracting time of both baseline tasks from the time of the interference task.
2.4.5.
Cerebral MRI assessment
Cerebral MRI was performed on a 1.5 T Siemens system, which included sagittal T1-weighted spin echo images (TR
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500 ms, TE 14 ms, 19 slices, 5 mm thickness), axial proton density weighted (TR 2800, TE 13 ms) and axial T2-weighted SE images (TR 2800, TE 117 ms) and inversion recovery T1weighted (TR 7000 ms, TI 500 ms, TE 65 ms) series. Two experienced radiologists blinded to the neonatal histories, earlier MRI results and to the results of the assessments of clinical function, studied the MRI examinations independently and thereafter in consensus if disagreement. Images were semi-quantitatively assessed; size of ventricles, degree of white matter reduction, degree of corpus callosum thinning, white matter gliosis and grey matter abnormalities were recorded and scored according to a standardized registration form with 67 items (Appendix). Complete agreement in the evaluations by the two radiologists was found in 86 cases (71.1%), in 35 cases there was minor disagreement and then a third consensus evaluation was done. The scoring was done as a modification of a classification system developed and used by Inder and colleagues for classifying perinatal MRI findings in term infants.1,26 This classification was used since MRI pathology among VLBW children has a perinatal origin.27 The MRI findings were graded into normal (modification of Inder grade 1), mild (modification of Inder grade 2), moderate and severe (modification of Inder grade 3) abnormalities (Table 1). Criteria for ventricular dilatation (VD) included focal or localized dilatation of the lateral ventricles, as well as angulations of the occipital horns as a mild abnormality. Mild diffuse dilatation was also registered as a mild abnormality. White matter reduction was graded as mild if unilateral reduction of periventricular white matter, moderate if bilateral reduction. Criteria for thinning of corpus callosum included focal thinning as mild and mild to moderate diffuse thinning as moderate abnormality. The images were compared with normal mature corpus callosum of the age group.28 Gliosis was recorded as no gliosis (normal), focal periventricular gliosis (mild), diffuse periventricular (moderate) and combined periventricular and subcortical (severe abnormality). Cortical grey matter abnormalities was graded as normal, unilateral (mild), bilateral (moderate) and extensive (severe abnormality). This grading was subsequently dichotomized between normal and abnormal (mild/moderate/severe abnormality)
Table 1 – Classification of the MRI findings in the study population
Normal Mild abnormality
Moderate abnormality Severe abnormality
Ventr. Dilat. (VD)
Wm reduct. (WMR)
Corp. call. thinning (CCT)
Gliosis
Gm abnorm. (GMA)
No VD Unilat. or bilat.focal dilatation (occipital, nonoccipital) Unilat. or bilat. mild diffuse dilatation Moderate diffuse dilatation
No WMR Unilateral reduction of periventricular wm
No CCT Focal thinning (posterior part, other parts)
No gliosis Focal periventricular gliosis
No GMA Unilateral GMA
Bilateral reduction of periventricular wm Severe loss of white matter
Mild/moderate diffuse thinning Severe diffuse thinning
Diffuse periventricular gliosis Diffuse periventricular and subcortical gliosis
Bilateral GMA Extensive GMA
Severe diffuse dilatation
Abbreviations: Ventr. Dilat. (VD): ventricular dilatation; Wm reduct. (WMR): white matter reduction; Corp. call. thinning (CCT): thinning of corpus callosum; Gm abnorm. (GMA): cortical grey matter abnormalities.
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results. Any pathology of cerebellum, basal ganglia and thalamus was also registered. A VD score was registered with the score 1 ¼ no dilatation, score 2 ¼ mild abnormality, score 3 ¼ moderate abnormality; and score 4 ¼ severe abnormality. A white matter reduction (WMR) score was registered in the same way. An abnormality score (AS) was defined as the sum of the following MRI findings: Ventricular dilatation (no: 0, yes: 1), white matter reduction (no: 0, yes: 1), corpus callosum thinning (no: 0, yes: 1) and gliosis (no: 0, yes: 1). AS ¼ 0 meant no pathology, while AS ¼ 4 indicated all four types of pathology. The AS for each child and the mean score for the separate groups were calculated.
