Preterm neuroimaging and neurodevelopmental outcome: a focus on intraventricular hemorrhage, post-hemorrhagic hydrocephalus, and associated brain injury.

Intraventricular hemorrhage in the setting of prematurity remains the most common cause of acquired hydrocephalus. Neonates with progressive post-hemorrhagic hydrocephalus are at risk for adverse neurodevelopmental outcomes. The goal of this review is to describe the distinct and often overlapping types of brain injury in the preterm neonate, with a focus on neonatal hydrocephalus, and to connect injury on imaging to neurodevelopmental outcome risk. Head ultrasound and magnetic resonance imaging findings are described separately. The current state of the literature is imprecise and we end the review with recommendations for future radiologic and neurodevelopmental research.

[Pathomorphology of periventricular leukomalacia and other white matter lesions in infants].

The paper describes white matter lesions that differ from periventricular leukomalacia (PVL), such as diffuse leukomalacia (DL) and telencephalic gliosis (TG). There are three types of cerebral leukomalacias: PVL, DL, and subcortical leukomalacia. The morphological differences between PVL and DL are considered. The diffuse form of PVL is described. It is pointed out that colliquation PVL foci frequently occur in infants with birth weight less than 1500 g. There are data on the morphology of TG in which generalized and occasionally large-focal astrogliosis develops in the cerebral hemispheric white matter. It is suggested that it is inexpedient to identify the focal and diffuse components of PVL. The immunihistochemical findings led to the conclusion that PVL, DL, and TG did not result from the direct effects of pathogens of inherited infections on brain tissue.

Neurodevelopmental outcomes of children with periventricular leukomalacia.

OBJECTIVES: To examine the neurodevelopmental outcomes of children with periventricular leukomalacia (PVL). MATERIALS AND METHODS: Twenty-five children diagnosed with grade 1, 2 or 3 PVL on the basis of magnetic resonance imaging (MRI) findings between January 2002 and December 2011 were enrolled and followed from 15 months to 10 years of age. RESULTS: Of the 25 children, one was a term and 24 were preterm-births. Nine (36%) had spastic diplegia and 12 (48%) had quadriplegia. Ten of the 25 (40%) were able to walk independently at 36 months utilizing short leg braces, whereas 13 children (52%) were unable to walk independently. MRI findings revealed grade 1 PVL in nine (36%), grade 2 in 12 (48%), and grade 3 in four (16%) of the 25 children. Eleven of the 16 children (69%) with grade 2 or 3 PVL had Papile III or IV intraventricular hemorrhage (IVH), and many of these children had severe neurologic motor abnormalities, severe psychomotor delay, and seizures. Five of the nine children (56%) with grade 1 PVL had normal psychomotor development. There were statistically significant differences in the motor impairment and walking ability between the children with grade 1 and those with grade 2 PVL (p = 0.008 and 0.005, respectively). CONCLUSION: Most children with grade 2 or 3 PVL had severe neurodevelopmental delays, but attention should also be paid to the 56% of children with grade 1 PVL who presented with normal psychomotor development. Further studies of larger populations, including long-term follow-up, are necessary to evaluate the outcomes of children with PVL.

[Research progress on periventricular white matter damage pathogenesis in preterm infants].

Periventricular white matter damage is one of the characteristics of brain damage in preterm infants, and it is the most important type of encephalopathy. The pathological changes including the white matter of coagulation necrosis, oligodendrocyte damage, myelin damage, axonal injury and reactive gliosis and microglia infiltration in necrotic areas. All of these lesions are closely related to the nervous system sequelae in later-neonatal period. The pathogenesis of periventricular leukomalacia in premature infants are mainly cause by its immature brain vascular, and precursor oligodendrocytes of the attack of hypoxia, ischemia, infection, oxygen free radicals, inflammatory cytokines, increasing glutamate, and other high-risk factors. In this paper, an overview of progress in the study of the pathogenesis of periventricular white matter damage in premature infants through literature review to provide a theoretical support for clinical prevention, diagnosis and treatment.

Hypoxic ischemic cerebral lesions of the newborn--ultrasound diagnosis. Pictorial essay.

