AIM To evaluate the correlation between visual function and neurodevelopmental outcome in children with periventricular leucomalacia at 1 and 3 years.
METHOD Visual acuity, visual field, ocular motility, and optokinetic nystagmus were tested in 29 infants with periventricular leucomalacia by brain magnetic resonance imaging. All infants also had a structured neurological examination and a Griffiths developmental assessment.
RESULTS 21 of the infants showed at least one abnormality of visual function. The degree of visual impairment—that is, the number of visual tests showing abnormal results—correlated well with the results on developmental assessment at both ages.
CONCLUSION Multivariate analysis showed that visual impairment was the most important variable in determining the neurodevelopmental scores of these infants, more than their motor disability and the extent of their lesions on magnetic resonance imaging.
- developmental score
- magnetic resonance imaging
- periventricular leucomalacia
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In the last decade there has been increasing evidence that infants with periventricular leucomalacia (PVL) show a high incidence of abnormalities on tests assessing various aspects of visual function, such as eye movements, visual acuity, visual fields, and visual evoked potentials.1-6 Visual abnormalities are significantly associated with the postchiasmatic visual pathway and, in particular, optic radiations and visual cortex on magnetic resonance imaging (MRI).4-6 Abnormal visual function can already be observed in the first months of life and seems to persist at preschool and school age.3 ,7 It is also known that visual abnormalities are often associated with motor, perceptual, and global neurodevelopmental abnormalities.7-10
The relation between visual function and neurodevelopment in children with brain lesions is not fully understood. The concomitant involvement of visual and neurodevelopmental abilities found in previous studies is not surprising, as children with visual impairment often showed extensive lesions which involved the underlying structures relevant for motor, cognitive, and visual functions.9 ,11 ,12 However, a causal and direct effect of visual impairment on development may also be hypothesised. Vision plays a crucial role in early motor and cognitive learning,13 and developmental retardation is often observed in congenitally blind infants, even in the absence of brain lesions.14
The aim of this study was to evaluate the correlation between visual function and neurodevelopmental outcome in the first year of life in infants with PVL. More specifically, we aimed not only to evaluate whether developmental scores correlated with the extent of visual impairment but also, by multivariate analysis, whether such a correlation, if confirmed, could be due to other variables, such as the severity of brain lesions, rather than directly to the visual impairment.
Subjects and methods
The patients included in this research are part of a continuing follow up study of newborns with brain lesions born at the Neonatal Unit of the University Hospital of Pisa between January 1989 and December 1994. As part of this study, all the newborns with brain lesions on sequential neonatal ultrasound, performed with 5 and 7.5 MHz probes, who present clinical neurological abnormalities at term, such as abnormal muscle tone or abnormal quality of spontaneous movements,15 are referred to the Division of Child Neurology and Psychiatry and are enrolled in a prospective clinical and MRI follow up study.
For the present research we selected all cases fulfilling the following criteria:
- clear signs of PVL on MRI, according to the criteria indicated in the literature16,17;
- comprehensive visual assessment performed at the mean (SD) age, corrected for prematurity, of 12 (4) months;
- neurological and neurodevelopmental assessments performed at the same age as the visual assessment.
As the aim of this study was to evaluate cerebral visual impairment, infants who showed severe ophthalmological abnormalities (such as ROP stage III or upwards, major refraction problems, optic nerve atrophy) were excluded. Similarly, we also excluded infants with congenital diseases.
This was performed by using an examination based on Touwen criteria.18 The infants were classified into three groups: (1) normal; (2) mildly abnormal (mild retardation and/or neurological signs, but not cerebral palsy); (3) cerebral palsy with relatively normal head and trunk control; (4) cerebral palsy without head and trunk control.
This included the assessment of various aspects of visual function as follows.
