Isolated neonatal MRI punctate white matter lesions in very preterm neonates and quality of life at school age

Abstract

OBJECTIVE:

To study the quality of life at school age of very preterm infants presenting isolated punctate periventricular white matter lesions (IPWL) on late-preterm or term magnetic resonance imaging (MRI).

METHODS:

In 1996–2000, 16 of the 131 very preterm neonates explored by MRI were found to have IPWL. At the age of 9–14, 12 children from the IPWL group were compared with 54 children born preterm but with a normal MRI (no lesion). Quality of life (Health Status Classification System Pre School questionnaire), school performance, and motor outcome were investigated.

RESULTS:

Overall quality of life did not differ between the groups (classified as perfect in 2/12 of the IPWL vs 20/54 in the no-lesion). The sub-items mobility and dexterity differed significantly between the two groups, with impairment in the IPWL group (p < 0.001 and p < 0.05). This group also displayed higher levels of motor impairment: they began walking later [20(4) vs. 15(3) months), p < 0.01], had higher frequencies of cerebral palsy (6/12 vs. 2/54, p < 0.05), and dyspraxia (4/12 vs. 0/54, p < 0.001). The rate of grade retention did not differ between the groups (3/12 in the IPWL group vs. 17/54 in the no-lesions group) but, as expected, was higher than that of the French general population (17.4%) during the study period.

CONCLUSION:

This long-term follow-up study detected no increase in the risk of subsequent cognitive impairment in very preterm infants with IPWL, but suggests that these children may have a significantly higher risk of dyspraxia, and motor impairment.

Keywords

Preterm infants white matter lesions quality of life dyspraxia motor impairment

1 Introduction

Improvements in neonatal intensive care have greatly increased the survival rates for very preterm (VPT) infants and have led to a gradual change in the incidences of complications of preterm birth, with fewer cases of cystic periventricular leukomalacia and periventricular hemorrhagic infarction [1, 2], and a higher incidence of more diffuse and subtle injuries of the developing white matter (WM) making a major contribution to subsequent neurodevelopmental disabilities. The prevalence of such disabilities remains high, with 5–15% of VPT infants having cerebral palsy, severe neurosensory impairment, or both, and 15–50% having cognitive, behavioral, and social difficulties requiring special educational support [3 –5]. Characterization of the neurological lesions decreasing quality of life (QOL) and school performance in VPT children is important for the early implementation of targeted intervention.

MRI can identify abnormalities of the WM, such as punctate WM lesions (Fig. 1) and so-called diffuse excessive high signal intensity (DEHSI) [6, 7]. Punctate WM lesions have been reported to occur in 7–30% of VPT infants [7 –11]. These lesions are most frequently detected along the corona radiata, in the posterior periventricular WM and along the optic radiation, their numbers decrease with time and they have been associated with delayed myelination and reduced cortical infolding [7 , 12]. Isolated punctate lesions are not identified as such in the current Woodward classification [13, 14]. They are classified as grade 2 or 3 in the area of the classification describing the nature and extent of WM signal abnormalities. They are therefore usually studied as mild WM abnormalities and not analyzed specifically. Assessments of outcome for isolated punctate WM lesions are currently restricted to the second year of life and remain controversial [7–12 , 15]. Significant associations have been found between punctate WM lesions and mental / psychomotor developmental delay, motor delay and cerebral palsy [9 , 16]. The presence of six or more punctate lesions has been reported to be predictive of alterations in mental developmental index (MDI) and behavioral problems [9]. However, favorable outcomes have also been reported [10] even for children with multiple lesions [8].

Fig.1

Cerebral MRI in a preterm neonate showing punctuate white matter lesions: a: T1 weighted images in axial plane showing hyperintense punctate lesions localise in left periventricular white matter (white arrow). b: T1 weighted images in coronal plane showing bilateral hyperintense punctate lesions localise in periventricular white matter (white arrow). c: T1 weighted images in sagittal plane showing hyperintense punctate lesions localise in periventricular white matter (white arrow). d: T2 weighted images in coronal plane showing bilateral hypointense non cystic punctate lesions localise in periventricular white matter (black arrow).

In this study, we tested the hypothesis of an association between isolated punctate WM lesions (IPWL) and alterations to long-term QOL, evaluated with the Health Status Classification System Pre School (HSPC-PC), and their possible implications for academic success. We therefore compared VPT infants at the age of 9–14 years of age as a function of the presence or absence of IPWL.

