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Adverse Effects of Pertussis and Rubella Vaccines (1991)

Chapter: 4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy

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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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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

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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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).

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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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

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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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

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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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.

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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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

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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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

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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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

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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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

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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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

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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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-

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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zure burden among children with tuberous sclerosis or increase the risk of neurologic handicap, the study design has weaknesses that reduce the utility of its results in addressing the question of an association between pertussis and the risk of infantile spasms. For example, the sampling frame from which subjects were chosen is not representative of all people with tuberous sclerosis, and the response rate was low. The age range of cases was also very wide, with some individuals being as old as 51 years, thus introducing the possibility of recall bias regarding immunization histories.

Summary

Case reports of children who develop infantile spasms after receipt of pertussis vaccine prompt concern regarding a possible relation between immunization and seizures. However, the reported time intervals between immunization and onset vary widely, from hours to months, and no consistent pattern of timing or associated neurologic disorders is reported. Given the insidious onset of infantile spasms, the temporal relation of immunization and onset is difficult to establish with certainty.

The body of evidence concerning the possible relation between vaccination with DPT or its pertussis component and infantile spasms includes a number of case reports, case series, and four controlled observational epidemiologic studies, which are summarized in Table 4-1. Risk estimates were not consistent and varied widely across studies, ranging from 0.3 to 6.0, depending on the time interval examined. None of the risk estimates was statistically significant, and the NCES had sufficient statistical power (80 percent) to detect an RR of 2.0 to 2.4, depending on which data are used to make the comparison. Direct comparisons between studies is hampered by differences in the definitions of infantile spasms cases and the time intervals used. Although the results tended to be inconsistent, most controlled studies did not observe an increased risk. Only two studies reported risks greater than 2.5: the analysis of voluntary reporting data from the North West Thames study and SONIC. The risk estimate from SONIC is highly uncertain because of the small number of cases on which it is based.

The strongest evidence bearing on the question of a relation between DPT immunization and the risk of infantile spasms comes from the controlled studies from Denmark that compared the distributions of ages at the time of onset of infantile spasms under two different immunization schedules and the large case-control study of infantile spasms from the NCES. Comparison of the ages at onset of cases of infantile spasms for two different time periods in Denmark showed nearly identical distributions (Shields et al., 1988). Odds ratios for infantile spasms calculated separately for DPT

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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or DT vaccines in the NCES (Bellman et al., 1983a) were essentially the same for each time interval investigated. These results argue against an excess risk of infantile spasms attributable to the pertussis component of the vaccine. Given the insidious onset of infantile spasms, it is difficult to establish a temporal sequence with certainty, and there are no other aspects of the clinical presentation that suggest a relation to DPT immunization. Considerations of the specificity of the association are not relevant since a causal relation is not suggested by the evidence. There are no data bearing on mechanisms or biologic plausibility.

Conclusion

The evidence does not indicate a causal relation between DPT vaccine or the pertussis component of DPT and infantile spasms.

HYPSARRHYTHMIA

Clinical Description

Hypsarrhythmia (mountainous arrhythmia), a term originally proposed in 1952 by Gibbs and Gibbs, refers to an EEG pattern that is frequently associated with infantile spasms. The EEG is characterized by high-voltage, arrhythmic, slow interictal patterns. Spikes and sharp waves with multifocal origins occur nearly continuously, and there is poor synchrony between hemispheres (Lombroso, 1983b). Although not pathognomonic for infantile spasms, this EEG pattern is seen at some time during the course of illness in 70 to 80 percent of cases of infantile spasms, whereas it is uncommon (<5 percent) in children with other types of seizure disorders (Jeavons and Bower, 1964).

Descriptive Epidemiology

There is no descriptive epidemiology available specifically for hypsarrhythmia. Information on infantile spasms may provide a reasonable estimate.

History of Suspected Association with Pertussis Vaccines

The suspected association between pertussis immunization and hypsarrhythmia probably derives from the case reports of vaccination and infantile spasms. Low (1955) investigated the EEGs of children before and after receipt of pertussis-containing vaccines, but did not observe hypsarrhythmia. Strom (1967) specifically used the term hypsarrhythmia in his report of neurologic conditions following vaccination in Sweden.

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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TABLE 4-1 Summary of Controlled Studies on DPT Immunization and Infantile Spasms (IS)

           

No. of Cases

 

Powerc

Reference

Designa

Years

Description

Sample Size

Time Interval

in Interval

RR (95% CI)b

50%

80%

Pollock and Morris, 1983

Cohort (voluntary reporting)

1975-1981

134,700 children completed a course of DPT;

5 IS cases

<6 weeks

4

4.0(0.6, 25.2)

6.4

14.0

     

133,500 children completed a course of DT

           
 

Cohort (hospital based)

1979

17,000 children completed a primary course of DPT;

2 IS cases

weeks

1

1.1(.01, 10.2)

9.6

25.4

     

18,000 completed a primary course of DT

           

Bellman et al., 1983a;
Miller et al., 1988

Matched case-control (NCES)

1976-1979

Ages 2-35 months; resident of England, Scotland, or Wales

262 IS cases/524 controls

DPT
0-6 days
0-28 days

 

9
24

 

1.2(.05, 2.6)
.07(0.4, 1.1)

 

2.3
1.6

 

3.2
2.0

         

DT
0-6 days
0-28 days

 

8
19

 

1.4(0.6, 3.5)
0.8(0.5, 1.4)

 

2.5
1.7

 

3.6
2.2

       

152 previously normal cases/304 controls

DPT
0-6 days
0-28 days

 

7
15

 

2.3(0.8, 6.7)
0.9(0.5, 1.7)

 

2.9
1.9

 

4.6
2.5

         

DT
0-6 days
0-28 days

 

4
8

 

2.0(0.5, 7.4)
0.8(0.3, 1.8)

 

3.8
2.3

 

6.6
3.2

Walker et al., 1988

Matched case-cohort

1972-1983

26,600 members of Group Health Cooperative, Puget Sound

2 IS cases/262 controls

<30 days

0

0

NCd

NCd

Gale et al., 1990

Matched case-control (SONIC)

1987-1988

-109,000 children aged

1-24 months; resi-

dent of Washington

or Oregon

10 IS cases/20 controls

<28 days

3

6.0(0.6, 57.7)

9.6

25.4

a NCES, National Childhood Encephalopathy Study; SONIC, Study of Neurologic Illness in Children.

b RR (95% CI), Relative risk (95 percent confidence interval). RRs and CIs for Pollock and Morris (1983), Bellman et al. (1983a), and Miller et al. (1988) were calculated by the committee using data from these reports (see Appendix D).

c "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.

d NC, Not calculated, given that no infantile spasms cases were identified within the time interval.

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Evidence from Studies in Humans
Case Reports and Case Series

Neurologic reactions reported to have occurred in conjunction with DPT immunization were identified from all vaccination clinics in Sweden for the years 1959 to 1965 (Strom, 1967). Among 516,276 children vaccinated during the 7 years of the study, 167 neurologic reactions were reported, 4 of which were cases of hypsarrhythmia. Two of the four cases were reported 2 to 3 days after DPT immunization and the two others were reported after 1 week. The clinical manifestations leading to identification of these children were not described.