Grating acuity—this was assessed binocularly by the Teller acuity card procedure.19 ,20This method is based on an inborn preference for a pattern (black and white gratings of different stripe widths) over a uniform field, depicted on cards with decreasing stripe widths. The location of the left/right position of the test stimulus varies randomly. An observer judges the infant's reaction as to the location of the test stimulus on the basis of eye and head movement. The threshold of acuity is taken as the finest stripe width for which the subject consistently responds correctly. Acuity values were expressed in minutes of arc (or cycles per degree) and compared with normative data reported in the literature.20 ,21
Visual field—its size was assessed using kinetic perimetry by the technique described in detail elsewhere.18 ,19 The apparatus consists of two 4 cm wide black metal strips, mounted perpendicularly to each other and bent to form two arcs, each with a radius of 40 cm. The perimeter is placed in front of a black curtain, concealing the observer, who can watch the infant's eye and head movements through a peep hole. The infant is held in the centre of the arc perimeter, with the chin supported. During central fixation of a 6° diameter white ball, an identical target is moved from the periphery towards the fixation point along one of the arcs of the perimeter at a velocity of around 3°/s. Eye and head movements towards the peripheral ball are used to estimate the outline of the visual fields. Normative data for full term and preterm infants are available.21 ,22
Horizontal optokinetic nystagmus (OKN)—this was elicited by moving a large piece of paper at a distance of 40 cm in front of the infant's face, at a velocity of about 15°/s. The paper is covered with black and white dots of 1 cm2. The number of saccades in response to left side stimulation is judged and compared with that of right side stimulation. Normally, binocular OKN is symmetrical from birth onwards, whereas monocular OKN (not systematically tested in this study) shows a better response to stimulation in a temporonasal direction up to about 3 to 6 months of corrected age.
Oculomotor behaviour (following and fixation) and strabismus—any abnormality of eye contact, spontaneous nystagmus, fixation and following in all directions, and convergence movements is also noted. Eye alignment was tested by commonly used orthoptic techniques, such as the cover test.
Each test of visual function was scored on a two point scale (0 = normal, 1 = abnormal). A visual function score was given to each infant on the basis of the number of impaired items. Scores ranged from 0 (no item impaired) to 5 (all items impaired).
This was assessed using the Griffiths developmental scales.23 General developmental quotients (DQs) and, separately, the DQ of each subscale (locomotor, personal-social, hearing-speech, hand-eye co-ordination, and performance) were obtained. Scores were classified as normal (85 or above), borderline (84–71), or abnormal (70 or below). The test was performed at about 1 year of age (range 8–16 months), and a follow up assessment was also performed at around 3 years of age (range 30–47 months).
MAGNETIC RESONANCE IMAGING
Brain MRI studies were performed under sedation using a 0.5 T system in sequence spin-echo. T1, proton density, and T2 weighted images were obtained in the axial, coronal, and sagittal planes with sections of 5 mm. The images were assessed retrospectively by a neuroradiologist (RC) and separately by a child neurologist (GC), unaware of the prenatal and perinatal histories or of the clinical evaluations. MRI findings were scored according to two different classifications used in our previous studies on PVL11 ,24(table 1).
Extent of the lesion
The following items were scored: size of lateral ventricles, evidence and extension of white matter damage (as shown by areas of prolonged T1 and/or T2 relaxation) and of white matter loss (as shown by abnormal infolding of cerebral gyri and sulci), thinning of corpus callosum, evidence and size of cystic areas (as shown by areas of hypointensity on T1 and proton density weighted images and hyperintensity on T2 weighted images), size of the subarachnoid space, and abnormalities of cortical grey matter. Each item was scored on a three grade scale, with score 3 indicating the most severe MRI abnormalities. The scores of the seven items were summed to obtain a total score for each infant. The total scores were also classified on a three grade scale.
Severity of the lesions in optic radiation and visual cortex (striate, parastriate, and peristriate areas)
Three degrees of impairment were scored: 1, no impairment; 2, moderate impairment; 3, severe impairment. The left and right sides were graded separately. In the few cases in which side differences were found, the most severe scores were taken.
