Influence of gestational age on the type of brain injury and neuromotor outcome in high-risk neonates

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1 DOI 1.17/s ORIGINAL PAPER Influence of gestational age on the type of brain injury and neuromotor outcome in high-risk neonates Christine Van den Broeck & Eveline Himpens & Piet Vanhaesebrouck & Patrick Calders & Ann Oostra Received: 16 July 27 / Accepted: 4 October 27 # Springer-Verlag 27 Abstract This study was an investigation of a possible correlation between either the gestational age (GA) and type of brain injury or between the gestational age and type, distribution and severity of cerebral palsy (CP). Four hundred sixty-one children with a birthweight 125 g and GA 3 weeks with a complicated neonatal period and/ or brain injury on serial cerebral ultrasound were selectively followed at the regional Center for Developmental Disorders. The children were divided into a pre and group. There were 4 children with cerebral palsy in the pre group and 38 children with cerebral palsy in the group. Various types of brain injury diagnosed by echography were nosologically classified. The type, distribution and severity of cerebral palsy were also registered. The type of brain injury most frequently occurring in the group was hypoxic-ischemic injury to the basal ganglia (39%), focal ischemia (18%), subcortical hemorrhage (13%) and parasagittal cerebral injury (1%). In the pre group 39% of the children with cerebral palsy had Christine Van den Broeck and Eveline Himpens equally contributed to this article. C. Van den Broeck : E. Himpens (*) : P. Calders Rehabilitation Sciences and Physiotherapy Ghent, University College Arteveldehogeschool-Ghent University, Campus Heymans (UZ) 1B3, De Pintelaan 185, 9 Ghent, Belgium eveline.himpens@ugent.be A. Oostra Center for Developmental Disorders, Ghent, Belgium P. Vanhaesebrouck Department of Neonatology, University Hospital Ghent, Ghent, Belgium periventricular leukomalacia, 24% intraventricular hemorrhage and 18% persistent flares. There was a significant correlation between the GA and type of brain injury (P<.1; Cramer s V=.76) and between the GA and type (P=.4; Cramer s V=.47) and distribution (P<.1; Cramer s V=.55) of CP. There was no significant correlation between the GA and severity of CP. The type of brain injury detected by serial ultrasound during the neonatal period, as well as the type and location of CP detected during later childhood, are all GA-dependent in at-risk newborn infants with a birthweight of 1,25 g and GA 3 weeks. Keywords Cerebral palsy. Gestational age. Type of brain injury. Distribution of cerebral palsy. Type of cerebral palsy Abbreviations CP cerebral palsy GA gestational age PVL periventricular leukomalacia IVH intraventricular hemorrhage Introduction Cerebral palsy (CP) is one of the most common causes of motor disability in childhood. CP describes a group of disorders of movement and posture causing activity limitation that are attributed to non-progressive disturbances occurring in the developing fetal or infant brain. Abnormal motor behavior is the core feature of CP [3]. Barkovich [2] has shown that the brain region most susceptible to hypoxic/ischemic damage changes as the infant matures. Pre and full- infants may thus experience

2 ischemia in different regions of the brain. Vohr [23] found that the prevalence of any type of cerebral palsy and the degree of severity of CP differed significantly for two groups of different gestational age. Therefore, probable relationships between either the gestational age (GA) and type of brain injury or between the GA and major characteristics of CP (i.e., type, distribution and severity) are described [6, 1 14, 21]. Registers of childhood impairments and large populationbased studies monitor trends in the rates of cerebral palsy according to gestational age, but focus particularly on the prevalence of CP as an assessor of the quality of perinatal care [6, 9, 21]. Other studies focus on the type, distribution and severity of cerebral palsy of and pretem infants [1, 3, 6, 7, 9, 12, 21, 26]. The aim of this study was to investigate a possible relationship either between the GA and type of brain injury, defined by serial echography, or between GA and characteristics of CP. Patients and methods During an 8-year period (January 1995 to December 22), 461 children with a birthweight 1,25 g and a GA 3 who had completed weeks with a complicated neonatal period and/or brain injury consulted the regional Center for Developmental Disorders. The children were assessed at the corrected age of 4, 7, 12, 18 and 24 months. In the Department of Neonatology of the University Hospital of Ghent, an echography was performed on day 1, 3, 7, 14 and 9 (or at the time of discharge). For children with GA 35 weeks major ultrasound findings were usually confirmed by MRI. The children were divided into two groups: a pre group (276 children) with a gestational age (GA) between 3 and 37 weeks and