Use of Thalamus L-Sign to Differentiate Periventricular Leukomalacia From Neurometabolic Disorders.

PURPOSE: To assess the diagnostic value of the thalamus L-sign on magnetic resonance imaging (MRI) in distinguishing between periventricular leukomalacia and neurometabolic disorders in pediatric patients. METHODS: In this retrospective study, clinical and imaging information was collected from 50 children with periventricular leukomalacia and 52 children with neurometabolic disorders. MRI was used to evaluate the L-sign of the thalamus (ie, injury to the posterolateral thalamus) and the lobar distribution of signal intensity changes. Age, sex, gestational age, and level of Gross Motor Function Classification System (only for periventricular leukomalacia) constituted the clinical parameters. Statistical evaluation of group differences for imaging and clinical variables were conducted using univariable statistical methods. The intra- and inter-observer agreement was evaluated using Cohen's kappa. Univariable or multivariable logistic regression was employed for selection of variables, determining independent predictors, and modeling. RESULTS: The thalamus L-sign was observed in 70% (35/50) of patients in the periventricular leukomalacia group, but in none of the patients with neurometabolic disorder (P < .001). The gestational age between groups varied significantly (P < .001). Involvement of frontal, parietal, and occipital lobes differed significantly between groups (P < .001). In the logistic regression, the best model included negative thalamus L-sign and gestational age, yielding an area under the curve, accuracy, sensitivity, specificity, and precision values of 0.995, 96.1%, 96%, 96.2%, and 96%, respectively. Both the lack of thalamus L-sign and gestational age were independent predictors (P < .001). CONCLUSIONS: The thalamus L-sign and gestational age may be useful in distinguishing between periventricular leukomalacia and neurometabolic disorders.

Periventricular Leukomalacia in Patients With Pseudo-glaucomatous Cupping.

PURPOSE: Periventricular leukomalacia (PVL) is a structural loss of white matter pathways that carry visual information from the lateral geniculate bodies to the visual cortex. It is observed radiologically in patients with a history of prematurity and is associated with visual field (VF) defects and optic disc cupping. Advances in perinatal care have improved survival for premature babies, so many now present as adolescents and adults to comprehensive eye doctors who are unaware of the relationship of cupping, field defects, and prematurity and who may diagnose manifest or suspected normal tension glaucoma. We describe 2 such patients to raise awareness of this entity. DESIGN: Case series. METHODS: Review of clinical information of 2 patients identified during clinical practice. Charts were reviewed for gestational age, optic nerve appearance, intraocular pressure (IOP), and sequelae of prematurity. Magnetic resonance imaging (MRI), optical coherence tomography (OCT), VF, and optic disc photographs were reviewed. RESULTS: Two young patients with a history of prematurity presented with enlarged cup-to-disc ratio and normal IOP. OCT thinning was most prominent superiorly, with VF defects more notable inferior and homonymous. No progression on VF or OCT was noted in the index case over almost 4 years. CONCLUSIONS: Periventricular leukomalacia should be added to the differential diagnosis of normal tension glaucoma (NTG) when there is a history of prematurity. Careful examination of the optic nerve will assist in differentiating from NTG. Specifically, horizontal cupping with minimal or no nasal displacement of vessels, and superior optic nerve thinning with inferior VF defects, suggest PVL.

Extent of altered white matter in unilateral and bilateral periventricular white matter lesions in children with unilateral cerebral palsy.

AIMS: To investigate the extent of white matter damage in children with unilateral cerebral palsy (UCP) caused by periventricular white matter lesions comparing between unilateral and bilateral lesions; and to investigate a relationship between white matter microstructure and hand function. METHODS AND PROCEDURES: Diffusion MRI images from 46 children with UCP and 18 children with typical development (CTD) were included. Subjects were grouped by side of hemiparesis and unilateral or bilateral lesions. A voxel-wise white matter analysis was performed to identify regions where fractional anisotropy (FA) was significantly different between UCP groups and CTD; and where FA correlated with either dominant or impaired hand function (using Jebsen Taylor Hand Function Test). OUTCOMES AND RESULTS: Children with unilateral lesions had reduced FA in the corticospinal tract of the affected hemisphere. Children with bilateral lesions had widespread reduced FA extending into all lobes. In children with left hemiparesis, impaired hand function correlated with FA in the contralateral corticospinal tract. Dominant hand function correlated with FA in the posterior thalamic radiations as well as multiple other regions in both left and right hemiparesis groups. CONCLUSIONS AND IMPLICATIONS: Periventricular white matter lesions consist of focal and diffuse components. Focal lesions may cause direct motor fibre insult resulting in motor impairment. Diffuse white matter injury is heterogeneous, and may contribute to more global dysfunction.

