Asghar Dadkhah, PhD. (Associate professor)
University of Social Welfare and Rehabilitation Sciences, Tehran, Iran

Corespodence to:
Dr Asghar Dadkhah
University of Social Welfare and Rehabilitation Sciences,
Evin, Kudakyar Ave., 19834 Tehran, Iran
Email: fsoleimani@uswr.ac.ir

ABSTRACT Objectives and Background: Cerebral Palsy (CP) is a non-progressive encephalopathy that may be accompanied by speech, auditory or visual abnormalities; seizure or learning disorder, and mental retardation. CP occurs as a result of injury in each phase of brain growth and usually the motor pathways are involved. We decided to investigate this problem, because there is limited study on CP (with respect to etiology, types and associated disorders) in Iran. Method: A descriptive-analytical study was carried out to investigate the etiology, types and associated disorders. Iranian children with CP, between one and six years of age, were studied over a two year period and were selected from children presenting to the referral neuro-developmental services of university rehabilitation clinics in the northern and eastern districts of the health centers of Tehran province with an estimated population of 20 million inhabitants, and evaluated at 3 monthly intervals for two years during 2004-2006. Results: 112 children with CP were seen during the study period. The main symptoms were delay milestones (91.1%), inability to walk independently (52.7%), delayed speech (41.1%) and seizures (30.4%). The main neurological features were motor weakness (63.4%), spasticity (55.4%), language dysfunction (33%), loss of head control (23.2%) and mental retardation (8.5%). Cranial computerized tomography abnormalities were mainly cerebral atrophy (18.8%). MRI abnormalities (18.7%) were mainly cerebral atrophy, demyelination and ventriculomegaly. The results showed that the perinatal factors were the most frequent causes of CP among which asphyxia was present in 52 (46.4%), and included low birth weight and very low birth weight with 51(45.4%), pre-term deliveries with 42 (37.5%), and neonatal seizure in 28 (25%) which were the most outstanding factors. Spastic hemiplegic CP was recorded as the most frequent type (36.6%). Conclusions: The main factors identified were birth asphyxia, pre-term delivery, low birth weight (especially VLBW). Our findings suggest that improved maternal and childcare particularly in the ante and perinatal periods may reduce the incidence of CP in this environment. Key Words: Cerebral palsy, perinatal factors, birth asphyxia, low birth weight.

Cerebral palsy, a persistent, non-progressive disorder of movement and posture which occurs during a period of cerebral growth and development (infancy and childhood)^(1,2) remains a globally common cause of pediatric morbidity despite the technological advances in neonatal intensive care and improved maternal care over the last two decades^(3,4). All of the children with CP suffer from a kind of brain damage and this usually involves motor pathways. More than 100 years have elapsed since the publication of Little's classic paper linking abnormal parturition, difficult labor, premature birth, and asphyxia neonatorum with a "spastic rigidity of the limbs⁽²⁾, the pathogenesis of cerebral birth injuries is far from completely understood. This is not because of lack of interest. The evolution and ultimate neurologic picture of cerebral palsy has been recorded in innumerable papers. Today it is known that most of the high risk pregnancies will have normal children. Indeed, many of the patients with CP have had extra CNS anomalies, which have been led to increased risk of asphyxia during delivery.

The etiologies of CP can be grouped into three categories: Prenatal (genetic, intrauterine infections), Perinatal (asphyxia, LBW, birth trauma), Postnatal (hemolytic disease of neonate that leads to kernicterous, metabolic derangements like hypoglycemia, hypocalcaemia, hypoxia, and inborn errors of metabolism, CNS infections such as meningitis and encephalitis)^(5,6).

Different types of CP can be grouped according to physiologic, topographic and functional capability. In this study different types of CP were grouped according to physiologic, spastic and non-spastic (hypotonic and atonic, attetoid or dyskinetic and mixed), and topographic (hemiplegia, diplegia, quadriplegia, monoplegia, triplegia paraplegia, double hemiplegia) parameters.

