Risk factors for seizures in very low birthweight infants with periventricular leukomalacia

This population-based observational study aimed to determine the perinatal factors that were associated with the occurrence of seizures in very low birthweight infants with periventricular leukomalacia. The study sample consisted of 545 infants from the Israel National Very Low Birthweight Infant Database, gestational age 24 to 36 weeks, who survived beyond 28 days of age, in whom a late cranial ultrasonographic examination was performed and in whom periventricular leukomalacia was diagnosed. To evaluate the association between periventricular leukomalacia and confounding variables on the occurrence of seizures, the chi-square test, univariate analysis, and a logistic regression model were used. Of the 545 infants who developed periventricular leukomalacia, 102 (18.7%) had seizures. Significant independent predictors of seizures among these infants were decreasing gestational age, intraventricular hemorrhage, posthemorrhagic hydrocephalus, sepsis, and necrotizing enterocolitis. Infants with both sepsis and necrotizing enterocolitis had a 4.6-fold increased risk of seizures, further suggesting a possible role of infection in the pathogenesis of brain injury in preterm infants.     

Progress in periventricular leukomalacia

Periventricular leukomalacia (PVL) is the predominant form of brain injury and the leading known cause of cerebral palsy and cognitive deficits in premature infants. The number of low-birth-weight infants who survive to demonstrate these neurologic deficts is increasing. Magnetic resonance imaging-based neuroimaging techniques provide greater diagnostic sensitivity for PVL than does head ultrasonography and often document the involvement of telencephalic gray matter and long tracts in addition to periventricular white matter. The neuropathologic hallmarks of PVL are microglial activation and focal and diffuse periventricular depletion of premyelinating oligodendroglia. Premyelinating oligodendroglia are highly vulnerable to death caused by glutamate, free radicals, and proinflammatory cytokines. Studies in animal models of PVL suggest that pharmacologic interventions that target these toxic molecules will be useful in diminishing the severity of PVL.     

Differences between periventricular hemorrhagic infarction and periventricular leukomalacia

Purpose: To clarify the differences between infants with periventricular hemorrhagic infarction (PVHI) and those with periventricular leukomalacia (PVL). Methods: We retrospectively evaluated the clinical features, ultrasonography, and electroencephalogram (EEG) findings in 22 preterm infants with PVHI and 49 with PVL. EEG and cranial ultrasonography were serially performed in all participants starting immediately after birth. Acute and chronic stage EEG abnormalities were evaluated separately. Results: Gestational age and birth weight were significantly lower in infants with PVHI than those with PVL. EEGs were normal in the majority of infants with PVHI on days 1–2. However, EEG abnormalities appeared after ultrasonography abnormalities. The majority of infants with PVL showed acute-stage EEG abnormalities on days 1–2. The rate of infants with acute-stage EEG abnormalities decreased with age, whereas the rate of infants with chronic-stage EEG abnormalities increased with age. Normal EEG before ultrasonography abnormalities was more common in infants with PVHI than in those with PVL. However, deterioration of acute-stage EEG abnormalities was more frequent in infants with PVHI than in those with PVL. Conclusions: PVHI was presumed to cause mostly postnatal injury, whereas PVL was presumed to cause mostly pre-or perinatal injury.     

Imaging diagnosis of periventricular leukomalacia

The neurodevelopmental prognosis of periventricular leukomalacia (PVL) has been predicted effectively by ultrasonography (US). US is the best imaging modality to identify both the early changes of PVL (echogenic phase) and the late changes (cystic phase). In cases with intraventricular hemorrhage, however, it was difficult to differentiate from periventricular hemorrhage in the echogenic phase by US. The PVL resolved to a discrete cyst separate from the ventricle, but periventricular hemorrhage developed a porencephalic cyst. Computed tomography is useful for distinguishing periventricular hemorrhage from PVL in the early changes. However, it is not particularly useful in the late changes, as only extensive cystic lesions can be seen. Magnetic resonance imaging is useful for following the progress in myelination.     

Epilepsy in children with periventricular leukomalacia

Objective

We aimed to analyze the development of epilepsy in a patient group with periventricular leukomalacia followed at a tertiary pediatric neurology center.

Patients and methods

The study included 108 children aged between 2 and 8 years with radiologically proven periventricular leukomalacia who had been regularly observed at the Istanbul University, Istanbul Faculty of Medicine, Department of Pediatrics, Pediatric Neurology outpatient clinic between January 2006 and December 2011.

