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NEURO-PSYCHISAL AND MOTOR DISABILITY IN CHILDREN WITH PERINATAL INJURY OFCENTRAL NERVOUS SYSTEM
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Introduction: In the structure of children’s disability at the world level and in the Republic of Moldova, the neuropsychological pathologies were varying spread. Th e consequences of perinatal anoxic pathology varies from 20-40 to 60% of children after brain damage. Scope of the study: determining of evolutive diagnoses in correlation with age of children with perinatal (anoxic) brain injuries.
Methodology of research: A longitudinal retro- and prospective case-control study ( January 1, 2003 – December 31, 2013) was carried out on a group of 1370 children of whom 1036 children suff ered from perinatal cerebral injuries of varying severity. All children have subjected to long-lasting monitoring, using methods of DENVER II and Amiel-Tison and Gosselin, the electroencephalographic and imaging studies, from 1 month to 48 ± 12 months of age. Control group comprises 334 “conventional healthy” children. Data analysis was performed using Statistics 7.0 (Statsoft Inc) software and MS EXCEL application using the functions and modules of these programs.
Results: Perinatal cerebral lesions were manifested by neonatal encephalopathy of grade I (mild) - 422 children, grade II (moderate) - 310 and grade III (severe) - 304 children. From the total number of examined patients (1370 children), 790 children (aged 3-5 years) were diagnosed with: behavioral disorders – 103, attention defi ciencies and hyperkinetic disorders – 150, language and communication disorders – 69, tonic-clonic stuttering – 24, tics disorders – 19, mild degree motor disorders – 74, EP – 79, CP – 272 cases.
Conclusions: Neurological surveillance is at the basis of identifying children with residual pathology (RP). Considering the cases of children with perinatal cerebral lesions were defi ned fi nal aspects of the study: (1) patient recovery (23,7%); (2) the development of remote neurological sequelae (76,3%), among which were registered major (44,4%) and minor (55,6%) RP.
Currently, in the share of the disability causes in children around the world, including in the Republic of Moldova (RM), neuropsychological pathologies occupying the first places. Neurological problems often develops as a consequence of the perinatal cerebral lesions (PCL) (anoxic) and constitute one of the main problems of Pediatrics in general and Pediatric Neurology, in particular. Dysfunction of central nervous system (CNS) in children lead to long-lasting sequelae, until the psychomotor disability. The official statistical data for last 6 years indicate an increased incidence of cerebral palsy (CP) – from the share of 58% to 63,1% in structure of registered neuropsychological pathologies (official date from State Center of Statistics, 2015). However, prospective studies and data about the actual incidence of pediatric residual pathology (PR) caused by perinatal cerebral lesions (PCL) are missing. Some authors argue that hypoxic-ischemic lesions developing during perinatal period are among the most prevalent causes of disability and infant mortality with effects on CNS [1, 2]. It is found that in 20 of 1000 of full-term newborns and nearly in 60% of pre-term newborns develop hypoxic-ischemic PCL , and neonatal encephalopathies (NE) are associated with about one-fourth of overall neonatal deaths .
The lack of universal neonatal definitions for NE made difficult incidence estimation of morbidity and identifying the risk factors for these pathologies . Definition of hypoxic-ischemic NE determine a variety of clinical forms having shared a decrease in oxygen transport to the brain tissue, lead to brain damage occurring at the newborn due to cerebral hypoxia secondary to chronic or acute fetal suffering, manifesting with severe consequences for CNS . RP of CNS is a sequelae or “remote effects” of any disease of the CNS, or current condition caused by a previous pathology , including the CP and EP. Some studies mentioned that about one-third of children with moderate NE and the vast majority of severe NE will have eventually residual pathology (RP), CP, EP, mental retardation, etc. . Other studies confirm the development of neurological deficiencies at about 20-40% of children suffered from an injury of the brain [9, 10]. Neonatal asphyxia is responsible for CP and neuropsychological retardation . Up to a third of these children dies or suffer lifetime cognitive and/or physical disabilities . CP registered at about two of 1000 births . The overall prevalence of CP, estimated in recent years, is 2,11 to 1000 live births(95CI, 1,98 – 2.25) . Some authors argue that, despite an adequate management of hypoxic-ischemic NE, in many cases perinatal anoxia can not be prevented . Several studies showed that NE continues to be an important cause of neonatal mortality and morbidity [1, 14], this injury being a devastating event and one of the most common causes of neonatal death and long-term neurological disability .
