High Prevalence of Collagenopathies in Preterm- and Term-Born Children With Periventricular Venous Hemorrhagic Infarction.

INTRODUCTION: The aim of this study was to evaluate genetic risk factors in term-born children with antenatal periventricular hemorrhagic infarction (PVHI), presumed antenatal periventricular venous infarction and periventricular hemorrhagic infarction in preterm neonates. METHODS: Genetic analysis and magnetic resonance imaging were performed in 85 children: term-born children (≥36 gestational weeks) with antenatal periventricular hemorrhagic infarction (n = 6) or presumed antenatal (n = 40) periventricular venous infarction and preterm children (<36 gestational weeks) with periventricular hemorrhagic infarction (n = 39). Genetic testing was performed using exome or large gene panel (n = 6700 genes) sequencing. RESULTS: Pathogenic variants associated with stroke were found in 11 of 85 (12.9%) children with periventricular hemorrhagic infarction/periventricular venous infarction. Among the pathogenic variants, COL4A1/A2 and COL5A1 variants were found in 7 of 11 (63%) children. Additionally, 2 children had pathogenic variants associated with coagulopathy, whereas 2 other children had other variants associated with stroke. Children with collagenopathies had significantly more often bilateral multifocal stroke with severe white matter loss and diffuse hyperintensities in the white matter, moderate to severe hydrocephalus, moderate to severe decrease in size of the ipsilesional basal ganglia and thalamus compared to children with periventricular hemorrhagic infarction/periventricular venous infarction without genetic changes in the studied genes (P ≤ .01). Severe motor deficit and epilepsy developed more often in children with collagenopathies compared to children without genetic variants (P = .0013, odds ratio [OR] = 233, 95% confidence interval [CI]: 2.8-531; and P = .025, OR = 7.3, 95% CI: 1.3-41, respectively). CONCLUSIONS: Children with periventricular hemorrhagic infarction/periventricular venous infarction have high prevalence of pathogenic variants in collagene genes (COL4A1/A2 and COL5A1). Genetic testing should be considered for all children with periventricular hemorrhagic infarction/periventricular venous infarction; COL4A1/A2 and COL5A1/A2 genes should be investigated first.

Maternal Pyelonephritis as a Potential Cause of Perinatal Periventricular Venous Infarction in Term-Born Children.

Introduction: The study was designed to assess the prevalence of pregnancy and delivery associated risk factors in children suffering from neonatal or presumed periventricular venous infarction. Methods: Antenatal records and pregnancy outcome data were retrospectively assessed in children with presumed periventricular venous infarction (n = 43, born ≥36 gestational weeks) or neonatal periventricular venous infarction (n = 86, born <36 gestational weeks) and compared to a matched control group (n = 2168, ≥36 gestational weeks) from a prospective study. Results: Children with presumed periventricular venous infarction had significantly more maternal bacterial infections compared to the control group (47% vs 20%, respectively, P < .001), whereas no difference was found compared to the neonatal periventricular venous infarction group (49%, P = .80). Mothers with bacterial infection in the presumed periventricular venous infarction group had significantly more often pyelonephritis compared to the control group (50% vs 3.4%, respectively, P < .001). Conclusions: Our data show an increased risk for developing periventricular venous infarction in the case of maternal bacterial infections, especially between gestational weeks 21 and 31.

Perinatal Ischemic Stroke: Etiology and Imaging.

Perinatal ischemic stroke is a common cause of lifelong disability.

Sensory-motor network functional connectivity in children with unilateral cerebral palsy secondary to perinatal stroke.