Concomitant disturbances, which are observed in this study are: communication and learning difficulties, epilepsy, mental retardation, speech, auditory, swallowing and visual disorders^(7-8).
The reported prevalence of CP ranges from 1.5 - 2.5 per 1,000 live births, and a higher ratein the lowest birth weight groups has been attributed more to the increased number of survivors as a result of improved care in itself^(9,10). The need for resuscitation and presence of congenital abnormalities were also identified as risk factors for CP⁽¹¹⁾.

More recent studies showed that the Apgar score equal or lower than 3 in the 5th minute of birth in many observed infants did not lead to CP; but the study of Apgar score in minutes 10th and 20th of birth is important⁽⁵⁾. In another study it was defined that in more than 50% of patients, asphyxia was not the sole reason of CP and a concomitant etiology also existed. It should be mentioned that in considering the etiology of CP the percent of asphyxia is not absolute and it is in conjunction with other factors such as LBW, prematurity, respiratory distress syndrome(RDS), NICU admission >3 days and environmental stresses and procedures⁽¹²⁾.

According to the WHO report 2006 , in Iran " perinatal factors " are the fourth common cause of mortality in all ages, and cause 10 years of life lost (YLL), which is the third most common cause for lost years in the country (after ischemic heart disease and road traffic accidents)⁽¹³⁾. According to the same report until 2004, the under 5 - mortality rate in Iran was 38 per 1000 live births, 63 percent of which was due to neonatal mortality which in comparison to 43 percent in the regional average

Eastern Mediterranean countries, is a significant figure. The same source has reported that among all etiologies for neonatal mortality in Iran, preterm birth (31%, in comparison to 22% in the Eastern Mediterranean area), congenital anomalies (15% in comparison to 9% in the Eastern Mediterranean area with high child and adult mortality), birth asphyxia (22%), and severe infections (22%) are the most common⁽¹³⁾.

One can conclude that congenital anomalies aside, the three other most common etiologies of neonatal mortality in Iran are somehow related to the perinatal period, and thus under 5 mortality, which as said before is mainly due to neonatal causes and occurs mainly in the neonatal period, is also strongly related to perinatal factors.

When considering years of life lost in Iran, one can also presume that childhood long-term morbidities and handicaps may be significantly related to the perinatal period as well⁽¹³⁾.
One report supporting this presumption suggests that in developing countries, among all etiologies of cerebral palsy, prematurity and intrauterine growth rate restriction (40 -50%) and birth asphyxia or birth trauma (25-30%) are the most common causes⁽¹⁴⁾.

In order to prevent neuro-developmental disorders, one of the most effective strategies universally, is early intervention following early detection of the most subtle and earliest signs of neuro-developmental disorders. Thus the early signs and symptoms for primary physicians is very important for referral for the second level of assessment which is performed by experts and with professional tests.

On the other hand, cerebral palsy is a common cause of disability in Iranian children. Because there has not been any research about the most frequent etiologies and kinds of CP and its associated disorders, this research has been done to specify the most frequent causes for better management and prevention for reducing incidence in Iran and developing countries such as Iran. Since prevention is superior to treatment especially for disease such as CP, the importance of this research will be noted.

This study was carried out in the years 2004-2006, on 112 one to six-year old children, who were referred from different health-care centers in the northern and eastern districts of Tehran to the child neuro-development service at the University Rehabilitation Clinic in the eastern and northern Tehran provinces of Iran and were evaluated at 3-monthly intervals for at least two years.

The reason for choosing the northern and eastern districts was easier geographical accessibility to this center for the referred children and their families. The gender and socio - economic status were the same of Tehran province, the capital city of Iran, with 20 million inhabitants, (all coming from the same districts in Tehran city).