2.4.6.
Ethics
The Regional Committee for Medical Research Ethics approved the study protocol. Written informed consent was obtained from both adolescents and parents.
2.4.7.
Statistical analysis
Data were analysed by using SPSS version 13.0 for Windows. Group differences were analysed using non-parametric tests (Kruskal–Wallis with Mann–Whitney U-test post hoc). Differences were considered statistically significant if pp0.05, two tailed. A clinical score more than 1 standard deviation (SD) from the mean score of an age-matched control group was defined as an impairment. Odds ratios (OR) with 95% confidence interval (CI) were calculated and used as an estimate of the relative risk of neuroimpairments in the adolescents with and without different MRI abnormalities. Nonparametric correlations by Spearman’s rho were calculated between different MR abnormality scores and the clinical test scores.
3.
Results
Group characteristics, number of major and minor neuroimpairments and MR pathology are listed in Table 2.
3.1.
Group characteristics
There were no adolescent with major impairments in hearing or vision that could have interfered with task performance. Cerebral MRI was performed in 55 VLBW adolescents, while psychometric testing was done in 54 adolescents.
3.2.
Table 2 – Child characteristics, number of major and minor neuroimpairments and MRI pathology in 55 VLBW adolescents Child characteristics Birth weight (g) Gestational age (weeks) Gender (boys/girls) Age at clinical assessment (years) Age at MRI examination (years) Mothers’ education (years)
Mean (SD) 1189 (244) 29.0 (2.7) 28/27 14.2 (0.3) 15.0 (0.6) 13.2 (3.3)
Major neuroimpairment Cerebral palsy Mental retardation Visuo-motor Visual perceptual (VP)
No (%) 6 (11.0) 16 (29.6) 2 (3.7) 10 (18.5)
Minor neuroimpairment Gross motor Fine motor Visuo-motor Visual perceptual (VP) Motor coordination (MC) Cognitive Executive
No (%) 8 (14.8) 3 (5.6) 12 (22.2) 5 (9.3) 16 (29.6) 9 (16.7) 9 (16.7)
MRI pathology Dilated ventricles Corpus callosum pathology Reduced white matter tissue Gliosis Abnormality score 0 (normal MRI) Abnormality scores 1–2 Abnormality scores 3–4
No (%) 45 (81.8) 26 (47.3) 29 (52.7) 16 (29.1) 9 (16.4) 21 (38.2) 25 (45.5)
Abbreviations: SD: standard deviation, VLBW: very low birth weight. A major motor impairment was defined as cerebral palsy. A minor motor impairment was defined as Movement ABC total scoreso fifth centile derived from an age-matched control group. A major cognitive impairment was defined as mental retardation (estimated full scale IQ score of 70 or less). A minor cognitive impairment was defined as estimated full scale IQ scores one SD or more from the mean of the control group, but higher than 70. Major and minor visuo-motor impairment was defined as VMI scores two and one SD or more from the mean of the control group, respectively. Major and minor visual perceptual impairment was defined as VP scores two and one SD or more from the mean of the control group, respectively. Motor coordination impairment was defined as MC scores one SD or more from the mean of the control group in non-CP adolescents. Executive functions impairment was defined as WCST non-perseverative errors score one SD or more from the mean of the control group in non CP adolescents.
Major neuroimpairments
Cerebral palsy (CP) was diagnosed in six (11%) of the adolescents (five with diplegia, one with hemiplegia). Mental retardation was found in 16 adolescents (29.6%). Major visuomotor and visual perceptual problems were seen in two (3.7%) and 10 (18.5%) VLBW adolescents, respectively.
3.3.
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visuo-motor impairments seen on VMI and five (9.3%) had visual perceptual impairments evaluated by the VMI supplementary VP test. Impairments in MC, cognition and executive functions were seen in 16 (29.6%), nine (16.7%) and nine (16.7%) adolescents, respectively.
Minor neuroimpairments 3.4.
