Cerebral Palsy. Etiology and Pathogenesis

R. A. Sergeyeva, M. F. Ismagilov
Kazan State Medical University
Neurological Bulletin
Issue 1-2, Kazan, 1998

Cerebral Palsy (CP) is a term used to describe a syndrome group of different clinical presentation. These syndromes appear as a result of brain hypoplasia and brain damage on different stages of ontogenesis. They are characterized by inability to retain physiological posture and to do voluntary movements. The definition of CP does not apply to any progressive hereditary diseases of the nervous system including different metabolic defects or injury of the spinal cord and the peripheral nerves. At present it is clear that the term “cerebral palsy” does not cover all the variety and essence of neurological disorders accompanying this disease. Nevertheless, it is widely used in the world literature, because no other term which could more thoroughly characterize these pathological states has been proposed as yet. To unite them in a nosologic group allows to plan organizational measures to ensure early recognition and treatment of CP, since this is not only a medical problem, but also a social one.

Epidemiological researches in industrial developed countries show that CP prevalence constitutes 2-2,5 cases per 1000 persons. The data about CP prevalence are changing in proportion as medical science develops. Some authors point out that the incidence of CP tends to be diminished in the last years thanks to better obstetric techniques, prophylaxis, and medical activities. Others, on the contrary, suppose that the prevalence of CP in industrial developed countries lately remains on the same level. Perhaps, it is bound up with affection of the nervous system mainly not during birth, but during prenatal life. None the less, the major part of authors maintain that nowadays the disease occurs much more frequently, and explain it with death-rate falling among premature new-born children with low-birth-weight where the risk of developing CP is very high.

There are many various opinions on etiology of CP. This disease is regarded as a polyetiological one. Estimations of the causes leading to development of CP show that in most cases it is impossible to pick out any of them as a predominant one, because very often it is a combination of several unfavorable factors that manifest themselves both during pregnancy and at labor stage.

According to some authors correlation of prenatal and perinatal factors of cerebral affection in case of CP fluctuates: antenatal types of CP vary within 35-60 per cent, intranatal types – within 27-54 per cent, postnatal types – 6-24 per cent. In accordance with the data of a number of authors, 80 per cent of observations demonstrate that cerebral affection causing CP occurs during antenatal life of the fetus. Subsequently, the antenatal pathology is aggravated with an intranatal one. However, in every third case one cannot manage to establish the cause of CP.

More than 400 factors have been described which influence the course of physiological antenatal development. But in 70-80 per cent of cases the cause of the beginning of cerebral palsy is an influence on the brain exerted by a complex of noxious agents. In his epidemiological research I. M. Volkov has discovered a relation between the beginning of CP and the age of a parturient woman: the largest part of women (60,8 per cent) were 19-30 years old, 29,2 per cent were 30-39 years old, 3,1 per cent were above 40, and 6,9 per cent – under 18.

Mother’s acute or chronic extragenital diseases are attributed to antenatal noxious agents, – first of all, essential hypertension, valvular defects, anemia, obesity, diabetes mellitus, and others diseases that accompany CP in 40 per cent of follow-ups. Apart from above-mentioned factors associated with level of mother’s health there are others, e.g. intake of drugs during pregnancy (10 per cent), occupational hazards (1-2 per cent), parents’ alcoholism (4 per cent), stresses, psychological discomfort (2-6 per cent), physical injuries during pregnancy (1-3,88 per cent).

Lately, great importance in etiology of CP is attached to harmful effect exerted on the fetus by infectious agents, in particular, ones of virus origin. According to the data of Potasman and his co-authors Toxoplasma gondii antibodies were detected in the blood serum of 22 per cent of CP patients (in a reference group – in 9 per cent).

A certain role in development of CP is allotted to derangement of physiological course of pregnancy on different stages. In his study I. M. Volkov noted that 29,5 per cent of mothers with children suffering from CP had had complications during pregnancy: intractable vomiting was observed in 15,5 per cent of them, neuropathy – in 6,75 per cent, risk of miscarriage – 6,45 per cent. Toxicosis of pregnancy was observed in past history of 41-75 per cent. Among other risk factors relating to troubles during pregnancy – metrorrhagia, derangement of placental circulation, placental presentation, or detachment of placenta can be mentioned. Such complications during pregnancy were determined in 2-13 per cent of follow-ups. According to a study carried out by A. Spiniollo intraventricular hemorrhage was identified in 17,5 per cent of survived children born by women whose pregnancy had had complications with premature detachment of placenta, and CP was diagnosed in 11,1 per cent of them.

