Impaired glymphatic system revealed by DTI-ALPS in cerebral palsy due to periventricular leukomalacia: relation with brain lesion burden and hand dysfunction.

PURPOSE: Preterm children with cerebral palsy (CP) often have varying hand dysfunction, while the specific brain injury with periventricular leukomalacia (PVL) cannot quite explain its mechanism. We aimed to investigate glymphatic activity using diffusion tensor image analysis along the perivascular space (DTI-ALPS) method and evaluate its association with brain lesion burden and hand dysfunction in children with CP secondary to PVL. METHODS: We retrospectively enrolled 18 children with bilateral spastic CP due to PVL and 29 age- and sex-matched typically developing controls. The Manual Ability Classification System (MACS) was used to assess severity of hand dysfunction in CP. A mediation model was performed to explore the relationship among the DTI-ALPS index, brain lesion burden, and the MACS level in children with CP. RESULTS: There were significant differences in the DTI-ALPS index between children with CP and their typically developing peers. The DTI-ALPS index of the children with CP was lower than that of the controls (1.448 vs. 1.625, P = 0.003). The mediation analysis showed that the DTI-ALPS index fully mediated the relationship between brain lesion burden and the MACS level (c' = 0.061, P = 0.665), explaining 80% of the effect. CONCLUSION: This study provides new insights into the neural basis of hand dysfunction in children with CP, demonstrating an important role of glymphatic impairment in such patients. These results suggest that PVL might affect hand function in children with CP by disrupting glymphatic drainage.

Clinical characteristics and long-term neurodevelopmental outcomes of leukomalacia in preterm infants and term infants: a cohort study.

BACKGROUND: Leukomalacia is a serious form of neonatal brain injury that often leads to neurodevelopmental impairment, and studies on neonatal leukomalacia and its long-term outcomes are lacking. The aim of this study was to analyze the clinical manifestations, imaging features, and long-term neurodevelopmental outcomes in preterm infants and term infants with leukomalacia. METHODS: Newborns diagnosed with leukomalacia by head magnetic resonance imaging (MRI) and who were admitted to intensive care units from January 2015 to June 2020 were enrolled. All infants were followed up to June 2022 (2-7 years old), and their neurodevelopmental outcomes were evaluated. The clinical data and long- term outcomes of preterm infants and term infants was analyzed by Chi-square tests. RESULTS: A total of 218 surviving infants with leukomalacia including 114 preterm infants and 104 term infants completed the follow-up. The major typesof leukomalacia on MRI were periventricular leukomalacia in the preterm group and subcortical cystic leukomalacia in the term group, respectively (χ2 = 55.166; p < 0.001). When followed up to 2-7 years old, the incidence of neurodevelopmental impairment in the preterm group and term group was not significantly different (χ2 = 0.917; p = 0.338). However, the incidence of cerebral palsy (CP) in the preterm group was significantly higher (χ2 = 4.896; p = 0.027), while the incidence of intellectual disability (ID) (χ2 = 9.445; p = 0.002), epilepsy (EP) (χ2 = 23.049; p < 0.001), and CP combined with ID andEP (χ2 = 4.122; p = 0.042) was significantly lower than that in the term group. CONCLUSIONS: Periventricular leukomalacia mainly occurred in preterm infants while subcortical cystic leukomalacia was commonly seen in term infants. Although the long-term neurodevelopmental outcomes of leukomalacia were both poor, preterm infants were more prone to CP, while term infants were more prone to ID, EP, and the combination of CP with ID and EP.

A screening method for visual attention disabilities in cerebral palsy with periventricular leukomalacia.

PURPOSE: Patients with periventricular leukomalacia (PVL) have been reported to have a variety of complications; however, whether these involve impaired visual attention disabilities remains unclear. Therefore, this study aimed to investigate the presence or absence and degree of visual attention disabilities in patients with PVL and propose a screening test that would allow anyone to check for visual attention disabilities easily. METHODS: The study participants were 14 patients with PVL and seven controls with dyskinetic cerebral palsy. All participants performed three types of visual attention tasks: spatial attention tasks, feature-based attention tasks, and object-based attention tasks. The participants also performed counting tasks to determine how many squares of the same size and color could be counted (up to nine). Receiver operating characteristic analysis was used to calculate cutoff values, with disability as the objective variable and the value of the counting task as the explanatory variable. RESULTS: The results revealed that patients with PVL often had visual attention disabilities, as indicated by a significant reduction in tasks requiring divided attention. Visual attention disabilities could be detected by a score of ≤8 in the square counting task. CONCLUSIONS: These findings suggest that family members and teachers of patients with PVL can easily screen for visual attention disabilities at home and school to improve mobility precautions in patients with this disability.