Among the 35 VLBW adolescents without cerebral palsy and/ or mental retardation, eight (14.8%) and three (5.6%) had gross and fine motor impairments, respectively, based on the Movement ABC test. Twelve adolescents (22.2%) had minor
Cerebral MRI findings
VD was found in 45 of VLBW (81.8%) and was mostly seen as focal dilatation of the occipital horns of the lateral ventricles (Fig. 1). Corpus callosum thinning (CCT), mainly of the
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Fig. 1 – VLBW adolescent with dilated occipital horns of lateral ventricles and reduced periventricular white matter occipitally (axial IR T1W image).
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and the abnormality score (AS) are shown in Tables 4 and 5 for all the VLBW and the non-CP VLBW adolescents, respectively. When the CP children were included, there was a correlation between the VD score and results on VMI, the performance IQ subtest picture arrangement and the WCST. The WMR score correlated with motor, visual motor and executive test results, while the abnormality score was only correlated with the WCST perseveration and non-perseveration errors count. Table 5 shows the results for the non-CP VLBW adolescents. The WMR score correlated with the motor balance test, otherwise there was only correlations between the MR scores and the WCST results.
3.6.
Major neuroimpairments and MRI findings (Table 6)
Table 6 reports the relationship between major neuroimpairments and MRI abnormalities. All the CP VLBW adolescents had extensive MRI pathology. Among the 16 mentally retarded adolescents 14, eight and nine had ventricular dilatation, corpus callosum thinning and white matter reduction, respectively. All adolescents with major visuo-motor and visual perceptual impairments also had pathology on MRI. Among the 10 with major visual perceptual impairments, all had ventricular dilatation and seven had corpus callosum thinning (odds ratio 3.4 (95%CI 0.8–14.8), p ¼ 0.09 vs. those with visual impairments without corpus callosum thinning). Fig. 2 – VLBW adolescent with thinning of posterior part of corpus callosum (sagittal T1W image).
posterior part (Fig. 2) was found in 26 of VLBW (47.3%). White matter reduction (WMR) was found in 29 of VLBW (52.7%). Gliosis was recorded in 16 of the VLBW (29.1%). Gliosis was found in the occipital and parietal lobes, mainly bilateral in the periventricular regions. None had subcortical gliosis. No abnormalities in cortical grey matter, in cerebellum, the basal ganglia and thalamus were reported. Normal MRI was found in nine VLBW (16.4%). Twenty-five VLBW (45.4%), including the six with CP, had an abnormality score of three and four.
3.5.
Clinical test scores and cerebral MRI findings (Tables 3–5)
When comparing the mean scores of the motor and perceptual tests no differences were found for those with and without MR pathology (data not shown). Table 3 shows the mean scores of the cognitive and executive tests in relation to different MRI abnormalities (ventricular dilatation, corpus callosum thinning, white matter reduction and gliosis) in the non-CP VLBW group. Estimated scores on performance, verbal and total IQ did not differ for those with and without abnormal MRI. On the WCST higher scores were reported in those with VD and with corpus callosum thinning. On the Stroop 1 test those with gliosis had higher scores while those with VD had lower scores than those without MR pathology. The significant correlations between the clinical test scores and the VD score, the white matter reduction (WMR) score
3.7.
Minor neuroimpairments and MRI findings (Table 7)
Table 7 reports the relationship between different neuroimpairments and MRI abnormalities among the 35 VLBW adolescents without cerebral palsy and mental retardation. Among the nine adolescents with executive functions impairment based on a WCST non-perseveration errors score of more than one SD from the mean of the controls, all had VD, while seven had corpus callosum thinning (odds ratio 9.5 (95%CI 1.6–57), po0.01 vs. those with neuroimpairments without thinning) and eight had white matter reduction (odds ratio 18.0 (95%CI 1.9–169), po0.01 vs. those without WMR). Five adolescents with minor visual perceptual impairments all had ventricular dilatation, while four of them also had white matter reduction (odds ratio 6.0 (95%CI 0.6–60), p ¼ 0.1 vs. those without WMR). Among those with minor visuo-motor impairments based on a score on the VMI test between one SD and two SD from the mean of the controls, 10 of 12 had VD. For the other minor neuroimpairments there were no increased odds for having MR pathology. The nine VLBW adolescents with normal MRI had none or only one neuroimpairment.
