Factors Affecting Epilepsy Development and Epilepsy Prognosis in Cerebral Palsy

A study was conducted between November 2006 and October 2009 to determine the factors predicting the presence and prognosis of epilepsy in patients with cerebral palsy. We enrolled 2 groups of patients: 42 with cerebral palsy in group 1 and 56 patients with cerebral palsy and epilepsy in group 2. The subjects in group 2 were considered to have good epilepsy prognosis if they were free of seizures for the previous year; otherwise they were considered to have poor epilepsy prognosis. In group 2, neonatal epilepsy, family history of epilepsy, and moderate to severe mental retardation were significantly higher than in group 1 (P < 0.05). In univariate analysis, neonatal seizures, epileptic activity as measured by electroencephalography, and polytherapy were found to be predictors of poor epilepsy prognosis. Additionally, the need for long-term medication to control seizures unfavorably affects prognosis. In logistic regression analysis, neonatal seizure and interictal epileptic activity in electroencephalography were found to be independent predictors of poor epilepsy outcome. In addition, logistic regression analysis revealed that increasing age reduces the success of epilepsy treatment. Neonatal seizures, family history of epilepsy, and mental retardation were found to be important and independent predictors of development of epilepsy in patients with cerebral palsy.     

Epilepsy in children with periventricular leukomalacia

Objective

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

Patients and methods

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

Results

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

Conclusion

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

Neuropathologic substrate of cerebral palsy

Animal models have assisted in understanding the mechanisms of brain injury underlying cerebral palsy. Nevertheless, no such models replicate every aspect of the human disease. This review summarizes the classic and more recent studies of the neuropathology of human perinatal brain injury most commonly associated with cerebral palsy, for use by researchers and clinicians alike who need to analyze published animal models with respect to their fidelity to the human disorder. The neuropathology underlying cerebral palsy includes white-matter injury, known as periventricular leukomalacia, as well as germinal matrix hemorrhage with intraventricular extension, and injury to the cortex, basal ganglia, and thalamus. Each has distinctive features while sharing some risk factors, such as prematurity and/or hypoxia-ischemia in the perinatal period. Periventricular leukomalacia consists of diffuse injury of deep cerebral white matter, with or without focal necrosis. Recent work directly in human postmortem tissue has focused on the role of free radical injury, cytokine toxicity (especially in light of the epidemiologic association of periventricular leukomalacia with maternofetal infection), and excitotoxicity in the development of periventricular leukomalacia. Premyelinating oligodendrocytes, which predominate in periventricular regions during the window of vulnerability to periventricular leukomalacia (24-34 postconceptional weeks), are the targets of free radical injury, as determined by immunocytochemical markers of lipid peroxidation and protein nitration. This maturational susceptibility can be attributed in part to a relative deficiency of superoxide dismutases in developing white matter. Microglia, which respond to cytokines and to bacterial products such as lipopolysaccharide via Toll-like receptors, are increased in periventricular leukomalacia white matter and can contribute to cellular damage. Indeed, several cytokines, including tumor necrosis factor-a and interleukins 2 and 6, as well as interferon-g, have been demonstrated in periventricular leukomalacia. Preliminary work suggests a role for glutamate receptors and glutamate transporters in periventricular leukomalacia based on expression in human developing oligodendrocytes. Germinal matrix hemorrhage, with or without intraventricular hemorrhage, occurs in premature infants and can coexist with periventricular leukomalacia. Studies in human germinal matrix tissue have focused on maturation-based vascular factors, such as morphometry and expression of molecules related to the structure of the blood-brain barrier. Gray-matter injury, seen more commonly in term infants, includes cortical infarcts and status marmoratus. Subtle cortical injury overlying periventricular leukomalacia is the subject of current interest as a possible substrate for the cognitive difficulties seen in patients with cerebral palsy. In summary, it is hoped that work in human tissue, in conjunction with experimental animal models, will lead to eventual therapeutic or preventive strategies for the perinatal brain injury underlying cerebral palsy.     