Results

Neonatal seizures were reported in 22 patients (20.3%), 14 of whom developed epilepsy. A significant correlation was found between neonatal seizures and prematurity and newborn asphyxia (p = 0.013 and p = 0.010, respectively). Epilepsy developed in 35 patients (32.4%), history of neonatal seizures and more severe loss of white matter, periventricular hyperintensity and corpus callosum involvement were found to be correlated with epilepsy (p = 0.001, p = 0.004, p = 0.016, and p = 0.004, respectively). The most common seizure pattern observed was generalized tonic clonic seizures (n = 13) and complex partial seizures (n = 11). Those with focal EEG findings had a significantly better neurodevelopmental and cognitive level than those with multifocal/generalized EEG findings (p = 0.024). Seizures continued with varying frequency in 14 epileptic patients (40%) despite antiepileptic treatment.

Conclusion

Almost a third of patients with periventricular leukomalacia develop epilepsy that can be intractable in substantial part. Neonatal seizures and severe MRI findings are important clues that can indicate the development of epilepsy in these patients.     

Possible antenatal and perinatal related factors in development of cystic periventricular leukomalacia

Cystic periventricular leukomalacia (cPVL), the principal ischemic brain injury in premature infants, is characterized by necrosis of the white matter in the periventricular region and the major neuropathology for spastic motor deficits in cerebral palsy or epilepsy. Recent reports strongly suggest that the brain injury associated with cPVL may have already occurred in utero. In this study we searched retrospectively for possible clinical situations related to cPVL to facilitate assessment of optimal management. A total of 201 babies born at gestational ages from 24 to 33 weeks were entered into the study (1992-1997) and examined for involvement of 18 factors in cPVL retrospectively. And psychomotor development was examined at least until 18 months of corrected age. Among 201 premature babies 35 cases were diagnosed as cPVL later developed spastic diplegia. There are 23 cases of preeclampsia, no infant suffering from cPVL. In the univariate analysis, exposure to antenatal indomethacin, cord length > or =40 cm, and a low Apgar score were significantly associated with a 2-3 risk increased of cPVL occurrence, while antenatal magnesium sulfate reduced the risk. Chorioamnionitis was positively correlated with the risk, but did not reach statistical significance. In the multivariate analysis we found the statistical significance in exposure to antenatal indomethacin, a low Apgar score, and antenatal magnesium sulfate. Our results suggested that preeclampsia and antenatal exposure of magnesium sulfate reduced the risk while antenatal exposure of indomethacin and low Apgar score associated with the occurrence of cPVL. These findings support a growing consensus that cPVL is often the result of maternal and fetal factors as well as antenatal treatment.     

Role of glutamate receptors in periventricular leukomalacia

Periventricular leukomalacia is a form of white-matter injury that occurs in the setting of either primary or secondary hypoxia-ischemia in the premature infant. Hypoxia-ischemia induces increases in cerebral extracellular glutamate levels, thereby activating glutamate receptors on a variety of cell types within the white matter. This review examines the evidence of a role for glutamate receptors in white-matter injury and periventricular leukomalacia. Multiple glutamate receptor subtypes exist, and these appear to play differential roles depending on cell type and time after injury. Glutamate receptors are developmentally regulated on neurons and glia, and certain subtypes are transiently overexpressed in developing rodent brain and are expressed on immature oligodendrocytes in human white matter in the premature period. Pharmacologic agents acting on glutamate receptors might represent age-specific therapeutic strategies for the treatment of periventricular leukomalacia.     

Characteristic neuropathology and plasticity in periventricular leukomalacia

The brains of extremely low-birth-weight infants with periventricular leukomalacia, who survived for more than 30 days, were examined by means of neuropathologic and immunohistochemical methods. The characteristic neuropathology of the brain is comprised of spongy changes with astrogliosis, a widespread distribution (i.e., in the deep to intermediate white matter), and a diffuse distribution of associated recent lesions. Also, these lesions, both remote and recent, are located in the frontal to occipital lobes. Regarding the correlation between the lesions and transneuronal connecting fibers, the lesions involved fibers of the motor, sensory, visual, and higher cerebral functions. This involvement may cause motor and intellectual disabilities. Furthermore, immunohistochemistry demonstrated nestin-positive astrocytes, and neurons increased around the lesions, suggesting the plasticity of the brains.     

Visual-perceptual impairment in children with periventricular leukomalacia

We set out to define visuo-perceptual impairment related to periventricular leukomalacia (PVL) using the Developmental Test of Visual Perception (DTVP). Correlations were sought between visual–perceptual deficits and DTVP profile and neuroradiological and neurophthalmological findings.

