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Page 65 4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy INFANTILE SPASMS Clinical Description Infantile spasms are a type of epileptic disorder in young children characterized by flexor (34 percent), extensor (22 percent), and mixed flexor-extensor (42 percent) seizures that tend to occur in clusters or flurries (Kellaway et al., 1979). The earliest manifestations of infantile spasms can be subtle and are easily missed, making it difficult to identify the precise age at onset. Infantile spasms, in combination with an electroencephalogram (EEG) pattern of hypsarrhythmia and psychomotor retardation or regression, is referred to as West syndrome. Approximately 80 percent of infants with infantile spasms have, at some time, a characteristic EEG pattern of hypsarrhythmia, whereas this pattern is seen in only ~4 percent of cases with other types of epilepsy (Jeavons and Bower, 1964). The hypsarrhythmic EEG pattern usually disappears with maturation, and ~50 percent of cases may have normal EEGs by age 8 years, although ~65 percent of children with infantile spasms will go on to have other types of seizures (Glaze and Zion, 1985). Descriptive Epidemiology Age-specific incidence rates are not available, although the vast majority of studies report a peak onset between ages 4 and 6 months (Cowan and
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Page 66 Hudson, in press). For 85 to 90 percent of cases, onset of spasms is within the first year of life. Incidence rates of infantile spasms range from 0.25 per 1,000 live births in Denmark and the United States to 0.4 per 1,000 live births in Finland (Leviton and Cowan, 1981). Most investigators divide infantile spasms cases into two categories which are defined on the basis of the presence or absence of a presumed cause and the child's developmental status prior to the onset of spasms. What are commonly referred to as "symptomatic cases" are those in whom a presumed cause can be identified. Idiopathic cases are defined as infants with no identifiable causes for their spasms. This group is further subdivided by some into cryptogenic (those for whom there is no known cause of infantile spasms and whose development was essentially normal prior to the onset of spasms; ~10 percent of all cases) and doubtful (those for whom there is no known cause of infantile spasms but whose development prior to the onset of spasms may have been delayed). Those cases considered to be idiopathic range between 30 and 50 percent (Cowan and Hudson, in press), although this proportion may be declining because of more sensitive diagnostic methods, such as neuroimaging techniques and positron tomography (Chugani et al., 1990). However, although approximately 70 to 90 percent of infantile spasms cases are reported to have abnormal computed tomography (CT) scans (Glaze and Zion, 1985; Pinsard and Saint-Jean, 1985), the significance of some CT diagnoses, for example, cortical atrophy, has been questioned (Ludwig, 1987). Thus, it is unclear that the proportion of infantile spasms cases considered to be idiopathic is really decreasing because of improved diagnosis of cerebral anomalies. Among symptomatic cases, presumed causes are frequently grouped according to the timing of the suspected insult as occurring pre-, peri-, or postnatally. Prenatal factors are thought to account for 20 to 30 percent of cases. This category includes cerebral anomalies, chromosomal disorders, neurocutaneous syndromes such as tuberous sclerosis, inherited metabolic disorders, intrauterine infections, family history of seizures, and microcephaly (Bobele and Bodensteiner, 1990; Kurokawa et al., 1980; Ohtahara, 1984; Riikonen and Donner, 1979). Perinatal factors are thought to account for from 25 to 50 percent of infantile spasms cases. This category includes perinatal hypoxia, birth trauma, and metabolic disorders (Kurokawa et al., 1980; Pollack et al., 1979). Approximately 8 to 14 percent of infantile spasms are attributed to postnatal factors, including central nervous system (CNS) infections, trauma, immunizations, and intracranial hemorrhage (Bobele and Bodensteiner, 1990; Gibbs et al., 1954; Kurokawa et al., 1980; Lombroso, 1983a). Few of these factors have been subjected to systematic investigation, however, and the etiology of infantile spasms remains unknown for 30 to 50 percent of cases (Cowan and Hudson, in press).
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Page 67 History of Suspected Association with Pertussis Vaccines Among the earliest case reports suggesting a possible link between infantile spasms and pertussis immunization are those of Baird and Borofsky (1957). They described 24 children who had hypsarrhythmia and infantile myoclonic seizures and whose development prior to the onset of spasms was apparently normal. Nine cases of infantile spasms were reported to have occurred between 1 and 5 days after DPT vaccination. Three of these nine children also had a history of perinatal complications that the authors thought might have been related to a risk of infantile spasms. The authors also stated, on the basis of a review of published EEG tracings, that hypsarrhythmia was present in two of the affected children described by Byers and Moll (1948). Since these early case reports, additional cases of infantile spasms in association with pertussis immunization have been described in the literature (Fukuyama et al., 1977; Millichap, 1987; Portoian-Shuhaiber and Al Rashied, 1986). The time intervals reported between vaccination and the onset of infantile spasms have been from minutes to weeks (Melchior, 1971). Evidence from Studies in Humans Case Reports and Case Series One of the largest case series of infantile spasms following pertussis immunization was published by Millichap (1987). Six children ranging in age from 2 to 9 months were included. The time interval from immunization to the onset of spasms was from 6.5 hours to 5 days, and first seizures were reported to have occurred in conjunction with the first, second, or third doses of pertussis vaccine. Except for one case who had experienced myoclonic seizures since birth, no mention was made of the children having seizures prior to immunization. In reviewing the etiology and treatment of infantile spasms, Millichap (1987) listed the postulated mechanisms for pertussis-related seizures as (1) a direct neurotoxic effect, (2) an immediate immune reaction, (3) delayed cellular hypersensitivity reaction, and (4) vaccine-induced activation of a latent neurotropic virus infection. In addition to the variability in age at the time of onset of spasms, associated vaccine dose, and time from immunization to the onset of spasms, there was no consistent pattern in the types of neurologic abnormalities reported in conjunction with infantile spasms. These included spastic diplegia, psychomotor retardation, hypotonic diplegia, and progressive neurologic deterioration. Not all children with infantile spasms have other neurologic or developmental problems, and when they do, diversity of expression of these associated neurologic conditions is typically reported (Lacy and Penry, 1976). This case series
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Page 68 provides some of the better clinical descriptions available in the published literature of seizures occurring after immunization with DPT. Although typical of many cases of infantile spasms, information from this series also suggests that there is no consistent syndrome of neurologic manifestations among children whose spasms follow DPT immunization. Fukuyama and colleagues (1977) studied 185 cases of infantile spasms seen in the Department of Pediatrics of the Tokyo Women's Medical College from 1968 to 1972. Table 2 of their paper lists "DPT or DT" as one of the types of vaccines to which cases were exposed, whereas the text and all other tables and figures refer to "DPT or DP." Thus, although there is some uncertainty about the precise vaccines to which these children were exposed, the committee considered DP to be the exposure the authors intended to describe. Complete information on immunization histories and health status prior to vaccination was available for 110 of the 185 infantile spasms cases. Of these 110 children, 22 (20 percent) had been immunized within 1 month of the onset of spasms, 10 with DPT or DP vaccine alone, 5 with DPT vaccine in combination with one or more other vaccines, 4 with smallpox vaccine alone, 2 with Japanese encephalitis vaccine alone, and 1 with polio vaccine alone. Of the 15 cases of