SCOPE OF THE STUDY
Determining of diagnosis in dynamic aspect depends of the age of children who suffered perinatal (anoxic) brain injury.
METHODOLOGY OF RESEARCH
Was performed a retrospective as well as prospective non-randomized, case-control, longitudinal study during the period of 10 years (from January 1, 2003 to December 31, 2013), on a group of 1370 children, of whom 1036 suffered from hypoxic-ischemic neonatal encephalopathy (NE). Initially, between the ages of 1 and 3 months, were formed working groups, to which they were applied tests according to a standardized questionnaire. The children were divided into 3 groups according to the degree of severity of NE: grade I (mild) (L1A) – 422 cases (30,8%; 95CI 29,55 – 32,05); grade II (moderate) (L1B) – 310 cases (22,6%, 95CI 21,48 – 23,73); grade III (severe) (L1C) – 304 cases (22,2%; 95CI 21,08 – 23,32). The control group comprises 334 “conventional healthy” children (L0). Children were subject of long-lasting monitoring from the the age of 1-3 months to the age of 48 ± 12 months. For the neurologic diagnosing have been applied Denver II test and Amiel-Tison and Gosselin neurological screening, in conjunction with electroencephalography examination and imaging. For analysis, we used software Statistica 7.0 by Statsoft Inc. and MS EXCEL application functions and modules.
The results of clinical neurological study showed spontaneous movement, congenital motor skills and passive mobility of the limbs, and intellectual functions of language, cognitive performance, behavioral abilities, communication and attention, etc. On the onset were appreciated more symptoms that suggested a delay in performance of neurological development (Table 1).
Were monitored all indicators of neuro-psychic development of the child. Global motor activity, determined by the status of muscle tone and stretch reflexes were determined at the age of 3 – 5 years, and was revealed fact what in 346 cases (25,3%, 95CI 24,13 – 26,47) there were determined motor disorders, among them: 170 (12.4%, 95CI 11,51 – 13,29) mild, 94 (6.9%, 95CI 6,22 – 7,58) – moderate, 82 (6%; 95CI 5,36 – 6,64) severe (Figure 1). The share of affected children was maximal at L1C and amounted to 273 cases (89,8%; 95CI 88,6 – 91,54). It was showed a strong correlation between results of Denver II test (rxy = 0,689) and Amiel-Tison and Gosselin tests (rxy = 0,876), which confirms the effectiveness of both scores in the assessment of motor skills in healthy children and those with neurological problems. Fine motor skills were more mildly affected compared to the global ones, e. g.: indicators from “normal” category at 12 months of age were more decreased – 906 (66,1%; 95CI 64,82 – 67,38). However, at 3 – 5 years, due to the maturity of the CNS, the indicators that characterize both types of skills become almost equal.
The data which reflects the evolution of the development of cognitive and intellectual performance at age of 3 months presented increased indicators in the “moderately” affected compartments – 203 (14,8%; 95CI 13,84 – 15,76) and “severely” – 130 (9,5%; 95CI 8,81 – 10,29); at the age of 2 years in the “moderately” affected compartment in 160 cases (11,7%, 95CI 10,83 – 12,57), “severely” – in 117 cases (8,54%; 95CI 7,78 – 9,3), “deeply affected” – in 13 cases (0,9%; 95CI 0,64 – 1,16). At the age of 2 years, the majority cases of cognitive disorders were revealed among the group of 346 children with CP and among 79 cases with EP, and among the group of 140 cases with minor RP. In children with age 3 – 5 years, in 575 cases (42%; 95CI 40,67 – 43,33) were presenting cognitive impairment with a different degree of severity. Most children with cognitive impairment were revealed among the group of 272 children with CP, among the group of 79 cases with EP, and 224 cases with attention and hyperkinetic disorders (AHD), language and communication disorders (DSC), behavioral disorders (BD) and light motor disorders (LMD). In the “mild” affected category was ranked 327 cases (23.9%; 95CI 22,75 – 25,05) from all three groups: “moderate” – 131 cases; “severely” and “profound” affected – 117 cases (8.5%; 95CI 7,74 – 9,26) (Figure 2). Other studied performances included sensory functions. Most children with impairment of visual functions were found in L1B – 73 (20,8%; 95CI 18,63 – 22,97) and L1C groups – 278 cases (79,2% 95CI 77,03 – 81,37), 11 cases (1.5%; 95CI 1,17 – 1,83) among L1C presented atrophy of an optic nerve.