The incidence of hypsarrhythmia is unknown, and thus, it is not possible to determine precisely whether the observed number of cases reported by Strom (1967) is in excess of the number expected. However, if the incidence of hypsarrhythmia is similar to that for infantile spasms, then the number of cases reported in that study is far smaller than the number that would be expected in a population of this size over the time interval studied (expected, ~18 to 30 cases; Leviton and Cowan, 1981).

Controlled Epidemiologic Studies

EEGs obtained before and after immunization with pertussis-containing vaccines were compared in 83 infants who had not previously had any type of immunization (Low, 1955). Each child served as his or her own control, and all second EEGs were done within 16.5 to 48 hours postimmunization. Of the 83 infants, 40 were given alum-precipitated DPT vaccine and 43 received pertussis vaccine alone. Eighty infants had normal EEGs, both before and after pertussis immunization. Of the remaining three, one child had the same abnormality on EEG both before and after immunization. Thus, two infants with previously normal EEGs showed some abnormality on the postimmunization EEG. Both cases were febrile and showed nonspecific EEG abnormalities on the initial postimmunization EEG (one described as "marked diffuse slowing" and the other as "less marked slowing") which disappeared within 1 week. Apart from these nonspecific, short-term EEG changes, neither child demonstrated any clinical abnormality.

This study has several strengths, including the facts that infants had not previously been exposed to any type of vaccine and that each child served as his or her own control. A major limitation of the study is that the EEGs were not read in a masked fashion. It is not possible to determine what effect, if any, this may have had on the results. It would also be helpful in interpreting the results to have compared EEG patterns before and during febrile illness in unimmunized children. This study demonstrated no asso-

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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ciation between exposure to pertussis vaccine and increased frequency of hypsarrhythmia or any other type of significant EEG abnormality. However, the number of children included was relatively small, and therefore, a small difference in pre- and postimmunization EEGs might have been missed.

Hughes and Tomasi (1985) reported a dramatic decline in the frequency of hypsarrhythmic EEGs over a 40-year interval. Data were obtained by counting the first EEG record with hypsarrhythmia for patients seen from 1943 to 1983 at the University of Illinois Medical Center. All EEG referrals for children less than age 1 year were also counted. A similar analysis was done of records from Children's Memorial Hospital, Chicago, Illinois, for the time period 1973 to 1984. The number of EEGs with hypsarrhythmia peaked in 1952, 1958, and 1963, at about 50 to 75 patients per year. After 1963, 10 or fewer cases of hypsarrhythmia were seen in each successive year. From 1974 to 1984, the percentage of referrals with hypsarrhythmia declined from 1.3 to 0.1 percent, although the total number of referrals remained relatively constant. A similar decline was noted over the same time period in records from Children's Memorial Hospital (1.6 to 0.4 percent).

Peaks in the frequency of EEGs with hypsarrhythmia appeared to correspond to measles outbreaks, with a 1-year lag, although no formal tests of the fit of the curves were done. The authors suggested that the frequency of hypsarrhythmia had decreased dramatically and that the decline could be linked to the institution of immunization programs for a number of viral diseases, especially measles, mumps, rubella, and polio.

A major deficiency of this study is that the data represent the number of EEG records with hypsarrhythmia, not rates of hypsarrhythmia referable to a defined population base. The authors considered the possibility that the incidence of hypsarrhythmia had not declined, but that referral patterns in the study area had changed, such that cases were being seen elsewhere. They argued against this, however, stating that the patient base had remained relatively stable over time. In addition, similar observations of a decline in the frequency of hypsarrhythmia were observed at both hospitals studied, and at least at the University of Illinois Medical Center, the number of referrals for EEGs in children less than age 1 year was relatively constant over the 1974 to 1984 interval.

A study in Finland by Riikonen and Donner (1979) found essentially no change in the incidence rates of infantile spasms between 1960 and 1976 in the county of Uusimaa (average annual rates per 1,000 live births were as follows: 1960 to 1966, 0.42; 1967 to 1971, 0.38; 1972 to 1976, 0.42). All cases had hypsarrhythmia. In the population and time interval studied, there appeared to be no temporal trend in the incidence of infantile spasms.

Among the 113 cases of infantile spasms admitted to pediatric departments in Denmark (Melchior, 1977), 72 percent had typical or atypical hypsarrhythmia on their EEGs, 21 percent had severely abnormal EEGs of

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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other types, and 6 percent had normal EEGs. Analysis of the age distributions of cases over the two time periods when different schedules of pertussis immunization were used was not done separately by EEG pattern.

Summary

Hypsarrhythmia refers to a particular EEG pattern that is almost always associated with infantile spasms, and its occurrence should be interpreted in conjunction with data on infantile spasms.

The body of evidence concerning the possible relation between vaccination with DPT or its pertussis component and hypsarrhythmia is limited to one case series and one nonmasked experimental study with a limited number of cases. The latter study was the only one that directly observed EEG patterns pre- and postimmunization. No EEGs with hypsarrhythmia were observed. 

Conclusion

Evidence does not indicate a causal relation between DPT vaccine or the pertussis component of DPT and hypsarrhythmia.

ASEPTIC MENINGITIS

Clinical Description

Aseptic meningitis is defined as inflammation of the meninges characterized by abnormal numbers of leukocytes in the cerebral spinal fluid (CSF) with a predominance of mononuclear cells, normal glucose, and an absence of bacteria on examination and culture (Berkow, 1987). Others consider the diagnosis of aseptic meningitis to apply only to meningitis of known or suspected viral etiology (Beghi et al., 1984). The course of the disease is relatively benign, with most patients (~95 percent) recovering completely and few (5 percent) experiencing mild residua (Beghi et al., 1984). In contrast to what is observed for other CNS infections such as viral encephalitis or bacterial meningitis, the risk of subsequent, unprovoked seizures after aseptic meningitis is not increased over the incidence in the general population (Annegers et al., 1988).

A variety of factors have been identified as causes of aseptic meningitis, including viruses, such as entero-, mumps, herpes simplex, Eastern and Western equine encephalitis, and infectious hepatitis viruses; bacteria (tuberculosis and syphilis); other agents (cat-scratch disease, toxoplasma); and parainfectious processes (varicella, measles, and rubella). Noninfectious causes include parameningeal disease (tumor, stroke, otitis media), reaction

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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to intrathecal injections, and lead poisoning. In addition, vaccine reactions, have been implicated (Berkow, 1987).

In their review of the 283 cases of aseptic meningitis occurring in Rochester, Minnesota, over a 30-year period, Beghi and colleagues (1984) reported the most common antecedent events (within 4 weeks prior to onset) were respiratory infections, including influenza (19 percent) and mumps (11 percent). Enteroviruses (15 of 33 isolates) and mumps virus (7 of 33 isolates) were the most frequently identified viruses. One of 283 cases had been immunized with DPT vaccine within 3 weeks of the onset of aseptic meningitis.

Descriptive Epidemiology

Aseptic meningitis is relatively rare, occurring in about 1 per 10,000 people each year. The population-based estimate of the average annual age-and sex-adjusted incidence rate from Rochester, Minnesota, was 10.9 per 100,000 for the time period 1950 to 1981 (Beghi et al., 1984). Rates were significantly higher in males than in females, and incidence rates varied considerably by age. The highest rate (82.4 per 100,000) was in those less than age 1 year, and in this age group, the incidence of aseptic meningitis was four to eight times higher than that in those of other ages.