In accordance with some data of a number of authors tissue incompatibility between mother and the fetus (ABO- and rhesus incompatibility) became the cause of development of CP in 2,0-8,7 per cent of follow-ups.

Most of aforementioned unfavorable factors that are characteristic for prenatal life lead to intrauterine hypoxia of the fetus and to disturbance of uterine placental circulation. Oxygen insufficiency depresses the synthesis of nucleic acids and protein, and leads to structural disorders in embryonic development. Development of an embryo by hypoxia can become the main cause of appearance of malformations and pathology in the development of the fetus.

Perhaps, autoimmune process can be regarded as an important pathogenetic mechanism that determines intrauterine brain damage. Destruction of cellular structure of the brain occurs as a result of the influence of a number of etiological factors during prenatal life which cause intrauterine affection of the fetus. On this occasion some destruction fragments can be found in the blood circulatory system as a substance foreign for a human organism – cerebral antigens. They lead to the appearance of antibodies. Thus, autoimmune process develops with subsequent alteration of the brain tissue which can last several months or even years.

Among important risk factors of CP development different complications in labor may be mentioned which rate exceeds 40,2 per cent: uterine inertia in labor (23,6 per cent), precipitated labor (4 per cent), cesarean section (11,36 per cent), prolonged labor (24 per cent), long anhydrous period (5 per cent), breech presentation (5-14 per cent), protracted period of stay of the fetal head in maternal passages (5 per cent), instrumental obstetrics (5-14 per cent). It should bear in mind that in case of disorders by the intrauterine development of a child his birth often happens in a difficult and prolonged way. It follows from this that favorable conditions are formed for mechanical head injury and asphyxia which are essentially secondary factors causing additional disorder in the initially affected brain.

The major part of home and foreign authors attribute premature delivery to one of the most predisposed factors of CP development. Prematurity has an appreciable specific gravity in past history of CP patients, and, in the opinion of a number of authors, makes 19-33,2 per cent. At the same time this parameter among all newborns equals 4-8 per cent. An epidemiological study carried out by B. Hagberg and his co-authors shows that correlation between full-term and premature infants in a group of healthy children constitutes 16 : 1, but in a group of CP patients such correlation is 2 : 1. Cerebral palsy develops in 8,7 per cent of premature children, and its prevalence comes down in proportion as their gestational age and body weight grow.

Pelvic delivery leads to asphyxia and birth injury three times more frequently than in case of easy delivery, and in 1 per cent of cases leads to CP. There is also a certain correlation between CP and a low birth weight. Researches have shown that cerebral palsy develops in future in 12,1 per cent of children with low birth weight. CP prevalence is 36,7 times higher in case of children with body weight of 500-1499 g and 11,3 higher in case of children with body weight of 1500-2499 g than in case of children with body weight of more than 2500 g.

According to the data of some authors multiple pregnancy takes place in past history of 4 per cent of persons suffering from cerebral palsy. CP incidence in case of multiple pregnancy is 6-7 times higher than in case of physiological pregnancy and constitutes 7,1-8,8 cases per 1000 newborns. CP prevalence at triplet birth constitutes 28 cases per 1000 newborns, and at twin birth – 7,3 per 1000 [45]. The CP risk for newborns with low weight in case of multiple pregnancy is the same as for children with low birth weight in case of monocyesis, and, on the contrary, CP incidence for children with normal body weight from twin birth is higher than for children with normal body weight born as a result of monocyesis (4,2 cases per 1000 live-born infants).

Till now birth asphyxia has been regarded as a main cause of brain affection in children. In accordance with information of different authors it is recorded in past history of 14-65 per cent of children affected by CP and as for healthy children – in past history of 3,2 per cent of them.

As follows from an epidemiological work by P. L. Yudkin and his co-authors, CP cases which are connected with birth asphyxia constitute 1 : 3700 for full-term live-born infants or 10 per cent in the structure of causes leading to CP. The study of anamnesis of the children with birth asphyxia has shown that most of them (75 per cent) had an extremely unfavorable background in prenatal life which was aggravated with risk factors of chronic hypoxia. Taking into account these circumstances it is possible that not so much acute influence on the brain at labor as foregoing intrauterine change of the brain structures under the influence of numerous unfavorable factors is of predominant importance in pathology of the fetus and the newborn.