a group (185 children) with GA 37 weeks. Each child was subjected to a detailed physical and neurological examination. Children were classified conforming to the definition proposed by the Surveillance of Cerebral Palsy in Europe [3, 2]. Children were classified as having spastic cerebral palsy if they had at least two of the following criteria: abnormal posture or movement, increased tone or hyperreflexia. An abnormal pattern of posture and/or movements with involuntary, uncontrolled, recurring, occassionally stereotyped movements was defined as dyskinetic cerebral palsy. Two types of dyskinetic cerebral palsy were discerned, i.e., dystonic and choreo-athetotic cerebral palsy. Dystonic CP is described as hypokinesia (reduced activity and stiff movements) and hypertonia. Hyperkinesia (increased activity with stormy movements) and hypotonia are classified as the choreo-athetotic form of dyskinetic CP. Two mixed forms of CP are also identified, i.e., dystonia with spasticity and athetosis with spasticity. Lastly, ataxia is a primary disorder of coordination. Children with ataxia show an abnormal pattern of posture and/or movements with loss of muscular coordination so that movements are performed with abnormal force, rhythm and accuracy. Different types of distribution of CP were nosologically defined. Hemiparesis is a unilateral impairment. Limbs on one side of the body are involved. Diparesis, triparesis and quadriparesis are bilateral motor involvements. When only the lower limbs are affected, CP is classified as diparetic. When four limbs are affected CP is classified as a quadriparesis. Triparesis is used when one arm is not or only minimally affected in a quadriparetic child [25]. The degree of severity of CP was classified as mild, moderate and severe. A child with a mild cerebral palsy performs gross motor skills independently, but speed, balance and coordination are reduced. CP was defined as moderate if the child reached a form of independent walking with or without walking aids. When the child had no basic antigravity postural control and/or could not walk, CP was classified as severe. Nowadays it is common practice to use the GMFCS for the degree of severity of CP. Bax et al. [4] describe a strong correspondence (K=.583; P<.1) between the classification of mild-moderate-severe and the GMFCS. Different types of brain injury detected by cerebral echography were identified. Fig. 1 Relative frequency of type of brain injury in the and pre group (PVL= periventricular leukomalacia; IVH=intraventricular hemorrhage; bas=injury to basal ganglia; para=parasagittal cerebral injury; focal=focal ischemia; haemor=subcortical hemorrhage) pre PVL flares IVH bas para focal haemor

3 Fig. 2 Relative frequency of type of cerebral palsy in the and pre group (spast= spastic; dyst=dystonic; ath=choreo-athetosis; dyst+ spast=dystonia with spasticity; ath+spast=athetosis with spasticity) pre spast dyst ath dyst + spast ath + spast ataxia Periventricular leukomalacia (PVL) is defined as periventricular areas of increased echogenicity evolving into small or extensive periventricular cystic lesions involving occipital and fronto-parietal white matter. Flares are defined as diffuse periventricular echodensities persistent beyond 7 days of age. Deep grey matter injury involves the thalamus and basal ganglia. Parasagittal cerebral injury refers to a lesion of the cerebral cortex and subcortical white matter with a characteristic distribution. Although the injury is usually symmetrical, it may be more striking in one hemisphere as well. Focal ischemia refers to necrosis in the territory of one or more large cerebral blood vessels. Hemorrhage can be subcortical or intraventricular. Intraventricular hemorrhage (IVH) is a hemorrhage into the germinal matrix and the ventricles. The subcortical hemorrhages are situated in the vascular boundery (watershed) zones. For infants these are the regions between the anterior and middle cerebral arteries and between the middle and the posterior cerebral arteries. All analyses were performed using SPSS 12 for Windows. Categorical measures were analyzed with chi 2 -analysis. The Cramer s V test was used to examine the strength of the association between two categorical variables. The level for statistical significance was set at P<.5. Results CP was unequivocally present in 2% (38/185) of the group and in 14% (4/276) of the pre group. The overall prevalence of CP was 17%. For the children with CP a highly significant (P<.1) correlation between the GA and the type of brain injury was found (Cramer s V=.76). The most common brain injury in the group with CP was an injury to the basal ganglia (39%), followed by focal ischemia (18%), subcortical hemorrhage (13%) and parasagittal injury (1%). The diagnosis for all four children with parasagittal injury was confirmed by MRI. In the pre group 39% had periventricular leukomalacia, 24% had an intraventricular hemorrhage and 18% of these prematurely born children had