For the most recent period covered in the Rochester study (i.e., 1976 to 1981), the incidence rate of aseptic meningitis in children less than age 1 year was 338 per 100,000 (Beghi et al., 1984), which represents a 26-fold increase in incidence in this age group compared with that of the earliest period studied (1950 to 1959). Increases of this magnitude were not observed in other age groups. A seasonal pattern was also observed, with the highest percentage of cases occurring in July to September.

History of Suspected Association with Pertussis Vaccines

The basis for suspecting an association between pertussis vaccination and aseptic meningitis is unclear, but it may have developed, in part, because of the difficulty inherent in identifying a causal agent in cases of viral meningitis. Data from Rochester, Minnesota, for the time period 1950 to 1981 indicate that in the absence of intensive laboratory investigation, evidence of a virus was obtained for only 12 percent of cases of aseptic meningitis (Beghi et al., 1984). Thus, many of these cases would have been considered to be of unknown etiology, and a recent immunization could have been suspected. Cavanagh and colleagues (1981) have postulated, on the basis of results from animal studies, that pertussis immunization may affect susceptibility to other infections, and thereby increase the risk of aseptic meningitis.

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Evidence from Studies in Humans
Case Reports and Case Series

The diagnosis of aseptic meningitis is difficult, since appropriate and timely cultures may not be obtained and it is frequently not possible to culture a virus from CSF. Thus, many cases reported as ''meningitis" may, in fact, be cases of aseptic meningitis. Case reports of meningitis in association with pertussis immunization have been reported (Coulter and Fisher, 1985).

Forty cases of aseptic meningitis (ICD 9 code 047.9) occurring within 28 days of DPT immunization were reported through the CDC's 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 40 cases, 32 (80 percent) also received at least one other vaccine at the time of DPT immunization. No follow-up of the cases was made, and a physician's diagnosis was not required. 

Controlled Epidemiologic Studies

Beghi and colleagues (1984) commented specifically on the possible link between pertussis immunization and CNS infection. Among 56 cases of encephalitis and aseptic meningitis combined in children less than age 1 year, 3 (5 percent) had been immunized with DPT and polio vaccines within 1 week prior to the onset of symptoms. Given the recommended immunization schedule in this age group, the expected frequency is 6 percent. Based on these data, the RR is 0.9 with a wide 95 percent CI: (0.2 to 4.1). The power is correspondingly low: 50 percent for an RR of 4.6 and 80 percent for an RR of 8.9.

The only other piece of information specifically related to the possible association of pertussis immunization and aseptic meningitis comes from the study of Shields and coworkers (1988). The ages at the time of diagnosis of children with aseptic meningitis in Denmark were compared for two calendar periods in which the immunization schedules for DPT differed. Although the recommended time for immunizations changed from ages 5, 6, 7, and 15 months prior to April 1970 to ages 5 and 9 weeks and 10 months after that date, there was no appreciable change in the distribution of ages at the time of onset of cases of aseptic meningitis. The power of this test was also low. As many as 21 percent of all cases of aseptic meningitis would have to be due to DPT to achieve 50 percent power, and 29 percent would be needed for 80 percent power.

The estimated rate of CNS infections in children less than age 2 years,

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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approximately one-third of which were aseptic meningitis, was significantly higher in the 1972 to 1973 interval (29 per 10,000) than in the 1967 to 1968 interval (16 per 10,000) (Shields et al., 1988). The authors concluded that the increase in frequency of CNS infections was due to a change in the referral patterns for cases over the time intervals studied, such that cases were more likely to enter the study hospitals during the second time interval than they were during the first. Thus, they did not consider the change in immunization schedule to have accounted for the increased rate of CNS infections.

Summary

With the exception of a single case occurring within 4 weeks of DPT vaccination reported during a 30-year interval from Rochester, Minnesota (Beghi et al., 1984), the committee found no evidence in the case report literature for a causal relation between DPT immunization and aseptic meningitis.

It has been postulated that pertussis immunization influences susceptibility to other infections (Cavanagh et al., 1981), and thus could increase the risk of aseptic meningitis. Data from Denmark (Shields et al., 1988) are not consistent with this hypothesis, since there was no change in the age distribution of cases of aseptic meningitis when the ages at the time of immunization were changed. Large increases over time in the incidence of aseptic meningitis observed in Rochester, Minnesota (Beghi et al., 1984), are also not consistent with a causal relation between DPT immunization and aseptic meningitis, since there were no known temporal changes in immunization practices or vaccines that could explain this large increase.  The July—September clustering of cases of aseptic meningitis in children less than age 1 year (Beghi et al., 1984) is also not consistent with a causal relation to DPT immunization, since there was no indication that immunizations also clustered during these months. In addition, data from Rochester, Minnesota, suggest that the risk of aseptic meningitis within 1 week of immunization with pertussis vaccine was not increased over the expected frequency (Beghi et al., 1984).

The body of evidence concerning the possible relation between vaccination with DPT or its pertussis component and aseptic meningitis consists of isolated case reports and two population-based comparative studies. Data from Rochester, Minnesota, indicated that 5 percent of cases followed DPT immunization, when 6 percent would have been expected. Comparisons of the age distributions of cases from Denmark under two different immunization schedules showed no significant differences in ages at the time of diagnosis for cases of aseptic meningitis. It has been proposed that immunization might activate a latent CNS infection, resulting in meningitis.

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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However, the committee found no data to evaluate the biologic plausibility of this hypothesis.

Conclusion

There is insufficient evidence to indicate a causal relation between DPT vaccine and aseptic meningitis.

ENCEPHALOPATHY

Clinical Description

Before discussing the evidence for an association between pertussis immunization and encephalopathy, it is reasonable to consider what is meant by the term encephalopathy. Encephalopathy has been used in the literature to characterize a constellation of symptoms and signs reflecting a generalized disturbance in brain function. Encephalopathy is used in a very general way to indicate a "disease of the brain" (Gove, 1981, p. 746). Others have defined encephalopathy as "a diffuse interference with brain function resulting from a generalized or multifocal insult that causes a widespread disorder in the function of neurons" (Dodson, 1978). In NCES, the terms acute or subacute encephalitis, encephalomyelitis, and encephalopathy were used to denote a spectrum of clinical characteristics, including "altered levels of consciousness, confusion, irritability, changes in behavior, screaming attacks, neck stiffness, convulsions, visual, auditory and speech disturbances, motor and sensory deficit" (Alderslade et al., 1981, p. 157). The term encephalopathy was used ''when the cause of the cerebral disorder is not immediately obvious" (Alderslade et al., 1981, p. 157). Stephenson (1987) recognized that encephalopathy represents a vague term, difficult to define, "used to denote any neurological abnormality of the brain" (p. 2).  He would apply the term acute encephalopathy to a clinical picture characterized by the sudden onset of convulsions, impaired consciousness, motor or sensory deficits, "or other evidence of acute illness involving the brain" (p. 2). Fenichel (1982) noted that the terms encephalopathy and encephalitis are used interchangeably to refer to a constellation of symptoms and signs, including alterations in behavior or level of consciousness, convulsions, headache, and focal neurologic deficits. In general, when fever or CSF pleocytosis is present as well, the term encephalitis is usually used, implying an inflammatory response within the brain. On the other hand, the term encephalopathy is used when an illness clinically appears like an encephalitis but no inflammatory response is evident (Cherry et al., 1988). In the remainder of this chapter, encephalopathy will be defined as it is in the controlled studies reviewed as encephalopathy, encephalitis, or encephalomyelitis.