The DTVP was administered to 20 children (m/f: 10/10), aged between 5 and 8 years (mean: 6.95 years), presenting with: spastic diplegia; PVL documented by brain MRI; normal or mildly impaired visual acuity; mild-moderate upper limb functional impairment.

The mean General Visual–Perceptual Quotient was impaired, showing a great variability among the patients. Despite this, an uneven DTPV profile, characterised by a significant difference between the VMIQ and the Non-Motor Visual–Perceptual Quotient (P<0.001), and a poor result on the Closure subtest (identification of whole figures from incomplete visual information) was observed in all the subjects. This profile reflects a deficit in eye–hand coordination and in praxic-constructional abilities and could be the expression of malfunctioning of the occipital–parietal pathway of visual integration, the so-called ‘dorsal stream,’ a hypothesis reinforced by the emergence of a statistically significant correlation between the neuroradiological data and the presence of visual–perceptual impairment.     

Correlation between cerebrovascular maturity and periventricular leukomalacia

This study disclosed the close correlation between the characteristic developmental change of human cerebral vessels and the occurrence of periventricular leukomalacia (PVL), as judged by anticollagen type 6 immunohistochemical analysis. The earlier appearance of collagen type 6-positive vessels in the deep white matter supports the concept that the medullary vein, a terminal branch of the internal cerebral vein, develops earlier than the cortical and subcortical veins and the perforating artery because the latter was not stained in early gestation. In cases with an old lesion of PVL the distribution of the lesions with abnormal vessels differed with gestation age. These results suggest that its distribution correlates with the development of perforating medullary arteries. Thus a discrepancy between the arteries, revealing slow maturation, and veins, revealing early maturation, in the deep white matter may be an important predisposing factor for PVL. Furthermore, the widespread lesions of PVL may be closely related to the involvement of transcortical tract damage, in terms of specific motor or intellectual disabilities.     

Physical condition of preterm infants with periventricular leukomalacia

The aim of this study is to determine the general condition of preterm infants with severe brain lesions and to compare it with that of normal preterm infants. The Score for Neonatal Acute Physiology (SNAP) was calculated in nine preterm infants with periventricular leukomalacia (PVL) whose initial electroencephalograms showed grade IV depression (PVL group), 18 preterm infants who did not require mechanical ventilation during the neonatal period, Spontaneous respiration (SR group), and 18 preterm infants who required mechanical ventilation (MV group). The sum of the following four items in SNAP was separately calculated and called the ‘lung score’: PaO₂, PaO₂/FiO₂ ratio, PaCO₂, and oxygenation index. In addition to SNAP, we evaluated some neonatal variables. SNAP is lower in the SR group than in the PVL (P<0.05) or MV (P<0.01) groups. The lung score was also lower in the SR group than in the PVL (P<0.05) or MV (P<0.01) groups. On the other hand, the residual score (SNAP minus lung score) was not significantly different among the three groups. The physical condition of infants with PVL was not poor, although respiratory distress was often observed.     

Sequential MRI in two cases with periventricular leukomalacia

We investigated two children with cystic periventricular leukomalacia, which we had detected by ultrasonography (US) during the neonatal period, with magnetic resonance imaging (MRI) of the brain at 4, 9, and 15 or 19 corrected months of age. Both inversion-recovery (IR) and T2-weighted spin-echo (SE) sequences were used for this study. We observed cysts involving the periventricular white matter at the region adjacent to bilateral frontal horns in case 1 and adjacent to the posterior horns of the lateral ventricles in case 2. MRI at 4 months showed the irregularity of the ventricular wall and delayed myelination, compared to that of an age-matched control. The T2-weighted SE and IR imaging at 9 months demonstrated abnormally increased signal in the white matter. These findings were more evident at the 3rd MRI examination. The location of end-stage periventricular leukomalacia lesions were consistent with the distribution of cystic lesions seen on US. MRI at sagittal sections was useful for the detection of main periventricular leukomalacia lesions. A possibility exists that MRI might be useful in detecting subtle lesions of periventricular leukomalacia in which we cannot find by US.     

Abnormal brushes in preterm infants with periventricular leukomalacia

OBJECTIVE: The aim of this study is to describe a new objective method of detecting white matter injury by use of refiltering function of digital EEG. STUDY DESIGN: The neonatal EEGs of 9 patients with PVL were analyzed retrospectively, and compared with EEGs of 18 normal infants without PVL. Abnormal brushes were counted on the refiltered EEG where low cut filter were set at 10 Hz so that slow waves were eliminated. Abnormal brushes were defined as spindle-like fast wave bursts with maximal amplitudes higher than 40 mV and frequencies between 13 Hz and 20 Hz, which were easily distinguishable from a flat background. RESULTS: The incidence of abnormal brushes in infants with PVL was 0.25/min, 0.45/min, 2.08/min, and 0.62/min on the frontal, central, occipital, and temporal region, respectively. The incidence in infants without PVL was 0.14/min, 0.08/min, 0.24/min, and 0.19/min, respectively. Abnormal brushes were observed more often in infants with PVL on the central, occipital, and temporal region than in infants without PVL. Localization of abnormal brushes was also correlated with the lesion of white matter injury on MR images and clinical outcome. CONCLUSION: Our results indicated that abnormal brushes on refiltered EEGs were strongly associated with white matter injury.     