Convergent strabismus was registered at 76 cases (7,3%, 95CI 6,49 – 8,11) from 3 to 5 years. Auditory functions were affected at 82 cases (6%; 95CI 5,36 – 6,64) (3 – 5 years of age). Speech, language and communication were appreciated affected (at age of 5 years) in 420 cases (30,7%; 95CI 29,45 – 31,95): in 272 cases with CP (64,8%; 95CI 62,47 – 67,13), in 79 cases with EP (18.8%; 95CI 16,89 – 20,71), in 69 cases with LCD (16,4%; 95CI 14,59 – 18,21). Severe disorders were in 82 cases (19,5% 95CI 17,57 – 21,43), moderate – in 94 cases (22,4% 95CI 20,37 – 24,43), mild – in 244 cases (58,1%; 95CI 55,69 – 60,51). At the age of 5 years in 528 of cases (38,5%; 95CI 37,19 – 39,81) there were determined behavioral disorders, i. e., “mild” in 280 cases (53%; 95CI 50,83 – 55,17), “moderate” in 131 case (24,8%, 95CI 22,92 – 26,68), “severe” in 117 cases (22,2%; 95CI 20,39 – 24,01). Attention skills have been affected at five years in 501 cases (36,6%; 95CI 35,3 – 37.9), of which 253 cases of “mild” grade (50,5%; 95CI 48,27 – 52,73), “moderate” in 131 cases (26,1%, 95CI 24,14 – 28,06), “severe” in 117 cases (23,4; 95CI 21,51 – 25,59).
Anomalies of brain structures were diagnosed using the imaging techniques. Mild enlargement of cerebral ventricles, minor glial foci and mild enlargement of subarachnoid space, as well as delay in the myelination of brain structures had related to minor RP (e. g., verbal language disorder, VLD, mild cognitive disorder, MCD, BD, LCD, LCD, LMD, AHD) (rxy=-0,24, p>0,05). Mild enlargement of cerebral ventricles was diagnosed in child suffered from tonic-clinic stuttering and tics disorders (rxy =-0,22, p>0,05) (Figure 3). Based on brain MRI CP and EP can be classified as the following clinical types: CP with hemiparesis – 43 cases (4,2%; 95CI 3,58 – 4,82), CP with spactic tetraparesis – 95 cases (9,2%; 95CI 8,3 – 10,1), CP diplegic – 94 cases (9,1%; 95CI 8,21 – 9,99), CP dyskinetic type (or dystonic type) – 27 cases (2,6%; 95CI 2,11 – 3,09), CP mixed types – 13 cases (1,3%; 95CI 0,95 – 1,65), EP with structural pathology (or symptomatic) – 241 cases (23,3%; 95CI 21,99 – 24,61), from which without CP – in 79 cases (32,8%; 95CI 29,78 – 35,82). Were showed strong correlation between structural visualized anomalies and neurological signs of CP and EP, as well as movement disorders (rxy=-0,74, p<0,05) and neuro-psychic decline (rxy=-0,78, p<0,01), and medium correlation (rxy=-0,53, p<0,05) between MRI findings and some types of pharmacologically controlled EP, siggesting relative positive evolutionof disease, but correlation with pharmacologically resistant EP (rxy=-0,72, p<0,05), reflects complicated prognosis.
Electroencephalography is one of the examinations of choice in patients with PCL for the diagnosinfg of EP. Interictal EEG patterns recorded were variable, amounting to about 9 – 11 types of patterns (rxy = -0,72) (Figure 4). Epileptic-type EEG changes, i. e., spike clusters, generalized periodic waves, spikeslow wave and spike-and-wave etc., were revealed at 241 cases (23.3% 95CI 21,99 – 25,29) with brain lesions (n = 1036). The presence of a specific EEG activity in children without seizures was valuable sign for assessing neuro-psuchical performance and diagnosing of minor seizures. Irritative changes of bioelectrical activity, i. e., sharp spikes of high frequency, and signs of immature bioelectric activity of brain, i. e., slow wave, mostly deformed theta and delta waves, at 267 cases (63,3%; 95CI 60,95 – 65,65) and in 146 cases (47,1%; 95CI 44,26-49,94) from L1C (from the age of 24 to 60 months) diagnosed with minor RP (rxy=-0,22).