The vulnerability of thalamocortical circuitry to hypoxic-ischemic injury in a mouse model of periventricular leukomalacia.

BACKGROUND: Periventricular leukomalacia (PVL) is the leading cause of neurological disabilities including motor and cognitive deficits in premature infants. Periventricular leukomalacia is characterized by damage to the white matter in the immature brain, but the mechanisms by which damage to immature white matter results in widespread deficits of cognitive and motor function are unclear. The thalamocortical system is crucial for human consciousness and cognitive functions, and impaired development of the cortico-thalamic projections in the neonatal period is implicated to contribute importantly to abnormalities of cognitive function in children with PVL. RESULTS: In this study, using a mouse model of PVL, we sought to test the hypothesis that PVL-like injury affects the different components of the thalamocortical circuitry that can be defined by vesicular glutamate transporters 1 and 2 (vGluT1 and vGluT2), both of which are required for glutamatergic synaptic transmission in the central nervous system. We combined immunocytochemistry and immuno-electron microscopy to investigate changes in cortico-thalamic synapses which were specifically identified by vGluT1 immunolabeling. We found that a drastic reduction in the density of vGluT1 labeled profiles in the somatosensory thalamus, with a reduction of 72-74 % in ventroposterior (VP) nucleus and a reduction of 42-82 % in thalamic reticular nucleus (RTN) in the ipsilateral side of PVL mice. We further examined these terminals at the electron microscopic level and revealed onefold-twofold decrease in the sizes of vGluT1 labeled corticothalamic terminals in VP and RTN. The present study provides anatomical and ultrastructural evidence to elucidate the cellular mechanisms underlying alteration of thalamic circuitry in a mouse model of PVL, and reveals that PVL-like injury has a direct impact on the corticothalamic projection system. CONCLUSIONS: Our findings provide the first set of evidence showing that the thalamocortical circuitry is affected and vulnerable in PVL mice, supporting a working model in which vGluT1 defined corticothalamic synapses are altered in PVL mice, and vGluT2 defined thalamocortical synapses are associated with such changes, leading to the compromised thalamocortical circuitry in the PVL mice. Our study demonstrates that the thalamocortical circuitry is highly vulnerable to hypoxia-ischemia in the PVL model, thus identifying a novel target site in PVL pathology.

Corticospinal Tract Injury Precedes Thalamic Volume Reduction in Preterm Infants with Cystic Periventricular Leukomalacia.

OBJECTIVES: To measure both fractional anisotropy (FA) values in the corticospinal tracts (CSTs) and volume of the thalami in preterm infants with cystic periventricular leukomalacia (c-PVL) and to compare these measurements with control infants. STUDY DESIGN: Preterm infants with c-PVL and controls with magnetic resonance imaging data acquired between birth and term equivalent age (TEA) were retrospectively identified in 2 centers. Tractography of the CST and segmentation of the thalamus were performed, and values from infants with c-PVL and controls were compared. RESULTS: Thirty-three subjects with c-PVL and 31 preterm controls were identified. All had at least 1 scan up to TEA, and multiple scans were performed in 31 infants. A significant difference in FA values of the CST was found between cases and controls on the scans both before and at TEA. Absolute thalamic volumes were significantly reduced at TEA but not on the earlier scans. Data acquired in infancy showed lower FA values in infants with c-PVL. CONCLUSIONS: Damage to the CST can be identified on the early scan and persists, whereas the changes in thalamic volume develop in the weeks between the early and term equivalent magnetic resonance imaging. This may reflect the difference between acute and remote effects of the extensive injury to the white matter caused by c-PVL.

Quantitative comparison of cortical and deep grey matter in pathological subtypes of unilateral cerebral palsy.