4.
Discussion
On cerebral MRI more than half of the VLBW adolescents had VD, thinning of the corpus callosum and cerebral white matter reduction. However, MRI pathology in the VLBW group was only to a limited degree related to poor clinical performance and neuroimpairments. Those with major
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Table 3 – Cerebral MRI findings and results on the cognitive and executive tests in 48 VLBW adolescents without cerebral palsy Ventricular dilatation
Corpus callosum thinning
White matter reduction
Gliosis
Yes n ¼ 38
No n ¼ 10
Yes n ¼ 19
No n ¼ 29
Yes n ¼ 22
No n ¼ 26
Yes n ¼ 13
No n ¼ 35
Mean (SD)
Mean (SD)
Mean (SD)
Mean (SD)
Mean (SD)
Mean (SD)
Mean (SD)
Mean (SD)
80.4 (23.0) 82.2 (27.9) 82.9 (18.8)
84.8 (17.9) 90.9 (23.6) 83.0 (18.7)
84.5 (26.6) 87.4 (32.0) 84.7 (22.1)
79.2 (14.4) 81.8 (23.7) 81.8 (16.2)
80.5 (20.9) 82.0 (26.9) 82.9 (18.6)
82.0 (23.1) 85.8 (27.7) 83.0 (18.9)
82.1 (23.5) 85.0 (31.7) 82.1 (23.5)
83.3 (16.8) 83.7 (25.7) 83.3 (16.8)
79.5 (10.2) 10.2 (3.3)
73.3 (19.4) 25.7 (36.6)
77.6 (14.4) 21.1 (28.2)
76.0 (16.2) 24.1 (34.4)
75.8 (17.1) 21.9 (29.5)
73.5 (17.5) 29.1 (40.5)
76.8 (16.3) 20.6 (27.8)
11.7 (3.8)
21.2 (12.8)
14.8 (7.9)
19.0 (10.6)
16.0 (10.4)
16.9 (7.8)
17.5 (11.4)
Errors of nonperseveration
75.0 (17.8) 26.3 (34.7)a 18.8 (11.2)a 24.1 (15.1)a
12.5 (6.6)
26.3 (13.3)a
18.7 (14.7)
24.1 (13.1)
19.7 (15.6)
28.8 (17.6)
19.0 (12.5)
Stroop colour-word test Stroop 1 Stroop2 Stroop interference
18.9 (3.7)a 26.7 (5.2) 53.3 (12.5)
22.0 (3.3) 28.6 (3.8) 56.4 (13.7)
19.4 (4.1) 28.4 (5.1) 53.3 (10.0)
19.7 (3.9) 26.3 (4.8) 54.3 (14.3)
19.3 (3.8) 27.8 (5.7) 54.0 (13.8)
19.8 (4.1) 26.5 (4.2) 53.9 (12.0)
21.8 (4.6)a 28.1 (5.0) 52.7 (11.8)
18.7 (3.3) 26.7 (4.9) 54.4 (13.1)
WISC-III Total IQest Performance IQest Verbal IQest Wisconsin card sorting test Total correct Trials to complete 1st category Errors of perseveration
Abbreviations: WISC: Wechsler Intelligence Scales; IQest: estimated IQ; WCST: Wisconsin Card Sorting Test; CP: cerebral palsy; VLBW: very low birth weight. a po0.05 vs. normal (Mann–Whitney test).