Transcranial ultrasonography is the most widely used neuroimaging technique in both premature and full term infants. The high susceptibility to hypoxia of the preterm brain explains the raised prevalence of intracranial haemorrhages at this group of patients. Ultrasound examination contributes to assessment of the neurologic status in children by diagnosing and staging of the intracranial bleeding, and brings informations about immediate and long term prognosis. The two major pictures of cerebral damage secondary to perinatal hypoxia are: peri and intraventricular haemorrhages and periventricular leucomalacia respectively. This paper present the major features for ultrasound diagnosis in both pathological situations.

West syndrome with periventricular leukomalacia: ten-year clinical study.

The aim of the study was to evaluate magnetic resonance imaging (MRI) findings in infants with periventricular leukomalacia (PVL) and West syndrome (WS) and determine the neurodevelopmental outcome in children with West syndrome and PVL. Ultrasound and brain MRI were performed in 37 infants with recognized PVL. PVL was categorized according to De Vries, whereas West syndrome was categorized according to International League Against Epilepsy 1989. West syndrome in our patients developed during the first 2 years of life. The most common interictal abnormality was hypsarrhythmia. All, except two patients had delayed development and various degrees of mental retardation. The most characteristic neuroimaging findings were major reduction in cerebral cortical gray matter volume, reduction in the volume of brain myelin, and delayed myelination. These findings may explain the anatomical association between the West syndrome onset and PVL and intellectual and cognitive deficit in premature infants with PVL.

Neurodevelopmental outcome in children with periventricular leukomalacia.

The purpose of this study was to question the correlation of different grades of periventricular leukomalacia (PVL) and subsequent neurodevelopmental outcome. In a prospective study we followed 52 preterm infants. Infants were divided into three groups according to their cranial ultrasound findings of PVL (De Vries classification). Seventeen children had PVL 1, 20 children had PVL 2, and 15 children had PVL 3. All 15 (100%) children with PVL 3 developed cerebral palsy with additional visual perceptual dysfunctions and epilepsy. Children with PVL 1 had high frequency of mild neuromotoric delay and visual impairment. PVL 2 and 3 have great predictive value for subsequent severe neurodevelopmental disorder which refers to cerebral palsy, different cognitive deficits, vision impairment and epilepsy. We have determined that due to high frequency of visual impairment and epilepsy we need to include neurophysiologic examinations very early in children with PVL lesions.

Analysis of the correlation between three methods used in the assessment of children with cerebral palsy.

The primary aim of this study was to assess the correlations between gait analysis, magnetic resonance imaging (MRI), and Gross Motor Function Measure (GMFM) scores in children with cerebral palsy (CP). These common diagnostic tools were used to evaluate 21 children affected by CP (mean age: 6 years, range: 5-13 years; 8 females and 13 males; 5 left hemiplegics, 4 right hemiplegics, 12 diplegics). In particular, in order to compare gait analysis data with other diagnostic evaluations, the Normalcy Index (NI) was used. The results showed a good correlation between the NI and the results of MRI, and between NI and the GMFM score (r=-0.76). Therefore, this investigation demonstrated that there exists a strong relationship between gait analysis and other clinical evaluation tools.

HRQL and severity of brain ultrasound findings in a cohort of adolescents who were born preterm.

PURPOSE: To determine whether health-related quality of life (HRQL) in a cohort of adolescents who were born prematurely is related to the severity of brain ultrasound examination findings during the newborn period. METHODS: This study uses a historical, prospective methodology to investigate the 84 members of a cohort of infants born prematurely (<33 weeks gestation) at Thomas Jefferson University Hospital during a 25-month period, from 1979 to 1981. We extracted the following information from their neonatal intensive care unit (NICU) records: ultrasound examination findings (graded for intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL); and records of medical illness (respiratory, gastrointestinal, and other) during the NICU stay. We followed-up the members of this cohort 18-19 years later, obtaining data on 53 (63%). We correlated the NICU data with the following self-report outcome measures: HRQL, Disabilities Questionnaire [parental report indicating the severity of complications of prematurity (DISAB)] and psychological assessment tests [Beck Depression Inventory (BDI), Coopersmith Self-Esteem Inventory (CSEI), and Body Shape Questionnaire (BSQ)]. We used the method of multiple discriminant function analysis to determine statistical significance of differences between the two ultrasound groups, grades 0-2 IVH, no PVL vs. grades 3-4 IVH and/or PVL. RESULTS: A statistically significant difference was obtained between the two ultrasound groups (grades 0-2 IVH, no PVL vs. grades 3-4 IVH and/or PVL) among the HRQL variables (Wilks' lambda =.764, df = 5, p <.470). The relative contribution of dependent variables (HRQL1, HRQL2, HRQL3, HRQL4, DISAB) to the group separation was assessed through the interpretation of discriminant function-variable correlation. HRQL1 and DISAB made the largest discriminant between groups, which is supported by results from univariate Student's t-tests. Study subjects with grades 3-4 IVH and/or PVL ultrasound findings obtained much lower HRQL1 scores (better overall estimation of HRQL) and much higher DISAB scores than subjects with grades 0-2 IVH, no PVL ultrasound findings. CONCLUSIONS: It appears that the lower an adolescent's score on overall HRQL (HRQL1), (i.e., the better the self-perceived overall quality of life), the more likely he or she displayed the higher severity of brain ultrasound examination findings during the NICU hospitalization. A larger study of premature infants who are followed into adolescence is required to better understand the factors that determine the association of IVH and PVL with HRQL.