2 Materials and methods

This controlled study was performed on VPT infants (gestational age≤32 weeks) admitted to the tertiary neonatal unit of Rennes teaching hospital between January 1996 and December 2000 and alive at hospital discharge, who underwent cerebral MRI between 32 and 41 weeks post-menstrual. The VPT infants were 9–14 years of age, at which their QOL was assessed with the HSPC-PC [17]. Informed parental consent was obtained for each participating child.

During 1996–2000, MRI was restricted to VPT infants presenting at least one of the following risk factors: Apgar score <5 at 5 minutes, complicated clinical course (sepsis, inotropic drug use, bronchopulmonary dysplasia), intrauterine growth restriction, abnormalities on cerebral ultrasound (systematically performed for all VPT infants on days 2±1, 5±1, 15±3, 21±3), EEG abnormalities (systematically performed for all VPT infants at least once during the first 10 days of life), clinical neurological abnormalities.

VPT infants with cerebral MRI scans showing isolated punctate lesions (grade 2 or grade 3 of the Woodward classification describing the nature and extent of WM signal abnormalities) were compared to the population of VPT infants with a normal MRI scan (grade 1 for all the items of the Woodward classification). Infants with genetic disease, congenital malformation or other cerebral lesions (such as cystic periventricular WM lesions, ventricular size >12 mm, intraventricular hemorrhage, congenital nervous system abnormalities) were excluded.

2.1 Perinatal data collection

We collected extensive perinatal data, including gestational age, birthweight, sex, Apgar score, multiple gestation, maternal data [prolonged rupture of membrane (>12 h), preterm labor, preeclampsia, metrorrhagia, chorioamnionitis], neonatal data [sepsis (defined as clinically symptomatic septicemia, meningitis, pneumonia or enterocolitis associated with a C-reactive protein concentration >10 mg/L), antenatal and postnatal steroid exposure, inotropic drug use, treated patent ductus arteriosus, bronchopulmonary dysplasia (defined as oxygen requirement at 36 weeks postmenstrual age), ultrasound findings, EEG results] from patient files.

The educational level of the parents was recorded according to the French national classification of occupations and social position (see Table 2).

Table 1
Characteristics of the study groups

Variables No lesion (n = 54) IPWL (n = 12) P value

Male/Female 28/26 6/6 0.91

Term (weeks + days), median (IQR) 28 + 4 (27 + 5 –29 + 4) 28 + 6 (27 + 5 –30 + 3) 0.30

Multiple/single pregnancy 23/31 6/6 0.64

Birth weight (g), mean (SD) 1064 (273) 1234 (336) 0.07

Antenatal steroid treatment, n (%) 38 (70) 8 (67) 0.80

Preterm labor n (%) 31 (57) 7 (58) 0.95

Chorioamnionitis, n (%) 11 (20) 3 (25) 0.77

Preeclampsia, n (%) 17 (32) 2 (17) 0.31

Metrorrhagia, n (%) 9 (17) 2 (17) 1.0

Apgar 5 min <7, n (%) 13 (24) 4 (33) 0.51

Ductus arteriosus treatment, n (%) 9 (17) 5 (42) 0.11

Inotrope use, n (%) 20 (37) 3 (25) 0.43

Sepsis, n (%) 11 (20) 3 (25) 0.72

O₂ at 36 weeks post-menstrual, n (%) 9 (17) 3 (25) 0.50

Postnatal steroid treatment, n (%) 22 (41) 5 (42) 0.66

Post-menstrual age at MRI (weeks + days), median (IQR) 35 + 1 (33 + 4 –37) 35 (32 + 4 –39 + 4) 0.51