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

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

Risk Factors of Infantile Spasms Compared with Other Seizures in Children Under 2 Years of Age

Summary: To analyze the magnitude of the risk factors for infantile spasms, we evaluated the records of 80 children with infantile spasms, 474 children with other types of epilepsy, 2,196 children with febrile seizures, and 262 children with CNS infections. There was a family history of seizures in 13.8% of children with infantile spasms, 28.5% of children with other forms of epilepsy, 25.5% of children with febrile seizures, and 5.3% of children with CNS infections. Children with a family history of seizures were 2.82 times more likely to have infantile spasms, 7.05 times more likely to have other epilepsy, and 6.08 times more likely to have febrile seizures than controls (children with CNS infections). However, a family history of seizures increased the risk for infantile spasms only in the cryptogenic group. Children with infantile spasms were significantly more likely to have cerebral palsy, microcephaly, hydrocephaly, CNS malformations, neonatal hypoxia, or neonatal seizures than children with other types of epilepsy, febrile seizures, or CNS infections. There was a modest genetic predisposition to seizures in children with infantile spasms. However, our data suggest a much stronger association with underlying neurologic abnormalities, mainly neonatal seizures, neonatal hypoxia, and CNS malformations.     

Neuroimaging in cerebral palsy: Patterns of brain dysgenesis and injury

Despite advances in obstetric and neonatal care, the overall prevalence of cerebral palsy has remained stable, supporting the belief that pathogenesis is primarily due to prenatal brain dysgenesis and injury. Neuroimaging studies have consistently shown abnormalities in 70% to 90% of affected children, facilitating clinical classification into groups with early brain malformations, white-matter injury, neonatal encephalopathies, and a heterogeneous group of postnatally acquired disorders. White-matter injury, well seen on conventional magnetic resonance imaging (MRI), is the leading cause of cerebral palsy in children born preterm. As many as 20% of very low birthweight infants have cystic and/or diffuse white-matter injury, termed periventricular leukomalacia, with evidence of associated pathology in other cortical and subcortical structures. In the group with acute, term perinatal pathology, a variety of imaging modalities, in addition to MRI, have diagnostic utility. In general, when added to conventional MRI, advanced techniques, such as diffusion tensor imaging, diffusion-weighted imaging, and magnetic resonance spectroscopy, provide a more complete picture of structural and functional brain abnormalities. The results have led to improved understanding of pathogenesis, especially in regard to periventricular leukomalacia and hypoxic-ischemic encephalopathy. This information might lead to interventions preventing brain injury in preterm infants and asphyxiated term newborns.     

Epilepsy in children with cerebral palsy

OBJECTIVE: To describe the prevalence and characteristics of epilepsy in patients with cerebral palsy in a tertiary center. METHODS: a total of 100 consecutive patients with cerebral palsy were retrospectively studied. Criteria for inclusion were follow-up period for at least 2 years. Types and incidence of epilepsy were correlated with the different forms of cerebral palsy. Other factors associated with epilepsy such as age of first seizure, neonatal seizures and family history of epilepsy were also analysed. RESULTS: follow-up ranged between 24 and 151 months (mean 57 months). The overall prevalence of epilepsy was 62%. Incidence of epilepsy was predominant in patients with hemiplegic and tetraplegic palsies: 70.6% and 66.1%, respectively. First seizure occurred during the first year of life in 74.2% of patients with epilepsy. Generalized and partial were the predominant types of epilepsy (61.3% and 27.4%, respectively). Thirty-three (53.2%) of 62 patients were seizure free for at least 1 year. Neonatal seizures and family history of epilepsy were associated with a higher incidence of epilepsy. CONCLUSIONS: epilepsy in cerebral palsy can be predicted if seizures occur in the first year of life, in neonatal period and if there is family history of epilepsy.     

A comparison of spastic diplegic and tetraplegic cerebral palsy

The aim of this study was to compare spastic diplegic and tetraplegic cerebral palsy. Thirty-eight children had spastic diplegic cerebral palsy and 48 spastic tetraplegic cerebral palsy. Risk factors of cerebral palsy, seizures, severity of cerebral palsy, electroencephalogram, and magnetic resonance imaging findings were analyzed. Gestational history, low birth weight, and perinatal pathologies were present in similar percentages in both groups. Lower values of the Apgar score were recorded more often in the tetraplegic cerebral palsy group than the diplegic group. The children with spastic diplegia were classified more frequently into levels I and II of the Gross Motor Function Classification System, but patients with spastic tetraplegia were classified more frequently into levels IV and V. Similarly, mental retardation was observed more frequently in the patients with spastic tetraplegia. In magnetic resonance imaging, periventricular leukomalacia was detected in a higher proportion of children with spastic diplegia than in patients with tetraplegia. Cerebral atrophy occurred more frequently in the tetraplegic group compared with diplegic patients. Twenty-four (50.0%) children with spastic tetraplegia had epilepsy compared with six children with spastic diplegia. The incidence of intractable epilepsy was higher in the tetraplegic patients than in the children with spastic diplegia.     