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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If a child fails to recover from the acute event, the terms chronic encephalopathy and irreversible encephalopathy are often used.

The occurrence of an encephalopathy in a child does not imply a particular severity or duration of illness, nor does the diagnosis of encephalopathy necessarily indicate that the child will exhibit symptoms and signs of irreversible brain injury. Similarly, the terms serious neurologic disease, serious neurologic injury, acute neurologic disorder, and acute neurologic reaction are sometimes confused with the terms permanent brain damage or brain damage. However, because many children with serious neurologic illness do, indeed, recover, it is important to recognize that a serious neurologic illness may or may not result in permanent brain damage.

Reports indicate a considerable variation in the clinical presentation of what various clinicians have termed pertussis vaccine-induced encephalopathy. Some reports have suggested a prototypic description of pertussis vaccine-induced encephalopathy. One presentation referred to as the "more classic" (Cherry et al., 1988, p. 961) is that of a generalized tonic-clonic (grand mal) seizure frequently associated with fever within 48 hours of receiving the first, second, or third pertussis immunization. According to this description, in most cases the initial seizure is brief and the child appears to recover. In days or weeks the seizures begin to increase in frequency and motor and mental retardation becomes evident. Stewart (1977, p. 236) described what he referred to as "a pertussis reaction syndrome" characterized by some or all of the following features: (1) persistent crying or screaming 4 to 48 hours after a pertussis immunization; (2) pallor and shock within 48 hours, usually 6 to 12 hours after immunization; (3) irritability and interrupted sleep; (4) refusal or vomiting feedings; (5) altered response to parents; (6) weakness or paralysis; (7) one or more convulsions, with or without fever. Stewart (1977) noted that in the majority of cases the symptoms resolved in days or weeks, but some children went on to develop recurrent seizures, paralysis, and progressive mental deterioration. This specific clinical picture has not been confirmed by other investigators. Symptoms such as irritability, fretfulness, or drowsiness, so commonly observed in the usual childhood febrile illnesses, do not in themselves represent encephalopathy, and reports dealing with these symptoms are not considered here. High-pitched crying is considered in Chapter 6.

Seizures in themselves are not sufficient to constitute a diagnosis of encephalopathy and, in fact, most seizures occur without encephalopathy. Seizures may occur with or without the loss of consciousness and can include a variety of sensory experiences (e.g., auditory seizures) and/or motor manifestations (e.g., focal motor or tonic-clonic seizures). The terms fits and convulsions are frequently used as synonyms for motor seizures. In addition to the various ways in which seizures may present clinically, they can occur with or without fever. Febrile seizures are well-defined, rela-

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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tively common events. In the National Collaborative Perinatal Project (NCPP), approximately 82 percent of all seizures in children under age 7 years were febrile seizures (Nelson and Ellenberg, 1976, 1986). These seizures are generally benign and of brief duration. If more than one of these seizures occurs within 24 hours or if they last longer than usual or are accompanied by transient focal neurologic features, they are termed complex febrile seizures. Acute symptomatic seizures are those that occur in association with an acute process that affects the brain, such as head trauma or a bacterial infection. Afebrile seizures are those that occur in the absence of fever or other acute provocation. Recurrent afebrile seizures are referred to as epilepsy.

Encephalopathies are frequently accompanied by seizures (both those occurring with fever and those occurring in the absence of fever). Most of the studies of neurologic events following pertussis immunization have included both encephalopathy and seizure as outcomes of interest. Given that seizures are much more common in children than is encephalopathy (Beghi et al., 1984; Hauser and Kurland, 1975), the great preponderance of cases in these studies are likely to be children with febrile or acute symptomatic seizures. In this report, encephalopathy and seizures are discussed separately, when the data permit. It is important to note, however, that there may not always be a clear distinction between the two, and that there may not be uniformity of clinical opinion on whether a particular illness in a child represents, for example, a complex febrile seizure or an encephalopathy.

Encephalopathy Following Whooping Cough

The clinical presentation, natural course, and pathology of encephalopathy following the natural occurrence of pertussis are relevant to the discussion of encephalopathy following pertussis immunization. Because the occurrence of pertussis in most developed countries is relatively rare (see Chapter 2), reports of the neurologic complications of pertussis are also quite rare. In the most comprehensive review in the English-language literature, Zellweger (1959) reviewed 148 cases of whooping cough encephalopathy. He noted two clinical presentations: (1) the sudden onset of convulsions followed by coma and (2) a more insidious onset with somnolence progressing to coma over a period of days. Cases of both types were more common in children under age 10 years and were more common in females. Onset was usually during the second to fourth weeks of illness. Laboratory findings indicated elevations of blood lymphocytes and normal CSF. The duration of the encephalopathy varied from several days to several weeks. One-third of the children died, one-third recovered completely, and one-third were left with varying degrees of neurologic disability, including mental retardation of varying severity, paralyses and palsies, focal or generalized

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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convulsions, ataxias, amauroses, and changes of personality or behavior (Zellweger, 1959).

Pathology

No signs of CNS inflammation have been noted in the majority of cases of whooping cough encephalopathy. Findings are generally nonspecific and include brain edema, eosinophilic degeneration, multiple petechiae, lymphocytic plugs in veins and capillaries, and small subarachnoid hemorrhages (Dolgopol, 1941). Zellweger (1959) notes that "[t]oxic effects and anoxemia due to circulatory stasis can account for most of the anatomical findings" (p. 383) noted above.

It is difficult to understand what Zellweger, writing over three decades ago, meant by the term toxic effects. There is no evidence that any of the toxins associated with pertussis vaccine have produced specific pathologic effects in either animals or children (see below). Certainly, the effects of anoxemia (used synonymously with asphyxia or hypoxia or hypoxic-ischemic encephalopathy) have been well described in both preclinical and human investigations (Volpe, 1987).

In theory, pathologic studies of children who have died after an encephalopathy temporally related to the administration of pertussis vaccine could help to clarify the vague clinical picture of encephalopathy in general and encephalopathy associated with pertussis immunization in particular. However, to date, only one systematic review of the neuropathologic features of children who have died following pertussis vaccination has been conducted. In that study, Corsellis and colleagues (1983) examined data on childhood deaths which, on circumstantial grounds, were considered to have been related to vaccines against pertussis. The authors conducted two reviews, one based on 12 previously published case reports or series of pertussis vaccine-associated deaths and the other based on their own retrospective review of infant or child deaths that occurred in England and Wales between 1960 and 1980 and that were reported as being associated with pertussis vaccines. In their review of the published case data, the authors identified 33 deaths; necropsy data were available for 27 of the deaths. The postmortem findings of these 27 cases were considered "difficult to interpret" because of the often imprecise terminology used to describe the cases and the frequently incomplete description of neuropathologic findings. Review of the data that were available, however, indicated no features of the cases that were consistently observed following administration of pertussis vaccine.