persistent flares on neonatal ultrasound scans. For two pre infants we had no neonatal ultrasound scan (Fig. 1). A significant correlation (P<.1; Cramer s V=.47) was also found between the GA and type of CP. In the group 31% of the children had a spastic type of CP, 29% had dystonia, and 24% had the mixed form of dystonia with spasticity. In the pre group 72% of the children with cerebral palsy had the spastic type of CP; 12% had the mixed form of dystonia with spasticity (Fig. 2). The Cramer s V correlation between gestational age and distribution of cerebral palsy was.55 (P<.1). In the group 37% of the children were classified as having hemiparesis and 58% as having quadriparesis. For the pre group 47% of the children had diparesis, 4% quadriparesis and 1% hemiparesis (Fig. 3). There was no significant correlation between the GA and severity of CP. For the group 47% of the children had a mild, 18% a moderate and 34% a severe degree of CP. For the pre group 45% of the children had a mild, 35% a moderate and 2% a severe degree of CP. Fig. 3 Relative frequency of distribution of cerebral palsy in the and pre group pre Hemiparesis diparesis triparesis quadriparesis

4 Discussion A large cohort of more than 45 pre and high-risk newborn infants with a GA 3 weeks and a birthweight 1,25 g was systematically selected for standardized developmental follow-up because of either an unfavorable course or because of the detection of significant cerebral lesions on serial cerebral ultrasound during their NICU stay. Firstly, a significant correlation was found between fetal maturation, i.e., GA, and type of brain injury. As mentioned earlier, the most susceptible region to hypoxic/ischemic damage changes as the infant matures. Pre infants and full- infants experience ischemia in different regions of the brain. Classically, this has been assumed to result from the changing location of the intervascular boundery zones [2]. This could be a possible explanation for the correlation between GA and type of brain damage. The most common brain injuries in pre infants are periventricular leukomalacia and intracranial hemorrhage. The pathogenesis of periventricular leukomalacia relates to three major factors. The first two of these, an incomplete state of development of the vascular supply to the cerebral white matter and a maturation-dependent impairment in regulation of cerebral blood flow, underlie a propensity for ischemic injury to cerebral white matter. The third major pathogenic factor is the maturation-dependent vulnerability of the oligodendroglial precursor cell that represents the major cellular target in PVL [24]. The germinal zones are most active between approximately 8 and 28 weeks of gestation. Intrauterine exposure to infection and fetal inflammation are also related to an increased risk for PVL and CP [4, 13, 22]. The most common site of intraventricular hemorrhage in the pre infant is the subependymal germinal matrix region. The germinal matrix area is highly vascularized. The integrity of the capillaries in the germinal matrix is tenuous because of the lack of supportive tissue. Germinal matrix hemorrhage may be unilateral or bilateral and occurs in isolation in most pre infants [18]. In infants the most common injuries are parasagittal cerebral injury, injuries to basal ganglia and focal ischemia. In infants the vascular boundary zones lie in the regions between the anterior and middle cerebral arteries and between the middle and the posterior cerebral arteries. The distribution of tenuous arterial supply has been ed parasagittal. This zone is the primary location of ischemic injury in prolonged partial asphyxia [19]. An acute, near-total intrauterine asphyxia at the end of labor shows a consistent pattern of injury in subcortical brain nuclei, including the thalamus, basal ganglia and brainstem in contrast with the relative sparing of the cerebral cortex and white matter. The distribution of injury in these infants reflects the hierarchy of metabolic needs that are unmet after severe, sudden disruption of substrate supply as occurs in an acute, severe asphyxia. The higher metabolic rate of subcortical nuclei compared with cerebral hemispheres explains the preponderance of subcortical damage [16]. Secondly, a significant correlation was found between the GA and type and distribution of cerebral palsy. The existence of periventricular leukomalacia is the strongest and most independent risk factor for the subsequent development of CP in pre infants. The grade of PVL is significantly correlated with the clinical type and severity of cerebral palsy [5, 7, 8, 12, 14, 15, 17]. Most of these children develop spastic di- or quadriplegia [1, 6, 21]. Pre infants with major intracranial hemorrhage develop spastic diplegia, triplegia or hemiplegia [9]. Term infants sustaining an acute, near-total intrauterine asphyxia tend to present with athetosis in addition to pyramidal symptoms, severe seizure disorders and mental retardation. These patients