Epilepsy in hemiplegic cerebral palsy due to perinatal arterial ischaemic stroke

Aim The aim of this study was to describe the frequency, risk factors, manifestations, and outcome of epilepsy in children with hemiplegic cerebral palsy (CP) due to perinatal arterial ischaemic stroke (AIS). Method The study group comprised 63 participants (41 males, 22 females) from a population‐based CP register whose brain imaging showed perinatal AIS. Information collected included occurrence of neonatal seizures, family history of epilepsy, motor function and epilepsy onset, treatment, and outcome. Electroclinical findings were classified according to seizure semiology, seizure type, and epilepsy syndrome. Results Mean age of participants at the time of study was 10 years 6 months (SD 4y 7mo, range 4–20y). Gross Motor Function Classification System levels I and II were reported in 96% of participants, and Manual Ability Classification System levels I and II were reported in 79% of children. Thirty‐four children (54%) developed epilepsy. Term delivery and more severe motor impairment were associated with epilepsy, but neonatal seizures and family history of epilepsy were not. Initial seizures were epileptic spasms, focal seizures, or myoclonic seizures. Focal seizure semiology suggested Rolandic or occipital seizure origin in the majority of children. Focal epileptic discharges in children with focal seizures had features of idiopathic partial epilepsy. Only 15% of children had active epilepsy 10 years after onset. Interpretation Despite a high incidence of epilepsy in children with hemiplegic CP due to AIS, the prognosis for seizure remission is good. Many children have clinical features, electroencephalography findings, and remission typical of idiopathic partial epilepsy.     

CRANIAL UL-RASONOGRAPHY AND THE PREDICTION OF CEREBRAL PALSY IN INFANTS WEGHING ≤ 1200 GRAMS AT BIRTH

The r?le of serial cranial ultrasonography in the prediction of cerebral palsy was examined in 116 surviving infants with birthweights less than or equal to 1200 g. All underwent serial real-time sonographic examinations of the brain on days one, five and 21, then monthly, until term corrected age. Intraventricular hemorrhage (IVH) was diagnosed in 48 infants, and three had periventricular leukomalacia. Of the 116 infants, 31 had ultrasound abnormalities at term. At 12 to 18 months corrected age 12 infants had cerebral palsy and 38 were classified as suspect; the other 66 were normal. There was a clear association between risk group, based on sonographic findings at term, and outcome. Infants with IVH whose cranial ultrasounds failed to become normal by term corrected age were at higher risk for cerebral palsy than those with normal examinations at term, regardless of the severity of IVH. Thus an abnormal ultrasound at term corrected age was highly predictive of cerebral palsy, especially among survivors of IVH. It remained the best predictor of cerebral palsy, even when other perinatal and neonatal variables were considered. In contrast, duration of mechanical ventilation, rather than sonographic findings, was the best predictor of suspect neuromotor status.     

White matter damage in neonatal enterovirus meningoencephalitis

The authors report six neonates with enteroviral meningoencephalitis. Five infants presented with prolonged seizures, and one presented with systemic enteroviral disease. Cranial ultrasonography showed increased echogenicity in the periventricular white matter, and MRI confirmed mild to severe white matter damage in all infants, which looked similar to periventricular leukomalacia. Two infants developed cerebral palsy: one was neurologically suspect at age 18 months, and three were developmentally normal.     

Association of cerebral palsy with other disabilities in children with perinatal arterial ischemic stroke

The association of cerebral palsy with other disabilities in children with perinatal stroke has not been well-studied. We examined this association in 111 children with perinatal stroke: 67 with neonatal presentation, and 44 with delayed presentation. Seventy-six children (68%) had cerebral palsy, which was hemiplegic in 66 and tri- or quadriplegic in 10. Fifty-five (72%) children with cerebral palsy had at least one other disability: 45 (59%) had a cognitive/speech impairment (moderate-severe in 20), and 36 (47%) had epilepsy (moderate-severe in 11). In children with neonatal presentation, cerebral palsy was associated with epilepsy (P = 0.0076) and cognitive impairment (P = 0.0001). These associations could not be tested in children with delayed presentation because almost all children in this group had cerebral palsy. In another analysis with multivariate logistic regression for children with cerebral palsy, children who had both neonatal presentation and history of cesarean-section delivery were more likely to have epilepsy (P = 0.001). Children with cerebral palsy after perinatal stroke who had neonatal presentation were more likely to have severe cognitive impairment (odds ratio, 7.78; 95% confidence interval, 1.80-47.32) or severe epilepsy (odds ratio, 6.64; 95% confidence interval, 1.21-69.21) than children with delayed presentation. Children with cerebral palsy after perinatal stroke are likely to have an additional disability; those with neonatal presentation are more likely to have a severe disability.     