AIM: The aim of this study was to quantify grey matter changes in children with unilateral cerebral palsy (UCP), differentiating between cortical or deep grey matter (CDGM) lesions, periventricular white matter (PWM) lesions, and unilateral and bilateral lesions. METHOD: In a cross-sectional study we obtained high resolution structural magnetic resonance images from 72 children (41 males, 31 females, mean age 10y 9mo [SD 3y 1mo], range 5y 1mo-17y 1mo) with UCP (33 left, 39 right hemiplegia; Manual Ability Classification System level I n=29, II n=43; Gross Motor Function Classification System level I n=46, II n=26), and 19 children with typical development (CTD; eight males, 11 females, mean age 11y 2mo [SD 2y 7mo], range 7y 8mo-16y 4mo). Images were classified by lesion type and analyzed using voxel-based morphometry (VBM) and subcortical volumetric analysis. RESULTS: Deep grey matter volumes were not significantly different between children with CDGM and PWM lesions, with the thalamus, putamen, and globus pallidus being reduced unilaterally in both groups compared with CTD (p≤0.001). Children with CDGM lesions additionally showed widespread cortical changes involving all lobes using VBM (p<0.01). Children with bilateral lesions had reduced thalamus and putamen volumes bilaterally (p<0.001). The thalamic volume was reduced bilaterally in children with unilateral lesions (p=0.004). INTERPRETATION: Lesions to the PWM cause secondary changes to the deep grey matter structures similar to primary changes seen in CDGM lesions. Despite having a unilateral phenotype, grey matter changes are observed bilaterally, even in children with unilateral lesions.

Repetitive administration of acetylcholine receptor agonist rescues brain inflammation and brain damage after hypoxia-ischemia in newborn rat.

OBJECTIVE: We examined the effect of repetitive administration of acetylcholine receptor agonist (carbachol) on brain damage and microglial accumulation in three brain regions after hypoxia-ischemia (HI) in newborn rat. STUDY DESIGN: Seven-day-old Wistar rats were divided into two groups, one receiving a 0.1 mg/kg dose of carbachol on days 7, 8 and 9 to examine the attenuating effect on brain damage with decreasing accumulation of microglia, and the other group receiving saline as a control. Rats were subjected to left carotid artery ligation followed by hypoxia. We evaluated brain damage and the number of microglias in three regions on days 10 and 14. RESULTS: Brain tissue was better preserved in the carbachol group on days 10 and 14. Microglial accumulation in the cortex was strong and persisted from day 10s to 14 in the control. Conversely, the accumulation of microglias was attenuated in the hippocampus and white matter on day 14. Carbachol significantly reduced the number of microglias in the hippocampus and white matter on day 10 and in the cortex on days 10 and 14. CONCLUSION: The main area of late inflammation was the cortex. Repetitive administration of carbachol reduces early and late inflammation after HI in the developing brain.

Zinc supplementation reduces morbidity and mortality in very-low-birth-weight preterm neonates: a hospital-based randomized, placebo-controlled trial in an industrialized country.

BACKGROUND: Zinc plays a pivotal role in the pathogenesis of many diseases and in body growth. Preterm neonates have high zinc requirements. OBJECTIVE: The objective of the study was to investigate the efficacy of zinc supplementation in reducing morbidity and mortality in preterm neonates and to promote growth. DESIGN: This was a prospective, double-blind, randomized controlled study of very-low-birth-weight preterm neonates randomly allocated on the seventh day of life to receive (zinc group) or not receive (control group) oral zinc supplementation. Total prescribed zinc intake ranged from 9.7 to 10.7 mg/d in the zinc group and from 1.3 to 1.4 mg/d in the placebo control group. The main endpoint was the rate of neonates with ≥ 1 of the following morbidities: late-onset sepsis, necrotizing enterocolitis, bronchopulmonary dysplasia, periventricular leucomalacia, and retinopathy of prematurity. Secondary outcomes were mortality and body growth. RESULTS: We enrolled 97 neonates in the zinc group and 96 in the control group. Morbidities were significantly lower in the zinc group (26.8% compared with 41.7%; P = 0.030). The occurrence of necrotizing enterocolitis was significantly higher in the control group (6.3% compared with 0%; P = 0.014). Mortality risk was higher in the placebo control group (RR: 2.37; 95% CI: 1.08, 5.18; P = 0.006). Daily weight gain was similar in the zinc (18.2 ± 5.6 g · kg⁻¹ · d⁻¹) and control (17.0 ± 8.7 g · kg⁻¹ · d⁻¹) groups (P = 0.478). CONCLUSION: Oral zinc supplementation given at high doses reduces morbidities and mortality in preterm neonates. This trial was registered in the Australian New Zealand Clinical Trial Register as ACTRN12612000823875.