Predictors of Risk for Cerebral Palsy: A Review.

PURPOSE: To identify the earliest predictors of risk for diagnosis of cerebral palsy (CP). METHODS: A comprehensive literature search was conducted using various databases. The publications were reviewed to identify risk factors for CP from conception to early infancy. Studies were critically appraised with Joanna Briggs Institute guidelines for quality appraisal and evaluated for risk of bias using the Agency for Health Care Research and Quality guidelines. RESULTS: The initial search yielded 129 studies and 20 studies were included. Forty-seven risk factors for CP were extracted of which several were duplicate terms. The significant risk factors found to be indicative of CP were low birth weight (<1500 g), birth at less than 28 weeks of gestational age, periventricular leukomalacia, grade 3 or 4 intraventricular hemorrhage, preeclampsia, prematurity, an Apgar score of less than 4 at the first minute, birth asphyxia, preterm premature rupture of membrane, and absent fidgety movements. CONCLUSION: Twenty-three factors were consistently reported as predictors of CP.

Long-term analysis of adrenocorticotropic hormone monotherapy for infantile epileptic spasms syndrome with periventricular leukomalacia.

PURPOSE: Infantile epileptic spasms syndrome (IESS) with periventricular leukomalacia (PVL) has a poor neurological prognosis. Adrenocorticotropic hormone (ACTH) and vigabatrin therapies are the recommended first-line treatments for IESS. However, ACTH monotherapy for IESS with PVL has not been studied in detail. We analysed long-term outcomes of ACTH monotherapy for IESS with PVL. METHODS: We retrospectively examined 12 patients with IESS and PVL at Saitama Children's Medical Center between January 1993 and September 2022. We evaluated seizure outcomes 3 months post-ACTH therapy and at the last visit. We also assessed electroencephalography findings and developmental outcomes. A positive response was defined as complete remission of epileptic spasms, no other seizure types, and hypsarrhythmia resolution post-ACTH therapy. RESULTS: The median onset age of epileptic spasms was 7 (range: 3-14) months. The median age at initiation of ACTH therapy was 9 (7-17) months. Seven of 12 patients (58.3%) showed a positive response. The median age at the last visit was 5 years and 6 months (1 year and 5 months-22 years and 2 months). At the last visit, only 2 of 7 initial responders remained seizure-free who demonstrated normal electroencephalography findings within 1-month post-ACTH therapy. Patients with epileptic discharge in the parieto-occipital region within 1-month post-ACTH therapy showed relapse of epileptic spasms or other seizure types. CONCLUSION: Patients having epileptic discharge in the parietal or occipital regions on electroencephalography within 1-month post-ACTH therapy may be at a high risk of epileptic spasm recurrence or other seizure types in the long term.

Association of Cystic Periventricular Leukomalacia and Postnatal Epilepsy in Very Preterm Infants.

INTRODUCTION: Cystic periventricular leukomalacia (PVL) is the most common white matter injury and a common cause of cerebral palsy in preterm infants. Postnatal epilepsy may occur after cystic PVL, but their causal relationship remains uncertain. Our aim was to validate the contribution of cystic PVL to postnatal epilepsy in very preterm infants and demonstrate their seizure characteristics. METHODS: This prospective cohort study enrolled 1,342 preterm infants (birth weight <1,500 g and gestational age <32 weeks) from 2003 to 2015. Cystic PVL was diagnosed by serial cerebral ultrasound, and other comorbidities were recorded during hospitalization. Neurological developments and consequences, including epilepsy, were serially accessed until the age of 5. RESULTS: A total of 976 preterm infants completed a 5-year neurological follow-up; 47 (4.8%) had cystic PVL. Preterm infants with cystic PVL were commonly associated with other comorbidities, including necrotizing enterocolitis stage III, neonatal seizures, and intraventricular hemorrhage during hospitalization. At age 5, 14 of the 47 (29.8%) preterm infants with cystic PVL had postnatal epilepsy. After adjusting for gender, gestational age, and three common comorbidities, cystic PVL was an independent risk factor for postnatal epilepsy (adjust OR: 16.2; 95% CI: 6.8-38.4; p < 0.001). Postnatal epilepsy after cystic PVL was commonly the generalized type (13 of 14, 92.9%), not intractable and most occurred after 1 year of age. DISCUSSION/CONCLUSION: Cystic PVL would independently lead to postnatal epilepsy. Preterm infants with cystic PVL are at risk of postnatal epilepsy after age 1 in addition to cerebral palsy.

