PEDIATRICS (doi:10.1542/peds.2007-1924)
ARTICLE |
Quality of General Movements Is Related to White Matter Pathology in Very Preterm Infants
a Victorian Infant Brain Studies, Murdoch Childrens Research Institute, Melbourne, Australia
b Departments of Paediatrics
c Obstetrics and Gynaecology
g Howard Florey Institute, University of Melbourne, Melbourne, Australia
d Division of Newborn Services, Royal Women's Hospital, Melbourne, Australia
e Queensland Cerebral Palsy and Rehabilitation Research Centre, University of Queensland, Brisbane, Australia
f Department of Pediatrics, Neurology, and Radiology, St Louis Children's Hospital, Washington University, St Louis, Missouri
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ABSTRACT |
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OBJECTIVE. Preterm infants are at an increased risk for abnormalities of general movements, which predict subsequent poor neurodevelopmental outcome. The cerebral lesion that predisposes the preterm infant to abnormal general movements remains unknown. The objective of this study was to determine the association between MRI-defined cerebral abnormalities and general movements at 1 and 3 months' corrected age in infants who were born very preterm.
METHODS. Eighty-six preterm infants (<30 weeks' gestation) were prospectively recruited and underwent brain MRI at term-equivalent age to investigate the relationship between qualitative white and gray matter pathology and abnormality of general movements. Standardized videotaped recordings of general movements were obtained at 1 and 3 months postterm (±1 week) and scored without knowledge of the MRI findings. At 1 month corrected age, general movements of a writhing character were classified as normal or abnormal (poor repertoire, cramped synchronized, or chaotic). At 3 months' corrected age, fidgety general movements were classified as present or absent.
RESULTS. At 1 month, 53 (62%) infants had abnormal general movements, 46 of whom had poor repertoire general movements and 7 of whom had cramped synchronized general movements. At 3 months, 23 (25%) infants had absent fidgety movements. At both 1 and 3 months of age, consistently abnormal general movement classifications were related to increasing white matter abnormality on MRI. In contrast, there were no significant relationships between general movement classifications and gray matter abnormalities, either individually or in total.
CONCLUSION. The significant relationships between general movements at 1 and 3 months and cerebral white matter abnormalities on MRI in the very preterm infant support the concept that abnormal general movements reflect white matter injury.
Key Words: developmental follow-up • magnetic resonance • neuromotor outcome • preterm infants
Abbreviations: GM—general movement • IVH—intraventricular hemorrhage • PVL—periventricular leukomalacia
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INTRODUCTION |
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Infants who are born very preterm are at increased risk for adverse neurodevelopmental outcomes as a result of prenatal or perinatal brain alterations.1 The rate of cerebral palsy is high, up to 15%, in surviving infants who are born very preterm, and up to 50% display more minor motor impairments, such as developmental coordination disorder.2,3 Prechtl's method of assessing spontaneous movements in infants, known as general movements (GMs), is a reliable, sensitive, nonintrusive method of assessing neonatal neuromotor behavior.4,5 Standardized observation of GMs is predictive of neurologic outcome, in particular cerebral palsy, in preterm infants.6
Assessment of GMs involves the observer's assessing movement quality by means of a gestalt perception that takes into account complexity and variability of movement.7 The assessment of GMs is based on the evaluation of the infant's repertoire of movement patterns displayed by all parts of the body and does not pay special attention to specific body parts.8 Normal GMs are complex, variable, and elegant, reflecting variability in neural function.8
MRI of the neonatal brain has improved our understanding of the nature and extent of cerebral abnormalities in preterm infants.9 Cerebral abnormalities that are identified on MRI at term-equivalent age in very preterm infants predict later neurodevelopmental outcomes, with moderate to severe white matter injury being associated with severe cognitive delay, psychomotor delay, cerebral palsy, and neurosensory impairment.1 Because the quality of GMs is believed to be modulated by cerebral functioning, there may be a relationship between quality of GMs and such cerebral abnormalities as defined by MRI in the preterm infant. The neuropathologic alterations that predispose infants who are born preterm to abnormal GMs have not been defined. The primary aim of this study was to determine any association between the quality of GMs at 1 month and/or 3 months' postterm age and cerebral abnormalities in the white and gray matter as measured using qualitative analysis of structural MRI at term age.
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METHODS |
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Patients
Between January 2005 and September 2006, 96 very preterm infants were admitted to the Royal Women's Hospital, Australia, and recruited for this study. Included infants were born at <30 weeks' gestation. Gestational age was based on the best obstetric estimate, usually confirmed by ultrasound scan before 20 weeks. Infants were excluded when they were born with major congenital anomalies associated with a poor neurodevelopmental outcome or were not living within a 100-km radius of the hospitals or when the families did not speak English. The study was approved by the Research and Ethics Committees at the Royal Children's Hospital and the Royal Women's Hospital. Infants were enrolled at 38 to 40 weeks' postmenstrual age, once parental consent was obtained.
