The prevalence of cerebral palsy in the world is, according to various authors, from 1.5 to 3.9 per 1,000 live births. In the last 20 years obstetric care is actively using the introduction of magnesium sulfate to expectant mothers as a neuroprotectant against development of severe forms of cerebral palsy, total hypothermia in the newborn with asphyxia at birth to reduce the severity of brain damage.
The use of antenatal courses of steroids (dexamethasone), cesarean section and preeclampsia reduces the risk of intraventricular hemorrhage.
The widespread use of modern diagnostic techniques (high-resolution MRI and molecular genetic studies) confirms polyetiological this disease. To date, cerebral paresis are considered as heterogeneous, not progressive skin lesions of the brain occurring in the prenatal, perinatal and early postnatal (up to 20 days of life) periods, in most cases leading to disability of the child.
The main risk factors for the development of the Central hemiparesis in full-term infants include birth asphyxia, chronic intrauterine hypoxia, intrauterine infection, preeclampsia, maternal obesity, use of assisted means of delivery. Premature babies are among the risk factors most typical low gestational age, low body weight, chorioamnionitis, multiple pregnancy, Apgar score < 5 points, surfactant deficiency, impaired metabolism and reduced partial pressure WITH2, respiratory distress syndrome and high-frequency ventilation 30.
In connection with improving care to premature babies and achievements for the nursing of very premature children with low and extremely low body weight (usually pronounced manifestations of intraventricular hemorrhage (ivh) and periventricular leukomalacia (PVL)), there is a growing number of premature infants with Central paresis of up to 50% of all cases. Over the past ten years increased the number of hemiplegia due to the greater prevalence of unilateral ivh 2-3 degrees of PVL and the asymmetric and reduce the number of diplegia in premature infants that differs from previously accepted ideas about the priority of bilateral lesions of the brain 33.
High comorbidity of cerebral paresis and epilepsy potentially impacts the formation of cognitive and motor functions of the child, long-term persistence of seizures and/or epileptiform activity high-index can strengthen motor, speech, mental and intellectual disorders. The combination of epilepsy and cerebral palsy (CP) leads to worsening of epileptic process, often causing the resistance of seizures to therapy.
Structural focal epilepsy are the most frequent forms of epilepsy in children with cerebral palsy (60-67%), dominating with spastic forms of the disease and accounting for more than half of all cases of the disease (according to some authors reaching 82-92%), correlating with the severity of motor disorders 3. Despite the fact that there are many classifications of the Central paralysis, little studied especially the impact of its etiological markers on semiology and electrophysiological manifestations of related forms of epilepsy, approaches to the treatment and prognosis of epileptic syndromes and rehabilitation of children with various forms of motor disorders.
According to scientific studies of children with hemiparetic form of cerebral palsy and epilepsy, perinatal risk factor for the development of epileptic seizures is more than 85% 3, 5 revealed the predominance of left-sided hemiparesis preterm (56,6%) and right sided in term infants (73.2 per cent) 7. In children with left-sided hemiparesis is marked by a more severe course of epilepsy with a frequent severe manifestation of regional epileptiform activity on electroencephalography (EEG). In the absence of epileptic seizures epileptiform activity on EEG is registered, 21.3% of children with hemiparesis 4.
The debut of epileptic seizures in early childhood with the decline of cognitive functions defined as adverse predictors of intractable seizures and epileptic encephalopathy, cortical absence of the type of brain damage according to the MRI is more favorable factor for epilepsy in children with hemiparetic form of cerebral palsy 7.
The most common, hemiparetic form of cerebral palsy is characterized by significant heterogeneity of etiological factors, often accompanied by epileptic seizures, and requires not only an effective antiepileptic therapy, but timely and intensive rehabilitation measures that provide the most favorable Outlook for a recovery in motor functions and further socialization of the child.
Analysis of clinical, MRI and EEG, to determine the influence of gene polymorphism of structural genes and homeostasis of connective tissue allow to clarify the etiology and determine the severity of hemiparetic forms of cerebral palsy, to assess the likelihood of accession of the attacks, the nature of their current and forecast, to identify opportunities antiepileptic therapy (AET) and rehabilitation.
Given the high neuroplasticity of the brain in the first two years of a child’s life, early and comprehensive rehabilitation allows you to maximize the possibility of movement of the child’s cognitive and language skills. In full-term infants with cerebral hemiparesis is most often associated with epilepsy in arterial ischemic strokes, cysts and cortical malformations, premature – with one-sided intraventricular hemorrhagic stroke, panencephalitis cysts of PVL and the asymmetric 20, 31.