Protective effects of pentoxifylline on lipopolysaccharide-induced white matter injury in a rat model of periventricular leukomalasia.

OBJECTIVE: To investigate the potential neuroprotective effect of maternal pentoxifylline (PNTX) treatment in endotoxin-induced periventricular leukomalasia (PVL) in the developing rat brain. METHOD: Intraperitoneal injection of lipopolysaccharide was administered on two of three Wistar pregnant rats to establish PVL. To obtain PNTX-treated group, one of the two dams were injected with PNTX. The control group was treated with saline. Rat pups were grouped as control, maternal LPS-treated group and PNTX + LPS-treated group. At 7th postnatal days, apoptosis and hypomyelination were evaluated. Apoptosis was evaluated by caspase-3 and terminal deoxynucleotidyl transferase [TdT] dUTP nick endlabelling reaction (TUNEL) immunostaining. To assess hypomyelination, myelin basic protein (MBP) staining, as a marker of myelination, was evaluated. RESULTS: MBP staining was significantly less and weaker in the brains of the LPS-treated group as compared with the PNTX-treated group. PNTX treatment significantly reduced the number of apoptotic cells in the periventricular WM shown on Tunel and caspase-3. CONCLUSIONS: Presented study is first indicated that PNTX may provide protection against an LPS-induced inflammatory response and WMI in the developing rat brain. Our results also suggest that PNTX treatment in pregnant women with maternal or placental infection may minimize the risk of PVL and cerebral palsy.

Early thalamic lesions in patients with sleep-potentiated epileptiform activity.

OBJECTIVE: To compare the prevalence and type of early developmental lesions in patients with a clinical presentation consistent with electrical status epilepticus in sleep either with or without prominent sleep-potentiated epileptiform activity (PSPEA). METHODS: We performed a case-control study and enrolled patients with 1) clinical features consistent with electrical status epilepticus in sleep, 2) ≥1 brain MRI scan, and 3) ≥1 overnight EEG recording. We quantified epileptiform activity using spike percentage, the percentage of 1-second bins in the EEG tracing containing at least 1 spike. PSPEA was present when spike percentage during non-REM sleep was ≥50% than spike percentage during wakefulness. RESULTS: One hundred patients with PSPEA (cases) and 47 patients without PSPEA (controls) met the inclusion criteria during a 14-year period. Both groups were comparable in terms of clinical and epidemiologic features. Early developmental lesions were more frequent in cases (48% vs 19.2%, p = 0.002). Thalamic lesions were more frequent in cases (14% vs 2.1%, p = 0.037). The main types of early developmental lesions found in cases were vascular lesions (14%), periventricular leukomalacia (9%), and malformation of cortical development (5%). Vascular lesions were the only type of early developmental lesions that were more frequent in cases (14% vs 0%, p = 0.005). CONCLUSIONS: Patients with PSPEA have a higher frequency of early developmental lesions and thalamic lesions than a comparable population of patients without PSPEA. Vascular lesions were the type of early developmental lesions most related to PSPEA.

Thalamic changes in a preterm sample with periventricular leukomalacia: correlation with white-matter integrity and cognitive outcome at school age.