[Periventricular leukomalacia in premature infants: prognostic role of ultrasonography and MRI]. / Leucomalacie périventriculaire du prématuré: rôle pronostique de l'échographie et de l'IRM.

PURPOSE: To evaluate the role of cranial US and MRI to establish the neurological prognosis of premature infants with periventricular leukomalacia (PVL). PATIENTS AND METHODS: Follow-up results of cranial US and early MRI evaluation (before 25 weeks*) of 28 premature infants were retrospectively reviewed and compared to the neurological outcome at 18 months* (*corrected age). RESULTS: Follow-up by cranial US was more sensitive (8/28) than early MRI to detect cystic PVL lesions because of the transient nature of these cysts. This has prognostic implications since all patients (8/8) with cystic PVL lesions had neurological sequelae. MRI was useful, as a complement to cranial US, for the evaluation of non-cystic PVL lesions. Indeed, patients with evidence of hemorrhage or paucity of white matter at MRI had a higher risk of neurological sequelae (9/11) than infants with echogenic periventricular white matter at US without evidence of white matter abnormality at MRI (p < 0.013). CONCLUSION: MRI was useful, as a complement to cranial US, to evaluate the prognosis of infants with non-cystic PVL lesions.

Expression of transforming growth factor-beta 1 in periventricular leukomalacia.

The expression of transforming growth factor-beta 1, which has neurotrophic effects, was investigated in 25 neonates with periventricular leukomalacia using immunohistochemistry. In controls, transforming growth factor-beta 1 immunoreactivity was not detected in the cerebral white matter or cortex. Of the 25 cases of periventricular leukomalacia, transforming growth factor-beta 1 immunoreactivity was found in 16, and was distributed mainly in the cytoplasm of astrocytes, being prominent around necrotic foci in the white matter. The immunoreactivity was negative or weak at the acute stage of periventricular leukomalacia, and increased at the subacute stage and then decreased or was absent at the chronic stage. Astrocytes that were moderately or markedly positive for transforming growth factor-beta 1 were not found before 27 weeks' gestation, but were observed after 32 weeks' gestation in the white matter of the brains of neonates with periventricular leukomalacia. Transforming growth factor-beta 1 expression tended to be more obvious in focal periventricular leukomalacia than in widespread or diffuse periventricular leukomalacia. Our results suggest that transforming growth factor-beta 1 could be involved in the delayed glial response rather than the initial glial activation, and could play a role in the inhibition and repair of injury in periventricular leukomalacia. Exogenous transforming growth factor-beta 1 could have therapeutic potential for periventricular leukomalacia.

Periventricular leukomalacia: relation to gestational age and axonal injury.

Eighty-five infants ranging from 22 to 41 weeks gestation were diagnosed as having periventricular leukomalacia (PVL) using traditional neuropathologic methods. The lesions were also studied by immunocytochemistry for beta-amyloid precursor protein (beta-APP), a glycoprotein that has been observed in PVL. Using this technique, the distribution of white matter tissue necrosis was defined as focal, widespread, and diffuse. The type of PVL correlated with the gestational age at birth. The youngest infants tended to demonstrate widespread necrosis, and the oldest infants exhibited more focal necrosis. beta-APP immunopositivity was present in the axons around the foci of white matter necrosis in 76% of the patients and in the neurons of the adjacent cortex in 66% of the patients. In age-matched control patients, there was no beta-APP reactivity in the cerebral white matter or the cortex. In most patients the distribution of beta-APP-positive axons proved to be a useful marker for demonstrating the type of PVL; however, the relationship of beta-APP to the pathogenesis of PVL requires further study.