The strokes play a key role in causing epileptic seizures in children with hemiparesis 20, 36. In recent years, decreased the number of cystic periventricular transformations of the substance, prevail periventricular hemorrhagic lesions whose frequency in preterm neonates ranges from 3% to 11% with gestational age < 32 weeks and from 5% to 8% in very preterm infants with extremely low birth body weight 17.
When this occurs, the circulatory disturbance of the medullary veins draining into the deep veins of the white matter that precedes unilateral intraventricular hemorrhage and may be associated with ischemic changes in white matter, causing periventricular leukomalacia asymmetric the. According to the literature, periventricular and intraventricular hemorrhage in newborns occurs due to the high vascularization of germ (embryonic) matrix, the most vulnerable during 24-32 weeks of gestation 16, 30, 33.
Identified genetic disorders and to define “genes-candidates” in children with hemiparetic form of cerebral palsy and epilepsy. The most often determined mutations of the factor V (Leiden), G20210A in prothrombin gene, mutation C677T in the gene for 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism and the 4G/5G gene plasminogen activator inhibitor-1 (PAI/1).
Most frequently in children with perinatal arterial ischemic stroke and venous thrombosis are determined by the mutation of factor V (Leiden) in combination with mutations in the gene of prothrombin or MTHFR. Mutations in the collagen 4 alpha-1 underlie the autosomal dominant porencephaly type I in combination with hemiparesis and epileptic seizures. Also, when hemiparesis is detected gene polymorphism of apolipoprotein E (ApoE), when combined with epileptic attacks usually determines the violation of the E4 allele 10, 19, 35.
Cerebral hemiparesis associated with epilepsy associated with damage to the cerebral cortex, subcortical white matter and deep gray matter. In full-term infants among the damages of the cerebral cortex high epileptogennogo have focal cortical dysplasia (18%), there are more rare cortical malformation – scienceasia, lissencephaly, polymicrogyria, hemimegalencephaly, pachygyria, the main causes of which are intrauterine TORCH infections (cytomegalovirus, herpes, toxoplasmosis, etc.) and genetic predisposition (predominantly spontaneous mutations that lead to violations of the structure of proteins involved in the transport of antiepileptic drugs, leading to resistance of epileptic seizures in cortical dysplasia) 8, 11.
Focal cortical dysplasia and focal polymicrogyria, often meeting with MRI-negative cases studies in children with hemiparesis and epilepsy (31%), are the cause of aggressive, drug-resistant currents of epileptic seizures, often leading to the development of epileptic encephalopathy 12, 18, 27. Focal cortical dysplasia type IIB with balloon cells c (transpontina cortical dysplasia) are common in children with hemiplegia 9, 13, 22.
In the MRI mode, FLAIR, T2 (infants – T1-, T2-modes) it is found that structural pathology spreads through the entire cerebral mantle from the crust to the medial wall of the lateral ventricles with a disruption of the lamination of the cortex and identification of abnormal cell types with the inclusion of large dysplastic neurons, and balloon atypical glial cells, which are found in the cerebral cortex and underlying white matter, with frequent spread to the wall of the lateral ventricle 24, 32.
Focal cortical dysplasia histologically, radiologically and genetically identical to tuberous sclerosis. Often reveals a breakdown in the gene TSC1, which is considered the cause of tuberous sclerosis. The protein encoded by TSC1, known as part of the target for rapamycin in mammals (m-TOR) involved in cell growth, apoptosis and cell cycle regulation 22, 36.
Terms of a violation of corticogenesis correlate with the severity of dysgenesis. Disorders originating in the late second and early third trimester of pregnancy leads to development of severe forms of pathology (hemimegalencephaly), and disorders of migration and differentiation of neurons in the end of the third trimester of pregnancy lead to the formation of cortical dysplasia. Observed the preferential localization of focal cortical dysplasia in the frontal and temporal lobes of the brain 25, 36.
Hemimegalencephaly – a rare congenital malformation characterized by enlargement of one hemisphere and congenital hemiplegia. Pathology may occur independently or exist as part of neurocutaneous diseases (neurofibromatosis), a syndrome of epidermal nevus, when hypomelanosis ito and Klippel–Trenaunay–Weber. In typical cases hemimegalencephaly characterized by severe developmental delay and early debut of epileptic seizures (up to 6 months of life) as the asymmetric tonic spasms, are often resistant to antiepileptic drugs (AEDs). The detection is shown holding hemispherectomy 15, 23.