Correlation analysis was performed by the Kendall correlation test (tau-b coefficient). A multiple regression analysis was conducted to assess effect of visual impairment, motor outcome, and MRI findings on cognitive development at 1 year. The correlation between DQs at 1 and 3 years was tested by the Spearman test.
Although the aim of this study was to correlate visual and developmental findings at the same age (1 year), we also correlated both visual and cognitive findings at 1 year with developmental scores obtained after 30 months.
Twenty nine infants fulfilled the inclusion criteria. Their gestational age at birth ranged from 27 to 36 weeks (mean (SD) 31 (2.8) weeks). Mean (SD) age at testing (corrected for prematurity) was 13 (2.1) months (range 8–16). Table 2 summarises the results of all infants tested. Cranial ultrasound results were available in 28 of the 29 infants studied. According to the classification suggested by de Vries et al,25 13 infants had grade 1 PVL, eight had grade 2, and seven grade 3. Table 2 gives the details of ultrasound findings.
One case showed normal and six mildly delayed motor development while the remaining 22 subjects had cerebral palsy. Seventeen infants showed relatively normal head and trunk control (15 diplegic and two hemiplegic cases), which was lacking in the other five infants (all tetraplegic cases).
Severe fixation and following disorders were present in eight of the 29 infants and strabismus in 19. Abnormal grating acuity was found in 13, reduced visual field in nine, and OKN abnormalities in 17.
Six infants had a visual function score of 0 (all the items were normal), seven had a score of 1, and five had a score of 2; two had a score of 3, and the other two a score of 4. The remaining seven infants had a score of 5 (all the items abnormal). Table 3 details the visual assessment.
The global DQs in the cohort at 1 year ranged from 26 to 101 (mean DQ = 74.7). Fourteen subjects had a normal DQ, four fell in the borderline range (70–84), and 11 had abnormal DQ (< 70). Table 3shows results obtained in each subscale.
The global DQ at follow up was available in 20 of the 29 infants. This ranged from 32 to 102 (mean DQ = 82).
MAGNETIC RESONANCE IMAGING
Table 2 shows details of the MRI findings. The total score, summating the results of the individual items assessing the extent of the lesions, ranged from 7 to 17. When optic radiation and visual cortex were assessed, 16 infants had involvement of the optic radiation. One of the 16 also showed involvement of the visual cortex.
CORRELATION BETWEEN VISUAL FUNCTION AND MRI FINDINGS
There was a significant correlation between visual function score and size of lateral ventricles (tau-b = 0.63; p < 0.000), white matter damage (tau-b = 0.40; p = 0.01), white matter loss (tau-b = 0.48; p = 0.003), and corpus callosum (tau-b = 0.35; p = 0.03).
A very high correlation coefficient was also found with optic radiation (tau-b = 0.76; p < 0.000). Visual cortex was not included in this kind of analysis because only one infant of our sample showed abnormalities; this infant presented severe visual impairment in all the items evaluated, as well as mental retardation and severe diplegia.
CORRELATION BETWEEN VISUAL FUNCTION AND DEVELOPMENTAL SCORES
There was a significant correlation between visual impairment and general DQ (tau = 0.58; p = 0.000); the correlation also reached significance for all subscale DQs (table 4).
CORRELATION BETWEEN BRAIN LESIONS AND MOTOR ABILITY AND DEVELOPMENTAL SCORES
Both brain lesions and motor impairment also showed a significant correlation with developmental scores (tau = −0.53, p = 0.000 and tau = 0.43 and p = 0.000, respectively). Table 4 shows details of the correlation with the subscale DQs.
DIRECT COMPARISON OF THE INFLUENCE OF VISUAL, MOTOR, AND MRI FINDINGS ON DEVELOPMENT ASSESSMENT
To examine the influence of visual, motor, and MRI impairment on developmental scores, we also did a multiple regression analysis (stepwise method), which always indicated the visual deficit to be the most important variable in determining cognitive performances of our sample (F = 40.9, p < 0.000); motor impairment entered as the second variable (F = 32.9, p < 0.000), while brain lesions, as detected by MRI, did not reach significance.