Time from birth to MRI (weeks), mean (SD) 7.1 (3.4) 6.8 (2.7) 0.82

TFU abnormalities, n (%) 15 (28) 7 (58) 0.04

Abnormal EEG, n (%) 22 (41) 2 (17) 0.12

Variables	No lesion (n = 54)	IPWL (n = 12)	P value
Male/Female	28/26	6/6	0.91
Term (weeks + days), median (IQR)	28 + 4 (27 + 5 –29 + 4)	28 + 6 (27 + 5 –30 + 3)	0.30
Multiple/single pregnancy	23/31	6/6	0.64
Birth weight (g), mean (SD)	1064 (273)	1234 (336)	0.07
Antenatal steroid treatment, n (%)	38 (70)	8 (67)	0.80
Preterm labor n (%)	31 (57)	7 (58)	0.95
Chorioamnionitis, n (%)	11 (20)	3 (25)	0.77
Preeclampsia, n (%)	17 (32)	2 (17)	0.31
Metrorrhagia, n (%)	9 (17)	2 (17)	1.0
Apgar 5 min <7, n (%)	13 (24)	4 (33)	0.51
Ductus arteriosus treatment, n (%)	9 (17)	5 (42)	0.11
Inotrope use, n (%)	20 (37)	3 (25)	0.43
Sepsis, n (%)	11 (20)	3 (25)	0.72
O₂ at 36 weeks post-menstrual, n (%)	9 (17)	3 (25)	0.50
Postnatal steroid treatment, n (%)	22 (41)	5 (42)	0.66
Post-menstrual age at MRI (weeks + days), median (IQR)	35 + 1 (33 + 4 –37)	35 (32 + 4 –39 + 4)	0.51
Time from birth to MRI (weeks), mean (SD)	7.1 (3.4)	6.8 (2.7)	0.82
TFU abnormalities, n (%)	15 (28)	7 (58)	0.04
Abnormal EEG, n (%)	22 (41)	2 (17)	0.12

GA, gestational age; MRI, magnetic resonance imaging; TFU, transfontanellar ultrasound; EEG, electroencephalography.

Table 2

Educational level of parents

Educational level	Father	Mother	Father	Mother
of the parents
I, n (%)	7 (13)	3 (5.6)	1 (11)	1 (11)
II, n (%)	1 (2)	5 (9.3)	2 (22)	1 (11)
III, n (%)	8 (15)	3 (5.6)	1 (11)	1 (11)
IV, n (%)	3 (6)	18 (33)	1 (11)	1 (11)
V, n (%)	32 (59)	22 (40.7)	4 (44)	4 (44)
VI, n (%)	2 (4)	2 (4)	0	1 (11)

Level VI and Level Vb: schooling stopped in the first three years of secondary education or abandoned during vocational training or shorter secondary education trajectories, before the final year; Level V: completion of the final year of short vocational training courses of dropped out of schooling during general secondary education, before the final year; Level IV: completion of secondary education or dropped out of education after the baccalaureate, without reaching level III; Level III: completion of a diploma equivalent to two years of higher education; Levels II and I: completion of diploma corresponding to more than two years of higher education. The educational level of the general population during the same time period was as follows: I = 16%; II = 14.6%; III = 17.1%; IV = 25.9%; V = 7.4%; VI = 17.6% (http://www.insee.fr/en/methodes/default.asp?page=definitions/niveaux-formation.htm).

2.2 MRI

MRI was performed without sedation. The infants were placed in a supine position, snugly swaddled in a purpose-designed hull with the head wedged by foam cushions in front of ears, well protected from noise. During imaging, an intensive care physician monitored the infants and their vital signs. All MRI examinations were performed with a 1.5 T imager (Sigma Horizon, General Electric) with a dedicated pediatric head coil. All MRI included a three-dimensional T1-weighted gradient-echo sequence (repetition time ms/echo time ms, 250/4.2, section thickness 5 mm) and a T2-weighted gradient-echo sequence (4000/120, section thickness 5 mm). All T1- and T2-weighted images were retrospectively analyzed by two pediatric radiologists (C.T and C.R) with more than 10 years of experience in the interpretation of neonatal imaging data, blind to the perinatal history, ultrasound findings and neurological outcome of the infant. Discrepancies were resolved by discussion and consensus. IPWL were identified on T1- and T2- weighted images as punctate high-T1 and low-T2 signal intensity lesions with a diameter of less than 5 mm, within the periventricular WM. The Cornette classification [8] was used to describe the isolated punctate lesions: number, appearance (organized into clusters in a confluent pattern or into a linear or mixed-type pattern), location [anterior to the frontal horn of the lateral ventricles (anterior region), posterior to the occipital horn of the lateral ventricles (posterior region), or in between (mid-region or centrum semiovale); and observed unilaterally or bilaterally].