infantile spasms with onset after immunization with either DPT or DP vaccine alone or DPT vaccine in combination with another vaccine, onset occurred after the first immunization in 3 cases, after the second in 10 cases, and after the third in 2 cases. The interval from immunization to the reported onset of spasms ranged from less than 48 hours to more than 7 days. The remaining cases had been vaccinated either more than 1 month before or more than 1 month after the onset of spasms (n = 44, 40 percent) or had never been immunized (n = 44, 40 percent). The authors gave no indication that any of the cases had had whooping cough, either before or after the onset of infantile spasms. The authors considered vaccination as the etiology of infantile spasms if cases met the following three criteria: (1) no other identifiable cause, (2) normal development prior to the onset of spasms, and (3) the interval from immunization to the onset of spasms was within 48 hours for pertussis-containing vaccines and within 18 days for smallpox, polio, and Japanese encephalitis vaccines. Given these criteria, 5 of the 110 cases were considered by the authors to have infantile spasms caused by vaccination. It was not possible to determine from the data given in the paper how many of these five cases followed administration of DPT vaccine, since detailed information was given only for three of the five cases. At least one of the five cases occurred following smallpox vaccination alone, and at least two occurred following administration of DP vaccine. It could not be determined from the information provided whether cases were representative of all those with infantile spasms from a defined geographic area or whether they were a selected group who were referred to
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Page 69 these experts in pediatric neurology. The investigators acknowledged that because there is no biologic marker for vaccine-associated infantile spasms, the assignment of cause was made "solely from the clinical standpoint." They stated that because of the diversity of the etiology of infantile spasms, "there is still free space for any agent to be suspected as an injurious factor causative of infantile spasms" (Fukuyama et al., 1977, p. 229). Jeavons and colleagues (1970) reported on a follow-up of 98 cases of infantile spasms, 13 of which were attributed to immunization (type not specified). The follow-up ranged from 4 to 12 years. Outcomes were similar in the cryptogenic and immunization groups, among whom the survivorship, percent without neurologic abnormality at follow-up, and percent in regular school were higher than for those cases of infantile spasms attributed to perinatal or other causes (e.g., tuberous sclerosis). Factors that should be considered in evaluating the study findings are that the patient groups were highly selected, the different lengths of follow-up were not considered in comparing outcomes among the groups, criteria for defining mental outcome were not given, and developmental status at follow-up was not ascertained uniformly for all cases. The first weakness affects the generality of the findings, and the last three problems given above make it difficult to compare outcomes between the groups studied. Fifty-eight cases of infantile spasms (International Classification of Disease [ICD] 9 code 345.6 includes hypsarrhythmia and drop seizures) occurring within 28 days of DPT immunization were reported through the Centers for Disease Control's (CDC's) Monitoring System for Adverse Events Following Immunization (MSAEFI) system from 1978 to 1990, a period in which approximately 80.1 million doses of DPT vaccine were administered through public mechanisms in the United States (J. Mullen, Centers for Disease Control, personal communication, 1990). Of these 58 cases, 41 (71 percent) also received at least one other vaccine at the time of DPT immunization. No follow-up of the cases was made, and a physicians's diagnosis was not required. Controlled Epidemiologic Studies If pertussis immunization were an important cause of infantile spasms, then one could expect a change in the ages at which immunizations were given to be followed by a change in the ages at the time of onset of infantile spasms. This issue was specifically addressed in a study by Melchior (1977) that examined changes in the distributions of ages of onset of infantile spasms and changes in the ages of immunization in Denmark. Prior to April 1, 1970, DPT vaccine was given to Danish children at ages 5, 6, 7, and 15 months. After that date, monovalent pertussis vaccine was given at ages 5 and 9 weeks and 10 months.
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Page 70 Melchior (1977) compared the distributions of ages at the time of onset of infantile spasms for two time periods, 1957 to 1967 and 1970 to 1975, which encompassed the different immunization schedules. Although there was some increase from the first to the second time period in the percentage of cases with onset under age 3 months (12 versus 23 percent), there was no significant difference in the overall distributions of age at onset for the two time periods. In both time intervals, the peak ages at onset for infantile spasms were in the 4- to 6-month range. In addition to the comparison of the age distributions, medical records of the 113 cases of infantile spasms from 1970 to 1975 were examined to determine possible etiologies. Sixty cases were considered by the authors to be symptomatic, 40 were considered to be cryptogenic, and 13 were due to immunization. Of the 13 cases attributed to vaccination, 6 occurred after receipt of the monovalent pertussis vaccine and 7 occurred after receipt of diphtheria-tetanus-polio triple vaccine. Thus, infantile spasms occurring after immunization were reported in approximately equal numbers following administration of pertussis- and non-pertussis-containing vaccines. After mid-1970, the "potency of the pertussis vaccine was reduced by 20 percent and the aluminum adjuvant was removed" (Shields et al., 1988, p. 802). Thus, immunization schedule was not the only factor that was different in the two time periods. In addition, the total number of immunizations given in the population for pertussis and for diphtheria-tetanus-polio was not reported, and therefore, the rate of infantile spasms associated with each type of immunization cannot be determined and, therefore, it is not possible to determine whether the risks are equivalent. Another potential limitation of Melchior's (1977) study is that cases identified for the first time interval (i.e., 1957 to 1967) were taken from a previous study and did not represent a nationwide survey or a national sample of all cases. Thus, it is possible that they had an unusual distribution of onset ages and were not appropriate for comparison with the 1970 to 1975 cases, which included all children with infantile spasms in Denmark. However, the range of peak age at the time of onset for the cases from the earlier interval corresponds to that usually reported, and thus, they are probably not a biased group with respect to age. A similar analysis, also based on data from Denmark, was done by Shields and colleagues (1988). The study considered the frequencies of epilepsy, febrile seizures, infantile spasms (as a subgroup of all cases of epilepsy), and CNS infections (bacterial meningitis and aseptic meningitis) in children aged 1 month to 2 years identified from hospital or outpatient clinic records from 12 of 22 pediatric departments in Denmark. Two time periods, 1967 to 1968 and 1972 to 1973, were selected for comparison to reflect changes in the immunization schedule and in vaccine composition. The exact dates of pertussis immunization were known for 372 children