The results were quite different when tetraplegic infants were not included in the sample. Both the global DQ and the subscale DQ remained correlated with visual impairment (except for personal-social DQ) but not with motor outcome and MRI findings. On multivariate analysis, visual function was the only variable to reach significance (F = 12.8, p = 0.002) (table 5).
CORRELATION BETWEEN EARLY AND LATE ASSESSMENT
There was a significant correlation between visual impairment at 1 year and general DQ at 3 years (tau-b = 0.40; p = 0.02). Moreover the DQs at the two assessments were significantly correlated (r = 0.65; p = 0.002).
Our results show a high incidence of abnormalities in various aspects of visual function, such as grating acuity, ocular motility, visual field, and OKN in infants with PVL. Twenty three out of 29 of our children had at least one abnormality on one of these tests, and more than 50% had multiple abnormalities. These are higher than in previous studies,1 ,5 ,6 ,9 and the difference may be explained by the different inclusion criteria used. In our study, only infants with PVL on ultrasound examination who had overt clinical signs at term underwent MRI, and those with PVL who had a normal neurological examination at term were not enrolled in the prospective clinical and imaging follow up study. The aim of this study, however, was not to replicate previous studies reporting the incidence of visual abnormalities in a population of infants with PVL,5 ,9 but to evaluate whether visual abnormalities at 1 year, if present, were associated with the extent of the lesions on MRI and with neurocognitive abnormalities assessed at the same time.
We were also able to show a significant correlation between visual function and neurodevelopmental quotients at 1 year. The infants with normal visual function had normal cognitive performances, while those with the most severe visual impairment also had the lowest DQ. The correlation was significant not only with the developmental assessment performed at 1 year, but also with that performed after 2 years of age. These results confirm our previous findings in full term infants with hypoxic-ischaemic encephalopathy,12 in whom we also found a strong correlation between visual function and DQ.
The only study to report an association between early visual and developmental abnormalities in preterm infants with PVL is by Ekenet al.9 Their findings, however, cannot be easily compared with ours, as they also included preterm infants with other types of brain lesion, and visual acuity was the only measure of visual function assessed.
Our study has also highlighted the importance of assessing various aspects of visual function, as these may play an important role in global development.
In this study we were also interested to evaluate whether the low developmental scores could be mainly due to the severity of the brain lesions or motor impairment, rather than to a direct effect of the visual impairment. The values of the correlation coefficients, as well as the results of multiple regression analysis in our cohort, suggest that visual function is crucial per se in the early development of these children. This finding is not surprising and is in agreement with previous studies,13 ,14 indicating the important role played by vision in the early phases of infant development.
Although in this study the correlation between visual function and DQ was significant, some exceptions were observed. For example, cases 12 and 13 had low DQs, despite normal visual function and a mild strabismus. In contrast, other infants had a DQ within the normal range for age, but showed a strabismus associated with asymmetrical OKN (case 14) or abnormal visual acuity (cases 17 and 19). These results can be explained by the fact that, although vision plays an important role in cognitive development, the latter is a complex and multifactorial event. Other factors, related partly to biological structure of each individual (including the presence of brain lesions) and partly to environmental conditions, will also influence the outcome.
In conclusion, our findings confirm the importance of a comprehensive assessment of infants with PVL. Further studies are also needed, including other aspects of cortical visual function such as orientation-reversal visual evoked potentials,26 ,27 to evaluate the relation between early abnormalities of visual function and cognitive and perceptual motor abilities at school age. Early detection of impaired visual function may permit these infants to be enrolled in early intervention programmes, which can improve their visual outcome.28 Longitudinal studies are needed to evaluate the plasticity of the central visual areas after early brain damage and the possible role of the environment in brain reorganisation.
This work was supported by grant RC 1/98 from the Italian Ministry of Health. The authors gratefully acknowledge the contribution of Jackie Van Hof-van Duin, Carlo Romano, and Michele Coluccini to the visual assessments, and Paola B Paolicelli to the neurological examinations.