The rate of children with RP with the age of 5 years, from which were minor (55,6%) and severe (44,4%) pathologies were dependent from the severity of PCL: L1A – 63,3% (minor RP); L1B – 47,1% (minor RP) and 23,5% (severe RP); L1C – 8,6% (minor RP) and 91,4 (severe RP); (mY=0,0021, p<0,001). From the overall estimated cohort (1370 children), in 790 cases (57,7%; 95CI 56,37 – 59,03) (aged from 3 to 5 years), the dollowing diagnoses were established: behavioral disorders in 103 cases (7,5%; 95CI 6,79 – 8,21), attention and hyperkinetic disorders in 150 cases (10,9%; 95CI 10,06 – 11,74), language and communication disorders in 69 cases (5%; 95CI 4,41 – 5,59), tonic-clonic stuttering in 24 cases (1,8%; 95CI 1,45 – 2,15), tics disorders in 19 cases (1,4%; 95CI 1,08 – 1,72), mild motor disorders in 74 cases (5,4%; 95CI 4,79 – 6,01), EP in 79 cases (5,8%; 95CI 5,17 – 6,43), CP in 272 cases (19,9%; 95CI 18,82 – 20,98). EP was diagnosed in 162 cases (59,6%; 95CI 56,62 – 62,58) from the overall number of cases with CP (Figure 5).
Discussions: It is known fact that early neurological syndromes of hypoxic-ischemic NE includes the following symptoms: convulsions, hypotonia, feeding disorders, disorders of consciousness and EEG abnormalities, which lasts from 7 to 14 days of life . The severity of neonatal neurological syndromes determines the severity of longterm neurological sequelae. Neurological syndromes of hypoxic-ischemic NE and, in some cases, the syndromes of traumatic injury (P10-P15), evolve over time. Until the age of 28 days the diagnosis of NE corresponds to the current classification (Table II) .
Following diagnosis is changed depending on the neurological symptoms assessed. The diagnosis confirmed based on a neurologic screening, including medical history, clinical examination and the laboratory data. The development of neurological complications following NE correlates with the duration of the injury, but also with the timely and eligibility of used resuscitation measures . Cerebrovascular disorders affecting grey and white matter  and intracerebral changes such as neuronal necrosis and destruction , lead to remote neurological sequelae, such as CP, EP, speech disorders, visual and mental disorders . Among the survivors after NE, 25% will develop severe and persistent and permanent sequelae (CP, EP, mental retardation, hyperactivity, etc.) . Several studies showed what NE sequelae can be short-term, but also can be persistent and remote, being related to the status of the newborn at birth: the severity and duration of hypoxia and asphyxia, the severity of the perinatal trauma. Short-term neurological manifestations are expressed through various syndromes, as follows: muscle tone disorders, neurological distress syndrome, disorders of breathing, etc. [19, 20, 21], which is confirmed by the present study. Residual pathology (or consequence) may develop as a result of direct action of NE, as cerebral vascular accident (CVA), or later, as CP and EP. The “sequels” can be diagnosed after the age of 2 years. For the diagnosis twi different codes are need, namely, residual lesions or nature of complication, as well as cause of complication, i. e., early pathology or current disease. E.g.: Behavioral Disorders (BD – F07.9); Sequelae of ischemic and hypoxic NE (Complications of pregnancy, childbirth and delivery – O94). Since the principal disease is not determined, the code for the acute form of the disease is not allocated . It was showed that for more than in 70% of cases of CP there is evidence of hypoxia . Jensen A. notes that disability in childhood, including CP, frequently occur in children who have suffered from hypoxic-ischemic NE, in pre-term newborns and in newborns with a low birth weight . For PCL after hypoxic-ischemic NE, obstetrical traumatism, intrauterine infections etc. is characteristic the delaying in the neuro-psychic and motor development and will be expressed by severe disorders such as mental delay, hearing and visual impairment and even up to blindness, CP, EP etc. and minor symptoms, i. e., mild motor disorders, mild cognitive and behavioral disorders, disorders of communication, speech and language, difficulties of school and social adaptation, tonic-clonic stuttering, tics disorders, etc. [20, 24, 25, 26]. Monitoring of motor, cognitive and behavioral functions should be done to all the children suffered from PCL. In addition, systematic neuropsychological examination is required, especially for children with mild and moderate forms of NE . Children with a positive history for severe hypoxic-ischemic NE suffered from delay of neurological development, cognitive and intellectual impairment. In contrast, children suffered from mild forms of NE are similar to healthy children. They have a good prognosis, at least until the middle childhood. Children with moderate NE form a heterogeneous group of patients with intellectual abilities lower than healthy children or children with mild NE. Their neuropsychological scores are in the average range. In this group, as well as in those with the severe form revealed prominent hyperactivity and autism, and at school age, some of the subjects will present difficulties