INTRODUCTION: Thalamic abnormalities have been well documented in preterms with periventricular leukomalacia (PVL), although their contribution to long-term cognitive dysfunctions has not been thoroughly investigated. RESULTS: Significant differences between groups were observed for global thalamic volume. Neuropsychological assessments showed that preterms with PVL scored within the normal range, although significantly below controls in the full intelligence quotient and the specific cognitive domains of processing speed and working memory. Correlations of several thalamic regions with Working Memory Index and FIQ were found in the PVL group. Moreover, thalamic atrophy correlated with white-matter (WM) damage indexes (fractional anisotropy and radial diffusivity) assessed by diffusion tensor imaging. DISCUSSION: The findings suggest that thalamic damage is a common correlate of WM microstructural alterations and might be involved in the cognitive deficits seen in premature infants with PVL at school age. METHODS: We analyzed the impact of PVL-associated thalamic injury on cognitive status at school age and its correlation with WM integrity as measured by magnetic resonance imaging techniques. Thalamic volume and shape of 21 preterm children with PVL were compared with those of 11 preterm children of similar gestational age and birth weight with no evidence of focal WM abnormality.

Blood urea nitrogen and serum bicarbonate in extremely low birth weight infants receiving higher protein intake in the first week after birth.

OBJECTIVE: To determine correlation between early protein administration and serum blood urea nitrogen (BUN) or bicarbonate (HCO(3)(-)) in extremely low birth weight (ELBW) infants during the first week of life. STUDY DESIGN: A retrospective review of 154 ELBWs was conducted. Laboratory and nutritional data from postnatal days 1, 4 and 7 were collected. Repeated measures models estimated the relationship of protein intake with BUN and HCO(3)(-) in the first week of life. RESULT: In total, 359 separate BUN and HCO(3)(-) values were analyzed. Each gram per kilogram of protein administered was associated with an increase in mean BUN of 3.3 mg/dl. This effect decreased daily by 2.1 mg/dl. Each gram per kilogram of protein administered was associated with a decrease in mean HCO(3)(-) by 0.9 mmol/l. CONCLUSION: The association between protein load and BUN is positive but decreasing over time. Protein is associated with a clinically insignificant decrease in HCO(3)(-). Concerns regarding metabolic derangement from early protein administration in ELBWs are unwarranted.

Abnormal microstructure of the atrophic thalamus in preterm survivors with periventricular leukomalacia.

BACKGROUND AND PURPOSE: The neuroanatomic substrate of cognitive deficits in long-term survivors of prematurity with PVL is poorly understood. The thalamus is critically involved in cognition via extensive interconnections with the cerebral cortex. We hypothesized that the thalamus is atrophic (reduced in volume) in childhood survivors of prematurity with neuroimaging evidence of PVL and that the atrophy is associated with selective microstructural abnormalities within its subdivisions. MATERIALS AND METHODS: We performed quantitative volumetric and DTI measurements of the thalamus in 17 children with neuroimaging evidence of PVL (mean postconceptional age, 5.6 ± 4.0 years) who were born prematurely and compared these with 74 term control children (5.7 ± 3.4 years). RESULTS: The major findings were the following: 1) a significant reduction in the overall volume of the thalamus in patients with PVL compared with controls (P < .0001), which also correlated with the severity of PVL (P = .001); 2) significantly decreased FA (P = .003) and increased λ(⊥) (P = .02) in the thalamus overall and increased axial, radial, and mean diffusivities in the pulvinar (P < .03), suggesting injury to afferent and efferent myelinated axons; and 3) a positive correlation of pulvinar abnormalities with those of the parieto-occipital white matter in periventricular leukomalacia, suggesting that the pulvinar abnormalities reflect secondary effects of damaged interconnections between the pulvinar and parieto-occipital cortices in the cognitive visual network. CONCLUSIONS: There are volumetric and microstructural abnormalities of the thalamus in preterm children with PVL, very likely reflecting neuronal loss and myelinated axonal injury. The selective microstructural damage in the pulvinar very likely contributes to abnormal cognitive visual processing known to occur in such survivors.

Serial ultrasonographic observation of bilateral thalami in low birth weight infants with periventricular leukomalacia.

