The 681 cases of CP included 457 born at term (>259 days) and 224 prematures. The 457 term cases included 189 hemiplegics, 136 diplegics, 54 dyskinetics, 46 ataxics and 26 tetraplegics. The 224 prematures included 55 hemiplegics, 138 diplegics and 25 dyskinetics. Nine of the prematures and 81 of the term deliveries had obvious etiologic diagnoses. The remaining 376 term births and 215 premature births were without any specific diagnosis other than a summary of the characteristics of the CP syndrome (e.g. spastic diplegia, dyskinesia). Together with a control group of 215 healthy children born at term they constitute the database to be analyzed. The relevant published data from the west Swedish study are presented in Tables 1a and 1b. The risk factors serving as the object of study are listed in Table 1c.
Analysis was conducted to estimate the proportions of genetic causation among the various_clinical CP syndromes. These proportions are group parameters, and they do not refer to the individual “genetic” subject, whose etiologic diagnosis would be better described as “probably genetic,” in view of the lack of positive evidence of genetic causation.
Analysis Consisted of the Following Operations
1.1 Let (u) = frequency of risk factors in pregnancy, and (v)= frequency of non-neuropathic risk factors in delivery. Then the likelihood that a subject with normal pregnancy and delivery will have no recorded risk factors is (1 −u) * (1 −v). This likelihood will be designated (w).
In a collection of cases of CP, causes other than pathologic prenatal or perinatal events will be given by (g = p/w), where (p) = proportion of CP subjects with no recorded prenatal or perinatal risk factors and (w) = proportion of non-CP subjects with no recorded risk factors.
Three samples of non-CP subjects were available for estimating the value of (w):
- 1215 term newborns serving as normal controls to a Swedish study of dyskinetic cerebral palsy (Kyllerman & Hagberg, 1983)
- 214 normal premature newborns, from the same Swedish study.
- 330 Israeli individuals suffering from severe genetically caused mental retardation. All had IQ < 50, at least one additional retarded sibling and closely consanguineous [F ≥ 1/16] parents (Costeff et al. 1983).
Table 1d summarizes the estimates of (w). In the 30 subjects with genetically caused mental retardation there were 7 non-neuropathic recorded risk factors, yielding an estimate of (w= 0.77), with 95% limits of confidence 0.51 - 1.0 The estimates based on the 215 term newborns (w= 0.75) and on the 14 prematures (w= 0.71) were not significantly different from this or from each other. Given this similarity, the estimate based on the 215 term newborns was preferred for further calculations, because of its smaller variance.
Table 1d. Estimated mean and variance of (w)
|Swedish term newborns||215||0.750||0.000872||0.69–0.81|
|Swedish prematures|| 14||0.714||0.0204||0.45–1.0|
|Israeli genetic retardates|| 30||0.773||0.0173||0.51–1.0|
In the simplest hypothesized model the varieties of cerebral palsy are exclusively caused either by pathologic prenatal events, or by pathologic perinatal events, or by genetic pathology similar to the causes of retardation in the 30 cases. The fraction attributed to genetic causes is (g = p/w), as described above.
A more complex model postulates the existence of covert nongenetic causes of CP which are not recorded as risk factors, and which are nonetheless neuropathic events to the fetus. The fraction (g = p/w) will estimate the sum of these causes together with the genetic causes. The random distribution of these nongenetic causes, if they exist, makes possible their independent estimation:
1.1a. The different CP syndromes have widely different values of (g = q + j) where (q) represents the frequency of covert causes of CP, and (j) represents the frequency of genetic causes. Each value of (g) can be taken as an upper bound of estimate of (q) for all the CP syndromes. The lowest estimated value of (g = q + j), (usually found in dyskinesia), is the upper bound estimate of (q). If it is subtracted from the various estimates of (g), the remainder will be the lower bound estimate of the respective values of (g).
1.1b. Calculation of (g) is based on estimates of (w). If (w) is calculated for a normal control group it will reflect both covert nongenetic causes (if they exist) and genetic causes. If it is calculated on the basis of a group of subjects with chronic neural handicap - not CP - with familial prevalence and/or inbreeding it will reflect only genetic causes. The difference between (g = p/w) and (j=p/w) is an unbiased estimate of (q), which can be subtracted from the various estimates of (g) to give estimated proportions of genetic causation corrected for covert nongenetic causes if they exist.
1.2 The correlation between cerebral palsy, which is an expression of existing brain damage, and single prenatal, perinatal and neonatal risk factors for present or future development of brain damage, is notoriously poor (Leviton, 1987). Attempts to improve the clinical-etiologic correlation have sometimes led to a hypothesized two-stage model of brain damage in which a mildly morbid pregnancy (such as placental insufficiency or any other factor compromising fetal growth) renders the fetal brain vulnerable to a degree of perinatal stress (such as anoxia), which would have been harmless in the absence of the earlier insult. This approach treats all pairs of risk factors - one factor in pregnancy and one in delivery - as possibly significant pathogens. How significant they are can be shown by a comparison of their frequency in cases of CP with their frequency among normal healthy children, such as those in our control group. This latter frequency of paired non-neuropathic risk factors among healthy children (S) is the product of the likelihood (u) of a non-neuropathic risk factor of pregnancy and the likelihood (v) of a non-neuropathic risk factor of the perinatal course (S = u*v). The overall frequency (T) of cases of CP with pairs of risk factors is the sum of (S), the non-neuropathic pairs and (D), the pairs responsible for brain damage.
Thus:(T = S+D), and (D = T−S). The likelihood of a given pair being pathogenic is therefore (D/T).
Parameters based on our control group are:
(u) = 0.22; (v) = 0.05; (u*v) = 0.011.
(T) is the principal variable in estimating the frequency of pathogenic pairs of risk factors in a given group of cases of CP. It is directly observed (e.g. 13% among hemiplegics born at term, and 15% among prematurely born spastic diplegics).
With the aid of the above formulae and parameters, this study estimates the proportions of the various idiopathic CP syndromes caused by genetic defects. It also estimates the role played in cerebral palsy by the two-stage model of brain damage. The raw data serving as substrate of this study are summarized in Tables 1a and 1b.