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Page 71 in the first time period and for 432 children in the second time period. Comparison of the distributions of the ages at the time of immunization for the two time intervals showed a marked difference in the frequency of immunization at different ages, corresponding with the ages at which immunizations were recommended. That is, in the 1967 to 1968 interval the peak ages at immunization were 5, 6, 7, and 15 months, while for the 1972 to 1973 interval immunizations peaked at ages 5 and 9 weeks and 10 months. Despite this difference, however, there was no significant difference in the age distributions of incident cases of infantile spasms in the two time periods. The results of this study are thus not consistent with the hypothesis that pertussis immunization is associated with the risk of infantile spasms, since there was no change in the distribution of ages at the time of onset when the ages at immunization were changed. However, only 80 cases were included in the study, and given this relatively small sample size, the study had a low statistical power to detect a difference in the distributions unless the association of infantile spasms and pertussis immunization was relatively large (see Appendix D). For instance, even if 29 percent of all cases of infantile spasms were caused by DPT immunization, the data of Shields and colleagues would have only about a 50 percent chance of finding a significant difference. To have an 80 percent power, about 40 percent of all infantile spasms cases would have to be caused by DPT. The data abstracters were not masked to the hypothesis of the study, but all events in a defined population were included, and no attempt was made during data collection to relate the events to the time of immunization. The North West Thames Study (Pollock and Morris, 1983) describes voluntary reports of suspected vaccine reactions from 1975 through 1981 and a separate review of hospitalized cases of neurologic disorders in children for 1979. During the 7 years of the study, approximately equal numbers of children in the population completed courses of DPT and DT immunizations (134,700 and 133,500, respectively). Most of these children were also given oral polio vaccine. During this 7-year interval, 1,172 reports of ''vaccine-associated" events were received. Of these, 926 (79 percent) were considered to be "simple" reactions. Of the remaining 246 reports, 114 (10 percent) children experienced anaphylaxis or collapse, convulsions, neurologic disorders, or death. Forty-five (39 percent) of these more serious events were observed following receipt of DPT or monovalent pertussis vaccines, 20 (18 percent) occurred following DT immunization, 37 (32 percent) followed administration of the measles vaccine, and the remaining 12 (11 percent) followed immunization for rubella or other infectious diseases. Five of the 114 children with more serious vaccine-associated reactions identified through the voluntary reporting system were diagnosed with infantile spasms. Among these five children, four had received DPT vaccine from 8 days to 6 weeks prior to the onset of spasms, and 1 had received the
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Page 72 DT vaccine. The onset of infantile spasms reportedly occurred 1 month prior to immunization in the latter case. On the basis of these data, the relative risk (RR) is 4.0, but the 95 percent confidence interval (CI) is wide: 0.6 to 25.2. Despite the large denominators for these rates, the power of this test is low: 50 percent for an RR of 6.3 and 80 percent for an RR of 14.0. In the review of discharge diagnoses for 1979, there were 682 children less than age 2 years who had relevant neurologic illnesses, and hospital records were obtained for 642 of them (94 percent). Five hundred twentysix (82 percent) of these children had febrile convulsions, but only three children with infantile spasms in association with immunization were reported from the review of discharge diagnoses. One child with infantile spasms attributed to Haemophilus influenzae meningitis had received DPT vaccine 19 days prior to the onset of spasms. A second child developed infantile spasms 6 weeks after DPT immunization, and the third child had onset of infantile spasms 12 weeks after immunization with the DT vaccine. Neither the expected number of cases of infantile spasms in a population of the size studied nor the number of cases identified in children who had not been immunized was reported. Thus, it is not possible to determine whether the observed cases were in excess of the expected number. Results based on data from voluntary reporting of events thought to be associated with immunization and those based on data from review of discharge diagnoses are somewhat different. Although the number of cases of infantile spasms is small in both instances, voluntary reporting might suggest that infantile spasms occurred more often after DPT than after DT immunization, whereas review of discharge diagnoses found one case occurring after DPT immunization and one after DT immunization. The opportunity for bias is greater in the voluntary reporting data, since if a particular exposure is under suspicion as a cause of infantile spasms (in this case, the exposure being DPT), it is more likely that events occurring in temporal association with that exposure will be reported. Walker and colleagues (1988) identified from medical and pharmacy records all cases of neurologic illnesses without an apparent predisposing cause in approximately 26,600 children born in Group Health Cooperative hospitals from 1972 to 1983. Medical records for cases and a control group born at the same hospitals during the same calendar period were reviewed for information on immunization status. Fifty-five cases of first afebrile seizures were identified; two of these children had infantile spasms, but the onset of spasms did not occur within 30 days of DPT immunization in either of them. The authors pointed out that since adrenocorticotropic hormone and steroids were not among the drugs for which pharmacy records were screened, some cases of infantile spasms may have been missed. However, only if these children had also not been hospitalized would they have been
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Page 73 completely excluded from the study. In addition, children recently immunized with DPT vaccine would have to be more likely to be missed than children immunized more than 30 days prior to the onset of spasms. The largest controlled study of the association between immunization and risk of infantile spasms was done among cases identified as part of the British National Childhood Encephalopathy Study (NCES) (Bellman et al., 1983a). This study is described in more detail later in this chapter. Briefly, the study included 269 children aged 2 to 35 months admitted to hospitals in England, Scotland, and Wales with a diagnosis of infantile spasms. Of these cases, 64 percent had EEGs with typical or atypical hypsarrhythmia, 30 percent had other EEG abnormalities, and 6 percent were reported to have normal EEGs (Bellman, 1983). Two controls were chosen for each case and were matched for age, sex, and area of residence. Immunization histories of cases and controls were obtained from the records of the children's general practitioners. Risk of infantile spasms associated with immunization was assessed within four time intervals, defined by the following days postimmunization: 0 to 6 days, 7 to 13 days, 14 to 20 days, and 21 to 28 days. For the first period, the RR was 1.2 with a 95 percent CI of 0.5 to 3.0 (Miller et al., 1988). With a sample of the size used, there was 50 percent power to detect an RR of 2.5 and 80 percent power to detect an RR of 3.7. Among the cases, 9 percent had been immunized with DPT vaccine within the preceding 28 days and 8 percent had been immunized with DT vaccine during the same time interval. Comparable percentages for the matched controls were 13 percent for DPT vaccine and 9 percent for DT vaccine. Immunization with neither DPT nor DT vaccine was statistically significantly associated with an increased risk of infantile spasms in any 7-day interval examined. However, risks of infantile spasms were higher within the first 7 days following administration of both DPT and DT vaccines than they were for the other three time periods, when there appeared to be a deficit of infantile spasms cases (RRs for the four time periods 0 to 6, 7 to 13, 14 to 20, and 21 to 28 days were 1.2, 0.6, 0.4, and 0.6, respectively, following DPT immunization and 1.3, 0.7, 0.8, and 0.5, respectively, following DT immunization). These differences in risk across time periods, however, were not statistically significant. Similar results were observed when analyses were confined to the 152 cases who were apparently neurologically normal prior to the onset of infantile spasms (RRs for the four time periods 0 to 6, 7 to 13, 14 to 20, and 21 to 28 days were 2.5, 0.3, 0.5, and 1.5, respectively, following DPT immunization and 2.0, 0.4, 1.0, and 0.3, respectively, following DT immunization). Whether the apparent clustering of cases that was observed within the first 6 days after immunization for both DPT and DT represents a triggering phenomenon, bias in assigning the date of onset of spasms, or simply a chance observation cannot be determined from these data. Looking at cases immunized within 28 days of