Procedure for MRI
MRI Acquisition
MRI was performed at term-equivalent age (38–44 weeks' postmenstrual age). MRI was obtained without sedation or anesthesia, as described previously.1 MRI was performed by using a 1.5 Tesla General Electric Signa System (GE-Medical Systems, Milwaukee, WI) on the first 51 infants using sequences previously published.10 The remaining infants underwent MRI by using a 3.0 Tesla Siemens Trio (software version 11b and 13b) using a standard 12-channel matrix head coil operating in CP mode as the scanner was changed. Seventy-six contiguous Coronal Dual Echo turbo spin echo T2-weighted images (1 x 1 x 2 mm) were acquired with a repetition time of 4900 ms, echo time of 64/179 ms, echo train length of 9, and a parallel imaging factor of 2 (GRAPPA algorithm) with refocusing flip angle 150°. T1-weighted imaging was performed by using 176 contiguous slices with FLASH 3D acquisition (1 x 1 x 1 mm) repetition time of 19 ms, echo time of 4.92 ms, flip 25°, and a parallel imaging factor of 2 (GRAPPA algorithm).
MRI Qualitative Scoring
A standardized scoring system was used to grade white and gray matter pathology.9,11 The white matter was scored on a scale from 1 to 3 for the following 5 areas: nature and extent of white matter signal abnormality, periventricular white matter volume loss, presence of any cystic abnormalities, ventricular dilation, and thinning of the corpus callosum.
The white matter pathology scores for the individual items were totaled and classified into 4 groups, as previously described: normal (score: 5–6) mild (score: 7–9), moderate (score: 10–12), and severe (score: 13–15). Gray matter was scored in a similar way with a scale from 1 to 3 for the following: gray matter signal abnormality, gyral maturation, and size of the subarachnoid space. The gray matter pathology scores for the individual items were totaled and classified into 2 groups, as previously described: normal (score: 3–5) and abnormal (score: 6–9).10
All scans were scored independently by a pediatric neuroradiologist or neonatologist without previous knowledge of clinical status or GMs assessment. Interrater agreement for group assignment was 96%.1
Procedure for GM Assessments
GM Acquisition
Videotaped recordings of GMs were obtained on 2 occasions. The first was at 1 month (±1 week) postterm, and the second at 3 months (±1 week) postterm. A standardized assessment technique was used to obtain the GM video footage.12 The infants were videotaped in their homes, lying supine during periods of alert wakefulness, wearing minimal clothing.
Qualitative Analysis of GMs
The GMs were classified as normal or abnormal according to the gestalt perception of the global quality of the movement pattern.13–15 Two distinct general movement patterns are observed from term age: writhing movements and fidgety movements. Writhing movements are present from term age up to 9 weeks. Fidgety movements appear during a major period of neural transformation as early as 6 weeks but usually at approximately 9 weeks and are present to 20 weeks, at which time antigravity movements start to dominate.12
At 1 month, writhing GMs were described as normal or abnormal (poor repertoire, cramped synchronized, or chaotic).15,16 Consistency of cramped synchronized movements is associated with cerebral palsy.16 For the second time period at 3 months, GMs of a fidgety nature were described as normal, abnormal, or absent.5 Trajectories for each infant were then described when GM assessments were obtained at both 1 and 3 months. An infant was classified as having a "normal trajectory" when he or she received a score of normal at both 1 and 3 months, "transient abnormal GM trajectory" when he or she received a score of abnormal (poor repertoire, cramped synchronized, or chaotic) at 1 month followed by a normal score at 3 months, or "consistently abnormal trajectory" when he or she scored abnormal at 1 month and absent at 3 months.
The quality of GMs was rated on the basis of the video recordings by 2 assessors (A.J.S. and N.C.B.); both assessors were masked to MRI results. All assessments were scored independently by raters who had completed formal GM training with the General Movements Trust.12 Interrater reliability between assessors was established for 22 infants by using Cohen's 
. At 1 month, there was 90.9% agreement ( = 0.79, SE = 0.16). At 3 months, there was also strong agreement (90.9%) between raters ( = 0.77, SE = 0.21).