Scienceasia – a rare congenital malformation of the cerebral cortex, occurring with a frequency of 1.5 per 1 000 000 newborns (1:1650 in children with epilepsy) and is characterized by dysmorphia gray matter with the splitting of the cortex of the linear form, extending from the ventricle to the subarachnoid space. The mechanism of pathology is not fully understood.
Perhaps the disease occurs as a result of a violation neuronal migration or as a result of local ischemia of brain. The expression of genetic factors, including mutations of the gene EMX2 suppress the growth of glial cells (astrocytes) during embryonic development in the period of 6-7 weeks of fetal development, is also being considered as a possible cause of lizenzfrei 14.
There are two types of pathology. Type I (closed lip), when the walls of the fissure against each other, often localized in the frontal or parietal lobes, mainly in the field of Sylvian sulcus). Type II, more common (with open lips), when the walls of the fissure separated from one another 26.
Scienceasia in 50-90% associated with other congenital anomalies – agenesis of the transparent septum and corpus callosum, polymicrogyria (defect of the cortex with numerous fine convolutions and a violation of the architectonics of the cortex), pachygyria (increase in the size of the convolutions of the brain), heterotopia (ectopic gray matter), septooptic dysplasia and hypoplasia of the optic nerve.
Main symptoms: when using the unilateral localization of the defect – hemiparesis, in bipolar – tetraparesis, epileptic seizures and psychomotor retardation. When I type lizenzfrei cerebral palsy and epileptic seizures are less common, and motor impairment scale GMFS belong to the I–III levels, the intelligence of the patients is close to normal or moderately reduced.
II type of lizenzfrei is characterized by a more pronounced psychomotor retardation, epileptic seizures, and cerebral palsy with locomotor disorders III–IV level on a scale of GMFS, combined with alalia and blurred vision. The only conservative treatment, mainly rehabilitation of locomotor and psycho-speech disorders, pharmacological control of seizures. Neurosurgical shunt surgery is performed in progressive hydrocephalus, often with type II pathology 31.
Unilateral polymicrogyria is one of the most common congenital malformations of the brain in hemiparetic forms of cerebral palsy may be isolated or part of various syndromes of congenital anomalies. Causes are congenital cytomegalovirus infection and fetal hypoxia. Genetic causes include metabolic disorders (peroxisomal disorders and syndrome deletions in the 22q11 locus and.2 and 1p36).
Today found mutations in over 30 genes associated with polymicrogyria. Discovered mutations of genes of signaling pathways PI3K/AKT/mTOR-related polymicrogyria and megalencephaly. For patients with polymicrogyria and hemiparesis is characteristic of the later debut of epileptic seizures (usually after two years), myoclonus (including negative), atypical absence seizures and complex focal seizures often with the formation of ESES. Treatment with medication 24, 32.
Lissencephaly, being one of the most severe malformations of the brain, is less common in the hemiparesis and is characterized by focal underdevelopment of the gyri, often associated with other malformations. Pathology is mainly caused by mutations in the genes associated with the function of microtubules. Mutations of RELN, DCX (involving mainly the cortex of the anterior brain), LIS1, 14-3-3e, ARX (with involvement of the cortex predominantly posterior brain).
When hemiparesis is found lissencephaly type I with the formation of four-layered cortex (instead of the six-layer). The characteristic mental retardation, early onset of epileptic seizures, often infantile spasms resistant to antiepileptic therapy. The only conservative treatment 28.
One of the main causes of hemiparesis associated with epilepsy in full-term infants are arterial strokes (especially in the basin of the left middle cerebral artery – 49%, right cerebrospinal artery, only 24%), most often resulting from prenatal hypoxia acute intrapartum asphyxia, disorders of coagulation factors and anatomical features of the middle cerebral artery, is a branch of the internal carotid artery, which goes to the left directly from the aorta, with a good forecast of damage in 85% of patients with this pathology. The risk of seizures is higher in lesions in right middle cerebral artery and damage of several cerebral arteries 34, 37.
Most patients with hemiparetic form of cerebral palsy and epilepsy have focal seizures with regional epileptiform disorders (63%) and respond well to treatment (83%) 4, 29, 37. Resistant forms of epilepsy in patients with spastic hemiparesis (often with cystic transformation of the glial tissue of the brain and principalities cysts), accompanied by epileptic encephalopathy, require the solution of a question on the possibility of neurosurgical treatment – early holding of hemispherectomy with a favorable outcome in relation to seizures and the child’s further development 1, 2, 6. Intellectual deficit is more pronounced when combined epilepsy and hemiparesis, reaching 52%. This feature is marked by a number of authors and applies to all forms of cerebral palsy 3-5.