H. Scheider [49] considers that birth asphyxia can be a real cause of CP only in 10 per cent of full-term newborns who will be affected by the disease afterwards. Cerebral palsy can be prognosticated only in case of difficult labor which entails asphyxia leading to brain tissue damage, in case of clinical symptomatology made known from the first days of life. However, even in case of severe birth asphyxia its causal connection with subsequent psychomotor deficit cannot be taken for granted at all, because brain damage can happen in the antepartum period and subsequently provoke the birth asphyxia.

Intracranial birth injury plays an essential role in the genesis of CP – that is local fetus damage at the moment of labor as a result of mechanical influences (cerebral compression, crushing and necrosis of medullary substance, tears of tissues, meningeal and cerebral hemorrhages, disturbances of dynamic cerebral blood flow), that can disturb the further development of brain and can lead to appearance of many cerebral symptoms. Nevertheless, it is impossible not to take into account that birth injury occurs mostly on a background of foregoing developmental defects of the fetus in case of pathologic and sometimes even of physiological labor. According to some authors the frequency of birth injuries in case of CP has come down in the last decades from 21,6 per cent to 4-5 per cent. It happens as a result of better obstetric conditions.

Factors of cerebral affection that are linked with development of CP in the first period of life are usually considered of infectious, more rarely of traumatic origin. Among many home and foreign publications dedicated to the problem of CP only some isolated works mention a hereditary component of their etiology. Thus, S. I. Kozlova regards cerebral palsy as a disease with hereditary predisposition, and a degree of genetic risk constitutes 2-3 per cent. P. Harper confirms in the opinion that making a diagnosis some people frequently try to cover up their ignorance of many diseases quite often defined by heredity. The author gives some data from a study carried out in Great Britain which shows that general recurrent risk of cerebral palsy constitutes about 1 per cent. But is pointed out that certain nosologic sub-groups are linked with higher risk (in particular, hereditary ataxia and symmetric tetraplegia) when the risk for sibs makes 10-12 per cent. Also, an athetoid type which formerly was strictly associated with nuclear icterus can have a vital genetic basis in the absence of outdoor environmental effects.

Genealogical investigation carried our by N. A. Fletcher in the families having CP patients of dyskinetic (hyperkinetic) type has brought out the availability of sick kinsmen and a certain proportion of affected parents and sibs. The author draws attention to the fact that the disease has progressed with most of patients of mature age. This suggests an idea about genetic heterogeneity of a disease with autosamal-recessive and dominant type of inheritance. And besides, the existence of an X-linked type cannot be ruled out, and the parents’ elderly age too suggests dominant intragenic mutation in most of CP sporadic cases.

In one of his papers P. Curatolo has studied possible combinations of cerebral palsy with epilepsy and mental disorders. The genealogical history of CP patients has shown an extremely high incidence of epilepsy cases among relatives of first degree, and in the author’s opinion this points to an important role of genetic factors in CP development.

In special literature some cases have been described where clinical presentations of some inherited diseases were taking their course in form of a CP syndrome: chromosomal alterations of a type of Patau’s syndrome and incomplete trisomy in the 18th pair of chromosomes, X-linked chromosomal hydrocephalus, Dopa-dependent dystonia.

It is of interest that chiefly males are affected in case of cerebral palsy. CP occurs to boys 1,3 times more often and takes its course more seriously with boys than girls. By the data provided by N. A. Fletcher three fourths of cases of moderate and serious tetraplegia in case of CP occur to males and tend to more serious movement disorders than with women.

Thus, the analysis of literary data with respect to the factors causing CP development shows that there is a considerable amount of them. None the less, till now etiology of the disease has not been properly understood as yet, and there is no clarity in what pathogenic factors (and under what conditions) can make CP develop. Therefore, we can establish only polyetiology of CP and necessity of more attention to studying both biological and environmental factors exerting influence upon a fetal organism and a newborn.

In conclusion it is appropriate to quote M. D. Hensleih’s words: “Prophylactic program shall not be successful until the cause of CP remains unknown”. The most effective results of a prophylactic work can be obtained only in case of early detection of risk factors with the object of prevention of a sick child’s birth.