The early diagnosis of periventricular leukomalacia in premature infants with positive rolandic sharp waves on serial electroencephalography.

OBJECTIVE: The objective of this study was to determine the specificity and the sensitivity of electroencephalography's positive rolandic sharp waves (PRSW) for the diagnosis of cystic and noncystic periventricular leukomalacia (PVL). METHODS: A retrospective study was performed on a population of 765 premature infants alive after 5 days who were divided into two groups; 166 infants born before 28 weeks (group 1) and 599 born between 28 and 32 completed weeks' gestation (group 2). Each infants underwent repeated ultrasound scanning and electroencephalography recordings during the first weeks of life. Magnetic resonance imaging was performed in infants with persisting hyperechoic periventricular densities on ultrasonography. RESULTS: A total of 83 (10.8%) newborns had PVL; 65 (8.5%) had cystic PVL PRSW, observed in 55 (7.2%) infants, always preceded the ultrasonic detection of cysts. PRSW were very specific markers of PVL in both groups (100% in group 1, 99.8% in group 2). PRSW sensitivity was found dependent on gestational age: 32.4% in group 1 in contrast to 87.8% in group 2. CONCLUSION: PRSW are an early and very specific marker of PVL in premature infants.

Diagnosis of intracranial lesions in very-low-birthweight infants by ultrasound: incidence and association with potential risk factors.

This study was designed to determine the frequencies of germinal matrix and ventricular haemorrhages as well as lesions in the white matter diagnosed by ultrasonography. In subsequent studies the effects of perinatal brain lesions on the cognitive and motor development of preterm children will be presented. Lesions of the white matter are probably more damaging than intraventricular and subependymal bleeds. Therefore, a modified classification of the lesions was used, clearly separating bleeds from white matter pathology. The study includes 291 infants with a body weight of < or = 1500 g consecutively admitted to the neonatal intensive-case unit at Karolinska Hospital from 1988 to 1993. Fifty-four (18.9%) died before 6 months. Two hundred and sixty-three infants were examined using ultrasound. Pathology due to bleeding was classified into three grades (B1-3) similar to Papile's first three grades. Pathology in periventricular white matter was classified into four groups (W1-4): W1 = subtle and We = distinctive white matter echodensities; W3 = cyst formation; W4 = large, intense echodensity. Forty-nine patients had abnormalities in the periventricular white matter (15 W1, 12 W2, 11 W3 and 11 W4) and 58 had subependymal (B1 = 29) or ventricular bleeding without (B2 = 13) or with dilatation (B3 = 16). Ventilator treatment was significantly associated with both B and W lesions. Low gestational age, low birthweight, small for gestational age, pre-eclampsia and caesarean section were significantly associated with B lesions whereas asphyxia, surfactant treatment, male patient sex and outborn were associate with W lesions; b 1-3 and W 1-4 lesions were thus partly associated with different potential risk factors. The pre- and perinatal potential risk factors could only partly explain the variance in the frequency of B and W lesions, indicating that there are yet unidentified risk factors for intracranial ultrasonographic pathology.

Effect of cerebral lesions on continuous performance test responses of school age children born prematurely.

Examined attention skills, as measured by the Continuous Performance Test (CPT), in a group of 64 children born premature and 40 full-term children, ages 6 to 8 years. Premature children were classified by neonatal cerebral lesions into no lesion, mild lesion, and severe lesion groups. It was predicted that severity of lesion would be associated with CPT performance. While mean differences among the groups of prematures did not reach significance, children with severe lesions made significantly more errors of omission and commission than the full-term comparison group. Children with mild lesions were poorer than full terms in errors of commission. Children with no lesions also made more errors of omission and commission than full terms, suggesting attention deficits secondary to prematurity even in the absence of identified brain lesion. With increasing severity of lesion, increasing percentages of each group were found to perform more than 2 SD below the mean in errors of commission. Results suggest that premature children, with and without identified lesions, are at risk for attention deficits.

Periventricular leukomalacia, glial development and myelination.