2.3 Health-related quality of life

The French translation of the Health Status Classification System Preschool (HSCS-PS) was completed by the parents, for the assessment of health-related quality of life. This questionnaire is one of the few tools to have been validated and adapted for the follow-up of VPT infants [2, 18]. This 12-item HS instrument assesses the following health attributes: seeing, hearing, speaking, getting around, using hands and fingers, taking care of oneself, feelings, learning and remembering, thinking and problem-solving, pain and discomfort, general health and behavior. There were three to five levels for each dimension, according to the intensity of the disorders concerned. QOL was considered “perfect” when the total score was≤12 (1 for each item). If a score >1 was obtained for at least one item, the child was considered to be encountering difficulties.

2.4 Schooling

For each child, school level and the type of school attended were noted. We considered three categories of school: Mainstream school; Specific class adapted to receive children with learning disabilities, within mainstream school, known as a “school integration class” or CLIS (“classe d’intégration scolaire”). About 1% of children in elementary school belong to such classes; Special school (“instituts medico-éducatifs”): most of the children sent to such schools required personalized follow-up in an environment other than mainstream school. The number and levels of repeated classes were recorded for each child. According to INSEE data, the proportion of children from the general population repeating a year over the same period was 15.8% in Rennes and 17.4% in France [19].

2.5 Requirement for special support

The need for paramedical or psychological support was taken into account (physiotherapist, psychomotor therapist, occupational therapist, speech therapist, psychologist, and psychiatrist). Global support from a medical and psychological center (CMP) or SESSAD (“service d’éducation specialisé $\overset{`}{a}$ domicile”) was also recorded.

2.6 Behavioral disorders

Attention and behavioral disorders were explored by non-standardized interview with the parents, taking into account the use of any specific treatment (methyl phenidate) and any psychological/psychiatric support.

2.7 Clinical neurological examination

For each child, a specialist neuromotor examination was carried out between the ages of nine and 14 years, to check for motor abnormalities (motor impairments, cerebral palsy, dyspraxia). The need for medical equipment was also assessed (splints, surgical corset, stander seat, wheelchair). The age at which the child started walking was collected retrospectively from patient files or from the French child health record booklet (available for all children in France).

2.8 Data analysis

Statistical analysis was carried out with SPSS13.0 Windows Software. Variables are described in terms of their means (standard deviation) or medians (interquartile range). We assessed the potential bias, for participants, background clinical and radiological variables, by comparing the study population with their peers excluded from the study or lost to follow-up, in χ², Mann-Whitney or Fisher’s exact tests, as appropriate. QOL and schooling were compared between the IPWL group and the no-lesion group, in χ² or Fisher’s exact tests, as appropriate. For continuous variables, differences between groups were evaluated in Student’s t tests or Mann-Whitney U tests, as appropriate. A post-hoc Bonferroni correction for multiple comparisons was used to measure p values with a limit set at 0.05.

3 Results

3.1 Population

In total, 431 VPT infants were admitted to and discharged alive from our institution’s neonatal intensive care unit during the five-year study period (January 1996 to December 2000). Brain MRI was performed at an age of 7 (3) weeks of life in 131 of these infants (30.4%), according to the standard protocol. The classification of the MRI images was similar between the two MRI scan raters in 128 cases and was obtained by consensus in three cases. The MRI was normal in 65 of these 131 infants (49%), cystic periventricular leukomalacia was observed in 29 (6.7% of the total population and 22% of MRI population), non-cystic WM signal abnormalities were diagnosed in 18 VPT infants (4.4% of the total population and 13.7% of the MRI population), 14 VPT infants had intraventricular hemorrhage (3.2% of the total population and 10.7% of the MRI population), and 5 had dilated or asymmetric ventricles.

Sixteen of the 18 WM signal abnormalities were considered to be isolated punctate white matter lesions (IPWL, Fig. 1) and two were classified as DEHSI (not included in the IPWL group). Cerebral ultrasound scan (WM hypersignal) was correlated with MRI for IPWL lesion in only two patients. Follow-up data obtained at an age of 9 to 14 years were available for 54 of the 65 children. Follow-up MRI findings performed 27 days (IQR: 14–35) days after the first MRI were normal in 12 of the 16 children with IPWL.

3.2 Perinatal characteristics

No difference in perinatal characteristics was observed between the two groups (Table 1).

Children excluded or lost to follow-up with no lesions on the MRI scan were compared with the other children from the “no lesion” group. Similarly, the children excluded or lost to follow-up who had IPWL on the MRI scan were compared with the other children from the IPWL group. No differences in continuous or discrete variables were observed between these groups.

There was no difference in EEG and cranial ultrasound findings between the two groups.