Table 4 – Significant correlations between clinical test scores and MR abnormality scores in 54 VLBW adolescents (CP included)
Clinical test VMI score Motor coordination score MABC—balance score MABC—total score WCST trials 1st category WCST perseveration errors WCST non-perseveration errors
VD score
MR abnormality scores WMR score
Abnormality score
0.268a – – – 0.278a 0.330a 0.359b
0.281a 0.275a 0.408b 0.312a – 0.365b 0.420b
– – – – – 0.344a 0.470b
Abbreviations: VLBW: very low birth weight; CP: cerebral palsy; VD: ventricular dilatation; WMR: white matter reduction; VMI: Visual Motor Integration; MABC: Movement ABC test; WCST: Wisconsin Card Sorting Test. VD score: 1: normal, 2: mild abnormality; 3: moderate abnormality; 4: severe abnormality (see Table 1 for explanations). WMR score: 1: normal, 2: mild abnormality, 3: moderate abnormality; 4: severe abnormality (see Table 1 for explanations.) Abnormality score: The sum of the following findings: Ventricular dilatation (no: 0, yes: 1), white matter reduction (no: 0, yes: 1), corpus callosum thinning (no: 0, yes: 1) and gliosis (no: 0, yes: 1). AS ¼ 0 means no pathology, while AS ¼ 4 indicates all four types of pathology. a pp0.05, b po0.01 (correlations by Spearman’s rho).
neuroimpairments, i.e., cerebral palsy, mental retardation and major visuo-motor and visual perceptual impairments, all had MRI pathology except for two adolescents with mental retardation. For minor impairments only those with executive
function impairments had increased odds for having MR pathology, while those with visual perceptual impairments showed a trend towards higher odds. The strongest correlation was to the results on the WCST that reflects problem
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Table 5 – Significant correlations between clinical test scores and MR abnormality scores in 49 non-CP VLBW adolescents
Clinical test MABC—balance score WCST trials first category WCST perseveration errors WCST non perseveration errors
VD score
MR abnormality scores WMR score
Abnormality score
– 0.270c 0.330a 0.365a
0.297a – – 0.314a
– – 0.270c 0.409b
Abbreviations: VLBW: very low birth weight; CP: cerebral palsy; VD: ventricular dilatation; WMR: white matter reduction; MABC: Movement ABC test; WCST: Wisconsin Card Sorting Test. VD score: 1: normal, 2: mild abnormality; 3: moderate abnormality; 4: severe abnormality (see Table 2 for explanations). WMR score: 1: normal, 2: mild abnormality, 3: moderate abnormality; 4: severe abnormality (see Table 2 for explanations). Abnormality score: The sum of the following findings: Ventricular dilatation (no: 0, yes: 1), white matter reduction (no: 0, yes: 1), corpus callosum thinning (no: 0, yes: 1) and gliosis (no: 0, yes: 1). AS ¼ 0 means no pathology, while AS ¼ 4 indicates all four types of pathology. a pp0.05, b po0.01, c p ¼ 0.06 (correlations by Spearman’s rho).
Table 6 – Odds ratios (OR) with 95% confidence intervals (CI) of different major neuroimpairments among 54 VLBW adolescents according to MRI abnormalities Ventricular dilatation (vd) n ¼ 44
Major neuroimpairment Cerebral palsy: n ¼ 6 Mental retardation: n ¼ 16 Major visuo-motor impairment: n ¼ 2 Major visual perceptual impairments: n ¼ 10
Corpus callosum thinning (cct) n ¼ 25
White matter reduction (wmr) n ¼ 28
na
OR
(95% CI)
na
OR
(95% CI)
na
OR
(95% CI)
6 14 2 10
– 1.9 – –
– (0.4–10.0) – –
6 8 1 7
– 1.2 1.2 3.4
– (0.4–4.0) (0.1–19.7) (0.8–14.8)b
6 9 2 7
– 1.3 – 2.6
– (0.4–4.2) – (0.6–11.2)
Reference is VLBW children with major neuroimpairments without MR pathology (vd, cct, and wmr, respectively). Abbreviations: VLBW: very low birth weigh; VMI: Visual Motor Integration Test; VP: Visual Perception Test. Mental retardation was defined as an estimated total IQ score of 70 or less. Major visuo-motor impairment was defined as VMI scores two SD or more from the mean of the control group. Major visual perceptual impairment was defined as VP scores two SD or more from the mean of the control group. a Number of those with neuroimpairments. b p ¼ 0.09 vs. without cct, w2-test (Fisher Exact test).