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Page 74 diagnosis (a period similar to that used in the other controlled studies on infantile spasms), the RR was 0.6 (95 percent CI, 0.4 to 1.0) for all children in the NCES study and 0.7 (95 percent CI, 0.5 to 1.6) for previously normal children (Bellman et al., 1983a). The power of a test based on these data is somewhat higher than one based on data from the early period only (i.e., 0 to 6 days). For all children in the study, there was 50 percent power to detect an RR of 1.6 and 80 percent power to detect an RR of 2.0. For the previously normal children, the respective RRs were 1.9 and 2.4. The NCES is the largest population-based, controlled study of the association of immunization and risk of infantile spasms. A limitation of the NCES data with respect to infantile spasms was the lack of a uniform case definition, in that children were considered infantile spasms cases if they were so designated by the admitting physician (Bellman et al., 1983b). Those conducting the NCES were notified of cases by physicians from all of England, Scotland, and Wales, and no set of standardized clinical criteria were used. In addition, 41 percent (48 of 116) of previously normal infantile spasms cases were in the "normal-normal" group (Alderslade et al., 1981). That is, they were considered to be neurologically normal both before their initial admission for infantile spasms and at 15 days postadmission or discharge. Although the prognosis for children with infantile spasms without a known cause and who are developmentally normal prior to the onset of spasms is reported to be better than that for symptomatic cases (Lacy and Penry, 1976), 41 percent is a rather high proportion of cases to "recover" from infantile spasms within 2 weeks. This raises the question as to whether these children really had infantile spasms, because the diagnosis was not confirmed and no uniform rules for diagnosis were applied to the group of potential cases. What effect the inclusion of children without infantile spasms would have had on the analysis depends on the true nature of the associations of their conditions with pertussis vaccination. Comparisons of the estimates of risk of infantile spasms done separately for DPT and DT vaccinees can be used to examine the influence of the pertussis component of the vaccine. The fact that nearly identical results were observed for children who received the DPT and DT vaccines suggests that exposure to the pertussis component of the DPT vaccine does not increase the risk of infantile spasms. The Study of Neurological Illness in Children (SONIC) was a large case-control investigation of the association between the risk of serious acute neurologic illness and DPT immunization in young children. A detailed description of SONIC is given later in this chapter. Briefly, the study was conducted in the states of Washington and Oregon from August 1, 1987, through July 31, 1988, and included children aged 1 to 24 months. Cases were identified primarily through systematic review of emergency room, outpatient clinic, and inpatient discharge listings. A panel of international
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Page 75 experts on neurologic illnesses in children confirmed diagnoses by review of medical records and the use of uniform, prespecified criteria. The panel was unaware of the immunization history of cases. Two controls per case were selected from birth certificate registries of the states of Washington and Oregon. Controls were matched to cases by age (within 5 days), sex, and county of birth. Immunization histories for both cases and controls were obtained from interviews with parents, and attempts were made to validate these data by using medical records. Preliminary findings from SONIC have been reported recently (Gale et al., 1990). In the population studied, 10 incident cases of infantile spasms were identified. Of these, three had onset of spasms within 28 days following immunization with DPT. A sixfold increased risk of infantile spasms among children exposed to DPT within 28 days was observed. These results suggest the possibility that recent exposure to DPT is related to an increased risk of infantile spasms. However, the number of cases on which this estimate is based is small, and thus, the confidence interval is wide (95 percent CI = 0.6-57.7), indicating that the estimate of risk of infantile spasms observed in SONIC was very imprecise. The power of the statistical test was correspondingly low: 50 percent for an RR of 9.6 and 80 percent for an RR of 25.4. Because of the small number of cases of infantile spasms, estimates could not be calculated for exposure intervals shorter than 28 days. Hunt (1983) reported on the association between the time of vaccination and the onset of seizures among individuals with tuberous sclerosis who responded to a survey questionnaire. Of 150 families contacted through the Tuberous Sclerosis Association of Great Britain, 97 (65 percent) responded. Of the responders, 82 (84 percent) had had seizures, 66 (80 percent) of whom had infantile spasms. The age range of cases in the survey was less than 1 to 51 years. Outcome was compared among subgroups of responders, defined on the basis of their immunization status at the time of their first seizure. Of the 82 people with tuberous sclerosis who had seizures, 20 had never been immunized, 27 had been immunized after their first seizure, 17 had been immunized within 1 month prior to their first seizure, and 18 had been immunized more than 1 month prior to their first seizure. Profoundly handicapped children, defined as those older than age 5 who could neither walk nor talk, were more often observed among the tuberous sclerosis cases with seizures who were immunized after their first seizure (8 of 27). Of those immunized after their first seizure and for whom the type of immunization was known, the frequency of profound handicap was 6 of 13 who received DT vaccine and 2 of 14 who received DPT vaccine. All of the profoundly handicapped children had their first seizure before the age of 7 months. Although this study suggests that DPT vaccine does not add to the sei-
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Representative terms from entire chapter:
Page 114 TABLE 4-7 Study of Neurologic Diseases in Children (SONIC) Estimated Relative Risks for Pertussis Vaccine Exposure by Case Class and Exposure Interval, With and Without Adjustment for Potential Confounders Matched Setsb Time Interval Powerd Analysis Groupa (No.) (days) RR (95% CI)c 50% 80% All cases 424 <7 1.1 (0.6-2.0) 1.82 2.35 <14 1.2 (0.8-2.0) 1.67 2.07 <28 0.9 (0.6-1.3) 1.44 1.69 Incident cases 358 <7 1.2 (0.6-2.3) 1.92 2.53 <14 1.2 (0.8-2.0) 1.67 2.07 <28 1.9 (0.6-1.3) 1.44 1.69 Incident cases, 358 <7 1.1 (0.5-2.3) 2.09 2.87 adjustede <14 1.2 (0.7-2.1) 1.75 2.22 <28 0.9 (0.6-1.5) 1.67 2.07 NCES eligible 100 <7 2.5 (0.7-9.3) 3.72 6.53 casesf <14 1.8 (0.8-4.4) 2.44 3.59 <28 1.1 (0.5-2.3) 2.09 2.87 NCES eligible 100 <7 3.6 (0.8-15.2) 4.22 7.83 cases, adjustede,f <14 2.1 (0.8-5.8) 2.76 4.27 <28 1.2 (0.5-2.9) 2.42 3.53 a NCES, National Childhood Encephalopathy Study. b Matched case-comparison study design. c RR (95% CI), Estimated relative risk (95 percent confidence interval). d "Power" denotes the probability that a statistical test based on a sample of the same size as the one in the study cited would find a statistically significant increased risk (with alpha = 0.05), given that the true RR in the population being studied is the number stated in the table. The numbers tabulated are the RRs such that the powers are 50 and 80 percent, respectively. e Incident cases adjusted for prior seizure, prior major DPT reaction, family history of seizures, and illness within 30 days. f NCES eligible cases, see Chapter 4. of 864,000 children. Six encephalopathies were recorded within 2 days, and two (in the SONIC study) were recorded as occurring within "1 week" of vaccination. Using a "background" rate of encephalopathy of 78 per 100,000 children per year,2it is possible to estimate the attributable risk for encephalopathies following vaccination. If data from all cited studies are included, the attributable risk estimate is 7.2 per million children. In these 2 This rate was calculated from data in the NCES (Alderslade et al., 1981; Miller et al., 1981), Walker et al. (1988), Griffin et al. (1990), and SONIC (Gale et al., 1990) studies, with an age adjustment derived from Beghi et al. (1984). For details, see Appendix D.