Risk factors for complex partial seizures: a population-based case-control study

This investigation is to our knowledge the first population-based case-control study of risk factors for complex partial seizures (CPS). Included in the study were all patients with onset of complex partial seizures before age 35, who were residents of Rochester, Minnesota, at the time of diagnosis between 1935 and 1979, and who were also born in Rochester (n = 82). Two control subjects were matched to each patient, and for both patients and control subjects, the unique records-linkage system for residents of Rochester was used to obtain information about possible risk factors. A history of epilepsy or febrile seizures in the mother, febrile seizures, neonatal convulsions, cerebral palsy, head trauma, and viral encephalitis were significantly more common in patients than in control subjects (p less than 0.05). None of the prenatal or perinatal factors investigated were found to be associated with complex partial seizures, except for being small for gestational age at birth. This factor lost significance after adjustment for cerebral palsy.     

Neurological signs and assessment of extremely and very low birth weight infants

The infants' brain during the prenatal, perinatal and neonatal periods is susceptible to injury. Many problems in the perinatal period often result in bleeding, ischemia and other pathological changes in the infant brain. Which can subsequently cause cerebral palsy or developmental disorders. Unless they are discovered early and measures are taken, permanent brain damage may remain. Although neurological examinations at this stage is very difficult, it is very important to be familiar with neurological signs and assessment of extremely and very low birth weight infants and to discover early any abnormal findings of diseases such as neonatal asphyxia, intraventricular haemorrhage, periventricular leukomalacia, neonatal seizures and hydrocephalus.     

Risk factors for neonatal seizures in very low birthweight infants: population-based survey

The developing brain has an increased susceptibility to seizure activity, and neonatal seizures can adversely affect neurodevelopmental outcome. This study aimed to determine the incidence of neonatal seizures in very low birthweight infants and to identify perinatal and postnatal factors associated with the occurrence of clinical seizures. A population-based cohort of 6525 very low birthweight infants born from 1995 through 1999 comprised the study group. Maternal, perinatal, or postnatal variables that showed a significant association with neonatal seizures in a univariate analysis were tested by a multiple logistic regression to assess the independent effect of each variable on the risk of seizures. The overall incidence of seizures was 5.6%. Significant independent predictors of neonatal seizures were decreasing gestational age, male gender, respiratory distress syndrome, pulmonary air leak (pneumothorax and pulmonary interstitial emphysema), intraventricular hemorrhage, periventricular leukomalacia, patent ductus arteriosus, surgical ligation of patent ductus arteriosus, necrotizing enterocolitis, and surgical treatment of necrotizing enterocolitis. Neonatal seizures appear to be associated with major morbidities and surgical interventions in very low birthweight infants. Continuous electroencephalographic monitoring could be warranted in infants following surgical treatment.     

Magnetic resonance imaging of periventricular leukomalacia and its clinical correlation in children

The prevalence of periventricular leukomalacia and its association with clinical neurological signs in school-age preterm children are unknown. We matched 42 eight-year-old children who were born before term with birth weights lower than 1,750 gm (mean, 1,410 gm; gestational age, 31 weeks) with 42 children who were born at term and of normal birth weight, to compare clinical neurological status and magnetic resonance imaging findings. Of the children born prematurely, 9.5% had cerebral palsy and 31% had minor neurological dysfunction whereas 9% of the children born at term had minor neurological dysfunction and none had cerebral palsy. Deviations in tongue movements, heel walking, Fogs test results, and finger opposition, as well as behavioral disturbances, differentiated the preterm from the full-term group. The prevalence of periventricular leukomalacia among all children born prematurely was 32%. It was observed in all children with cerebral palsy, in 25% with minor neurological dysfunction, and in 25% of the clinically healthy preterm children. None of the children born at term had evidence of periventricular leukomalacia. Children with periventricular leukomalacia especially demonstrated poor performance on heel walking and Fogs test. Though commonly found in preterm children, periventricular leukomalacia is not uniformly associated with abnormal neurological findings. A through neurological examination is a better predictor of later developmental problems than is magnetic resonance imaging.     