Bradykinesia assessment in children with cerebral palsy and periventricular leukomalacia.

OBJECTIVE: To analyse the motor phenotype with a focus on bradykinesia in children with Cerebral Palsy (CP) in the setting of periventricular leukomalacia (PVL). METHODOLOGY: Analysis of a cohort of 25 children with CP and PVL. The Gross Motor Function Classification System (GMFCS) and the Manual Ability Classification System (MACS) were used to classify the severity of motor function. Spasticity was rated using the Modified Ashworth Scale (MAS), dystonia was rated using the Burke-Fahn-Marsden Scale (BFMS), and bradykinesia was rated using the Unified Parkinson's disease rating scale (UPDRS). All patients were video-recorded following a standard protocol. RESULTS: Bradykinesia was observed in 96% of patients. It was noted mainly in the limbs, and it was moderate-to-severe in the legs and mild-to-moderate in the arms. Bradykinesia correlated with functional level, as classified by GMFCS and MACS; also with dystonia, as rated by BFMS but did not correlate with a measure of spasticity (MAS). CONCLUSIONS: This study confirms the existence of bradykinesia in patients with CP in the setting of PVL. Bradykinesia and dystonia appear to be important interrelated factors influencing the level of gross and fine motor skills in patients with PVL.

Dystonia in individuals with spastic cerebral palsy and isolated periventricular leukomalacia.

AIM: To determine the prevalence of dystonia in individuals with periventricular leukomalacia (PVL) and spastic cerebral palsy (CP), but without basal ganglia and thalamic injury (BGTI) on brain magnetic resonance imaging (MRI). METHOD: This was a retrospective study of individuals with spastic CP and PVL on MRI evaluated between 2005 and 2018 in a CP center. Individuals with non-PVL brain lesions on MRI, including BGTI, were excluded. Dystonia was assessed via blinded review of neurological exam videos by pediatric movement disorders specialists. RESULTS: Eighty-five participants (45 males, 40 females; mean age at videotaping 12 years [standard deviation 5 years 6 months], range 4-26 years) met inclusion and exclusion criteria. Of these participants, 50 (59%) displayed dystonia in their exam videos. The most common locations of dystonia were the fingers and hip adductors. The prevalence of dystonia was unaffected by the gestational age or severity of PVL, and was affected by Gross Motor Function Classification System level. INTERPRETATION: Dystonia is common in individuals with spastic CP and PVL, even without BGTI on MRI. Our findings suggest vigilance for dystonia in individuals with spastic CP should remain high, even without MRI evidence of BGTI. WHAT THIS PAPER ADDS: Individuals with spastic cerebral palsy and isolated periventricular leukomalacia on magnetic resonance imaging commonly display dystonia. Common sites of dystonia are in the fingers and hip adductors.

Prevalence of the Infantile Strabismus Complex in Premature Children With and Without Periventricular Leukomalacia.

PURPOSE: To determine whether rates of strabismus and associated visuomotor deficits differed among children with different severities of periventricular leukomalacia (PVL). DESIGN: Retrospective, case-control study. METHODS: Brain magnetic resonance images (MRI) obtained from 98 children aged ≥2 years were analyzed using a standardized scoring system: 67 of 98 had PVL (mean GA 31 weeks) and 31 of 98 did not have PVL (mean GA 29 weeks). Severity of PVL was scored as degree of damage to the posterior optic radiations and the splenium of the corpus callosum on MRI. Ophthalmologic examination data were collated to assess the prevalence of visuomotor deficits and the relationship to PVL severity (grades 1-3, mild to severe). RESULTS: Infantile strabismus was documented in 61% of children with mild, 74% with moderate, and 88% with severe PVL (esotropia: exotropia ratio 3.5:1). Associated ocular motor deficits also increased systematically with PVL severity: latent ("fusion maldevelopment") nystagmus (20%, 47%, and 40%, respectively), dissociated vertical deviation (13%, 28%, and 30%), and nasotemporal pursuit/optokinetic nystagmus asymmetry (23%, 38%, and 54%). Additionally, the prevalence of retrograde optic neuropathy increased with PVL severity (5%, 26%, and 38%). The prevalence of each of these signs was substantially lower in children who had no PVL. CONCLUSIONS: Children who suffer PVL are likely to develop the deficits of the infantile strabismus complex. The deficits tend to increase systematically as a function of PVL severity. These findings provide evidence that infantile strabismus is linked to perinatal damage to cerebral vergence and gaze pathways.