BACKGROUND: Perinatal stroke is the most common cause of unilateral cerebral palsy. Mechanisms of post-stroke developmental plasticity in children are poorly understood. To better understand the relationship between functional connectivity and disability, we used resting-state fMRI to compare sensorimotor connectivity with clinical dysfunction. METHODS: School-aged children with periventricular venous infarction (PVI) and unilateral cerebral palsy were compared to controls. Resting-state BOLD signal was acquired on 3 T MRI and analyzed using CONN in SPM12. Functional connectivity was computed between S1, M1, supplementary motor area (SMA), and thalamus of the left/non-lesioned and right/lesioned hemisphere. Primary outcome was connectivity expressed as a Fisher-transformed correlation coefficient. Motor function was measured using the Assisting Hand Assessment (AHA), and Melbourne Assessment (MA). Proprioceptive function was measured using a robotic position matching task (VarXY). RESULTS: Participants included 15 PVI and 21 controls. AHA and MA in stroke patients were negatively correlated with connectivity (increased connectivity = poorer performance). Position sense was inversely correlated with connectivity (increased connectivity = improved performance) between the non-lesioned S1 and thalamus/SMA. In controls, VarXY was positively correlated with connectivity between the thalamus and bilateral sensorimotor regions. CONCLUSIONS: Resting state fMRI measures of sensorimotor connectivity are associated with clinical sensorimotor function in children with unilateral cerebral palsy secondary to PVI. Greater insight into understanding reorganization of brain networks following perinatal stroke may facilitate personalized rehabilitation.

Epilepsy after perinatal stroke with different vascular subtypes.

OBJECTIVE: With an incidence up to 63 per 100,000 live births, perinatal stroke is an important cause of childhood epilepsy. The aim of the study was to find the prevalence of and predictive factors for epilepsy, and to describe the course of epilepsy in children with perinatal stroke with different vascular subtypes. METHODS: Patients were retrieved from the Estonian Paediatric Stroke Database with follow-up time at least 24 months. Patients were divided into 5 perinatal stroke syndromes: neonatal arterial ischemic stroke (AIS), neonatal hemorrhagic stroke, neonatal cerebral sinovenous thrombosis, presumed AIS, and presumed periventricular venous infarction. RESULTS: The final study group included 73 children with perinatal stroke (39 boys). With a median follow-up time of 8.6 years, epilepsy was diagnosed in 21/73 (29%) children, most of whom had AIS (17/21, 81%). The 18-year cumulative poststroke epilepsy risk according to the Kaplan-Meier estimator was 40.8% (95% confidence interval [CI] 20.7-55.9%). The median age at epilepsy diagnosis was 50 months (range 1 month to 18.4 years). Children with neonatal AIS had the highest risk of epilepsy, but children with presumed AIS more often had severe epilepsy syndromes. Cortical lesions (odds ratio [OR] 19.7, 95% CI 2.9-133), and involvement of thalamus (OR 9.8, 95% CI 1.8-53.5) and temporal lobe (OR 8.3, 95% CI 1.8-39.6) were independently associated with poststroke epilepsy. SIGNIFICANCE: The risk for poststroke epilepsy after perinatal stroke depends on the vascular subtype. Patients with perinatal AIS need close follow-up to detect epilepsy and start with antiepileptic treatment on time.

Long-term neurodevelopmental outcome after perinatal arterial ischemic stroke and periventricular venous infarction.

BACKGROUND: Long-term follow-up data after different vascular types of ischemic perinatal stroke is sparse. Our aim was to study neurodevelopmental outcomes following neonatal and presumed perinatal ischemic middle cerebral artery territory stroke (arterial ischemic stroke, AIS) and periventricular venous infarction (PVI). METHODS: A prospective consecutive cohort of 40 term-born children with perinatal stroke (21 AIS, 19 PVI) was identified through the Estonian Paediatric Stroke Database. While 48% of the children with AIS were diagnosed during the neonatal period, all the children with PVI had presumed perinatal stroke. Outcomes based on the Paediatric Stroke Outcome Measure (PSOM) and Kaufman Assessment Battery for Children - Second Edition (K-ABC-II), in relation to extent and laterality of stroke, were defined. RESULTS: At a median age of 7 years 6 months (range 3.6-13y), there was a trend towards worse neurodevelopmental outcome in participants with AIS when compared to PVI (mean total PSOM scores 3.1 and 2.2, respectively; p = 0.06). Combined deficits of motor, language and cognitive/behavioural functions were significantly more common among children with AIS (90%) when compared to children with PVI (53%, p = 0.007). General cognitive ability (by K-ABC-II) was significantly lower in the AIS subgroup (mean 79.6; 95% CI 72.3-87.0), but children with PVI (91.6; 95% CI 85.5-97.8) also had poorer performance than the age-equivalent normative mean. Large extent of stroke was associated with poorer neurodevelopmental outcome and lower cognitive performance in children following AIS but not in PVI. CONCLUSION: In this national cohort, poor long-term neurodevelopmental outcome after perinatal ischemic stroke was seen irrespective of the vascular type or time of diagnosis of stroke. However, the spectrum of neurological deficits is different after perinatal AIS and PVI, with combined deficits more common among children following AIS.