Risk factors for isolated periventricular leukomalacia

Periventricular leukomalacia, a major cause of neurologic disabilities in preterm infants, can be isolated or associated with intraventricular and periventricular hemorrhage. To determine the risk factors for isolated periventricular leukomalacia, we retrospectively studied the characteristics of all very low birth weight infants affected by isolated periventricular leukomalacia who were delivered over a 5-year period and compared them with a control group of very low birth weight infants, matched within 2 weeks for gestational age, with no central nervous system pathology, and born during the same period. In total, 20 affected infants were compared with 98 control infants. Neonatal sepsis caused by coagulase-negative Staphylococcus (P = 0.014) and neonatal seizure (P = 0.026) were associated with isolated periventricular leukomalacia only on univariate analysis. Three variables demonstrated statistically significant associations with isolated periventricular leukomalacia on both univariate and multivariate logistic regression analysis as independent risk factors: birth weight (odds ratio, 4.31; 95% confidence interval, 1.54-12.06; P = 0.005), early neonatal hypotension requiring combined inotropic therapy (odds ratio, 4.90; 95% confidence interval; 1.22-19.68, P = 0.025), and delayed surgical closure of hemodynamically significant patent ductus arteriosus beyond age 7 days (odds ratio, 1.20; 95% confidence interval, 1.06-1.35; P = 0.003).     

Risk factors and prognosis of epilepsy in children with cerebral palsy in north-eastern Poland

Though epilepsy occurs in 15-90% of children with cerebral palsy (CP) its clinical course is not well defined. We therefore conducted studies of 198 children with CP seen in Pediatric Neurology Department of the Medical Academy in Bia?ystok between 1994 and, 2001. The aim was to evaluate the risk factors, incidence and prognosis of epilepsy in CP. The overall epilepsy incidence was 41.4%. Epilepsy most commonly affected children with spastic tetraplegia 65.6%. Low birth weight, neonatal seizures, seizures during the first year of life, family history of epilepsy, severity of CP and computer tomography findings were found to be related to significantly increased risk of epilepsy in children with CP in the logistic regression analysis. Intractable epilepsy occurred in 51.2%, while in spastic tetraplegia it was even higher (60%). Controlled epilepsy was observed in 83.3% of spastic diplegia and in 72.7% of spastic hemiplegia. Polytherapy was commonly used in children with spastic tetraplegia 59.5%. Partial seizures secondarily generalized, infantile spasms and Lennox-Gastaut syndrome were the most frequently observed seizures in epileptic children with CP. Epilepsy is common in children with CP and has poor prognosis.     

Epilepsy in patients with cerebral palsy--analysis of frequency and clinical prognosis

This study was designed to investigate the incidence and prognosis of epilepsy in 109 patients with cerebral palsy and to attempt to correlate these clinical data with the type of palsy. The incidence of epilepsy, the onset of age and the type of first seizure were associated with the regions affected by palsy. A good association exists between tetraplegia and age-dependent epileptic encephalopathy. In patients with cerebral cortical lesions demonstrated by radiological examination, the incidence of epilepsy was significantly increased. The prognosis of epilepsy is not related to the type of palsy. In spastic palsy, the patients with epilepsy showed more severe intellectual disabilities.     

Midline electrographic abnormalities and cerebral lesions in the newborn brain

Electroencephalographic (EEG) abnormalities arising from the midline region were identified in 154 of 1008 (15.2%) consecutive neonatal EEGs during a 24-month period. These records were obtained on 97 neonates with a variety of clinical diagnoses. Premature infants made up 79% (77/97) of this group. All patients received at least one cranial ultrasound at 7 to 10 days of life. Sixty-two percent (60/97) of the patients had radiographic and/or neuropathological documentation of cerebral lesions: intraventricular hemorrhage (25), periventricular leukomalacia (18), cerebral infarction (10), cerebral malformation (4), and miscellaneous lesions (3). Six types of midline EEG abnormalities are described: negative sharp waves, positive sharp waves, electrographic discharges associated with myoclonus, electrographic seizures, attenuation of background, and rhythmic monofrequencies. Approximately 90% of the patients with background attenuation, discharges with myoclonus, and positive sharp waves and 72% of patients with EEG seizures had cerebral lesions. Midline positive sharp waves were associated with periventricular leukomalacia as well as intraventricular hemorrhage. No midline positive sharp waves, attenuation, EEG seizures or discharges with myoclonus were found in 25 healthy, asymptomatic neonates. Besides positive sharp waves, other specific midline EEG abnormalities can be associated with cerebral lesions in the neonate. The rapid identification of midline EEG abnormalities in neonatal recordings can enhance the accuracy of both electrographic diagnosis and anatomic localization of associated cerebral lesions.