Development of muscle tone impairments in high-risk infants: Associations with cerebral palsy and cystic periventricular leukomalacia.

AIM: To assess the prevalence and development of muscle tone impairments in infants at high risk of developmental disorders, and their associations with cerebral palsy (CP) and cystic periventricular leukomalacia (cPVL). METHOD: Longitudinal exploration of muscle tone in 39 infants at high risk of CP (LEARN2MOVE 0-2 project) mostly due to an early lesion of the brain. Muscle tone was assessed ≥4 times between 0 and 21 months corrected age (CA) with the Touwen Infant Neurological Examination. Diagnosis of CP was determined at 21 months CA. Neonatal neuro-imaging was available. Developmental trajectories were calculated using generalized linear mixed effect models. RESULTS: Infants showed atypical muscle tone in three or four body parts in 93% (172/185) of the assessments. The most prevalent muscle tone pattern was hypotonia of neck and trunk with hypertonia of the limbs (28%). From 7 months CA onwards hypertonia of the arms was associated with CP. Asymmetric arm tone during infancy was associated with unilateral CP. At 18-21 months CA ankle hypertonia was associated with CP at 21 months; leg hypertonia in infancy was not associated with CP. Leg hypertonia was associated with cPVL, regardless of age. INTERPRETATION: High-risk infants due to an early lesion of the brain often present with muscle tone impairment. In these infants, hypertonia and asymmetric muscle tone of the arms were from 7 months onwards associated with the diagnosis of CP at 21 months; hypertonia of the legs was not.

Ocular signs, visual and general developmental outcome in Indian children with radiologically proven periventricular leukomalacia.

PURPOSE: Owing to the paucity of literature on Indian children with periventricular leukomalacia (PVL), this retrospective study aimed to describe the visual and associated developmental abnormalities in a series of affected children attending a tertiary level eye care facility. METHODS: Children with radiologically confirmed PVL who attended the Pediatric Department of a tertiary eye hospital were included and underwent a detailed ocular and general developmental assessment. RESULTS: Of the 75 children, the mean age was 2.3 years, the mean follow-up was 3.1 years, 68% were males and 43% were born preterm. Grade I PVL was identified in 13 children (17%), Grade 2 PVL in 39 (52%), and Grade 3 PVL in 23 (31%). Premies with ≤2 kg (72.5%) and term babies with >2 kg (75%) had a greater association of PVL occurrence with a preponderance to severe PVL; 46% of the children were visually impaired which was significantly higher in the children with Grade 3 PVL (74%) than those with Grade 2 PVL (15%). Strabismus was common (80%) with a change in deviation over time. Seventy-one percent of the children had a refractive error, frequently myopic astigmatism. All the children except two had a delay in one or more general developmental milestones. CONCLUSION: PVL occurrence is observed both in the babies born at term and premies, resulting in significant ocular and systemic morbidities. We recommend a system in place for early identification and referral to initiate an early intervention program which goes a long way toward improving the quality of life in these children.

Vojta Therapy in Neuromotor Development of Pediatrics Patients with Periventricular Leukomalacia: Case Series.

Background and Objectives: Vojta therapy is used by physiotherapists and is based on stimulation through peripheral pressure that leads to the activation of involuntary motor response patterns, thus triggering patterns of reflex locomotion, hence also called reflex locomotion therapy. Objective: To analyze the changes produced by Vojta therapy in the evolution of infant motor development in patients with maturational delay due to periventricular leukomalacia. Materials and methods: One session of Vojta Therapy per week for eleven months, patients' neuromotor development was evaluated through the Denver II Test and the Baleys Scale. Results: A clinically significant increase in the development of the patients is observed. Conclusions: Neuromotor development seems to generate an adequate progression in the motor area.

Dystonia assessment in children with cerebral palsy and periventricular leukomalacia.