Educational level was lower in our population than in French general population of the same time according to INSEE data, but there was no significant difference between the two groups (Table 2).

3.3 MRI

Mean post-conceptional age and postnatal age at MRI were similar in the two groups. The clinical and radiological characteristics of the children with IPWL are presented in Table 4, according to the Cornette classification [8].

Table 3
Quality of life (HSCS-PS results), motor, behavioral and cognitive outcomes.

No lesion (n = 54) IPWL (n = 12) P value

n (%) n (%) Bonferroni correction

Quality of life

Visual problems 17 (31%) 6 (50%) NS

Hearing 3 (5%) 2 (16%) NS

Speech 3 (5%) 1 (8%) NS

Getting around 1 (2%) 6 (50%) 0.0002

Using hands and fingers 2 (4%) 4 (33%) 0.02

Taking care of oneself 1 (2%) 2 (17%) NS

Learning and remembering 18 (33%) 3 (25%) NS

Thinking and solving problems 12 (22%) 3 (25%) NS

Pain and discomfort 12 (22%) 5 (42%) NS

General health 5 (9%) 1 (8%) NS

Behavior 6 (11%) 3 (25%) NS

Motor, behavioral and cognitive outcome [n (%) or mean (SD)]

Started walking: months (SD) 15 (3) 20 (4) 0.004

Cerebral palsy 0 2 (16%) 0.04

Spastic diplegia 2 (4%) 3 (25%) NS

Medical equipment use 0 5 (42%) 0.0002

Dyspraxia 0 4 (33%) 0.0002

Behavioral difficulties: n (%)

ADHD 18 (33%) 3 (25%) NS

Autism spectrum disorders 1 (2%) 1 (8%) NS

Special schooling: n (%) 29 (52%) 7 (57%) NS

Special care: n (%) 10 (18.5%) 6 (50%) NS

	No lesion (n = 54)	IPWL (n = 12)	P value
Quality of life
Visual problems	17 (31%)	6 (50%)	NS
Hearing	3 (5%)	2 (16%)	NS
Speech	3 (5%)	1 (8%)	NS
Getting around	1 (2%)	6 (50%)	0.0002
Using hands and fingers	2 (4%)	4 (33%)	0.02
Taking care of oneself	1 (2%)	2 (17%)	NS
Learning and remembering	18 (33%)	3 (25%)	NS
Thinking and solving problems	12 (22%)	3 (25%)	NS
Pain and discomfort	12 (22%)	5 (42%)	NS
General health	5 (9%)	1 (8%)	NS
Behavior	6 (11%)	3 (25%)	NS
Motor, behavioral and cognitive outcome [n (%) or mean (SD)]
Started walking: months (SD)	15 (3)	20 (4)	0.004
Cerebral palsy	0	2 (16%)	0.04
Spastic diplegia	2 (4%)	3 (25%)	NS
Medical equipment use	0	5 (42%)	0.0002
Dyspraxia	0	4 (33%)	0.0002
Behavioral difficulties: n (%)
ADHD	18 (33%)	3 (25%)	NS
Autism spectrum disorders	1 (2%)	1 (8%)	NS
Special schooling: n (%)	29 (52%)	7 (57%)	NS
Special care: n (%)	10 (18.5%)	6 (50%)	NS

ADHD: attention-deficit hyperactivity disorder; Special care: physiotherapist or speech therapist or occupational therapist or psychologist; Special schooling: special school or special school in mainstream school or mainstream school with grade retention.

Table 4

Description of isolated white matter lesions and clinical outcome

Patient	MRI and characterization of punctate lesions									Neurological outcome
				Distribution
					Ant		Mild		Post
				region		region		region
	PM age	N	Type	R	L	R	L	R	L
	(weeks)
1	37	>10	Mixed			+	+			Spastic diplegia
										GMFCS Level II
2	39	3–10	Linear			+	+			No abnormality
3	35	3–10	Mixed			+	+	+	+	Autism
4	32	3–10	Linear	+	+	+	+	+	+	Cerebral palsy (level 3)
										GMFCS Level III
5	32	3–10	Linear			+	+	+	+	Anxiety disorders
6	41	>10	Cluster			+	+			Spastic diplegia
										GMFCS Level II
										Learning disorders
7	32	3–10	Linear			+	+			No abnormality
8	34	3–10	Cluster	+	+	+	+			Cerebral palsy
										GMFCS Level III
										Attention disorders
9	33	3–10	Linear			+	+			No abnormality
10	40	3–10	Linear			+	+			Spastic monoplegia
										GMFCS Level II
11	39	>10	Cluster	+	+	+	+	+	+	Polyhandicap
										Spastic diplegia
										GMFCS Level IV
12	37									Lost to follow-up
13	33	3–10	Linear	+	+	+	+		+	No abnormality
14	38									Lost to follow-up
15	35									Lost to follow-up
										Started walking at 18 months
16	34		Linear				+			Lost to follow-up