In order to detect etiology, a questionnaire was completed for each child, including the prenatal, perinatal, neonatal and infantile medical history, with the aid of the mother and the child's medical and health records. At the initial assessment, information on their demographic characteristics, clinical data including the duration of gestation and labor, place and method of delivery, number of fetuses and outcome, birth weight, maternal past and current medical and social histories, complications during pregnancy and labor was collected. In addition, information on stillbirths, abnormal children, ante partum hemorrhage, and exposure to drugs, exanthemata, and febrile illness severe enough to warrant admission to the hospital in the mother during the current pregnancy, was also obtained.

Baseline investigations included complete blood count, serum electrolytes, renal, thyroid and liver function tests. Organic acid screen, TORCH study, serum lactate and pyruvate, electroencephalography (EEG) and cranial computerized axial tomography (CT) or MRI, visual and hearing evaluation were obtained on clinical suspicion and were not performed in any of the children. Information on intrauterine growth and details of monitoring of fetal growth for any of the children was also not available.

The questionnaire had been previously evaluated for content validity and pilot studies had been carried out.

The diagnosis of CP was reached using predefined criteria for the study. CP was defined as a chronic disability characterized clinically by non progressive aberrant control of movement that appears early in life and is not caused by a recognized progressive disease or identified etiology such as encephalitis or meningitis.

These patients were grouped according to physical examination and standard protocols.
For study of concomitant disorders a group of developmental pediatrician, neuro-rehabilitation pediatrician, ophthalmologist, pediatric neurologist and psychiatrist was used. Assessment of severity of motor, mental retardation, speech and swallowing disorders, was carried out by a professional rehabilitation team including occupational and physical therapist, speech and language pathologist and special psychologist.

In this study, the term perinatal restricts itself to the period extending from the onset of labor to the end of the first week of postnatal life.

The collected data was verified and entered into a standard database file and analyzed using the statistical package for social sciences.

During the study period, 112 CP patients (53 males, 59 females) aged 12 to 72 months were seen with an overall male: female ratio of 0.89: 1. The mean age +standard deviation (SD) for males was 33.3 ±35.2 months and females 24.8±22.5 months. The mean head circumference + SD for males was 45.30 + 3.5 cm and females 43.93 + 3.7 cm. Microcephaly (head circumference <5th percentile using NCHS reference chart) was found in 40 (35.1%) of the patients during examination and 12(10.7%) at birth; that was a skewed pattern.

The initial presenting symptoms and signs are shown in Table 1. None of the patients had numeric chromosomal abnormalities, or hypothyroidism. The total number of EEG that was obtained was 37 (33%), of which 16 (14.3%) was abnormal. The total number of cranial CT that were obtained was 51 (45.6%), of which 36 (32.2%) were abnormal with predominant cerebral atrophy in 21 (18.8%); hydrocephalus (2.7%) and porencephaly (0.9%), but agenesis of the corpus callosum was not detected. The total number of MRIs that were obtained was 26 (23.2%), of which 21 (18.7%) were abnormal with predominant cerebral atrophy(6.3%), demylination (2.7%) and ventriculomegaly (2.7%). There was no attempt made to correlate the EEG findings or cranial CT and MRI abnormalities with the spectrum or clinical presentation or severity of the handicap in this study.

The mothers were generally healthy with history of hypertension (1), epilepsy (1), gestational diabetes (3), depression (1), uterine structural abnormalities (4), and renal disease (2) noted in 12 mothers only.

The main etiologies in the perinatal period are shown in Table 2, and Table 3 shows the different types of cerebral palsy in this study.

The majority of pregnancies were singletons and 9.2% were twin pregnancies. Preterm delivery was found in 42 (37.5%) and post term delivery in 6 (5.5%). Breech delivery was noted in 4 (3.6%) and antepartum hemorrhage in 10 (8.9%). Birth asphyxia was encountered in 52 (46.6%). The overall mean birth weight was 2.49 + 0.88 kg and low birth weight (<2500 gms) was found in 51 (45.4%) patients. This distribution is shown in Table 4.