The purpose of this study was to determine the main cause of structural focal epilepsy in children with cerebral hemiparesis, to clarify features of treatment and prognosis of epileptic seizures and the possibility of rehabilitation of hemiparesis in children with epilepsy.
Materials and methods
The study included 119 children (76 boys and 43 girls) with structural focal epilepsy and hemiparetic form of cerebral palsy ages 3 months to 7 years observed in NPC DP from 2014 to 2016, All children clinically examined by a neurologist. Diagnosis of cerebral palsy was made on the basis of the International classification and the classification Semenova with assessment of clinical symptoms of hemiparesis in accordance with the age of the child.
All children underwent routine EEG study, video-EEG monitoring of wakefulness and sleep, CT scan/MRI of the brain with the tension of magnetic field of 1.0–1.5 Tesla. According to MRI/CT identified ischemic and hemorrhagic perinatal stroke, cortical dysplasia, venous sinus thrombosis, stroke of gray matter, the asymmetric periventricular leukomalacia, intraventricular hemorrhage, unilateral, porencephaly, hydrocephalus and hemiatrophia.
The estimation of the age of the onset, nature and peculiarities of epileptic seizures, the effectiveness of AET (mono – or polytherapy, resistance of epilepsy by AEDs), intellectual disabilities (IQ < 70). A comparison between groups of full-term and preterm infants (full-term – 37 weeks age of gestation, premature infants under 37 weeks of gestation, and very premature less than 30 weeks of gestation). The identified features of the main etiological factors, clinical course and prognosis for each of the groups. From the study excluded children with progressive neurological pathology (Rasmussen encephalitis, a disease the Sturge–Weber, tuberous sclerosis).
The results of the study
The study included 119 children with congenital hemiparesis and epilepsy, of which 68 (57%) full-term and 51 (43%) prematurity (7 very preterm infants and 4 children of twins) (table. 1). According to the classification of GMFS 111 (93%) children referred to the I and II levels, MACS classification 92 (77%) patients assigned to the I and II levels of movement disorders.
The main reason for the development of the Central hemiparesis in patients with structural focal epilepsy in the group of term infants are perinatal stroke diagnosed in 48 children (70,6%), cortical dysplasia in 7 children (10,3%), thrombosis of the venous sinus in 2 children (2.9%) and hemiatrophia have 3 children (4,4%), hydrocephalus in 3 children (4.4 per cent), the stroke gray matter, porencephaly, lampetia periventricular and intraventricular hemorrhage, and 1 child (1.5 percent).
In the group of preterm infants was dominated by intraventricular hemorrhage – 15 (29.4%), and perinatal stroke, 17 (27.5%) and asymmetric periventricular leukomalacia – 13 (19,1%). Hydrocephalus diagnostirovanna have 2 children (2.9 percent), venous sinus thrombosis, stroke, gray matter, hemiatrophy and porencephaly – 1 child (1.7%). Patients with cortical dysplasia in the group of preterm infants was not.
In full-term infants with hemiparesis epilepsy often accompanied by arterial ischemic stroke in the basin of the spinal arteries, 26 children (70%), less often in the posterior cerebral artery, 11 patients (30%), including principalities formation of cysts, and unilateral cortical dysplasias, which are dominated by FKD – 3 children (43%) and scienceasia – 2 children (29%).
For term infants with perinatal strokes is characteristic: the gender predominance of boys and 70.8%, the predominance of right-sided hemiparesis – 26 patients (54%), neonatal convulsions in history – in 33 children (69%), identifying the symptoms of hemiparesis predominantly on the second half of life – 40 children (83%), the prevalence of movement disorders in the hand – in 32 children (68%), accession of epileptic seizures mainly after three years – 36 children (75%) with a maximum at the age of 4-6 years and relatively favourable in the treatment of the nature of the attacks (table. 2).
Focal epileptic seizures are more prevalent in term infants with perinatal stroke, 39 patients (81%), secondarily generalized seizures was 7 children (15%). 35 children (73%) with perinatal stroke, seizures cropped on monotherapy, 12 (25%) were on polytherapy, 1 child (2%) seizures resistant to antiepileptic therapy.
Data for arterial stroke in preterm infants is not significantly different from those in term infants. In the group of children with ischemic and hemorrhagic strokes in 8 patients with atypical stroke and the absence of traumatic factors in the analysis of blood by polymerase chain reaction on gene polymorphisms of hemostasis identified double heterozygotes for mutations in the genes of factor V Leiden and prothrombin 20210 G-A. in one child with congenital hemiparesis, infantile spasms, principalities cyst and microcephaly identified heterozygous missense mutations in the gene COL4 A1.