Growth of preterm infants with cystic periventricular leukomalacia

Etiology of the high rates of growth failure in children with cerebral palsy (CP) remains unclear. The purpose of this study was to evaluate the relation between growth failure in preterm infants with cystic periventricular leukomalacia (CPVL) and neonatal health complications. The population consisted of all preterm infants. (51) with a gestational age of ≤33 weeks who were admitted to the Children's Hospital of Buffalo from 1988 to 1993 and who had CPVL. Out of the 41 survivors with CPVL who were followed, 39 developed CP and 18 developed growth failure during infancy. At the time of greatest growth failure, the majority (72%) of infants had signs of undernutrition as denned by the Waterlow (1972) classification. Oral feeding impairment was the sole risk factor for the occurrence of growth failure. Undernutrition appears to be important in the occurrence of growth failure in preterm infants with CPVL and CP.     

Inflammatory cytokines in the pathogenesis of periventricular leukomalacia

BACKGROUND: Periventricular leukomalacia (PVL) affects the developing white matter of neonatal brain. Inflammatory and infectious conditions are implicated in the cause of PVL. METHODS: The authors investigated the in situ expression of proinflammatory cytokines (interleukin-1beta and -6, tumor necrosis factor alpha [TNFalpha]), adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1) and inflammatory cell markers (CD68, leukocyte common antigen, human leukocyte antigen II) in 19 neonatal brains with PVL. The authors compared the findings with matched non-PVL brains. RESULTS: The inflammatory reaction detected at the early stage of PVL extends until the latest phase of cystic cavitation, though at an attenuated level. There is high expression of TNFalpha and to a lesser extent interleukin-1beta; interleukin-6 remains undetectable. Cytokine immunoreactivity is detected in PVL cases both with and without infection. However, cytokine production was higher with infection. A different pattern of cytokine expression was observed in anoxic brains without PVL: TNFalpha immunoreactivity was significantly lower than the PVL group. CONCLUSIONS: An immune-mediated inflammatory process may play a role in PVL. TNFalpha, a myelinotoxic factor, may be the major mediator.     

Relationship between serum lactate level and periventricular leukomalacia

In a case control study, we evaluated the serum lactate levels during the early days of life in preterm infants with periventricular leukomalacia (PVL), who were presumed to have suffered injury around birth. Thirteen infants diagnosed by ultrasonography as suffering from cystic PVL during the neonatal period and 26 normally developed infants matched by gestational age were enrolled in the study. The serum lactate level was measured repeatedly during the 72 h after birth. The mean serum lactate levels on admission were 2.95 ± 0.43 and 3.21 ± 0.29 mmol/L in the PVL and control groups, respectively. There was no statistically significant difference in the serum lactate level between the groups at any point during the first 72 h after birth. In conclusion, the serum lactate level was not elevated in preterm infants with PVL suggesting that the serum lactate level is not a useful predictor for the development of PVL in infants.     

Popliteal angle in preterm infants with periventricular leukomalacia

The aim of this study is to clarify the usefulness of popliteal angle in infants with periventricular leukomalacia. The popliteal angle was measured at 1, 4, 8, and 12 months of corrected age in 47 infants with periventricular leukomalacia and in 103 control infants with normal development. The popliteal angle was categorized into two groups; tight, when it was < or =120 degrees , and wide, when it was >120 degrees . The severity of diplegia was defined at 2 years as follows: mild, when an infant could walk; moderate, when an infant could sit but could not walk; severe, when an infant could not sit. Tight popliteal angle was more often observed in infants with periventricular leukomalacia than in normal infants at any corrected age. The rate of tight popliteal angle was significantly lower in infants with mild diplegia than in those with moderate or severe diplegia at 8 and 12 months of corrected age. Specificity and positive predictive value were high at 8 and 12 months of corrected age, whereas sensitivity was relatively low. The results of this study suggest that evaluation of popliteal angle is useful for detection of infants with periventricular leukomalacia, although false-negative rate is high during late infancy.