In perinatal leukomalacia, the brain pathology exhibits several different distribution patterns, according to cerebrovascular and glial maturity or various causal factors. Periventricular leukomalacia occurs in the prenatal as well as the postnatal period, and is caused by, in addition to predisposing factors, cerebral hypoperfusion which is in turn caused by systemic hypotension or intracranial vascular constriction and circulatory disturbance. Oligodendroglial damage or diffuse astrogliosis associated with leukomalacia may lead to delayed or reduced myelination in the cerebral white matter.

Haemorrhagic-ischaemic lesions of the neonatal brain: correlation between cerebral visual impairment, neurodevelopmental outcome and MRI in infancy.

The relationship between the degree of cerebral visual impairment, established using the acuity card procedure, and the extent of neurological sequelae was assessed in 65 at-risk neonates in a prospective follow-up study. MRI and CT scans were performed in all infants with severe neurological sequelae. 11 of 12 children with an acuity at or below the 10th centile at 18 months developed cerebral palsy: the underlying condition was extensive cystic leukomalacia in all. An acuity above the 10th centile was no guarantee of normal development, as 10 out of 52 such infants developed cerebral palsy. MRI and CT scans showed that periventricular high signal intensity in the occipital area was a non-specific finding with regard to visual function. Extensive periventricular white matter loss and involvement of the striate/parastriate cortex was found in the most severely visually impaired infants.

Neonatal encephalopathies as classified by EEG-sleep criteria: severity and timing based on clinical/pathologic correlations.

Neonatal encephalopathies can be characterized in functional terms using electroencephalography. Severity of an encephalopathic state can also be estimated by electrographic interpretation independent of the time of disease process onset. Moderately or markedly abnormal electroencephalographic patterns on serial studies are highly correlated with neurologic sequelae in survivors. Electroencephalography is rarely pathognomonic or specific in determining when a condition initially occurred. However, electroencephalographic abnormalities are associated with different clinical situations, and brain lesions documented on neuroimaging or with postmortem neuropathologic examination are observed in infants with certain abnormal electrographic patterns. When interpreted in the context of history, clinical findings, and other laboratory information, the neurophysiologic studies augment the understanding of both the severity and timing of an encephalopathic state.

MRI in motor delay: important adjunct to classification of cerebral palsy.

Cranial magnetic resonance imaging (MRI) was performed prospectively in 45 children (ages 3-27 months) with clinically documented motor delay to evaluate the ability of MRI to determine etiologic factors, to determine whether myelination correlated with motor delay, and whether the clinical category corresponded with the imaging findings. Of the 22 children diagnosed clinically as having major motor delay (i.e., cerebral palsy), 77% had magnetic resonance imaging abnormalities. In 23%, etiologic associations were established from MRI alone and in 32% a clinically suspected etiology was supported. No children had myelination delay as the sole abnormality. In 23 children with minor motor delay, only 17% had abnormal scans. Clearly, MRI provided useful information in the majority of children with cerebral palsy; therefore, a classification system is proposed in which MRI can be used in conjunction with clinical assessment to specify more precisely the etiologic factors in cerebral palsy.

Correlation between the degree of periventricular leukomalacia diagnosed using cranial ultrasound and MRI later in infancy in children with cerebral palsy.

During a period of 30 months, 504 infants of 34 weeks gestation or less were enrolled in a prospective cranial ultrasound study. Ninety-two (18.4%) infants developed different degrees of periventricular leukomalacia (PVL), being transient periventricular echogenicities (PVE) in 75, localised cystic lesions in 7 and extensive cysts in 10. Eight of 75 (10.6%) infants with PVE, 4 of the 6 (66.6%) survivors with localised cysts and all 8 survivors with extensive cysts developed cerebral palsy in infancy and MRI studies could be performed in 15 of these 20 infants between 11 and 32 months of age. Neurological sequelae were most severe among the infants with extensive cysts and none were able to walk, while 6 of the 12 who developed cerebral palsy following either PVE or localised cysts had learned to walk independently. There appeared to be a good correlation between the degree of PVL, diagnosed using ultrasound, and the extent of MRI changes noted in infancy. Ventricular enlargement and delay in myelination were more common in infants with cystic lesions and periventricular hyperintensity (PVHI) was present in all infants, but most extensive in the cases with extensive cysts. MRI performed later in infancy may, even in the absence of neonatal cranial ultrasound, provide information about both the presence as well as the degree of leukomalacia, which the child may have suffered in the neonatal or antenatal period.