Page 115 studies, children received on average three DPT immunizations; therefore, the estimated attributable risk of encephalopathy is 2.4 per million immunizations. If the studies of Pollock and Morris (1983) and Strom (1967), which relied on spontaneous reports for ascertainment, are excluded, the attributable risk estimate is 2.3 per million immunizations. Relying only on the data in controlled studies of well-defined populations (Gale et al., 1990; Griffin et al., 1990; Walker et al., 1988), the estimate of the attributable risk is 3.3 per million immunizations. In the case of febrile and afebrile seizures, the committee was able to carry out a meta-analysis of the other studies in defined populations (Gale et al., 1990; Griffin et al., 1990; Walker et al., 1988). Three of these studies provide information specifically on afebrile seizures (Gale et al., 1990; Griffin et al., 1990; Walker et al., 1988). Using the methods described in Appendix D, the pooled RR estimate from these studies is 0.6 (95 percent CI = 0.4-1.1), assuming a fixed-effects model, and 0.7 (95 percent CI = 0.3-1.5), under a random-effects model. Thus, even pooling of the available data provides no evidence of a statistically significant increase in the risk of afebrile seizures following DPT vaccination. Combining data from the same three studies on febrile seizures yields a pooled RR of 1.8 (95 percent CI = 1.2-2.7), assuming a fixed-effects model, and 1.9 (95 percent CI = 1.0-3.3), under a random-effects model. Thus, regardless of the kind of statistical model assumed, the pooled data from these three studies indicate an increased relative risk for febrile seizures following DPT immunization. Evidence from Studies in Animals The same limitations that apply to the use of animal models to gain understanding of pathogenesis and immunity in human whooping cough (see Chapter 3) pertain to their use for the study of pertussis vaccine-induced encephalopathy. Superficial understanding of the effects on the human brain of various putative virulence factors and of pertussis vaccine makes it impossible to interpret previous results in animals with any certainty. Unless the basic nature of the postulated vaccine-induced encephalopathy in humans is understood, preferably at the molecular and cellular levels, it is not possible to determine whatever abnormalities produced in an animal represent a valid "model." Retrospective analysis of work that has been done to date yields little useful information. Mice die from an apparent toxemia after intraperitoneal inoculation of large numbers of viable B. pertussis organisms (Pittman, 1970; Proom, 1947). The reasons for death are not understood, as is the case for most infectious diseases. Intracerebral inoculation of viable B. pertussis organisms in mice induces an encephalopathy (Cameron, 1988), which is not
Page 116 surprising. Any relationship of this encephalopathy to the cerebral effects of injecting a vaccine at an extracerebral site is speculative. Amiel (1976) and Bergman and colleagues (1978) found changes in the permeability of the cerebral vasculature of rodents given pertussis vaccine, but it has not been clear how this might relate to encephalopathy in rodents or humans. Steinman and colleagues (1982) have proposed a mouse model for pertussis vaccine-induced encephalopathy that is linked to the genetic locus H-2. In this model, animals with a certain H-2 type that had been given a large number of heat-killed B. pertussis organisms 2 days earlier died within 30 minutes to 2 hours after injection of bovine serum albumin. Postmortem examination of the brain revealed diffuse vascular congestion and parenchymal hemorrhage, which the authors believed resembles the findings in human cases in whom death occurred quickly after immunization. The model raises interesting questions regarding possible genetic control and a role for immediate hypersensitivity in postulated vaccine-induced encephalopathy, but the relationship of these variables to the proposed response in humans is speculative. Moreover, it is not clear whether these pathologic changes represent a primary encephalopathy or the agonal effects of shock, hypovolemia, and the like. Presumably, the vaccine lots that have been suspected of causing irreversible encephalopathy in children have passed the intracerebral mouse protection test or the intranasal mouse protection test for vaccine potency and the mouse weight gain test for toxicity. Therefore, the capacity to cause serious encephalopathy in mice, if present, has been missed. The endpoint of the intracerebral mouse protection test is death from active infection within 14 days. The interval between injection of vaccine and intracerebral injection of viable organisms, a matter of a few weeks, might not be sufficient for detection of late neurologic effects. More importantly, neurologic sequelae that might relate to changes in memory, learning ability, emotional control, and the like might not be obvious in mice. Similar considerations apply to the mouse weight gain test, which is carried out for up to 7 days and which focuses on weight gain as an endpoint. In summary, it is not evident that the studies in animals completed to date provide information useful to understanding the possible relation of encephalopathy to pertussis immunization in children. Aluminum Salts The possibility has been raised that the aluminum salts regularly present in DPT vaccines might play a role in the occurrence of encephalopathy following DPT immunization (see Appendix E for discussion). There are no data bearing on this possible mechanism.
Page 117 Summary Case reports and case series offer no consistent evidence for a clinically distinctive pertussis vaccine-induced encephalopathy. The limited understanding of the underlying disease process and an inability to diagnose encephalopathy accurately or uniformly, particularly in infants, also hinder the design, conduct, and interpretation of human studies. Comparisons of results among different studies are difficult, since different types of events are included under the term encephalopathy in different studies. The animal models of pertussis vaccine-induced encephalopathy (e.g., Cameron, 1988; Steinman et al., 1982) do not appear to be pertinent to human disease (e.g., they require intracerebral inoculation). In addition, the superficial understanding of the pathophysiology of encephalopathy, the difficulties of accurately diagnosing even severe cases, the lack of understanding of pertussis virulence factors, and the variability in pertussis vaccine composition across manufacturers and time make it almost impossible to extrapolate animal findings to humans with any certainty. There are no data to indicate a mechanism of cerebral injury. In light of the considerations listed above and given the limitations of case reports and animal studies (see Chapter 3), the studies that could best address the question of the possible relation between pertussis vaccination and encephalopathy have been controlled epidemiologic studies. To date, four such studies have been reported (Alderslade et al., 1981; Gale et al., 1990; Griffin et al., 1990; Walker et al., 1988). The NCES reported a statistically significant RR of encephalopathy of 3.1 (associated with an attributable risk of 2.7 per million immunizations) in the early postimmunization period. None of the other studies demonstrated a statistically significant risk. However, the total number of cases reported in the other three studies was consistent with the attributable risks found in the NCES. Data bearing on the question of a possible relation between pertussis vaccination and chronic neurologic damage are limited to one controlled study (Alderslade et al., 1981; Miller et al., 1988), in which the neurologic status of children prior to their acute illness was not directly measured and the definition and measurement of late outcomes were not uniformly applied to all participants. In addition, the total number of children with chronic conditions on which risk estimates were based was very small, and estimates of chronic neurologic damage following specific types of acute illnesses, especially encephalopathy, could not be calculated. The results of studies comparing rates of febrile seizures following DPT versus DT vaccine (Cody et al., 1981; Pollock and Morris, 1983; Pollock et al., 1984), the ecologic study of Shields and colleagues (1988) showing a shift in occurrence of febrile seizures following change in time of DPT immuniza-
Page 118 tion, the NCES results on seizures (80 percent of which were febrile) (Alderslade et al., 1981), and the findings of three additional controlled studies on febrile seizures (Gale et al., 1990; Griffin et al., 1990; Walker et al., 1988) suggest that DPT vaccine may cause a doubling or tripling of the febrile seizure rate in the first few days following immunization. The three controlled studies that directly addressed afebrile seizures (Gale et al., 1990; Griffin et al., 1990; Walker et al., 1988) were consistent in showing no relation to DPT vaccination, although each had limited statistical power to detect risks unless they were on the order of 2.4 or larger. Only the study of Shields and colleagues (1988) addressed epilepsy specifically, and it found no relation between the onset of epilepsy and the timing of DPT immunization. However, the power of this study was limited. No animal models for seizures and DPT vaccine have been developed. Conclusion The evidence is consistent with a causal relation between DPT vaccine and acute encephalopathy,3defined in the controlled studies reviewed as encephalopathy, encephalitis, or encephalomyelitis. On the basis of a review of the evidence bearing on this relation, the committee concludes that the range of excess risk of acute encephalopathy following DPT immunization is consistent with that estimated for the NCES: 0.0 to 10.5 per million immunizations. There is insufficient evidence to indicate a causal relation between DPT vaccine and permanent neurologic damage. REFERENCES Aicardi J, Chevrie JJ. 1975. Accidents neurologiques consecutifs a la vaccination contre la coqueluche. [Neurological complications following immunization against pertussis.] Archives Francaises de Pediatrie 32:309-317. Alderslade R, Bellman MH, Rawson NSB, Ross EM, Miller DL. 1981. The National Childhood Encephalopathy Study: a report on 1000 cases of serious neurological disorders in infants and young children from the NCES research team. In: Whooping Cough: Reports from the Committee on the Safety of Medicines and the Joint Committee on Vaccination and Immunisation. Department of Health and Social Security. London: Her Majesty's Stationery Office. 3 Although the committee was not asked expressly to examine febrile seizures, afebrile seizures, or epilepsy in relation to DPT vaccine, it did so because these conditions are considered by some to be components of encephalopathy. The committee's conclusions on the relation of these adverse events to DPT immunization are as followsfebrile seizures: the evidence indicates a causal relation between DPT vaccine and febrile seizures; afebrile seizures: the evidence does not indicate a causal relation between DPT vaccine and afebrile seizures; epilepsy: there is insufficient evidence to indicate a causal relation between DPT vaccine and epilepsy.