OBJECTIVE: To describe the frequency, motor phenotype, clinical patterns and functional consequences of dystonia in patients with cerebral palsy (CP) in the setting of periventricular leukomalacia. METHODS: Retrospective analysis of a cohort of 31 patients with CP and periventricular leukomalacia. Gross Motor Function Classification System (GMFCS) and Manual Ability Classification System (MACS) were used to classify functional ability. Spasticity was rated using the Modified Ashworth Scale. Presence of dystonia was assessed by reviewing video recordings, and its severity by using the Burke-Fahn-Marsden Dystonia Rating Scale. RESULTS: All patients showed evidence of dystonia involving upper and/or lower limbs, neck, trunk, mouth and eyes in order of frequency. In 29% of patients dystonia involved only the limbs and in 71% it was multifocal. Dystonia severity ranged from slight to severe. Severity and distribution of dystonia did not correlate with gender, age, weeks of gestation or duration of neonatal unit stay. GMFCS and MACS correlated with dystonia but not with spasticity. CONCLUSIONS: Severity of dystonia, but not spasticity is associated with the severity of motor functional disability in CP patients with periventricular leukomalacia and demonstrates the key role of dystonia in the motor function of these patients.

Gait features of dystonia in cerebral palsy.

AIM: To determine the features cited by motor phenotyping experts when identifying dystonia in people with cerebral palsy (CP). METHOD: Dystonia identification in CP, particularly when comorbid with spasticity, can be difficult. The dystonia diagnostic criterion standard remains subjective visual identification by expert consensus. For this qualitative study, we conducted an inductive thematic analysis of consensus-building discussions between three pediatric movement disorder physicians as they identified the presence or absence of dystonia in gait videos of 40 participants with spastic CP and periventricular leukomalacia. RESULTS: Unanimous consensus about the presence or absence of dystonia was achieved for 34 out of 40 videos. Two main themes were present during consensus-building discussions as videos were evaluated for dystonia: (1) unilateral leg or foot adduction that was variable over time, and (2) difficulty in identifying dystonia. Codes contributing to the first theme were more likely to be cited by a discussant when they felt dystonia was present (as opposed to absent) in a video (χ2 test, p=0.004). DISCUSSION: These results describe the gait features cited by experts during consensus-building discussion as they identify dystonia in ambulatory people with CP. Qualitative thematic analysis of these discussions could help codify the subjective process of dystonia diagnosis.

Cortical thickness of primary visual cortex correlates with motion deficits in periventricular leukomalacia.

Impairments of visual motion perception and, in particular, of flow motion have been consistently observed in premature and very low birth weight subjects during infancy. Flow motion information is analyzed at various cortical levels along the dorsal pathways, with information mainly provided by primary and early visual cortex (V1, V2 and V3). We investigated the cortical stage of the visual processing that underlies these motion impairments, measuring Grey Matter Volume and Cortical Thickness in 13 children with Periventricular Leukomalacia (PVL). The cortical thickness, but not the grey matter volume of area V1, correlates negatively with motion coherence sensitivity, indicating that the thinner the cortex, the better the performance among the patients. However, we did not find any such association with either the thickness or volume of area MT, MST and areas of the IPS, suggesting damage at the level of primary visual cortex or along the optic radiation.

Structural brain damage and visual disorders in children with cerebral palsy due to periventricular leukomalacia.

AIM: To systematically explore the relationship between type and severity of brain lesion on Magnetic Resonance Imaging (MRI) and visual function in a large cohort of children with periventricular leukomalacia (PVL). METHODS: 94 children with bilateral cerebral palsy (CP) and history of PVL were recruited at Stella Maris Scientific Institute in Pisa (Italy). We included data of participants (72) with at least one MRI after the age of three years and an evaluation of visual function including fixation, following, saccades, nystagmus, acuity, visual field, stereopsis and color perception. Brain lesions location and extent were assessed by a semi-quantitative MRI-scale for children with CP. RESULTS: Brain lesion severity strongly correlated with visual function total score (global MRI score p = .000; hemispheric score p = .001 and subcortical score p = .000). Moreover, visual acuity, visual field, stereopsis and colour were compromised when a cortical damage was present, while ocular motricity (and in particular fixation and saccades) were compromised in presence of subcortical brain damage. INTERPRETATION: Structural MRI is valuable for understanding the relationship between brain lesion severity and visual function in children with CP.

Neonatal Functional and Structural Connectivity Are Associated with Cerebral Palsy at Two Years of Age.