with reading, spelling and mathematics . According to the data obtained by a study lasting for 5 – 6 years, in a group of children who have suffered from hypoxic-ischemic NE, have been determined motor difficulties, cognitive impairment, as well as the normal development (47%). In 80% of cases with minor dysfunction presented mild or moderate changes at the level of the basal ganglia or white matter. In 83% of children with normal neuro-psychological results presented minor lesions in white matter . In another prospective study, it was determined the depreciation of language skills at the age of 4 years in children with damage of cerebral ventricles without the motor deficits . And in 6% of children with moderate NE and in 42% of children with severe EN, followed along for 7 years, were diagnosed severe disabilities with CP and severe cognitive deficit. Among children with minor neurological dysfunction have been recorded lower cognitive scores in the group with severe or moderate NE, with mean difference comparative to classmates . The authors of another study showed the role of NE in behavioral and cognitive difficulties, particularly at children after severe NE. Were noted the difficulties of prognosis in children with NE and low estimations of cognitive disorders in children after moderate NE . The results corresponds to above mentioned data were obtained also in present study.
The problem of behavioral disorders has been studied at children aged 9 to 10 years suffered from mild or moderate grade of NE. These children have experienced increased risk for behavioral difficulties, including social problems, anxiety and depression, attention problems, etc. It suggests the necessity of neuropsychological assessment as well as education of parents and teachers, to help in cognitive and behavioral rehabilitation of these children . Communication and behavioral disorders, with elements of excitability (F90), are high prevalent in children suffered from NE , creating difficult problems in severe cases or in children with CP .
The results showed the prevalence of attention deficit and hyperactivity disorders after NE, at preschool and school age groups . Disorders of speech and language appear in less than 25% in children with PCL [33, 34]. Cerebral MRI suggests ipsilateral lesions related to organization of language, and the contralateral lesions with injury of mixed expressive and receptive functions . Mental retardation (F70 – F79) may be a common syndrome in children with EP and CP. It can be isolated or associated with other symptoms (emotional, behavioral disorders, speech and language disorders, disorders of social adaptation, left-handedness, hypokinesia, stereotyped movements, etc.)  which may be of variable intensity and represents one of the main CP comorbidity .
Another frequent problem in children with NE are EP. Neonatal seizures are associated with an increased incidence of EP, including syndromes with extremely severe evolution , in particular after hypoxic-ischemic NE . Motor disorders (F82) are present in various pathologies. They can appear at birth or occur after a few weeks, is manifested through disorders of muscle tone and stretch reflexes (SR). Perinatal trauma may be accompanied by decreasing or increasing of muscle tone as well as abnormalities of stretch reflexes, and abnormalities of the SR . These may be early signs of CP or other motor dysfunctions. Some studies suggesting using these signs for early diagnosis of CP . From the age of 6 months, a significant number of cases presenting neurological deficits, in other cases, the clinical picture becomes apparent later – to 1,5 – 2 years with hemiplegias, to 4 – 5 years as diskinetic syndromes. Motor deficits during development are dynamic, representing a weakness, spasticity, orthopedic complications, etc., and in childhood is associated with additional cognitive deficits and behavioral disorders, etc. . CP, representing a chronic disorder of posture and motion, manifesting in pre-, intra- or early postnatal period of life, constitute a major cause of walking disorders, as well as a wide range of stable nonprogressive and non-hereditary disabilities, which are results of motor system injury . Is developed the term CP, generally used in European and in other countries, reflecting a motor impairment after a fixed brain lesion . However, Boyd R. N. et al. have found that, while the brain injury is static, physical and medical problems from CP may progress, leading to motor patterns altered . Imaging investigations are indicated for all patients with CP, for the appreciation of its etiology and understanding the pathogenesis . One of the prospective cohort studies show correlation the diagnosis from 18 months to 5 years. On the basis of complex evaluation the authors found that the age of 24 months is best suited for structural cerebral imaging, because the brain reaches a full myelination, when it clearly differentiates the border between the white and grey matter . Anatomical substrates in dyskinetic form of CP are located deeply in the region of basal ganglia. In turn, in spastic type the substrate is located in the white matter near paracentral lobe .