Ant, anterior; Post, posterior; GMFCS, gross motor function classification system; PM Age, post-menstrual age; N, number of lesions; R, right; L, left.

3.4 Health-related quality of life

Health-related QOL was considered “perfect” in 20/54 children from the “no lesion” group and 2/12 children from the IPWL group (p = 0.15). Table 3 summarizes the questionnaire responses for the two groups: the IPWL group displayed had poorer scores than the no lesion group for the items “getting around” and, “using hand and fingers”.

3.5 Motor outcome (Table 3)

The children of the IPWL group began to walk later than those of the “no lesion” group [20 (4) vs. 15 (3) months, p < 0.01], and had a higher frequency of cerebral palsy (p < 0.05), medical equipment requirements, and dyspraxia (p < 0.01).

Motor impairment was observed in six children from the IPWL group: two were unable to walk and needed a wheelchair and the other four presented spastic monoplegia or spastic diplegia requiring an orthesis.

A descriptive analysis of MRI characteristics as a function of motor outcome in the IPWL group revealed several trends (Table 4). A favorable motor outcome was observed in cases of small lesions with a pinhead or linear appearance, with unilateral or asymmetric lesions, or with only a few spatially restricted lesions.

3.6 Schooling (Table 3)

No significant difference was observed between the two groups in terms of class (special school or special school in mainstream school) and school attended or grade retention [3/12 (25%) vs. 17/54 (31%)] (Table 3). As expected, we observed more grade retention in our study population than was reported for the general populations of Rennes (15.8%) and France (17.4%) over the same period in INSEE data [19].

3.7 Attention and behavioral disorders

Attention and behavioral disorders did not differ in frequency between the two groups, but a need for special care was more frequently reported in the IPWL group (6/12 vs. 10/54, p < 0.05)

4 Discussion

The results of this study of 66 VPT infants followed up and explored at school age provide no evidence of a difference in health-related QOL between the two groups. However despite the relatively small number of subjects demonstrating isolated neonatal MRI punctate white matter lesions, we have observed that these lesions are associated with alterations in mobility item-getting around, dexterity item-using hands and fingers and motor outcomes. This observation is consistent with previous studies reporting an association between punctate lesions and adverse motor outcomes at the age of two years [9 , 16]. The mechanisms leading to this neurodevelopmental disability are not known but we think that these transient multi-focal lesions could be associated with widespread abnormalities in microstructural and metabolic white matter maturation leading to alterations in brain development [20]. Schooling was similar in the two groups, but the frequency of grade retention in the total population of VPT children studied here was twice that for the general population over the same period. In our study, the low level of parental education may have had an effect on the frequency of these disorders.

Due to the small sample size and therefore to a lack of statistical power we cannot rule out the possibility of a decrease in global QOL associated with the IPWL. Moreover a selection bias is possible because we analyzed a selected population of very preterm infants who underwent cerebral MRI and because it is known that some IPWL may be transient [16]. Usual practice at the time at which these children were born was to limit MRI to cases of VPT infants with risk factors for neurological lesions. It is therefore possible that some cases of IPWL were missed. It is also possible that the prognosis of the control group (normal MRI) does not exactly reflect the prognosis of the population without cerebral lesions (normal MRI or absence of cerebral lesion but without MRI performed). However motor outcome in the no lesion group was similar to that reported from other studies on unselected VPT population with normal term MRI [13 , 22]. The evaluation of attention and behavioral disorders was only based on a non-standardized interview and has therefore to be cautiously interpreted but we observed a higher prevalence of these disorders than usually reported in the general population. Similar observations have already been reported in previous studies on VPT [23].

Eleven children from the “no lesion” group (17%) and four from the IPWL group were lost to follow-up. These findings are consistent with those for other studies with eight to 13 years of follow-up [24, 25]. Furthermore, no differences in perinatal characteristics were observed between the children lost to follow-up and the population studied.