In their population-based review, Corsellis and colleagues (1983) identified 40 deaths and obtained information that included details of a general postmortem examination for 29 of these deaths. The 29 cases were categorized into one of two groups: an "acute group" of infants dying within 3

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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weeks of immunization (n = 18) and a "chronic group" of children dying 6 months to 12 years after vaccination (n = 11). Clinical documentation on most of the acute cases was incomplete; that on the chronic cases generally was complete. Review of both the acute and chronic groups again indicated no specific findings that were consistently observed following administration of pertussis vaccine. The authors concluded that "neither [the cerebral changes] in the present study nor those abstracted from the previous literature have provided evidence of a pattern of damage in the brain identifiable as a specific reaction to immunization against whooping cough" (p. 267). The authors acknowledged deficiencies in the neuropathologic data examined, for example, sparse documentation of immunization and confounding with associated neurologic problems. They recommended more careful and complete collection of such data in the future.

Descriptive Epidemiology

There are few studies from which to obtain information on the frequency and distribution of encephalopathy. The problems and variations in defining encephalopathy, which were described above, also make it difficult to compare rates among studies. Average annual incidence rates from Rochester, Minnesota, for the years 1950 to 1981 were 22.5 per 100,000 for children less than age 1 year and 15.2 per 100,000 for those aged 1 to 4 years (Beghi et al., 1984). Cases were defined as individuals with diagnoses of encephalitis or encephalopathy. Peak incidence rates were observed in 5- to 9-year-olds and in the months of July through September. On the basis of data provided in several other studies (Gale et al., 1990; Pollock and Morris, 1983; Walker et al., 1988), most estimated rates of encephalopathy for children less than age 2 years were somewhat lower than those reported from Rochester, Minnesota, and ranged from 5 per 100,000 (Walker et al., 1988) to 10 per 100,000 (Gale et al., 1990).

Considering seizure disorders separately, annual incidence rates in children range from 0.53 per 1,000 in Carlisle, England (Brewis et al., 1966), to 1.52 per 1,000 in England and Wales (Crombie et al., 1960), depending on whether or not febrile seizures are included in the rate calculation. The cumulative incidence rate of one or more seizures by age 12 months is 3.3 per 1,000 children (Van den Berg and Yerushalmy, 1969). The cumulative incidence of febrile seizures through age 5 years ranges between 2.3 and 4.6 per 100 children (Harker, 1977; Hauser and Kurland, 1975; Nelson and Ellenberg, 1976; Van den Berg and Yerushalmy, 1969). Reported prevalence rates of epilepsy, that is, recurrent afebrile seizures, in children tend to range between 4 and 5 per 1,000 (Leviton and Cowan, 1982).

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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History of Suspected Association with Pertussis Vaccines

The possibility that pertussis immunization might cause adverse neurologic events resulting in permanent brain injury was first raised following a report of two cases by Madsen (1933) and case reports published in the 1940s (e.g., Byers and Moll, 1948; Globus and Kohn, 1949; Toomey, 1949). Subsequent descriptions of encephalopathies of various types occurring at differing time periods after pertussis immunization followed (e.g., Berg, 1958; Cockburn, 1958; Globus and Kohn, 1949; Malmgren et al., 1960; Sutherland, 1953). On the basis of these reports, Strom (1960) questioned whether the risk of adverse neurologic effects following immunization might be more of a concern than the risk of pertussis itself, a view reiterated in reports by Aicardi and Chevrie (1975), Cavanagh et al. (1981), Ehrengut (1980), Kulenkampff et al. (1974), and Stewart (1977, 1979). (See Appendix B for further historical details.)

Evidence from Studies in Humans
Case Reports and Case Series

The earliest report of an adverse event following administration of pertussis vaccine came from an era when pertussis vaccine was prepared by emulsifying a culture of Bordetella pertussis with saline solution and 1 percent formaldehyde. Madsen (1933) reported two cases of sudden death in infants administered the preparation. The first death occurred after the second immunization and was characterized by contractions of the arms and legs, cyanosis, hiccups, convulsions, and death within 30 minutes. The age and weight of the infant were not recorded.

Generalized hypotonia and weakness with increased deep tendon reflexes in the lower extremities were reported by Brody and Sorley (1947) in a 10-month-old, 3 days following his third pertussis immunization. Similar episodes occurred 2 weeks after his first immunization and 1 week after his second immunization. A fourth episode occurred spontaneously at age 25 months. Neurologic disability persisted, with spasticity in the left arm and both legs. At age 43 months, the child received a fourth pertussis immunization and within 25 minutes became somnolent. Severe flaccid paralysis developed within 12 hours, and he died of bronchopneumonia 7 weeks later. No autopsy was performed.

Despite these early reports, it was the report by Byers and Moll (1948) of encephalopathy following pertussis immunization in 15 children that spurred interest in the possibility of adverse consequences of pertussis immunization. That report contains the largest group of reasonably full clinical de-

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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scriptions of what they termed "pertussis-induced encephalopathy." These 15 cases occurred between 1939 and 1947 in children ages 5 to 18 months and were identified from a review of the records of the Children's Hospital in Boston. The presentations were explosive, consisting of fever, irritability, convulsions, and coma occurring within 12 hours of a pertussis immunization. At follow-up, only one child was normal, two had died of pneumonia, six had cerebral palsy with or without seizures, and the others had seizures and mental retardation. Two additional case reports with clinical pictures similar to those described by Byers and Moll (1948) were reported the following year by Globus and Kohn (1949).

Berg (1958) reviewed 107 cases of neurologic illness following pertussis vaccination that had been previously reported by Köng (1953) and an additional case whom he had treated at Fountain Hospital, London. The neurologic illnesses observed in these 108 cases followed any one of the four immunizations in the pertussis series, and most occurred within 48 hours of the immunization.

A number of similar cases have been reported (Aicardi and Chevrie, 1975; Baird and Borofsky, 1957; Bower and Jeavons, 1960; Cockburn, 1959; Dick, 1972, 1974; Dudgeon et al., 1981; Forrester, 1965; Halpern and Halpern, 1955; Meade et al., 1981; Stewart, 1977; Strom, 1960, 1967; Tonz and Bajc, 1980). Ehrengut (1974) reported on 59 cases of encephalopathy from Hamburg, Germany, that had occurred since 1950. All but 10 were cases of seizures associated with fever. Thirty-nine cases occurred within the first 48 hours after immunization, and 11 of the cases had pathologic EEG findings. Most cases recovered completely. In the same year, Kulenkampff and colleagues (1974) reported on 36 cases of encephalopathy referred to the Hospital for Sick Children at Great Ormond Street, London, between 1961 and 1972. The adverse events occurred usually within 24 hours after pertussis immunization, with the majority (32 of 36) of events being convulsions. Two of the children died within 6 months of symptom onset, and only four recovered completely. Of the remaining 30 cases, 4 were moderately or severely retarded, 3 had epilepsy, and 22 had both epilepsy and mental retardation. One child with persistent hemiparesis developed normally otherwise.

Stewart (1977) collected a case series of adverse events following administration of pertussis vaccine and following whooping cough from retrospective data obtained from parent organizations, hospital records, physician reports, and parent reports. From the 160 reported cases of adverse effects of pertussis vaccine, Stewart postulated the pertussis reaction syndrome described earlier in this section.