OBJECTIVE: The accuracy of structural magnetic resonance imaging (MRI) to predict later cerebral palsy (CP) in newborns with perinatal brain injury is variable. Diffusion tensor imaging (DTI) and task-based functional MRI (fMRI) show promise as predictive tools. We hypothesized that infants who later developed CP would have reduced structural and functional connectivity as compared with those without CP. STUDY DESIGN: We performed DTI and fMRI using a passive motor task at 40 to 48 weeks' postmenstrual age in 12 infants with perinatal brain injury. CP was diagnosed at age 2 using a standardized examination. RESULTS: Five infants had CP at 2 years of age, and seven did not have CP. Tract-based spatial statistics showed a widespread reduction of fractional anisotropy (FA) in almost all white matter tracts in the CP group. Using the median FA value in the corticospinal tracts as a cutoff, FA was 100% sensitive and 86% specific to predict CP compared with a sensitivity of 60 to 80% and a specificity of 71% for structural MRI. During fMRI, the CP group had reduced functional connectivity from the right supplemental motor area as compared with the non-CP group. CONCLUSION: DTI and fMRI obtained soon after birth are potential biomarkers to predict CP in newborns with perinatal brain injury.

Impact of peri-intraventricular haemorrhage and periventricular leukomalacia in the neurodevelopment of preterms: A systematic review and meta-analysis.

CONTEXT: Whether all degrees of periventricular leukomalacia (PVL) and peri-intraventricular haemorrhage (PIVH) have a negative impact on neurodevelopment. OBJECTIVE: To determine the impact of PVL and PIVH in the incidence of cerebral palsy, sensorineural impairment and development scores in preterm neonates. Registered in PROSPERO (CRD42017073113). DATA SOURCES: PubMed, Embase, SciELO, LILACS, and Cochrane databases. STUDY SELECTION: Prospective cohort studies evaluating neurodevelopment in children born preterm which performed brain imaging in the neonatal period. DATA EXTRACTION: Two independent researchers extracted data using a predesigned data extraction sheet. STATISTICAL METHODS: A random-effects model was used, with Mantel-Haenszel approach and a Sidik-Jonkman method for the estimation of variances, combined with Hartung-Knapp-Sidik-Jonkman correction. Heterogeneity was assessed through the I2 statistic and sensitivity analysis were performed when possible. No funnel plots were generated but publication bias was discussed as a possible limitation. RESULTS: Our analysis concluded premature children with any degree of PIVH are at increased risk for cerebral palsy (CP) when compared to children with no PIVH (3.4, 95% CI 1.60-7.22; 9 studies), a finding that persisted on subgroup analysis for studies with mean birth weight of less than 1000 grams. Similarly, PVL was associated with CP, both in its cystic (19.12, 95% CI 4.57-79.90; 2 studies) and non-cystic form (9.27, 95% CI 5.93-14.50; 2 studies). We also found children with cystic PVL may be at risk for visual and hearing impairment compared to normal children, but evidence is weak. LIMITATIONS: Major limitations were the lack of data for PVL in general, especially for the outcome of neurodevelopment, the high heterogeneity among methods used to assess neurodevelopment and the small number of studies, which led to meta-analysis with high heterogeneity and wide confidence intervals. CONCLUSIONS: There was no evidence supporting the hypothesis that PIVH causes impairment in neuropsychomotor development in our meta-analysis, but review of newer studies show an increased risk for lower intelligence scores in children with severe lesions, both PIVH and PVL. There is evidence to support the hypothesis that children with any degree of PIVH, especially those born below 1000 grams and those with severe haemorrhage, are at increased risk of developing CP, as well as children with PVL, both cystic and non-cystic.

Association of perinatal factors of epilepsy in very low birth weight infants, using a nationwide database in Japan.

OBJECTIVE: To determine clinical features of very low birth weight infants (VLBWIs) who had developed epilepsy by age 3 years. STUDY DESIGN: Multicenter cohort study using the Neonatal Research Network of Japan database. We analyzed clinical variables of 8431 VLBWIs who had recorded data of neurological sequelae at age 3 years. Logistic regression identified the association between variables and development of epilepsy. RESULT: One hundred and forty-three (1.7%) infants developed epilepsy, 683 (8.1%) showed cerebral palsy (CP), and 1114 (13.2%) had psychomotor delay. Epilepsy was associated with history of sepsis [adjusted odds ratio (AOR) 3.23], severe intraventricular hemorrhage (IVH; AOR 5.13), and cystic periventricular leukomalacia (PVL; AOR 12.7). Severe IVH and cystic PVL were also frequently associated with CP and psychomotor delay. CONCLUSION: Severe IVH and cystic PVL are strongly associated with development of epilepsy, as well as other neurological sequelae, and are potential critical therapeutic targets.