Unilateral focal cortical dysplasia, meeting in full-term infants is pretty rare and almost absent in premature infants, characterized by early onset of symptoms of hemiparesis – 5 (71%), equal involvement of arms and legs – 4 (57%), a concomitant reduction in intelligence – 7 (100%), with the debut of epileptic seizures in the first years of life – 6 (87%) and relatively high frequency of seizures (both focal and secondarily generalized).
When the cortical dysplasia focal epileptic seizures was 2 (29%) children had secondary generalized seizures, 3 patients (41%), infantile spasms and 2 (29%). In 3 (43%) children with cortical dysplasia seizures cropped in the polytherapy of AEDs, 2 patients (29%) were on monotherapy, 1 (14%) patients seizures resistant to therapy.
For premature infants with intraventricular hemorrhage (15 patients, 29.4 percent) characteristic: early detection of symptoms of hemiparesis – 11 (61%), neonatal convulsions in 13 (72%) children, the accession of epileptic seizures in the first years of life – 12 (66%) with a maximum at the age of 4-6 years and relatively favourable in the treatment of the nature of the attacks. Intellectual impairment was diagnosed in 10 (56%) patients (table. 3).
The likelihood of developing epilepsy correlates with the severity of ivh, one of the development factors which is the degree of prematurity. Most often, seizures are accompanied by 2nd and 3rd degree courses, dominating in very preterm infants. In children with ivh is dominated by generalized epileptic seizures (57%), focal seizures are much less common (43%). In 11 (61%) of children with ivh seizures cropped on monotherapy, 6 (33.3%) and in polytherapy, 2 children (11%) seizures resistant to therapy.
Asymmetric PVL, being one of the reasons for the development of epilepsy in premature infants, characterized by early onset of symptoms of hemiparesis and 7 (54%), which correlates the degree of severity of the clinical manifestations with the degree of involvement of the white matter, the debut of epileptic seizures mainly after three years of life – 9 (69%) and relatively favourable in the treatment of the nature of the attacks.
When PVL is dominated by focal seizures – 10 (76%), secondarily generalized seizures occur in 3 (34%) children. In 8 (62%) children with PVL seizures cropped on monotherapy, 4 (30%) on polytherapy, 1 (8%) seizures resistant to antiepileptic therapy.
Perinatal strokes are the main cause of hemiparetic forms of cerebral paralysis in full-term children with structural focal epilepsy. In premature infants, in addition to arterial strokes, among the causes of hemiparetic form of cerebral paresis is dominated by intraventricular hemorrhage and periventricular leukomalacia. Children with atypical for stroke and the absence of a traumatic factor in the development of cerebral palsy history require the exclusion of genetically determined disorders of hemostasis (mutations in the genes of thrombophilia).
Most commonly in full-term infants epilepsy accompanied by arterial stroke in the basin of the spinal arteries, premature – intraventricular haemorrhages (mostly 2-3 degrees). Cortical dysplasia, meeting with the hemiparetic form of cerebral palsy is relatively rare (5,6%), not specific to prematurity and are found mainly in full-term infants (10.3 per cent), characterized by its extremely high probability of debut of epilepsy and epileptic seizures resistant to drug therapy. At CDF, polymicrogyria and hemimegalencephaly is considered an effective surgical treatment with a significant positive effect against seizures and cognitive dysfunction in the early conduct of hemispherectomy.
The majority of children with hemiparetic form of cerebral palsy is associated with epilepsy, according to evaluation scales for movement disorders GMFS and MACS correspond to the I and II levels with good prognosis for motor development and socialization of the child with early, intensive, comprehensive treatment.
Full-term children with perinatal stroke and preterm children with PVL asymmetric, given the more recent debut of the attacks and the relatively favourable course of epilepsy in the first two years of life may conduct active rehabilitation with the use of dynamic proprioceptive correction by Semenova, massage, exercise therapy, physiotherapy and electroprocedure, osteopathy and modern methods of treatment of movement, induced by restriction.
Full-term children with focal cortical dysplasia and premature children with ivh (particularly prematurity, ivh grade 3-4), given the high likelihood of developing epilepsy with an early debut of epileptic seizures, the need to limit physical and electroprocedure, it is possible to use massage and physical therapy combined with treatment of the movement, induced by restriction, kinesiotherapy, locomotor training and cognitive rehabilitation given the high neuroplasticity in children of early age.