Hennessen and Quast (1979) reported on 149 infants who experienced adverse events following pertussis vaccination. All cases were reported to vaccine manufacturers in Switzerland and/or Germany (location not speci-

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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fied). Thirteen (9 percent) of the reports concerned infants who died following vaccination. Fifty-nine (40 percent) of the cases were characterized as severe adverse events; these included fever, convulsion, shock, persistent screaming, and "various involvement of the CNS" (p. 96). The remaining 77 (51 percent) reports concerned infants who had local reactions only. Severe reactions were more frequently reported after the first dose of vaccine. Fatalities and local reactions were more common after the second dose. The former observation may reflect a decreased rate of subsequent vaccination in infants exhibiting severe reactions after the first dose.

Murphy and colleagues (1984) investigated 22 children with recurrent seizures following DPT vaccination. To identify potential study subjects, the authors sent questionnaires to 80 families who had responded to one of the authors following the 1982 television program "DPT: Vaccine Roulette," first broadcast by NBC affiliate WRC-TV in Washington, D.C., or whose names had been submitted by Dissatisfied Parents Together. Questionnaires were returned by 43 (54 percent) of the 80 families, and 22 (28 percent) children met the criteria for study inclusion: a history of recurrent seizures, with the occurrence of the first seizure within 24 hours of a DPT immunization. The authors concluded that "patients with recurrent seizures starting immediately after a DTP immunization have a poor prognosis for normal development" (p. 910). The authors cautioned, however, that their findings were probably biased because of weaknesses in case ascertainment (e.g., the mailing of questionnaires to parents who already suspected that their child had had an adverse reaction to the vaccine) and the low response rate.

Siddiqui and colleagues (1989), using data from the MSAEFI system, identified 10 cases of seizures occurring within 28 days of DPT vaccination in the state of Maryland in 1987. Seven cases had elevated temperatures and none had a prior history of seizures or neurologic illness. The onset of seizures occurred within 24 hours of immunization in 8 of 10 cases, with the other two cases having onset several days after immunization. Three of the cases received measles-mumps-rubella vaccine (MMR) and one case received oral polio vaccine (OPV) at the time of DPT immunization. No information on long-term outcome was provided.

Menkes (1990) followed 46 children who reportedly experienced the first onset of neurologic symptoms within the 72 hours following DPT immunization. No other cause of symptoms was found. The reported events (74 percent of which occurred between 4 and 24 hours postimmunization) were acute encephalopathy (2 cases); SIDS (2 cases); hypotonic, hyporesponsive state (1 case); possible hypoglycemia (1 case); and seizures (40 cases). The seizures ranged in duration from 1 to 210 minutes, and temperature at the time of seizure was less than 101.5°F in 77 percent of the children whose temperatures were recorded. Of the surviving children, 58 percent were moderately or severely retarded and 72 percent had uncontrolled seizures,

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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some of which fit the criteria for severe infantile myoclonic epilepsy described by Lombroso (1990).

Blumberg and colleagues (in press) examined physician and nurse reports from the Los Angeles area to identify severe adverse events following DPT vaccination.  Cases were considered eligible for study if the onset of the adverse event was within 48 hours of immunization and if the study staff was able to evaluate the child within 24 hours of symptom onset. Fifty-six cases of severe adverse events meeting the above study criteria were identified. Thirty-seven cases were seizures, with 33 of these having a documented temperature greater than or equal to 38°C. Laboratory tests offered no evidence that altered insulin/glucose metabolism or biologically active lymphocytosis-promoting factor (also known as pertussis toxin) were related to the onset.

Baraff and colleagues (1989) prospectively studied 9,920 infants and children immunized with DPT vaccine from 25 different vaccine lots. Local reactions (redness, swelling, pain), fever, drowsiness, fretfulness, and anorexia were common (from 10 to 69 percent of subjects across lots), with vomiting and screaming being less frequent (0 to 11 percent across lots). Convulsions were rare. Differences between the rates of reactions by lot were significant for all examined events except convulsions, of which there were insufficient cases (number not given) for analyses. There was a significant positive association between endotoxin unit content and the percentage of vaccine recipients who developed fever. There were also significant positive associations between all local reactions and both pertussis vaccine potency and percent mouse weight gain, a test of pertussis vaccine toxicity (see Appendix C for description). For the majority of reactions, however, the differences, although statistically significant, were small and of questionable clinical relevance.

A total of 708 cases of encephalopathy/encephalitis (ICD 9 code 348.3) occurring within 28 days of DPT immunization were reported through the MSAEFI system from 1978 to 1990, a period in which approximately 80.1 million does of DPT vaccine were administered through public mechanisms in the United States (J. Mullen, Centers for Disease Control, personal communication, 1990). Of these 708 cases, 545 (77 percent) also received at least one other vaccine at the time of DPT immunization.

A total of 2,531 cases of febrile seizures (combined ICD 9 codes 780.3 [idiopathic convulsions] plus 780.5 [fever]) and 344 cases of afebrile seizures/idiopathic convulsions (ICD 9 code 780.3) occurring within 28 days of DPT immunization were also reported through the MSAEFI system from 1978 to 1990. A total of 1,284 (75 percent) of the 2,531 cases of febrile seizures and 258 (75 percent) of the 344 cases of afebrile seizures/convulsions also received at least one other vaccine at the time of DPT immunization. No follow-up of the cases was made, and a physician's diagnosis was

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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not required. No cases of epilepsy (ICD 9 code 345.9) were reported within this 13-year period.

Studies in Defined Populations

There are three studies (Cody et al., 1981; Pollock and Morris, 1983; Pollock et al., 1984) in which rates of selected events in children who were immunized with DPT vaccine were compared with those immunized with DT vaccine (Table 4-2). In most reports the number of encephalopathies and seizures that occurred within 48 hours of immunization can be ascertained. In these three studies (excluding the data from Pollock and Morris voluntary reports), children were evaluated following a total of 51,794 DPT immunizations and 35,385 DT immunizations. Pooling these data, there were 17 (3.3 per 10,000 doses) and 6 (1.7 per 10,000 doses) seizures reported in the 48 hours following DPT and DT immunizations, respectively. If the data from Pollock and Morris voluntary reports are included, the incidence rates of seizure are 7.2 per 10,000 DPT doses and 2.0 per 10,000 DT doses. At least 81 percent of all seizures reported in Table 4-2 were febrile (Cody et al., 1981; Pollock and Morris, 1983; Pollock et al., 1984). Thus, the results of pooling these data should be interpreted cautiously since age at the time of immunization should affect the incidence of febrile seizures and these data could not be age adjusted. Five additional studies (Feery et al., 1985; Harker, 1977; Hirtz et al., 1983; Long et al., 1990; Strom, 1967) tried to ascertain the rates of selected events in defined populations of children immunized with DPT (Table 4-2). Thus, five of the eight studies listed in Table 4-2 attempted to identify cases of encephalopathy. There were two cases of encephalopathy reported among 555,570 children within 48 hours of receipt of DPT vaccine if one excludes the data from Pollock and Morris based on voluntary reports, and six cases of encephalopathy among 690,270 children if one includes those data. All eight of these studies are discussed in more detail below.