are described as having dyskinetic cerebral palsy [2, 16]. Term infants subjected to prolonged partial asphyxial episodes most often have lesions of the cerebral cortex in a watershed type of distribution. They have pyramidal-spastic signs of cerebral palsy. We conclude that for high-risk infants with a birthweight 1,25 g and GA 3 weeks, GA is highly predictive of the preferential type of brain injury in accordance with the maturational cerebrovascular redistribution. The type and distribution of CP are also related to GA, indirectly due to specific injuries of maturation-dependent susceptible brain regions. References 1. Ancel PY, Livinec F, Larroque B, Marret S, Arnaud C, Pierrat V, Dehan M, N Guyen S, Escande B, Burguet A, Thiriez G, Picaud JC, Andre M, Bréart G, Kaminski M (26) Cerebral palsy among very pre children in relation to gestational age and neonatal ultrasound abnormalities: the EPIPAGE cohort study. Pediatrics 117: Barkovich J (25) Pediatric Neuroimaging. 4th edn. Raven Press, New York 3. Bax M, Goldstein M, Rosenbaum P, Leviton A, Paneth N, Dan B, Jacobsson B, Damiano D, Executive committee for the definition of cerebral palsy (25) Proposed definition and classification of cerebral palsy, April 25. Dev Med Child Neurol 47: Bax M, Tydeman C, Flodmark O (26) Clinical and MRI correlates of cerebral palsy-the European cerebral palsy study. JAMA 296: De vries LS, Eken P, Groenendaal F, van Haastert IC, Meiners LC (1993) Correlation between degree of periventricular leukomalacia diagnosed using cranial ultrasound and MRI later in infancy in children with cerebral palsy. Neuropediatrics 24: Drummond PM, Colver AF (22) Analysis by gestational age of cerebral palsy in singleton births in north-east England Paediatr Perinat Epidemiol 16: Han TR, Bang MS, Lim JY, Yoon BH, Kim IW (22) Risk factors for cerebral palsy in pre infants. Am J Phys Med Rehabil 81:297 33

5 8. Hamrick SE, Miller SP, Leonard C, Glidden DV, Goldstein R, Ramaswamy V, Piecuch R, Ferriero DM (24) Trends in severe brain injury and neurodevelopmental outcome in premature newborn infants: the role of cystic periventricular leukomalacia. J Pediatr 145: Himmelmann K, Hagberg G, Beckung E, Hagberg B, Uvebrant P (25) The changing panorama of cerebral palsy in Sweden. IX. Prevalence and origin in the birth-year period Acta Paediatr 94: Joseph KS, Allen AC, Lutfi S, Murphy-Kaulbeck L, Vincer MJ, Wood E (23) Does the risk of cerebral palsy increase or decrease with increasing gestational age? BMC Pregnanacy Childbirth 23: Krägeloh-Mann I, Petersen D, Hagberg G, Vollmar B, Hagberg B, Michalelis R (1995) Bilateral spastic cerebral palsy-mri pathology and origin. Analysis from a representive series of 56 cases. Dev Med Child Neurol 37: Krägeloh-Mann I, Horber V ( 27) The role of magnetic resonance of cerebral palsy: a systematic review. Dev Med Child Neurol 49: Nelson KB (22) The epidemiology of cerebral palsy in infants. Ment Retard Dev Disabil Res Rev 8: Okumura A, Kato T, Kuno K, Hayakawa F, Watanabe K (1997) MRI findings in patients with spastic cerebral palsy. II: correlation with type of cerebral palsy. Dev Med Child Neurol 39: Okumura A, Hayakawa F, Kato K, Kuno K, Watanabe K (1997) MRI findings in patients with spastic cerebral palsy. I: correlation with gestaional age at birth. Dev Med Child Neurol 39: Pasternak JF, Gorey MT (1998) The syndrome of acute neartotal intrauterine asphyxia in the infant. Pediatr Neurol 18: Ryoon HT, Moon B, Young LJ, Hyeon B, In Wom K (22) Risk factors of cerebral palsy in pre infants. Am J Phys Med Rehabil 81: Shankaran S (23) Hemorrhagic lesions of the central nervous system. In: Stevenson DK, Benitz WE, Sunshine P (eds) Fetal and neonatal brain injury. University Press, Cambridge, pp Sunshine P (23) Perinatal asphyxia: an overview. In: Stevenson DK, Benitz WE, Sunshine P (eds) Fetal and neonatal brain injury. University Press, Cambridge, pp Surveillance of cerebral palsy in Europe: a collaboration of cerebral palsy surveys and registers (2) Surveillance of Cerebral Palsy in Europe (SCPE). Dev Med Child Neurol 42: Topp M, Uldall P, Greisen G (21) Cerebral palsy births in eastern Denmark, : implications for neonatal care. Pediatr Perinat Epidemiol 15: Vermeulen GM, Bruinse HW, Gerards LJ, de Vries LS (21) Perinatal risk factors for cranial untrasound abnormalities in neonates born after spontaneous labour before 34 weeks. Eur J Obstet Gynecol Reprod Biol 94: Vohr BR, Wright LL, Poole WK, McDonald SA (25) Neurodevelopmental outcomes of extremely low birth weight infants <32 weeks gestation between 1993 and Pediatrics 116: Volpe JJ (21) Hypoxic-ishemic encephalopathy. In: neurology of the newborn. 4th ed. W.B. Saunders CO, Philadelphia 25. Wichers MJ, van der Schouw YT, Moons KG, Stam HJ, van Nieuwenhuizen O (21) Prevalence of cerebral palsy in The Netherlands ( ). Eur J Epidemiol 17: Wu YW, Croen LA, Shah SJ, Newman TB, Najjar DV (26) Cerebral palsy in a population: Risk factors and neuroimaging findings. Pediatrics 118:69 697