An analysis of the literature based on several tests for prognosis, suggested the role of electroencephalography and cerebral MRI. The authors recommend the prospective studies on larger cohorts of patients for comprehensive clinical neurological evaluation for children suspected for CP  taking into account the fact that EP is common and occur in approximately 50% of these children , and seizures associated with CP can cause various complications that include behavioral disorders, language and communication disorders, and disorders of attention and hyperactivity, etc. . Another study evaluated the correlations of clinical and radiological findings of cerebral CT and MRI in children with various forms of CP. Obtained results presented consecutively ventricle enlargement, focal infarction, periventricular leukomalacia, foci of atrophy located cortically and subcortically, basal ganglia lesions, impaired cortical migration and myelination . Imaging investigations correlate with neurological outcomes within the CP, by encouraging the appreciation and understanding of the etiology of prognosis in these patients . Thus, PCL on the early stage lead to abnormal development of affected children with severe functional consequences. Neuropsychological deficits including disorders of language, attention, behavioral and other dysfunction of associative activity occur up to 60% of these children . Long-term complications can be “ mild” as motor disorders (F82), cognitive disorders (TCU–F06.7); behavioral disorders (BD – F07.9); communication disorders (BD); speech and language disorders (SLDD – F80); language and communication disorders (LCD – F90.1); disorders of social adaptation (F81.9); disorders of attention and hyperactivity (AHD – F90); tics (F95); tonicclonic stuttering (F98.5) etc.; and “major” (severe): mental retardation (F70-F79); impaired hearing and vision up to blindness; cerebral palsy (CP – G80) with or without psychomotor and verbal delaying; structural epilepsy (G40) [7, 48, 49], what as been demonstrated in the present study.
Standardized screening, together with neurological follow-up, imaging and electrophysiological investigation, as part of an individualized program, is recommended after birth for all children who have suffered hypoxic-ischemic brain injuries. By this approach we can register the sequence of neurological symptoms to make the complex diagnosis, also, this approach allow the detection of children at risk for development of complications, offering the possibility of initiating a rehabilitation therapy at early stages. Dynamic diagnosis between the ages from 1 month to 2 years can be variable, and consists from the part of syndromes, i. e., developmental disorders (motor, psychological, mixed, global), which favors the staging of the diagnosis and the application of a management properly adapted individually.
Neurological surveillance is the background of identification of children with residual pathologies. Progressive neurological syndromes are major predictors for major residual disorders (44,4%), such as cerebral palsy and epilepsy, but may be inadequate for minor residual disorders (55,6%), due to the maturity of the brain functions at older ages. Cerebral lesions of mild and medium grade can suggest the risk of following disorders: behavioral, language and communication, attention, motor, tonic-clonic stuttering, tics, etc., confirmed at the age of 3 – 5 years.
Residual pathologies, especially cerebral palsy, epilepsy and mental retardation, represents the major causes of neurological morbidity for the children with neonatal hypoxic-ischemic encephalopathy and occupying the first places among the neuropsychological handicaps.
Cerebral palsy is a disease with polymorphic etiologies, correlates with the severity of brain injuries (rxy=0,76), has a non-progressive evolution and associated with much co-morbidities, including epilepsy (59,6%). It can develop on the background of structural predisposition from the perinatal period (the data confirmed by imaging techniques). Structural epilepsies are frequent in children with perinatal cerebral lesions (23,3%), (in the group of moderate course is 21,3% and in group of severe pathology in 57,6% of cases), are common for children with cerebral palsy and are cause of neuropsychic decline.