Whereas in the past mechanical damage to the brain contributed significantly to mortality during the neonatal period and to subsequent persistent neurologic deficits, mortality and neurologic deficits are now more commonly the consequences of developmental anomalies and hypoxic-ischemic encephalopathy (HIE), acting singly or in concert.

HIE is the consequence of a deficit of oxygen supply to the brain. This can result from a reduced amount of oxygen in the blood (hypoxia) or a reduced supply of blood to the brain (ischemia). No generally accepted definition exists for asphyxia⁽²⁾. It can be inferred on the basis of indirect clinical markers: depressed Apgar scores, cord blood acidosis, or clinical signs in the neonate caused by HIE such as neonatal seizure and meconium-stained amniotic fluid (ASMF). The most traditional of these has been the Apgar score, even though it is now evident that a low Apgar score does not indicate the presence of asphyxia in either term or premature infants⁽¹⁵⁾.

Nelson and Ellenberg have calculated that in the National Collaborative Perinatal Project, the proportion of cases of cerebral palsy owing to intrapartum asphyxia ranged between 3% and 13% and did not exceed 21%⁽¹⁶⁾. In an Australian study, intrapartum asphyxia produced cerebral palsy in 4.9% to 8.2% in infants⁽¹⁷⁾. Whereas the predictive value of the 1- and 5-minute Apgar score in terms of subsequent neurologic deficits is limited, term infants with 5-minute Apgar scores of 6 or less are three times as likely to be neurologically abnormal at 1 year of age as those with scores of 6 to 10⁽¹⁸⁾. The likelihood of permanent brain damage increases even more significantly when depressed Apgar score persists. Of infants with scores of 3 or less at 10 minutes of age, 68% die during the first year of life, and 12.5% of survivors are neurologically damaged. The prognosis is even worse when an Apgar score of 3 or less persists for 20 minutes. Of those infants, 87% die, and 36% of survivors have cerebral palsy⁽¹⁸⁾.

About postnatal etiologies, septicemia and meningitis with 20% had the highest frequency⁽⁷⁾. In other reports the most frequent etiology is LBW and if this is accompanied with other risk factors like asphyxia, the risk for CP will be higher.

Limited research has been done about the etiology of CP in Iran. In one study in a rehabilitation center in Tehran in 1993, prevalence of still birth was shown to be more than fifty, in comparison with other reports that blame unknown factors in creating non suitable and insecure environment for growth of fetus and also can be a predictor of non adequate prenatal care⁽¹⁹⁾ In another study in Tehran in 1992 over 83 cases, of hypertension and UTI of mother were the most frequent prenatal etiologies⁽¹⁹⁾. Also in 53% of cases there was history of neonatal icter, which 80% of were of medium and severe type, and in 38.7% blood exchange has been done. In another study in Tehran the most frequent causes of CP were perinatal etiologies, of which 29% were asphyxia, 24.5% were prematurity and 13% were LBW⁽¹⁹⁾.

The other studies report that, different types of CPs are as follows:
Hemiplegic (25-40%), diplegic (10-23%), mixed (9-22%), quadriplegic (9-43%), extra pyramidal (9-22%) which is similar to our study^(1,6), but in another study in Iran, frequency of different types of CP were spastic diplegic, mixed spastic quadriplegic, extra pyramidal and hemiplegic⁽¹⁹⁾.

In our study it was observed that 97.3% of patients were delivered in hospital and 46.4% had birth asphyxia with persistent low Apgar score, 25% neonatal seizure and 5.4% ASMF, that is according to the recent studies that indicate the role of intrapartum events and CP⁽²⁰⁾. Thus, maternal factors during pregnancy and labor appear to play a major role in the etiopathogenesis of CP in our patients.