Page 119 American Academy of Pediatrics. 1980. Consensus statement. Febrile seizures: long-term management of children with fever-associated seizures. Pediatrics 66:1009-1012. Amiel SA. 1976. The effects of Bordetella pertussis vaccination on cerebral vascular permeability. British Journal of Experimental Pathology 57:653-662. Annegers JF, Hauser WA, Beghi E, Nicolosi A, Kurland LT. 1988. The risk of unprovoked seizures after encephalitis and meningitis. Neurology 38:1407-1410. Baird H, Borofsky LG. 1957. Infantile myoclonic spasm. Journal of Pediatrics 50:332-339. Baraff LJ, Shields D, Beckwith L, Strome G, Marcy SM, Cherry JD, Manclark CR. 1988. Infants and children with convulsions and hypotonic-hyporesponsive episodes following diphtheria-tetanus-pertussis immunization: follow-up evaluation. Pediatrics 81:789-794. Baraff LJ, Manclark CR, Cherry JD, Christenson P, Marcy M. 1989. Analyses of adverse reactions to diphtheria and tetanus toxoids and pertussis vaccine by vaccine lot, endotoxin content, pertussis vaccine potency and percentage of mouse weight gain. Pediatric Infectious Disease Journal 8:502-507. Beghi E, Nicolosi AN, Kurland LT, Mulder DW, Hauser WA, Shuster L. 1984. Encephalitis and aseptic meningitis, Olmsted County, Minnesota, 1950-1981. I. Epidemiology. Annals of Neurology 16:283-294. Bellman MH. 1983. Serious acute neurological diseases of children: a clinical and epidemiological investigation with special reference to whooping cough disease and immunization. Unpublished thesis submitted for the degree of Doctor of Medicine, University of London. Bellman MH, Ross EM, Miller DL. 1983a. Infantile spasms and pertussis immunisation. Lancet 1:1031-1034. Bellman MH, Ross EM, Miller DL. 1983b. Pertussis vaccine and infantile spasms (letter). Lancet 2:278-279. Berg JM. 1958. Neurological complications of pertussis immunization. British Medical Journal 2:24-27. Bergman RK, Munoz JJ, Portis JL. 1978. Vascular permeability changes in the central nervous system of rats with hyperacute experimental allergic encephalomyelitis induced with the aid of a substance from Bordetella pertussis. Infection and Immunity 21:627-637. Berkow R, ed. 1987. Pertussis. Merck Manual of Diagnosis and Therapy, 15th edition. Rahway, NJ: Merck Sharpe & Dohme Research Laboratories. Blumberg DA, Mink CM, Lewis K, Chatfield P, Leach C, Smith LP, Christenson PD, Guravita L, Steinfeld MBJ, March SM, Levin SR, Baraff LJ, Schonfeld N, Cherry JD. In press. Pathophysiology of reactions associated with pertussis vaccine. Developments in Biological Standardization. Bobele GB, Bodensteiner JB. 1990. Infantile spasms. Neurologic Clinics 8:633-645. Bower BD, Jeavons PM. 1960. Complications of immunization. British Medical Journal 2:1453. Brewis M, Poskanzer DC, Rolland C, Miller H. 1966. Neurological disease in an English city. Acta Neurologica Scandinavica 42(Suppl. 24):9-89. Brody M, Sorley RG. 1947. Neurologic complications following the administration of pertussis vaccine. New York State Journal of Medicine 47:1016-1017. Byers RK, Moll FC. 1948. Encephalopathies following prophylactic pertussis vaccination. Pediatrics 1:437-457. Cameron J. 1988. Evaluation of control testing of pertussis vaccines. In: Wardlaw AC, Parton R, eds. Pathogenesis and Immunity in Pertussis. New York: John Wiley & Sons. Cavanagh NPC, Brett EM, Marshall WC, Wilson J. 1981. The possible adjuvant role of Bordetella pertussis and pertussis vaccine in causing severe encephalopathic illness: a presentation of three case histories. Neuropediatrics 12:374-381. Cherry JD, Brunell PA, Golden GS, Karzon DT. 1988. Report of the task force on pertussis and pertussis immunization1988. Pediatrics 81(6, part 2):939-984. Chugani HT, Shields WD, Shewmon DA, Olson DM, Phelps ME, Peacock WJ. 1990. Infantile
Page 120 spasms: I. PET identifies focal cortical dysgenesis in cryptogenic cases for surgical treatment. Annals of Neurology 27:406-413. Cockburn WC. 1958. Incidents et accidents consecutifs a la vaccination cochelucheuse. Bulletin of the World Health Organization 19:109-122. Cockburn W. 1959. Hazards of Pertussis Vaccination: Proceedings of a Symposium on Immunization in Childhood. London: E & S Livingston Ltd. Cody CL, Baraff LJ, Cherry JD, Marcy SM, Manclark CR. 1981. Nature and rates of adverse reactions associated with DTP and DT immunizations in infants and children. Pediatrics 68:650-660. Corsellis JAN, Janota I, Marshall AK. 1983. Immunization against whooping cough: a neuropathological review. Neuropathology and Applied Neurobiology 9:261-270. Coulter HL, Fisher BL. 1985. DPT: A Shot in the Dark. New York: Harcourt Brace Jovanovich. Cowan LD, Hudson LS. In press. Epidemiology of infantile spasms. Journal of Child Neurology. Crombie DL, Cross KW, Fry J, Pinsent RJFH, Watts CAH. 1960. A survey of the epilepsies in general practice: a report by the Research Committee of the College of General Practitioners. British Medical Journal 2:416-422. Dick G. 1972. Immunization in childhood. Community Medicine 127:73-77. Dick GWA. 1974. Convulsive disorders in young children. Proceedings of the Royal Society of Medicine 67:371-372. Dodson WE. 1978. Metabolic encephalopathies in neurological pathophyphysiology. In: Eliasson SG, Prensky AL, Hardin WB, Jr., eds. Neurological Pathophysiology. New York: Oxford. Dolgopol VB. 1941. Changes in the brain in pertussis with convulsions. Archives of Neurolology and Psychiatry 46:477-503. Dudgeon JA, Brett EM, Corsellis JAN, Gilliatt RW, Lambert HP, Walford D, Hempsall J. 1981. Advisory panel on serious reactions to vaccines: report on the assessment of the summarised histories of 50 cases of reported serious reactions following immunisation with vaccines containing pertussis antigen. In: Whooping Cough: Reports from the Committee on the Safety of Medicines and the Joint Committee on Vaccination and Immunisation. Department of Health and Social Security. London: Her Majesty's Stationery Office. Ehrengut W. 1974. Über konvulsive Reaktionen nach Pertussis-Schutzimpfung. [Convulsive reactions after pertussis immunization.] Deutsche Medizinische Wochenschrift 99:2273-2279. Ehrengut W. 1980. Lässt Sich die Reserve gegenüber der Pertussis-Schutzimpfung begründen? [Is the reserve in respect of protection against pertussis by immunization well-founded?] Paediatrische Praxis 23:3-13. Ellenberg JH, Nelson KB. 1978. Febrile seizures and later intellectual performance. Archives of Neurology 35:17-21. Ellenberg JH, Hirtz DG, Nelson KB. 1986. Do seizures in children cause intellectual deterioration? New England Journal of Medicine 314:1085-1088. Feery BJ, Finger WK, Kortus Z, Jones GA. 1985. The incidence and type of reactions to plain and adsorbed DTP vaccines. Australian Pediatric Journal 21:91-95. Fenichel GM. 1982. Neurological complications of immunization. Annals of Neurology 12:119-128. Forrester RM. 1965. Immunization against whooping-cough. British Medical Journal 2:232. Fukuyama Y, Tomori Y, Sugitate M. 1977. Critical evaluation of the role of immunization as an etiological factor of infantile spasms. Neuropadiatrie 8:224-237. Gale JL, Thapa PB, Bobo JK, Wassilak SGF, Mendelman PM, Foy HM. 1990. Acute neurological illness and DTP: report of a case-control study in Washington and Oregon. In: Manclark CR, ed. Sixth International Symposium on Pertussis, Abstracts. DHHS Publication No. (FDA) 90-1162. Bethesda, MD: Public Health Service, U.S. Department of Health and Human Services.