solving aspects of executive functions. Other correlations mostly disappeared when adolescent with CP were excluded. Normal MRI was related to no or only one neuroimpairment. There were no differences in background data between participants and those who did not consent to participate. Thus, it is unlikely that the results of this population based cohort study are caused by selection bias. During assessment of motor and neuropsychological functions the investigator was blinded to group assignment, and the radiologists assessing the MR images did not know the results of previous MRI findings or the clinical tests. It is thus also unlikely that the results are caused by assessment bias. The weak relation between MRI findings and clinical test results especially with regard to minor neuroimpairments is not very surprising and has been reported before. In a paper from 1999 Cooke and Abernethy found MRI abnormalities in 42.5% of VLBW adolescents at 15–17 years of age, but no
significant differences in IQ, motor clumsiness or frequency of attention deficit/hyperactivity disorder were observed between those with and without MRI abnormalities.9 Stewart et al.10 found that 55% of a cohort of 72 participants born at o33 weeks’ gestation had evidence of brain abnormalities on MRI at 14–15 years of age. They reported VD in 39 and white matter abnormalities (thinning of corpus callosum, abnormal white matter signal, or reduced white matter volume) in 36 of the preterm adolescents. There was no clear relation between brain structure and neurological outcomes, except for scores on the neurobehavioural measure (Rutter behavioural score) which showed a clear effect of abnormal brain MRI in the premature group. Other studies have found correlations between neuropsychological functioning and the size of corpus callosum. Nosarti et al.29 found that verbal IQ and verbal fluency scores were positively associated with total mid-sagittal corpus callosum size and mid-posterior surface
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Table 7 – Odds ratios (OR) with 95% confidence intervals (CI) of different minor neuroimpairments among 35 non-CP and non-MR VLBW adolescents according to MRI abnormalities Ventricular dilatation (vd) n ¼ 27
Minor neuroimpairment Gross motor/balance impairment: n ¼ 8 Fine motor impairment: n ¼ 3 Total motor impairment: n ¼ 6 Visuo-motor impairment: n ¼ 12 Visual perceptual impairments: n ¼ 5 Motor coordination impairment: n ¼ 16 Cognitive impairment: n ¼ 9 Executive functions impairment: n ¼ 9
Corpus callosum thinning (cct) n ¼ 14
White matter reduction (wmr) n ¼ 16
na
OR
(95% CI)
na
OR
(95% CI)
na
OR
(95% CI)
6 2 4 10 5 11 7 9
0.8 0.6 0.5 1.8 – 0.4 1.1 –
(0.1–4.9) (0.1–7.1) (0.1–3.2) (0.3–10.5) – (0.1–2.1) (0.2–6.5) –
1 0 1 5 2 5 1 7
0.2 – 0.3 1.1 1.0 0.5 0.1 9.5
(0.1–1.5) – (0.1–2.4) (0.3–4.6) (0.1–6.9) (0.1–2.0) (0.01–1.1) (1.6–57)b
4 2 3 6 4 8 3 8
1.3 2.6 1.3 1.3 6.0 1.4 0.5 18.0
(0.3–6.3) (0.2–31) (0.2–7.3) (0.3–5.3) (0.6–60)c (0.4–5.2) (0.1–2.4) (1.9–169)b
Reference is VLBW children with minor neuroimpairments without MRI pathology (vd, cct, and wmr, respectively). Abbreviations: CP: cerebral palsy; MR: mental retardation; VLBW: very low birth weigh; VMI: Visual Motor Integration Test; VP: Visual Perception Test; MC: Motor Coordination Test; WISC: Wechsler Intelligence Scales; WCST: Wisconsin Card Sorting Test. Motor impairment was defined as Movement ABC scores ofifth centile derived from the control group. Visuo-motor impairment was defined as VMI scores one SD or more from the mean of the control group. Visual perceptual impairment was defined as VP scores one SD or more from the mean of the control group. Motor coordination impairment was defined as MC scores one SD or more from the mean of the control group. Cognitive impairment was defined as estimated total IQ scores (WISC-III) one SD or more (IQ o79) from the mean of the control group. Executive functions impairment was defined as WCST non-perseverative errors score one SD or more from the mean of the control group. a Number of those with neuroimpairments. b po0.01 vs. without cct and wmr, respectively, c p ¼ 0.1 vs. without wmr, w2 test (Fisher Exact test).