Fetal stroke and cerebrovascular disease: Advances in understanding from lenticulostriate and venous imaging, alloimmune thrombocytopaenia and monochorionic twins.

Fetal stroke is an important cause of cerebral palsy but is difficult to diagnose unless imaging is undertaken in pregnancies at risk because of known maternal or fetal disorders. Fetal ultrasound or magnetic resonance imaging may show haemorrhage or ischaemic lesions including multicystic encephalomalacia and focal porencephaly. Serial imaging has shown the development of malformations including schizencephaly and polymicrogyra after ischaemic and haemorrhagic stroke. Recognised causes of haemorrhagic fetal stroke include alloimmune and autoimmune thrombocytopaenia, maternal and fetal clotting disorders and trauma but these are relatively rare. It is likely that a significant proportion of periventricular and intraventricular haemorrhages are of venous origin. Recent evidence highlights the importance of arterial endothelial dysfunction, rather than thrombocytopaenia, in the intraparenchymal haemorrhage of alloimmune thrombocytopaenia. In the context of placental anastomoses, monochorionic diamniotic twins are at risk of twin twin transfusion syndrome (TTTS), or partial forms including Twin Oligohydramnios Polyhydramnios Sequence (TOPS), differences in estimated weight (selective Intrauterine growth Retardation; sIUGR), or in fetal haemoglobin (Twin Anaemia Polycythaemia Sequence; TAPS). There is a very wide range of ischaemic and haemorrhagic injury in a focal as well as a global distribution. Acute twin twin transfusion may account for intraventricular haemorrhage in recipients and periventricular leukomalacia in donors but there are additional risk factors for focal embolism and cerebrovascular disease. The recipient has circulatory overload, with effects on systemic and pulmonary circulations which probably lead to systemic and pulmonary hypertension and even right ventricular outflow tract obstruction as well as the polycythaemia which is a risk factor for thrombosis and vasculopathy. The donor is hypovolaemic and has a reticulocytosis in response to the anaemia while maternal hypertension and diabetes may influence stroke risk. Understanding of the mechanisms, including the role of vasculopathy, in well studied conditions such as alloimmune thrombocytopaenia and monochorionic diamniotic twinning may lead to reduction of the burden of antenatally sustained cerebral palsy.

Outcome of hemiplegic cerebral palsy born at term depends on its etiology.

OBJECTIVES: To elucidate the etiology and its relationship to the outcomes of hemiplegic cerebral palsy (HCP). PARTICIPANTS AND METHODS: MR images and outcomes of 156 children with HCP born at term and older than three years were investigated in two major centers for cerebral palsy in Japan. Etiologies were classified into perinatal ischemic stroke (PIS), cerebral dysgenesis (CD), and others. PIS was divided into periventricular venous infarction (PVI) and two types of arterial infarction; middle cerebral artery infarction (MCAI) and deep gray matter infarction (DGMI). Initial signs and the time of presentation were investigated among the three types of PIS. As functional outcomes, laterality of paresis, age at initial walk, affected hand's function, intellectual development, and occurrence of epilepsy were compared among all the four types. ETIOLOGY: PIS was found in 106 children (68%), while CD accounted for 28 (18%). Among PIS, venous infarction was more common than arterial infarction (62:44). OUTCOMES: PVI revealed later presentation of motor asymmetry and more involvement of lower extremity as the initial sign among PIS groups. Only MCAI showed right-side predominance in laterality of paresis. DGMI related to better intellectual development and PVI showed lower occurrence of epilepsy, while there was no significant difference in affected hand's function among the four groups. PIS groups showed significantly earlier attainment of independent walk, better intellectual development, and lower occurrence of epilepsy than CD. CONCLUSIONS: PVI was the most common cause of HCP born at term, and the etiology closely related to the initial signs of hemiplegia and overall outcomes.