Page 121 Gibbs EL, Fleming MM, Gibbs FA. 1954. Diagnosis and prognosis of hypsarrhythmia and infantile spasms. Pediatrics 13:66-73. Gibbs FA, Gibbs EL. 1952. Atlas of Electroencephalography, Vol. 2, Epilepsy. Reading, MA: Addison-Wesley. Glaze DG, Zion TE. 1985. Infantile spasms. Current Problems in Pediatrics 15:1-39. Globus JH, Kohn JL. 1949. Encephalopathy following pertussis vaccine prophylaxis. Journal of the American Medical Association 141:507-509. Gove PB, ed. 1981. Webster's Third New International Dictionary of the English Language, Unabridged. Springfield, MA: Merriam-Webster, Inc. Griffin MR, Ray WA, Mortimer EA, Fenichel GM, Schaffner W. 1990. Risk of seizures and encephalopathy after immunization with the diphtheria-tetanus-pertussis vaccine. Journal of the American Medical Association 263:1641-1645. Griffith AH. 1989. Permanent brain damage and pertussis vaccination: is the end of the saga in sight? Vaccine 7:199-210. Halpern SR, Halpern D. 1955. Reactions from DPT immunization and its relationship to allergic children. Journal of Pediatrics 47:60-67. Harker P. 1977. Primary immunisation and febrile convulsions in Oxford 1972-5. British Medical Journal 2:490-493. Hauser WA, Kurland LT. 1975. The epidemiology of epilepsy in Rochester, Minnesota, 1935-1967. Epilepsia 16:1-66. Hennessen W, Quast U. 1979. Adverse reactions after pertussis vaccination. International Symposium on Immunization: Benefit vs. Risk Factors, Brussels. Developments in Biological Standardization 43:95-100. Hirtz DG, Nelson KB. 1983. The natural history of febrile seizures. Annual Review of Medicine 34:453-471. Hirtz DG, Nelson KB, Ellenberg JH. 1983. Seizures following childhood immunizations. Journal of Pediatrics 102:14-18. Hughes JR, Tomasi LG. 1985. The diminishing incidence of hypsarrhythmia. Clinical Electroencephelography 16:178-182. Hunt A. 1983. Tuberous sclerosis: a survey of 97 cases. I. Seizures, pertussis immunization and handicap. Developmental Medicine and Child Neurology 25:346-349. Jacobsen V, Nielsen C, Buch D, Shields WD, Christenson P, Zachau-Christiansen B, Cherry JD. 1988. Relationship of pertussis immunization to the onset of epilepsy, febrile convulsions and central nervous system infections: a retrospective epidemiologic study. Tokai Journal of Experimental and Clinical Medicine 13(Suppl.):137-142. Jeavons PM, Bower BD. 1964. Infantile spasms: a review of the literature and a study of 112 cases. In: Clinics in Developmental Medicine, No. 15. London: Spastics Society. Jeavons PM, Harper JR, Bower BD. 1970. Long-term prognosis in infantile spasms: a followup report on 112 cases. Developmental Medicine and Child Neurology 12:413-421. Kellaway P, Krachoby RA, Frost JD, Zion T. 1979. Precise characterization and quantification of infantile spasms. Annals of Neurology 6:214-218. Köng E. 1953. Zur Pertussisimpfung und Ihren Gegenindikationen. Helvetica Paediatrica Acta 8:90-98. Kulenkampff M, Schwartzman JS, Wilson J. 1974. Neurological complications of pertussis inoculation. Archives of Disease in Childhood 49:46-49. Kurokawa T, Goya N, Fukuyama Y, Suzuki M, Seki T, Ohtahara S. 1980. West syndrome and Lennox-Gastaut syndrome: a survey of natural history. Pediatrics 65:81-88. Lacy JR, Penry JK. 1976. Infantile Spasms. New York: Raven Press. Leviton A, Cowan LD. 1981. Methodological issues in the epidemiology of seizure disorders in children. Epidemiological Reviews 3:67-86.
Page 122 Leviton A, Cowan LD. 1982. Epidemiology of seizure disorders in children. Neuroepidemiology 1:40-83. Livengood JR, Mullen JR, White JW, Brink EW, Orenstein WA. 1989. Family history of convulsions and use of pertussis vaccine. Journal of Pediatrics 115:527-531. Livingston S. 1972. Comprehensive Management of Epilepsy in Infancy, Childhood and Adolescence. Springfield, IL: Charles C Thomas. Lombroso CT. 1983a. A prospective study of infantile spasms: clinical and therapeutic correlations. Epilepsia 24:135-158. Lombroso CT. 1983b. Infantile spasms. In: Browne TR, Feldman RG. Epilepsy. Diagnosis and Management. Boston: Little, Brown & Co. Lombroso CT. 1990. Early myoclonic encephalopathy, early infantile epileptic encephalopathy, and benign and severe infantile myoclonic epilepsies: a critical review and personal contributions. Journal of Clinical Neurophysiology 7:380-408. Long SL, Deforest A, Smith DG, Lazaro C, Wassilak SGF. 1990. Longitudinal study of adverse reactions following diphtheria-tetanus-pertussis vaccine in infancy. Pediatrics 85:294-302. Low NL. 1955. Electroencephalographic studies following pertussis immunization. Journal of Pediatrics 47:35-39. Ludwig B. 1987. Review: neuroradiological aspects of infantile spasms. Brain and Development 9:358-360. MacRae KD. 1988. Epidemiology, encephalopathy, and pertussis vaccine. In: Mebel S, Stompe H, Drescher M, Rustenbach, eds. FEMS SymposiumPertussis: Proceedings of the Conference Organized by the Society of Microbiology and Epidemiology of the GDR, April 20-22, 1988, Berlin. Madge N, Miller D, Ross E, Wadsworth J. 1990. The National Childhood Encephalopathy Study: a 10-year followup. In: Manclark CR, ed. Sixth International Symposium on Pertussis, Abstracts. DHHS Publication No. (FDA) 90-1162. Bethesda, MD: Public Health Service, U.S. Department of Health and Human Services. Madsen T. 1933. Vaccination against whooping cough. Journal of the American Medical Association 101:187-188. Malmgren B, Vahlquist B, Zetterstrom R. 1960. Complications of immunisation. British Medical Journal 2:1800-1801. Marcuse EK, Wentz KR. 1990. The NCES reconsidered: summary of a 1989 workshop. Vaccine 8:531-535. Meade TW, Ross EM, Stewart GT, Vessey MP, Wilson J, Walford D, Hempsall J, Allen P. 1981. The collection of data relating to adverse reactions to pertussis vaccine: report of the advisory panel. In: Whooping Cough: Reports from the Committee on the Safety of Medicines and the Joint Committee on Vaccination and Immunisation. Department of Health and Social Security. London: Her Majesty's Stationery Office. Melchior JC. 1971. Infantile spasms and immunization in the first year of life. Neuropadiatrie 3:3-10. Melchior JC. 1977. Infantile spasms and early immunization against whooping cough. Danish survey from 1970 to 1975. Archives of Disease in Childhood 52:134-137. Menkes JH. 1990. Neurologic complications of pertussis vaccination (abstract). Annals of Neurology 28:426-427. Miller DL, Ross EM, Alderslade R, Bellman MH, Rawson NSB. 1981. Pertussis immunisation and serious acute neurological illness in children. British Medical Journal 282:1595-1599. Miller DL, Wadsworth J, Ross E. 1988. Severe neurological illness: further analyses of the British National Childhood Encephalopathy Study. Journal of Experimental Clinical Medicine 13(Suppl.):145-155. (Paper presented at 5th International Symposium on Pertussis, September 22-23, 1988, Copenhagen, Denmark.)