area, while Caldu et al.30 reported a significant correlation between corpus callosum size and gestational age, Wechsler performance IQ, and memory performance. We have already reported that attention-deficit/hyperactivity disorder symptoms, assessed by ADHD-Rating Scale IV, were associated with white matter reduction and thinning of corpus callosum in the same study group.16 In the present study we find a correlation between MRI abnormalities and the results of the WCST, which measures executive functions that are crucial for normal behaviour. The WCST is specifically thought to assess executive functions mediated by the prefrontal cortex such as problem solving, strategic planning, use of environmental feedback to shift set, and inhibition of impulsive responding.31 Executive dysfunction is generally attributed to structural or functional frontal pathology.23 However, normal function of prefrontal cortex depends on the normal integrity of several white matter tracts connecting it to other brain regions. Christ et al.32 investigated a group of CP children born prematurely and found that white matter damage due to periventricular leukomalacia (PVL) most likely contributed to impairments in executive function. Another study reported more executive dysfunction in a large group of ELBW children compared with controls, but where not able to say whether this was a primary deficit in prefrontal cortex or secondary to impairments in other domains as neuroimaging was not done.33 In our study however, VLBW adolescents with cerebral MRI pathology, which was mainly located in the posterior regions of the brain, were at a disadvantage on executive functions compared with those without MRI pathology. The increased numbers of errors of both perse-
veration and non-perseveration on the Wisconsin Card Sorting Test may indicate that planning and work was less effective with unsystematic problem solving and repetition of errors in those with pathological MRI. As the majority of the frontal lobe is subcortical white matter,25 we speculate whether these higher order cognitive deficits can be explained by loss of white matter tracts connecting occipital, parietal and temporal lobe functions to prefrontal areas. Dilatation especially of the occipital horns of the lateral ventricles and thinning mainly of the posterior part of the corpus callosum in this group of VLBW adolescents may indicate loss of periventricular white matter due to perinatal PVL.12 This is consistent with the view that executive processes are mediated by networks that incorporate multiple cortical regions (posterior as well as prefrontal regions) with collaborative and overlapping functions.23 Thus although the prefrontal cortex is a vital component of the circuitry subserving executive function, posterior cortical regions and subcortical structures collaborate with prefrontal cortex to mediate successful executive processing. We speculate whether the relationship between MRI pathology in the posterior part of the brain and executive dysfunction seen in the VLBW adolescents in our study is caused by damage to or reduced function of association fibres in tracts like superior occipitofrontal fasciculus compromising executive abilities. There was a trend towards significance between MR pathology and major and minor visual perceptual impairments. All adolescents with visual perceptual impairments had ventricular dilatation and most of them had signs of
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white matter loss. Among the 35 VLBW without CP and mental retardation, 10 of 12 with low performance on the visual motor integration (VMI) test had VD. When the CP children were included, there was a negative correlation between VMI scores and the VD score and the white matter reduction (WMR) score (Table 4). There was also a relationship between the Movement ABC Balance subtest score and white matter reduction seen on MRI, also when the CP children were excluded. Olsen et al.34 reported that VLBW children with VD performed poorly on tasks requiring spatial and visual perceptual abilities. The relationship between MRI pathology and problems on visuo-motor, including balance and visual perceptual tasks may be due to damage of neuronal networks including visual fibres and association fibres between posterior visual and anterior motor areas. In our study IQ scores were not related to MRI abnormalities in the VLBW adolescents. However, only estimated IQ scores based on four subtests were used and not a full scale IQ scores. This may have influenced the absence of a correlation between cognitive function and MRI findings. We speculate that more sophisticated and quantitative MR techniques like morphometric analysis and diffusion tensor imaging may better determine the relationship between brain abnormalities and minor neuroimpairments in VLBW survivors that are reaching adolescence and early adult life. In fact, we have recently published a paper showing the relationship between subnormal neuropsychological performances and reduced fractional anisotropy values on diffusion tensor imaging in regional white matter in the same study population, supporting the findings from this MRI study and indicating more widespread involvement of white matter microstructure also in areas that look normal on conventional MRI.19
5.