Periventricular leukomalacia is a major form of neuropathology in preterm infants that is associated with adverse motor and cognitive outcomes. The volume of periventricular white matter and corpus callosum has been reported to be diminished in infants with PVL, and the degree of the volume loss is correlated with the severity of neurological impairment. The thalamic index was calculated from the length, height, width of the thalamus, and thalamic volume was calculated using the formula for an ovoid in 62 low birth weight infants with gestational ages of 24-35weeks, 51 control infants (cerebral palsy, 1 case), and 11 infants diagnosed with PVL (cerebral palsy, 7 cases) at postnatal days0-70. The indices of the right thalamus were lower in infants with PVL than in control infants from day0 to day70, and there were significant differences on days 21, 28, 35, 42, 49, 56, 63, and 70. The indices of the left thalamus were lower in infants with PVL than in control infants from day0 to day70, and there were significant differences on days 21, 28, 35, 42, 49, 56, 63, and 70. The results of the present study suggest that the volume of the thalami is reduced and that thalamic injury is associated with white matter lesions in infants with PVL.

Diffuse axonal injury in periventricular leukomalacia as determined by apoptotic marker fractin.

Periventricular leukomalacia (PVL), the major substrate of neurologic deficits in premature infants, is associated with reduced white matter volume. Using immunomarkers of axonal pathology [beta-amyloid precursor protein (beta-APP) and apoptotic marker fractin], we tested the hypothesis that widespread (diffuse) axonal injury occurs in the gliotic white matter beyond the foci of necrosis in PVL, thus contributing to the white matter volume reduction. In a cohort of 17 control cases and 13 PVL cases with lesions of different chronological ages, diffuse axonal damage in PVL was detected by fractin in white matter sites surrounding and distant from acute and organizing foci of necrosis. Using beta-APP, axonal spheroids were detected within necrotic foci in the acute and organizing (subacute) stages, a finding consistent with others. Interestingly, GAP-43 expression was also detected in spheroids in the necrotic foci, suggesting attempts at axonal regeneration. Thirty-one percent of the PVL cases had thalamic damage and 15% neuronal injury in the cerebral cortex overlying PVL. We conclude that diffuse axonal injury, as determined by apoptotic marker fractin, occurs in PVL and that its cause likely includes primary ischemia and trophic degeneration secondary to corticothalamic neuronal damage.

Parasagittal lesions and ulegyria in hypoxic-ischemic encephalopathy: neuroimaging findings and review of the pathogenesis.

Hypoxic-ischemic brain injury is a very important neurological problem of the perinatal period and a major cause of chronic disability later in childhood. The subsequent neurological deficits are a variety of motor defects-especially spasticity but also choreoathetosis, dystonia and ataxia, often grouped together as "cerebral palsy," mental retardation, and seizures. The gestational age determines the neuropathology of the brain injury. One of the patterns of hypoxic-ischemic encephalopathy, typically affecting full-term infants, consists of parasagittal lesions and ulegyria. The aim of this study is to describe the magnetic resonance imaging (MRI) features and discuss the "suggested" pathogenetic mechanisms of this pattern, which affects the cortex and the white matter in a mainly parasagittal distribution; in this type of brain injury, the damage usually involves the deeper sulcal portion while sparing the apex, thus resulting in the so-called mushroom gyri characteristic ulegyric pattern. We discuss the MRI findings of parasagittal lesions and ulegyria in the brain examinations of 14 patients with a clinical history of perinatal hypoxia/anoxia presenting with mental retardation, seizures, and cerebral palsy. Differential diagnosis from polymicrogyria is discussed.

Diffusion tensor imaging in infants with basal ganglia-thalamic lesions.

We performed diffusion tensor imaging in two infants with neonatal hypoxic-ischemic encephalopathy. MRI revealed basal ganglia-thalamic lesions in both patients during the neonatal period. Patient 1 had severe neurological sequelae, whereas patient 2 achieved normal development. Conventional MRI at 12 months of age showed abnormal high-intensity areas in bilateral basal ganglia and thalami in patient 1, whereas no abnormal intensities were recognized in patient 2. Diffusion tensor tractography demonstrated poor depiction of white matter tracts above the level of centrum semiovale in patient 1. Region of interest analysis showed that fractional anisotropy of white matter of centrum semiovale and deep white matter was markedly reduced in patient 1 compared with patient 2, although apparent diffusion coefficient was not largely different between them. Our study suggested that abnormalities of diffusion property will be more widely present than those of conventional MRI. Diffusion tensor imaging will be useful to detect white matter abnormalities in normal-appearing white matter on conventional MRI.