Page 123 Miller DL, Wadsworth MJH, Ross EM. 1989. Pertussis vaccine and severe acute neurological illnesses: response to a recent review by members of the NCES team. Vaccine 7:487-489. Millichap JG. 1987. Etiology and treatment of infantile spasms: current concepts, including the role of DPT immunization. Acta Paediatrica Japonica 29:54-60. Murphy JV, Sarff LD, Marquardt KM. 1984. Recurrent seizures after diphtheria, tetanus, and pertussis vaccine immunization: onset less than 24 hours after vaccination. American Journal of Diseases of Children 138:908-911. Nelson KB, Ellenberg JH. 1976. Predictors of epilepsy in children who have experienced febrile seizures. New England Journal of Medicine 295:1029-1033. Nelson KB, Ellenberg JH. 1978. Prognosis in children with febrile seizures. Pediatrics 61:720-727. Nelson KB, Ellenberg JH. 1986. Antecedents of seizure disorders in early childhood. American Journal of Diseases of Children 140:1053-1061. Niswander KR, Gordon M. 1972. The Women and Their Pregnancies. DHEW Publication No. (NIH) 73-379. Washington, DC: U.S. Department of Health, Education, and Welfare. Ohtahara S. 1984. Seizure disorders in infancy and childhood. Brain and Development 6:509-519. Pinsard N, Saint-Jean M. 1985. West's syndrome. Neuroscience 35(EEG Suppl.):59-69. Pittman M. 1970. Bordetella pertussisbacterial and host factors in the pathogenesis and prevention of whooping cough. In: Mudd S, ed. Infectious Agents and Host Reactions. Philadelphia: W.B. Saunders Co. Pollack MA, Zion TE, Kellaway P. 1979. Long-term prognosis of patients with infantile spasms following ACTH therapy. Epilepsia 20:255-260. Pollock TM, Morris J. 1983. A 7-year survey of disorders attributed to vaccination in North West Thames Region. Lancet 1:753-757. Pollock TM, Miller E, Mortimer JY, Smith G. 1984. Symptoms after primary immunisation with DTP and DT vaccine. Lancet 2:146-149. Portoian-Shuhaiber S, Al Rashied AA. 1986. First reported cases of permanent neurological damage after pertussis vaccine among children born and vaccinated in Kuwait. Saudi Medical Journal 7:270-274. Proom H. 1947. The immunological aspects of experimental Haemophilus pertussis infection. Journal of Pathology and Bacteriology 59:165-180. Riikonen R, Donner M. 1979. Incidence and aetiology of infantile spasms from 1960 to 1976: a population study in Finland. Developmental Medicine and Child Neurology 21: 333-343. Shields WD, Nielsen C, Buch D, Jacobsen V, Christenson P, Zachau-Christiansen B, Cherry JD. 1988. Relationship of pertussis immunization to the onset of neurologic disorders: a retrospective epidemiologic study. Journal of Pediatrics 113:801-805. Siddiqui MA, Lin FY, Trostel B, Israel E, Dwyer DM. 1989. Adverse events following DTP immunization in Maryland, 1987. Maryland Medical Journal 38:556-559. Steinman L, Sriram S, Adelman NE, Zamvil S, McDevitt, HO, Urich H. 1982. Murine model for pertussis vaccine encephalopathy: linkage to H-2. Nature 299:738-740. Stephenson JBP. 1987. Critical analysis of the concept of ''pertussis vaccine damage" and opinion on the evidence relating to Patrick Rothwell, December 22. Unpublished. Stetler HC, Mullen JR, Brennan JP, Orenstein WA, Bart KJ, Hinman AR. 1985a. Adverse events following immunization with DTP vaccine. Developments in Biological Standardization 61:411-421. Stetler HC, Orenstein WA, Bart KJ, Brink EW, Brennan J, Hinman AR. 1985b. History of convulsions and use of pertussis vaccine. Journal of Pediatrics 107:175-179. Stewart GT. 1977. Vaccination against whooping-cough: efficacy versus risks. Lancet 1:234-237.
Page 124 Stewart GT. 1979. Toxicity of pertussis vaccine: frequency and probability of reactions. Journal of Epidemiology and Community Health 33:150-156. Strom J. 1960. Is universal vaccination against pertussis always justified? British Medical Journal 2:1184-1186. Strom J. 1967. Further experience of reactions, especially of a cerebral nature, in conjunction with triple vaccination: a study based on vaccinations in Sweden, 1959-1965. British Medical Journal 4:320-323. Stuart-Smith S. 1988. Judgment in Loveday vs. Renton & Wellcome. Royal Courts of Justice, London, March 29-30, 1988. Sutherland JA. 1953. Encephalopathy following diphtheria-pertussis inoculation. Archives of Disease in Childhood 28:149-150. Tonz O, Bajc S. 1980. Zerebrale Krampfanfalle nach Pertussis-Impfung. [Convulsions after whooping cough vaccination.] Schweizerische Medizinische Wochenschrift 110:1965-1971. Toomey JA. 1949. Reactions to pertussis vaccine. Journal of the American Medical Association 139:448-450. Van den Berg BJ, Yerushalmy J. 1969. Studies on convulsive disorders in young children. I. Incidence of febrile and nonfebrile convulsions by age and other factors. Pediatric Research 3:298-304. Volpe JJ, ed. 1987. Neurology of the Newborn, 2nd ed. Philadelphia: W.B. Saunders. Walker AM, Jick H, Perera DR, Knauss TA, Thompson RS. 1988. Neurologic events following diphtheria-tetanus-pertussis immunization. Pediatrics 81:345-349. Wentz KR, Marcuse EK. 1991. Diphtheria-tetanus-pertussis vaccine and serious neurologic illness: an updated review of the epidemiologic evidence. Pediatrics 87:287-297. Zellweger H. 1959. Pertussis encephalopathy. Archives of Pediatrics 76:381-386.
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