Cody and colleagues (1981) compared the reactions that occurred in the first 48 hours after vaccination in 15,752 children receiving DPT vaccine and in 784 children receiving DT vaccine. The children were ages 0 to 6 years. Nine seizures were reported following receipt of DPT vaccine, while none were reported following receipt of DT vaccine. No cases of diagnosed encephalopathy, permanent neurologic damage, or death were observed in the first 48 hours following immunization. The cases of seizures occurred following any one of the three primary series or the first booster DPT immunization. All cases experienced the onset of symptoms within 24 hours of immunization, with a median time of 14 hours. All but two of the seizure cases had elevated temperatures following immunization, and two of these had a history of previous febrile convulsions. None of the other

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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TABLE 4-2 Studies of Acute Neurologic Events Occurring Within 48 Hours of DPT Immunization in Defined Populations 

Reference

Years

Age

Vaccine

Children (No.)

Immunizations (No.)

Encephalopathy (No.)

Seizures (No.)

     

Including DPT and DTa

     

Cody et al., 1981

1978-1979

0-6 years

DPT

15,752

15,752

0

9

     

DT

784

784

0

0

Pollock and Morris,

             

1983b

1979

<2 years

DPT

134,700

404,100

4

16

     

DT

135,500

406,500

1

3

     

DPT

~17,000

~21,000

1?

6c

     

DT

~ 18,000

~24,000

0

5c

Pollock et al., 1984

1978-1980

3 months-

DPT

6,004

15,042

0

2

   

1 year

DT

4,024

10,601

0

1

     

Including DPT only

     

Strom, 1967

1959-1965

NRd

 

516,276

NAe

1

59

Harker, 1977

1972-1975

0-5 years

 

~11,028

~32,000

NAe

0

Hirtz et al., 1983

1959-1966

0-7 years

 

~54,000

NAe

NAe

8

Feery et al., 1985

1983

<1 year

 

1,075

2,041

NAe

2

Long et al., 1990

1984-1985

2-20 months

 

538

1,771

0

0

a Relative risks (RRs) and 95 percent confidence intervals (95% CIs) for these studies were calculated by the committee using data from the reports (see Appendix D) and are presented in the text.

b First study based on voluntary reporting; second study based on systematic hospital activity analysis.

c Events within I week.

d NR, Not reported.

e NA, Not available.

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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children had a past history of seizure activity or neurologic illness. In most cases, seizures were of brief duration, lasting from 10 seconds to 5 minutes. EEGs were performed in four cases, and eight cases were later examined neurologically; findings were reported to be normal in all cases. A followup examination of the nine seizure cases was attempted 7 years later (Baraff et al., 1988). Eight of the nine children were contacted by study personnel, and seven of the eight were given a complete neurologic and psychometric evaluation, the latter consisting of the Wechsler Intelligence Scale for Children—Revised. Verbal IQ scores were less than 80 in two of the seven cases tested, and complete IQ was less than 80 in one of these. The authors attributed the lower mean verbal IQ scores in the overall sample (91.8 ¬ 18.4) to the proportion whose primary language was not English.

Pollock and Morris (1983) analyzed data from the North West Thames region of England, where an intensified effort over the previous 7 years had been undertaken to identify all severe adverse events following immunization. The authors studied events identified in two different ways: one from physicians' voluntary reports from 1975 through 1981 and the other from systematic review of hospital discharge diagnoses for 1979 only.

In the study which relied on physicians' voluntary reports, approximately 134,700 and 135,500 children completed courses of three doses of DPT and DT vaccines, respectively. Sixteen children with seizures (without associated encephalopathies) within 48 hours of DPT vaccination were identified. About half had subsequent seizures, but all were noted to be developmentally normal on follow-up. There were three reports of seizures within 48 hours of DT immunization: one associated with primary DT vaccination and two with a boosting dose of DT vaccine. Temporary or permanent neurologic impairment with or without associated seizure (encephalopathy) was reported in an additional four children in the 48 hours following DPT and in one child following DT immunizations, respectively. Two of the children with an event following DPT immunization were impaired on follow-up. Of note is that six and two similar events were reported more than a week following DPT and DT immunizations, respectively. Comparing children vaccinated with DPT to those receiving DT, the RR of seizures within 48 hours was 5.3, with a 95 percent CI of 1.7 to 16.8. Although the voluntary reports of neurologic events in the 48 hours postimmunization were more frequent with DPT immunization than with DT immunization, these reports also reveal differences in the rates of events for several weeks following immunization, and no such differences in events were found when hospital discharges were routinely screened. This suggests that events following DPT immunization were preferentially reported and that the results of the study which relied on voluntary reports are unreliable.

The systematic review of hospital discharge diagnoses included surveillance of approximately 17,000 children who had received approximately

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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21,000 DPT immunizations and 18,000 children who had received 24,000 DT immunizations. Review of hospital discharge diagnoses for 1979 identified six children who had been hospitalized with febrile seizures within 1 week of DPT vaccination and five children who had been hospitalized with febrile seizures within 1 week of DT vaccination (the review was unable to determine the number hospitalized with febrile seizures within 48 hours). There was one child with a transient hemiparesis 36 hours following DPT immunization (possible encephalopathy) and no encephalopathies within 48 hours of DT immunization. Comparing DPT to DP immunized cases, the RR of febrile seizures within 1 week of vaccination was 1.3, with a 95 percent CI of 0.4 to 4.0. The power of this study was relatively weak: 50 percent for an RR of 3.1 and 80 percent for an RR of 5.7.

Pollock and colleagues (1984) compared rates of adverse events in 10,028 infants, of whom 6,004 started primary immunization with DPT vaccine and 4,024 with DT vaccine. The DPT group was further divided into those receiving plain versus those receiving adsorbed vaccine. The first vaccine dose for each child was scheduled at age 3 months, the second dose 6 to 8 weeks later, and the third, final dose 4 to 6 months following the second dose. A total of 25,643 doses of vaccine were given: 1,125 of plain DPT, 13,917 of adsorbed DPT, and 10,601 of adsorbed DT. Children were followed throughout the immunization series, and their parents were contacted both within 48 hours and 6 to 8 weeks following each vaccination. Rates of twitching or jerking were similar in the adsorbed DPT and DT groups (2.3 and 2.2 per 1,000 doses, respectively). Convulsions were reported within 48 hours of immunization in one child given DPT vaccine and in one child given DT vaccine. Another child had a brief episode of staring eyes and stiffened limbs 3 hours after receiving the adsorbed DPT vaccine. None of these children had sequelae. At the 6- to 8-week follow-up, one additional child in the DPT group was reported to have developed epilepsy about 1 month after the first dose. Epilepsy was diagnosed in two additional children in the DT group during the same interval.

In 1967, Strom (1967) examined adverse neurologic events in 516,276 Swedish children vaccinated for DPT between 1959 and 1965. Case notification was obtained through voluntary reports from vaccination clinics, through annual reports of treated cases of postvaccinal complications from children's hospitals, and for the years 1962 to 1964, from special reports from welfare clinics where vaccination had been carried out. Adverse events included 3 children with cerebral injury, 80 with convulsions, 4 with hypsarrhythmia, 54 with shock, 2 with abnormal spinal fluid, and 24 with abnormal screaming. Three cases of ''cerebral injury" were reported, only one of which could be classified as a possible encephalopathy within 48 hours of immunization. The second child had an adverse event onset 9 days following DPT vaccination, and the third child, who had a febrile seizure with focal

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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features shortly after DPT, developed recurrent seizures and developmental regression weeks later (this was included in Strom's analysis as a seizure). Of the 80 reported convulsions, 58 were known to have occurred within 48 hours, and 2 were known to have occurred more than 48 hours later, but for 20 the time of onset was unknown.

