The thalamus and basal ganglia are smaller in children with epilepsy after perinatal stroke.

Background: Epilepsy is one of the most serious consequences of perinatal stroke. Epilepsy itself has been proposed as a risk factor for impaired cognitive, language, and behavioral functioning. It is still unclear which children develop epilepsy after perinatal stroke. The current study aimed to evaluate the volume of the thalamus and the basal ganglia in children after perinatal stroke in relation to poststroke epilepsy. Methods: The follow-up study included 29 children with perinatal arterial ischemic stroke (AIS), 33 children with presumed periventricular venous infarction (PVI), and 46 age- and sex-matched healthy controls. Magnetic resonance imaging was performed in children between the ages of 4 and 18 years, and volumetric analysis by segmentation was used to evaluate the size of the thalamus, caudate nucleus, putamen, globus pallidus, hippocampus, amygdala, and nucleus accumbens. Results: During a median follow-up time of 12.8 years [interquartile range (IQR): 10.8-17.3] in the AIS group and 12.5 years (IQR: 9.3-14.8) in the PVI group (p = 0.32), epilepsy developed in 10 children (34.5%) with AIS and in 4 (12.1%) children with PVI, p = 0.036 [odds ratio (OR) = 3.8, 95%, confidence interval (CI): 1.04-14]. Epilepsy and interictal epileptiform discharges (IEDs) without clinical seizures were more often expressed in children with AIS (n = 16, 55%) than in children with PVI (n = 7, 21.2%), p = 0.0057 (OR = 3.8 95% CI: 1.04-14). In the AIS group, the ipsilesional and contralesional thalamus, ipsilesional caudate nucleus, and nucleus accumbens were significantly smaller in children with epilepsy compared to children without epilepsy. In the PVI group, the ipsilesional thalamus, caudate nucleus, and nucleus accumbens were smaller in the pooled group of epilepsy plus IED alone compared to children without epilepsy. Conclusion: In children with AIS, epilepsy or IED occurred more often compared to children with PVI. Both patients with AIS and PVI with severe damage to the basal ganglia and the thalamus have a higher risk of developing poststroke epilepsy and should be monitored more closely throughout childhood to initiate timely antiseizure medication and rehabilitation.

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.

Language lateralization and outcome in perinatal stroke patients with different vascular types.

Perinatal stroke affects child's language development and can change language lateralization. Language generation and comprehension tasks in functional magnetic resonance imaging were used to determine language lateralization in term born children with perinatal left-side arterial ischemic stroke (AIS) (n = 9, mean age (SD) 13.4 (3.1) y.) and periventricular venous infarction (PVI) (n = 12, 11.8 (2.8) y.), and in healthy right-handed controls (n = 30, 11.6 (2.6) y.). Lateralization index was calculated for the Broca and Wernicke areas and correlated with language and cognitive outcomes measured by the Kaufman Assessment Battery for Children II ed. Language outcome in children with perinatal stroke is poorer compared to healthy controls. Children with small AIS lesions and most children with PVI showed left-side language activation. Most children with large AIS lesions and one child with large PVI had language activation reorganized to the right hemisphere. Language reorganization to the unlesioned right hemisphere did not ensure normal language outcome.

Ipsilesional volume loss of basal ganglia and thalamus is associated with poor hand function after ischemic perinatal stroke.