The clinical characteristics of our 112 CP children are similar to those reported in other studies^(21-23). Our findings of low birth weight (45.4%), prematurity (37.1%), (8.8% with <28 weeks and 28.3% with 28-37 weeks of gestational age), SGA (33.9%), and breech delivery (3.6%), which have been identified as risk factors for CP are consistent with the results from other studies^(24-25). In a study of 187 Saudi children with cerebral palsy, 73% had microcephaly, 34% LBW, 30% pre-term delivery, 88% birth asphyxia and breech presentation in 8%⁽²³⁾.

It is notable that a high proportion of our patients are microcephalic (35.7%) with no abnormally shaped skull and 32.2% have CT abnormalities with prominent brain atrophy, except in cases of premature closure of the sutures (craniosynostosis), size of the brain that determines the presence of mental retardation, rather it is the underlying structural pathology of the brain. An abnormally small brain results either from anomalous development during the first 7 months of gestation (primary microcephaly), or from an insult incurred during the last 2 months of gestation or during the perinatal period (secondary microcephaly). Hack and coworkers believe that perinatal growth failure, as reflected in a subnormal head circumference at 8 months of age, predicts impaired cognitive function and academic achievement⁽²⁶⁾. In our study most children had a normal head circumference at birth, and predominant brain atrophy in CT scan and MRI, perinatal events are responsible for impairment in head growth, and, by inference, brain maturation. The studies more recently published continue to show similar results^(27,28).

The CT and MRI abnormalities are comparable to those reported in other studies⁽²⁹⁾. It is suggested that further studies are required in this environment to correlate the different types of cranial CT abnormalities with the various forms of CP, underlying cerebral pathology and the possible mechanisms involved in their respective pathogenesis. The relative rarity of identifiable etiologies such as meningitis and encephalitis reflects selection bias as cases with identifiable etiologies were excluded from the study. In addition, it was not possible to validate any presumptive diagnosis of meningitis or encephalitis in the absence of accurate information on the clinical presentation or ancillary laboratory investigations particularly cerebrospinal fluid analysis.

Coexistence of seizure with CP in different reports is between 25-33%, which was 34(30.4%), in this study. The frequency of seizures in our patients is comparable to the reported overall prevalence of epilepsy in patients with CP^(19,30,31).

Delay in speech development has been mentioned in extra pyramidal CP because of lack of coordination of muscle engaged in speech which is resolved with time and speech ability is regained^(32,33). In this study speech disorders was 41.1%.

In other studies the most frequent visual disorder is strabismus (which is the same as in our study with 16.1% frequency)⁽³⁴⁾.

The observation that some of the cases had a positive history of previous CP and disability 18(16.1%) in the family is worthy of note. The pattern of seen presentation and the associated clinical features, particularly the absence of associated urinary bladder dysfunction and peripheral neuropathy does not conform to any of the various clinical forms of hereditary spastic paraplegia described in the literature, even though molecular genetic studies were not carried out in any of the cases. These factors with a high rate of consanguity 35(42%) suggest the need for further clinical and genetics studies on CP in Iran.

In this study the most frequent type of CP was spastic hemiplegia, which had the least motor problems, and not suitable for early diagnosis, so it seems that the primary physicians should pay more attention to early signs and symptoms and risk factors for CP especially asphyxia, prematurity and low birth weight.

Significant numbers of children with CP (92%) had normal IQ or were educable, therefore with early diagnosis and determination of those with normal IQ and use of specialized educational programs (with special attention to their functional disabilities), they can have a normal life like others and enjoy themselves.

According to this study seizure is observed frequently in CP children, so good treatment of it can prevent the accentuation of mental retardation.

The pattern of identified risk factors for CP in our study suggest that preventive measures directed at improving maternal ante and perinatal care might effectively reduce the incidence of CP in this environment.

I would like to thank Shahid Beheshti Medical Health Sciences University and Dr. Mahmoodi F. and Mr. Biglarian A. for their active participation in this study.

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