Conclusion
MR pathology suggestive of perinatal PVL; that is VD especially of the posterior horns of the lateral ventricles, periventricular white matter reduction and corpus callosum thinning, was related to disadvantages in performances on executive functions based on the WCST in non-CP VLBW adolescents. We speculate whether these higher order cognitive deficits may be due to loss of projectional, association and commissural fibre networks that connect prefrontal areas with other brain regions. IQ scores were not related to MRI abnormalities in VLBW adolescents, and IQ score could not explain the reduced executive functions. The relationship between MRI findings and other minor neuroimpairments was very weak. We speculate that this is due to the insufficiency of conventional MRI to depict minor changes in white matter microstructure and to visualize the organization in the white matter tracts, and not that there are no anatomical correlate to those impairments. Conventional MRI seems not sensitive enough to be a method that can depict brain pathology that explains minor neurological impairments in VLBW adolescents. However, those with normal MRI seem to have a normal or near normal neurological functioning.
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Acknowledgement The study was funded by Department of Child and Adolescent Psychiatry, Norwegian University of Science and Technology, and Research Funds at St. Olav’s Hospital, Trondheim University Hospital. Part of the study group was recruited from a multicenter study sponsored by the US National Institute of Child Health and Human Development, NIH (NICHD Contract nos. 1-HD-4-2803 and 1-HD-1-3127).
Appendix.
MRI registration form
A) Qualitative judgement 1. Size of lateral ventricles Normal Focal enlargement (not occipital)
Enlargement of occipital horns
Unilat. diffuse enlargement—mild
Unilat. diffuse enlargem.—moderate
Unilat. diffuse enlargem.—severe
Bilat. diffuse enlargement—mild Bilat. diffuse enlargement—moderate Bilat. diffuse enlargement—severe Description of abnormalities:
right side -left side bilat right side -left side bilat right side -left side right side -left side right side -left side
——
(0) (1)
——
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2. White matter (WM) gliosis (hyperintensity signal T2w images) Normal WM —— (0) Focal PV-WM —— (1) right side
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Diffuse PV-WM
Unilat. SC-WM
Diffuse bilat. PV-WM and bilat. SC-WM Description of abnormalities 3. Localization of gliosis Occipital region No gliosis Gliosis unilat. right side Gliosis unilat. left side Gliosis bilat Parietal region No gliosis Gliosis unilat. right side Gliosis unilat. left side Gliosis bilat Temporal region No gliosis Gliosis unilat. right side Gliosis unilat. left side Gliosis bilat Cerebellum No gliosis Gliosis unilat. right side Gliosis unilat. left side Gliosis bilat Frontal region No gliosis Gliosis unilat. right side Gliosis unilat. left side Gliosis bilat 4. White matter reduction (WMR) Not reduced Unilat. reduction of WM—right side Unilat. reduction of WM—left side Bilat. reduction of WM Severe loss of white matter Description of abnormalities: 5. Cysts in white matter No cysts Small cysts (no3) unilat. in PV regions—right side
-left side bilat right side -left side bilat right side -left side
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Small cysts (no3) unilat. in PV regions—left side Small cysts (no3) bilat. in PV regions Bilat. multiple cysts in PV regions and/or deep WM Description of abnormalities: 6. Corpus callosum (CC) Normal corpus callosum Thinning involving the posterior body Mild/moderate diffuse thinning Severe diffuse thinning Description of abnormalities:
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7. Grey matter (GM)—cortex and subcortical structures No cortical abnormalities —— (0) Unilat. abnormalities (ulegyria, —— (1) cort. dysplasia)—right side Unilat. abnormalities (ulegyria, —— (2) cort. dysplasia)—left side Bilat. cortical abnormalities —— (3) Description of abnormalities: Hippocampus—abnormalities
Cerebellum-abnormalities
Basal ganglia+thalamus—abnormalities
—— No (0) —— No (0) —— No (0)
—— Yes (1) —— Yes (1) —— Yes (1)
Description of abnormalities:
R E F E R E N C E S
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