BACKGROUND: Perinatal stroke (PS) is the leading cause of hemiparetic cerebral palsy (CP). Involvement of the corticospinal tract on neonatal magnetic resonance imaging (MRI) is predictive of motor outcome in patients with hemiparetic CP. However, early MRI is not available in patients with delayed presentation of PS and prediction of hemiparesis severity remains a challenge. AIMS: To evaluate the volumes of the basal ganglia, amygdala, thalamus, and hippocampus following perinatal ischemic stroke in relation to hand motor function in children with a history of PS and to compare the volumes of subcortical structures in children with PS and in healthy controls. METHODS: Term born PS children with arterial ischemic stroke (AIS) (n = 16) and with periventricular venous infarction (PVI) (n = 18) were recruited from the Estonian Pediatric Stroke Database. MRI was accuired during childhood (4-18 years) and the volumes of the basal ganglia, thalamus, amygdala and hippocampus were calculated. The results of stroke patients were compared to the results of 42 age- and sex-matched healthy controls. Affected hand function was evaluated by Assisting Hand Assessment (AHA) and classified by the Manual Ability Classification System (MACS). RESULTS: Compared to the control group, children with AIS had smaller volumes of the ipsi- and contralesional thalami, ipsilesional globus pallidus, nucleus accumbens and hippocampus (p < 0.005). Affected hand function in children with AIS was correlated with smaller ipsilesional thalamus, putamen, globus pallidus, hippocampus, amygdala and contralesional amygdala (r > 0.5; p < 0.05) and larger volume of the contralesional putamen and hippocampus (r < - 0.5; p < 0.05). In children with PVI, size of the ipsilesional caudate nucleus, globus pallidus, thalamus (p ≤ 0.001) and hippocampus (p < 0.03) was smaller compared to controls. Smaller volume of the ipsi- and contralesional thalami and ipsilesional caudate nucleus was correlated with affected hand function (r > 0.55; p < 0.05) in children with PVI. CONCLUSIONS: Smaller volume of ipsilesional thalamus was associated with poor affected hand function regardless of the perinatal stroke subtype. The pattern of correlation between hand function and volume differences in the other subcortical structures varied between children with PVI and AIS. Evaluation of subcortical structures is important in predicting motor outcome following perinatal stroke.

Neurologic phenotypes associated with COL4A1/2 mutations: Expanding the spectrum of disease.

OBJECTIVE: To characterize the neurologic phenotypes associated with COL4A1/2 mutations and to seek genotype-phenotype correlation. METHODS: We analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with COL4A1/COL4A2 mutations. RESULTS: Childhood-onset focal seizures, frequently complicated by status epilepticus and resistance to antiepileptic drugs, was the most common phenotype. EEG typically showed focal epileptiform discharges in the context of other abnormalities, including generalized sharp waves or slowing. In 46.4% of new patients with focal seizures, porencephalic cysts on brain MRI colocalized with the area of the focal epileptiform discharges. In patients with porencephalic cysts, brain MRI frequently also showed extensive white matter abnormalities, consistent with the finding of diffuse cerebral disturbance on EEG. Notably, we also identified a subgroup of patients with epilepsy as their main clinical feature, in which brain MRI showed nonspecific findings, in particular periventricular leukoencephalopathy and ventricular asymmetry. Analysis of 15 pedigrees suggested a worsening of the severity of clinical phenotype in succeeding generations, particularly when maternally inherited. Mutations associated with epilepsy were spread across COL4A1 and a clear genotype-phenotype correlation did not emerge. CONCLUSION: COL4A1/COL4A2 mutations typically cause a severe neurologic condition and a broader spectrum of milder phenotypes, in which epilepsy is the predominant feature. Early identification of patients carrying COL4A1/COL4A2 mutations may have important clinical consequences, while for research efforts, omission from large-scale epilepsy sequencing studies of individuals with abnormalities on brain MRI may generate misleading estimates of the genetic contribution to the epilepsies overall.

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.

Incidence of Childhood Epilepsy in Estonia.

The aim of this prospective epidemiological study was to establish the incidence rate of childhood epilepsy in Estonia, to describe the clinical spectrum and to identify etiology of childhood epilepsy. The overall incidence rate was 86.3/100 000. The incidence rate was the highest (141.9/100 000) in the age group from 5 to 9 years. Specific electroclinical syndromes were identified in 22.8% of cases. Structural or metabolic etiology was identified in 20.0% of cases, presumed genetic origin was identified in 33.9% of cases, and in 46.1% of cases the cause of epilepsy remained unknown. The incidence rate of childhood epilepsy in Estonia (86.3/100 000) is similar to the other European countries. In comparison with the results of the first epidemiological study of childhood epilepsy in Estonia (incidence rate 45/100 000; Beilmann et al), the incidence rate in this study is almost 2 times higher, what can be explained with better case collection and improved diagnostic modalities in Estonia.

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.

Symptomatic Neonatal Arterial Ischemic Stroke With Prenatal and Postnatal Neuroimaging.