Statistical Analysis
Data were analyzed by using Stata 9.0 (Stata Corp, College Station, TX). The significance of the relationships between the quality of GMs at 1 and 3 months and the trajectory of GMs, on the one hand, and white and gray matter pathology, both individual items and the total scores, on the other hand, were tested by Spearman's rank order correlation coefficient. Because several other clinical variables may influence early development, we investigated whether there was a relationship on Spearman's rank order correlation coefficient between GM trajectories and gender, gestational age, birth weight, multiple births (singleton versus multiple), postnatal corticosteroids, oxygen at home, intraventricular hemorrhage (IVH) grade III/IV, and cystic periventricular leukomalacia (PVL).
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RESULTS |
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Ninety-nine infants were recruited, 86 of whom had MRI performed at term-equivalent age (Fig 1). The 86 infants were at high risk for adverse long-term outcomes, with mean birth weight of 1014 g and mean gestational age of 27.3 weeks (Table 1).
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At 1 month, GM assessments were obtained for 85 infants; 32 (38%) infants had normal GMs, 46 (54%) had poor repertoire GMs, and 7 (8%) had cramped synchronized GMs; none had chaotic movements. One infant was in a hip spica at this time, and GM assessments could not be performed. At 3 months, GM assessments were obtained for 85 infants, including the infant who was previously in a hip spica at 1 month; however, 1 infant was withdrawn from the study because her mother returned to employment outside the home. At 3 months, 64 (76%) infants had normal GMs, 21 (24%) had absent GMs, and no infants had abnormal GMs.
The trajectory of GMs was obtained for 84 infants, with 32 (38%) infants having consistently normal GMs, 32 (38%) having transient abnormal GMs with poor repertoire GMs at 1 month followed by normal GMs at 3 months, and the remaining 20 (24%) having consistently abnormal GMs. Of the infants with consistently abnormal GMs, 13 had poor repertoire GMs at 1 month followed by absent GMs at 3 months, and 7 infants had cramped synchronized GMs at 1 month followed by absent GMs at 3 months. No infant had normal GMs at 1 month followed by absent GMs at 3 months.
At term-equivalent age, 22 (25%) infants had no white matter abnormalities on MRI, whereas 54 (63%) infants had mild white matter abnormalities, 6 (7%) had moderate white matter abnormalities, and 4 (5%) had severe white matter abnormalities. Seventy-three (85%) infants had no gray matter abnormality, and 13 (15%) did have gray matter abnormalities. There was a significant relationship between white and gray matter injury (P < .001), with gray matter injury being present in 7 of the 10 patients with white matter injury.
At both 1 month and 3 months of age, consistently abnormal GM classifications were related to increasing cerebral white matter abnormalities on all 5 individual items, and the total score (Table 2). All infants with consistently normal GM trajectories had no or mild white matter abnormality, whereas all infants with moderate to severe white matter abnormality, except for 1, had consistently abnormal GM trajectories (Table 2). Of infants with transient GM abnormalities, 19 (60%) had mild white matter injury. In contrast, there were no significant relationships between GM classifications and gray matter pathology, either on individual items or on the total score (Table 3).
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IVH grade III/IV and cystic PVL on cranial ultrasound also had a significant correlation with GMs at 1 and 3 months, although the correlation coefficient for white matter abnormalities was substantially higher at 3 months than it was for either IVH or PVL (Table 4). There were no significant relationships with GMs for the other perinatal variables, except for multiple births at 3 months only, but with a weaker correlation coefficient than for the other 3 variables (Table 4).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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This study identified a significant relationship between GMs at 1 and 3 months and the nature and extent of cerebral white matter abnormalities at term-equivalent age in infants who were born very preterm. IVH and PVL also had a significant relationship with GMs at 1 and 3 months; because they can be intermediate steps along the pathway leading to white matter abnormalities, we did not look for interactions among these 3 variables in their effects on GMs. There were no significant relationships between GMs at 1 and 3 months and gray matter pathology. No other perinatal clinical variables, apart from multiple births at 3 months, correlated with abnormal GMs.
Diffuse cerebral white matter abnormalities are the most common abnormality found on MRI in very preterm infants, with a high incidence in our study of 53% of infants with mild abnormalities and 12% of infants with moderate-to-severe abnormalities. This high incidence is consistent with other studies.10,17 White matter abnormalities have been shown to relate to adverse motor outcomes at later ages,1,18 but this study confirms that alterations in motor behavior (GMs) are present much earlier, during infancy.