An established qualitative scoring system is generally used to classify WM abnormalities (WMA) as normal, mild or moderate to severe according to a five-scale grading system, including (1) the nature and extent of the white matter signal abnormality, (2) periventricular white matter volume loss, (3) the presence of any cystic abnormalities, (4) ventricular dilatation, and (5) thinning of the corpus callosum. Punctate lesions are not included as such. Instead, they are considered under item 1 of this classification, with grade 1 corresponding to a normal T1- and T2-weighted signal throughout the WM, grade 2 corresponding to focal regions of high T1- or T2-weighted signal (2 or fewer regions per hemisphere), and grade 3 corresponding to multiple regions of high T1- or T2-weighted signal (more than 2 regions per hemisphere). The IPWL reported in this study would have been classified as mild or moderate WMA (Table 4). Moderate to severe WMA are present in 15 to 20% of VPT infants [13 , 22] and are predictive of severe motor delay and cerebral palsy at two years of age [13], moderate to severe motor impairment at five years of age [22], neurocognitive delay at four years of age and 6 years of age [14] cognitive delay, cerebral palsy and a requirement for special assistance at school at nine years of age [24]. In our study, the child with the most severe WMA suffered from multiple disabilities. Mild WMA are reported in 50 to 57 % of VPT infants [13 , 22] and their repercussions remain a matter of debate: most children with a normal or mildly abnormal MRI were free from severe impairments at two years of age in the Woodward study [14], but Spittle et al observed that mild WMA increased the risk of moderate to severe motor impairment and mild to severe motor impairment at five years of age, consistent with our findings [22]. At the age of four to six years, children with mild WMA are at higher risk of neurocognitive delay than VPT children with no WMA and children born at term [14].

VPT infants with no WMA are also at risk of motor impairment: 7% had moderate to severe motor impairment and 31% had mild motor impairment at five years of age in the series reported by Spittle et al. [22]. We observed excess grade retention in our population with respect to the general population in both groups. This finding is consistent with observations that cognitive and/or behavioral difficulties can occur in the absence of WM lesions on MRI.

Most follow-up studies of children born VPT have tended to focus on the risks of severe impairment and/or disability. However, given the substantial numbers of very preterm survivors with mild cognitive impairment, it is important to improve knowledge in this field. These less severe, but clinically significant impairments may damage the children’s health-related quality of life and have cumulative impacts on achievement and the need for remedial support. Targeting these children during the important preschool and early school years may therefore be a more effective strategy for reducing the morbidities associated with very preterm birth than focusing solely on those with the most severe impairments. The recognition of milder impairments is also consistent with the secular trend towards a decrease in the frequency of the major cystic white matter lesions traditionally associated with more severe disability. Instead, an increasing number of children will probably experience milder forms of white matter abnormality resulting in high-incidence, low-severity conditions (e.g., learning disabilities, attention-deficit hyperactivity disorder, and developmental coordination disorder) that compromise classroom learning and health-related QOL.

Given the extended developmental trajectories of many neurologic skills, longer-term follow-up is essential to provide an accurate assessment of clinically important neurologic impairments. This need is supported by the finding that early measures are only moderately correlated with longer-term neurologic outcome [26] and with the significant changes in neurologic function that may occur under the influence of numerous intrinsic/extrinsic factors, such as plasticity, compensation, and reorganization of the injured brain, environment and education.

The qualitative rating system proposed by Woodward et al. for classifying the severity of white matter abnormalities cannot discriminate between the respective impacts on neurodevelopment prognosis of the different types of lesion (e.g. white matter lesions, ventricular abnormalities). Examination of the individual white matter abnormality subscales in relation to neurocognitive outcomes suggested that contributed to subsequent risk, but that white matter signal abnormalities and volume loss were of particular relevance [14]. We therefore chose to focus this study specifically on isolated punctate lesions and their repercussions for health-related QOL.

5 Conclusion

This study considering neurodevelopmental outcomes and quality of life at middle-school age and in teenagers as a function of MRI findings at a later-preterm or term time point with a high rate of follow-up provides new information on the long-term follow-up of isolated punctate lesion for assessment of their repercussions. We agree that the early diagnosis of mild impairment remains challenging [26, 27] but our findings highlight the potential benefits of carrying out cerebral MRI after very preterm birth, to identify the subsets of infants most likely to require additional support during follow-up.

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