The authors report a girl born at term via planned cesarean delivery. Three days earlier, an antenatal magnetic resonance imaging study, showing no cerebral lesions in the fetus, was performed. Ten minutes after delivery, signs of progressive respiratory failure developed and the infant was transferred to the intensive care unit. On the next day, a computed tomography (CT) scan showed acute ischemic lesions in the areas of the left middle and posterior cerebral arteries. The exact mechanism of stroke remained unidentified. It is possible that emboli occluded the left middle cerebral artery and left posterior cerebral artery. At the age of 1 year and 4 months, the patient demonstrated a slight right-sided hemiparesis more pronounced in the hand. To our knowledge, there are no prior published case studies reporting a healthy fetal brain, which then undergoes an acute neonatal arterial infarction near or during birth following an elective cesarean delivery.

Resting-State Functional Connectivity and Cognitive Impairment in Children with Perinatal Stroke.

Perinatal stroke is a leading cause of congenital hemiparesis and neurocognitive deficits in children. Dysfunctions in the large-scale resting-state functional networks may underlie cognitive and behavioral disability in these children. We studied resting-state functional connectivity in patients with perinatal stroke collected from the Estonian Pediatric Stroke Database. Neurodevelopment of children was assessed by the Pediatric Stroke Outcome Measurement and the Kaufman Assessment Battery. The study included 36 children (age range 7.6-17.9 years): 10 with periventricular venous infarction (PVI), 7 with arterial ischemic stroke (AIS), and 19 controls. There were no differences in severity of hemiparesis between the PVI and AIS groups. A significant increase in default mode network connectivity (FDR 0.1) and lower cognitive functions (p < 0.05) were found in children with AIS compared to the controls and the PVI group. The children with PVI had no significant differences in the resting-state networks compared to the controls and their cognitive functions were normal. Our findings demonstrate impairment in cognitive functions and neural network profile in hemiparetic children with AIS compared to children with PVI and controls. Changes in the resting-state networks found in children with AIS could possibly serve as the underlying derangements of cognitive brain functions in these children.

Presumed Perinatal Stroke: Risk Factors, Clinical and Radiological Findings.

It is unknown why some infants with perinatal stroke present clinical symptoms late during infancy and will be identified as infants with presumed perinatal stroke. The risk factors and clinical and radiological data of 42 infants with presumed perinatal stroke (69% with periventricular venous infarction and 31% with arterial ischemic stroke) from the Estonian Pediatric Stroke Database were reviewed. Children with presumed perinatal stroke were born at term in 95% of the cases and had had no risk factors during pregnancy in 43% of the cases. Children with periventricular venous infarction were born significantly more often (82%) vaginally (P = .0213) compared to children with arterial stroke (42%); nor did they require resuscitation (P = .0212) or had any neurological symptoms after birth (P = .0249). Periventricular venous infarction is the most common type of lesion among infants with the presumed perinatal stroke. Data suggest that the disease is of prenatal origin.

Different plasticity patterns of language function in children with perinatal and childhood stroke.

Plasticity of language function after brain damage can depend on maturation of the brain. Children with left-hemisphere perinatal (n = 7) or childhood stroke (n = 5) and 12 controls were investigated using functional magnetic resonance imaging. The verb generation and the sentence comprehension tasks were employed to activate the expressive and receptive language areas, respectively. Weighted laterality indices were calculated and correlated with results assessed by neuropsychological test battery. Compared to controls, children with childhood stroke showed significantly lower mean scores for the expressive (P < .05) and receptive (P = .05) language tests. On functional magnetic resonance imaging they showed left-side cortical activation, as did controls. Perinatal stroke patients showed atypical right-side or bilateral language lateralization during both tasks. Negative correlation for stroke patients was found between scores for expressive language tests and laterality index during the verb generation task. (Re)organization of language function differs in children with perinatal and childhood stroke and correlates with neurocognitive performance.

Long-term cognitive outcomes after pediatric stroke.

This study assessed neurocognitive and neurologic outcomes of children with neonatal and childhood strokes. Twenty-one children with neonatal (mean age, 6.86 years) and 10 children with childhood (mean age, 8.21 years) strokes, identified via the Estonian Pediatric Stroke Database (1995-2006), participated. A developmental neuropsychologic assessment was used for neurocognitive outcomes, and the Paediatric Stroke Outcome Measure for neurologic outcomes. Neuromotor impairment was evident in 62% of children with neonatal strokes, and in 70% of children with childhood strokes. Compared with control subjects, children with strokes exhibited worse attention, language, memory, and sensorimotor functions. The sensorimotor domain comprised the most impaired neurocognitive area, whereas executive functions remained intact in both stroke groups. A well-preserved executive function may account for the normal range of intelligence in children with strokes. More severe impairment in neurocognitive skills was evident after neonatal strokes, and the visuospatial domain was more impaired than in children from the childhood group. Prognoses were worse after left hemisphere strokes associated with epilepsy. Our results on emerging neurocognitive deficits in several areas underline the importance of neuropsychologic testing and the follow-up of children with pediatric strokes.