This study examined the relationship between brain structure using MRI and GMs in very preterm infants; however, several studies investigated the relationship of GMs in infants with other neuropathologies. Guzzetta et al19 assessed the correlation among GMs, MRI, and outcome in term infants at risk for hemiplegia. The quality of GMs correlated with the MRI findings and predicted hemiplegia, particularly for infants with concomitant ipsilateral involvement of a cerebral hemisphere, basal ganglia, and internal capsule on the MRI scan. Cioni et al6 investigated the relationship among early neurologic examination, GMs, and outcome at 2 years in a group of 16 preterm infants with unilateral brain lesions. They also reported that cerebral injury resulted in early alterations in motor behavior: all infants with abnormal outcomes had abnormal GM trajectories.6 For preterm infants, a small study of 21 infants reported a strong correlation between the duration of echodensities in the parieto-occipital white matter on cranial ultrasound and abnormal GM trajectories.4 The authors also reported that infants with echodensities in the frontal area had no significant alterations in GM trajectories, indicating that the location of white matter abnormality may also be important.4
Our data focus on a larger prospective cohort of preterm infants and define a strong relationship between GMs and the presence and severity of cerebral white matter abnormalities. The strong correlation between normal GMs and no white matter abnormality is consistent with previous literature that normal GMs have the highest sensitivity and are nearly 100% predictive for normal outcome.12 Poor repertoire GMs have been reported to be the least predictive of later outcome,20 because not all infants with poor repertoire GMs have abnormal outcomes. It is interesting that our data showed that many of the infants with transient abnormalities with GM trajectories—that is, poor repertoire GMs at 1 month followed by normal GMs at 3 months—displayed mild white matter injury. Although mild white matter injury has been shown to be very common (up to 50%) in very preterm infants,17 many infants with mild white matter injury have normal outcomes.1 Ferrari et al13 also reported that transient GM abnormalities are likely to be linked to minor or transient cranial ultrasound abnormalities. Cioni et al20 hypothesized that GM abnormalities at a young age might be related to lesions of subsystems where their role in motor control ceases after 2 to 3 months. Thus, the persistence of abnormality and/or the evolution of absent fidgety movements is more supportive of a more substantial disturbance in motor development.
This study further supports that cramped synchronized movements are strong indicators of a more severe cerebral lesion, with the uniform presence of white matter abnormality. All infants with cramped synchronized movements in this study had evidence of white matter injury: 2 with mild abnormality, 2 with moderate abnormality, and 3 with severe white matter abnormality. Previous studies examined the efficacy of cramped synchronized movements in predicting cerebral palsy and found that the specificity of the cramped synchronized GMs was 92.5% to 100%.16
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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This study identified that the nature and severity of cerebral white matter abnormalities related to the persistence of abnormal motor behavior in the first 3 months of life, as assessed by GMs, suggesting that cerebral white matter is the major neuropathology responsible for such early functional motor abnormalities. In contrast, although GMs are regarded as a complex cerebral task for the immature brain, there was no relationship to qualitative gray matter disturbance on MRI. Infants who are born preterm may benefit from both MRI and GM assessments to assist in delineating both cerebral structure and motor functioning. Abnormality in GMs is likely to be related to underlying white matter abnormalities, and both evaluations may assist in delineating infants at risk for referral to early intervention services. Perinatal clinical variables have been shown to be poorly predictive of long-term neurodevelopmental outcomes for the vast majority of preterm infants21; therefore, combining functional, nonintrusive, inexpensive GM assessments, which may be repeated through early infancy, with structural MRI in high-risk infants is rational. Additional studies will be conducted to assess the long-term neurodevelopmental outcomes of the infants in this study to establish the comparative or complimentary long-term predictive value of early GM assessments and MRI scans for preterm infants.
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ACKNOWLEDGMENTS |
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Dr Spittle received a scholarship from the National Health and Medical Research Council (NHMRC) of Australia (grant 334390) to complete her PhD studies. Dr Boyd is supported by an NHMRC Post Doctoral Fellowship (grant 284571). This study was funded in part by NHMRC project grant 284512.
We thank Jane Orton and the VIBeS Plus team, Murdoch Childrens Research Institute, for assistance with collecting data.
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FOOTNOTES |
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Accepted Oct 1, 2007.
Address correspondence to Alicia J. Spittle, MSc, BPhysio, Victorian Infant Brain Studies, Murdoch Childrens Research Institute, 2nd Floor, Royal Children's Hospital, Flemington Road, Parkville, Melbourne, Australia 3052. E-mail: alicia.spittle{at}rch.org.au
The authors have indicated they have no financial relationships relevant to this article to disclose.
| What's Known on This Subject Very preterm infants are at an increased risk of abnormal general movements, which are predictive of long-term, adverse neurological outcome. Little is known about the cerebral lesions that result in abnormal general movements in preterm infants.
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| What This Study Adds Abnormal general movements in very preterm infants are associated with white matter pathology, which results in alterations in movement quality as early as 1 month corrected age in very preterm infants.
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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics
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