Epidemiology of childhood stroke in Estonia.

We investigated the incidence and 30-day case-fatality of childhood stroke in Estonia, and clinical signs and risk factors of childhood stroke. A retrospective (1995-2003) and prospective study (2004-2006) of childhood stroke (arterial ischemic, hemorrhagic, and sinovenous thrombosis) and transient ischemic attack was conducted. Stroke-incidence calculation was based on the prospective study. Clinical diagnoses of stroke were confirmed by neuroradiology. The incidence rate of childhood stroke in Estonia was 2.73/100,000 person-years for children aged 30 days to 18 years: 1.61/100,000 for arterial ischemic stroke, 0.87/100,000 for hemorrhagic stroke, 0.25/100,000 for sinovenous thrombosis, and 0.37/100,000 for transient ischemic attack. No arterial ischemic stroke patients died within 30 days, but case-fatality for intracerebral hemorrhage was 46%. Focal signs occurred in 100% of arterial ischemic strokes and 64% of intracerebral hemorrhage cases. Risk factors were identified in 35/48 (73%) children with cerebrovascular attacks. Six children with arterial ischemic stroke (6/24, 25%) manifested more than one risk factor. The incidence rate of childhood stroke in Estonia is similar to that in earlier data.

Vehicle-associated closed trauma-induced stroke in a 27-day-old girl.

Birth trauma, but not postnatal trauma, has been recognized as a cause of cerebral infarction in newborns. We report a case of cerebral infarction in a 27-day-old girl after a car accident. During the car accident, the child was properly restrained to the child's safety seat. The patient was admitted to the hospital for observation because of pronounced irritability. There were no focal neurological symptoms on admission. Twenty-eight hours after the accident, the child developed focal tonic-clonic seizures and mild right-sided hemiparesis. The seizures were successfully treated with phenobarbital at a dose of 30 mg per day. Computed tomography and magnetic resonance imagining performed on the second and third days after the accident, respectively, showed subdural hemorrhage in the occipital regions and cerebral ischemia in the left parieto-occipital region. Control imaging 10 days later showed signs of reperfusion. Persistent child irritability after head trauma is one of the indicating factors for performing an emergency computed tomography scan of the head.

Acutely and retrospectively diagnosed perinatal stroke: a population-based study.

BACKGROUND AND PURPOSE: There are not very many epidemiological studies on perinatal stroke, and many authors suggest that this may be an underdiagnosed condition. The aim of the study was to estimate the incidence of perinatal arterial ischemic and hemorrhagic stroke in Estonia, to study the first clinical signs and to identify possible differences in predisposing factors and outcome between acutely and retrospectively diagnosed cases of perinatal stroke. METHODS: A retro- and prospective study of acutely (within the first month) and retrospectively diagnosed ischemic and hemorrhagic cases of perinatal stroke was conducted in a children population born in the eastern and southern regions of Estonia during the years 1994 to 2003. Patients were identified from a pilot study, hospital records, and an inquiry of child neurologists and general practitioners. The diagnosis was confirmed in 38 (12 were diagnosed acutely and 26 retrospectively) cases by neuroradiology (MRI or CT). RESULTS: The incidence rate of perinatal stroke in Estonia is 63 per 100,000 live births. Main clinical findings in the neonatal period were seizures, abnormalities of muscular tone, and disturbed level of alertness. Previously identified risk factors occurred in 32% of cases. Children with early diagnosis had more often adverse events during pregnancy and delivery (P<0.05) and developed more severe stage of hemiparesis compared with children with late diagnosis (P<0.05). CONCLUSIONS: The incidence rate of 63 per 100,000 live birth is higher than previously reported. Detailed analysis of the first signs of perinatal stroke may improve the early diagnostics of perinatal stroke.