Harker (1977) attempted to identify all febrile seizures occurring in children from Oxford, England, up to age 5 years during a 3-year period (19721975). One hundred seventeen children with febrile seizures were identified through notifications from general practitioners and health visitors. Additional information was obtained by hospital and physician record reviews. No seizures were reported within 48 hours of DPT immunization, and only one was reported within 28 days.

Hirtz and colleagues (1983) reported on children who exhibited seizures within 2 weeks of immunization. The children were identified from data collected in the NCPP (Niswander and Gordon, 1972). Of approximately 54,000 children registered in the NCPP, 2,766 experienced one or more seizures during the first 7 years of life. Eight of these children had their seizures within 48 hours and one at an unknown time following DPT vaccination.  On follow-up at age 7, one child who had multiple right focal seizures for 6 hours following her third DPT dose had an expressive speech disorder, with a normal performance IQ but a verbal IQ of 69. None of the other children had mental retardation or an underlying neurologic disease on follow-up that was unrecognized at the time of the seizure.

Feery and colleagues (1985) compared the incidence and types of adverse events following administration of plain or adsorbed DPT vaccines in a masked prospective study of 2,041 vaccinations in 1,075 infants receiving routine childhood immunization. One recipient of each type of vaccine suffered a single convulsion within 48 hours; there were no sequelae.

Long and colleagues (1990) assessed the rates of adverse events following pertussis vaccination in 538 children who were recruited into the study at age 2 months and who were observed longitudinally to age 20 months. Subjects were randomized either to the standard four-dose immunization schedule or to a three-dose schedule with a saline injection substituted for DPT vaccine at age 6 months. In all, 1,553 doses of DPT vaccines were given. No cases of seizures, encephalopathy, or temperature greater than 40.5°C (104.9°F) were observed in either group.

The National Childhood Encephalopathy Study

The NCES was a large, case-control study initiated in 1976 in response to concerns about declining levels of DPT immunization among children in Great Britain (Alderslade et al., 1981). Because this study is much larger in number of cases than any of the other studies that have addressed the rela-

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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tion between DPT immunization and acute neurologic events in children, it has received intense scrutiny and merits special attention here as well. The stated goals of the NCES were "to assess the risks of certain serious neurological disorders associated with immunization in early childhood and to identify factors that might cause or predispose to such disorders" (Alderslade et al., 1981, p. 80). The study included 1,182 cases of serious acute neurologic illnesses in infants and children ages 2 to 35 months in England, Scotland, and Wales between July 1976 and June 1979. Physicians were asked to notify the NCES of all children who were admitted to a hospital with confirmed or possible diagnoses of:

1. acute or subacute encephalitis, encephalopathy, or encephalomyelitis (including postinfectious encephalitis but not pyogenic infections);

2. unexplained loss of consciousness with or without abnormalities in CSF or EEG;

3. convulsions complicated by one or more of the following: seizures lasting 30 minutes or more, coma lasting 2 hours or more, paralysis, or other neurologic signs not previously present lasting 24 hours or more;

4. infantile spasms; or

5. Reye syndrome.

Cases were subsequently divided into two groups on the basis of their neurologic status prior to the onset of the acute illness: previously normal and previously abnormal. In addition, neurologic status of cases at 15 days postadmission or at the time of discharge was categorized as normal or abnormal. Immunization data were available for 1,167 (99 percent) of the 1,182 cases.

Two control children were selected for each case from immunization or birth registers and were matched to the case by sex, age (within I month), and residential area. Information on immunization histories for both cases and controls was obtained from the child's medical record, which was kept by the local health authority or family doctor. A total of 2,307 controls with recorded immunization histories were included in the study.

In order to address the long-term sequelae of acute neurologic events, two follow-up contacts were made, the first within 12 to 18 months of the initial hospitalization and the second approximately a decade later, when the children were ages 10 to 12 years. For the first follow-up contact, only those cases who were classified as abnormal 15 days after admission were examined at home. Otherwise, information on the developmental and functional status of the case was obtained by mail. Thus, information on the condition of cases approximately 1 year after their acute illness was not obtained in the same manner for all children, and no follow-up data were available for controls. For the second, later follow-up contact, attempts were made to trace all cases and controls who participated in the initial

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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study, and information on their neurologic, developmental, and behavioral status was obtained by questionnaires submitted to parents, teachers, and physicians.

This study addressed two major questions about DPT immunization. First, does DPT immunization cause an increase in serious acute neurologic events in children; and second, does DPT immunization cause permanent brain damage? The former is considered first.

Of the 1,167 cases of acute neurologic disease, 263 were infantile spasms, which were discussed above. Of the remaining 904 cases, the onsets for 30 (3.3 percent) were within 7 days of DPT immunization compared with 23 (1.3 percent) controls, whose index date was within 7 days of DPT immunization, yielding an estimated RR of 3.3 (95 percent CI = 1.7-6.5) for acute neurologic illness within 7 days of DPT immunization (Miller et al., 1988) (Table 4-3). Of the 515 cases of seizures and 389 cases of encephalopathy, onsets were within 7 days of DPT vaccination for 18 (3.5 percent) and 12 (3.1 percent), respectively; the RRs associated with DPT immunization within 7 days were 3.3 (95 percent CI = 1.4-8.2) for convulsions and 3.1 (95 percent CI = 1.010.5) for encephalopathy (Miller et al., 1988). Of the 904 cases, 770 were in children with no previously identified neurologic abnormality. Twenty-six (3.4 percent) of these children had the onset of their acute neurologic event within 7 days of DPT immunization, yielding an RR of 3.0 (95 percent CI = 1.5-6.2). Corresponding to these significant results, the power of the statistical tests on which the results were based was high. As Table 4-3 shows, the tests had 50 percent power for RRs of as low as 2.0.

These results suggest that DPT immunization is associated with an increased risk, within 7 days, of seizures and encephalopathy. The potential for error and bias in this study has been extensively discussed by others (Griffith, 1989; MacRae, 1988; Marcuse and Wentz, 1990; Miller et al., 1989; Stuart-Smith, 1988; Wentz and Marcuse, 1991). Major criticisms have involved potential bias and error in (1) case ascertainment, (2) determination of onset of illness, and (3) lack of control for potential confounding factors. Each of these is discussed briefly below.

(1) Case Ascertainment Incomplete case ascertainment, if it was nondifferential with respect to immunization status, would reduce the ability of the study to demonstrate an effect if one existed and, if differential, could result in either over- or underestimation of the true relative risk. The NCES would have missed those cases that did not result in a hospital admission; however, it is likely that most cases meeting the NCES case definition would have been hospitalized. In the Olmsted County, Minnesota, study of encephalitis that included a review of all inpatient and outpatient records, about 90 percent of all cases of encephalitis in young children resulted in hospital admission (Beghi et al., 1984).

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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TABLE 4-3 National Childhood Encephalopathy Study Estimated Relative Risks of Specific Acute Neurologic Conditions Following DPT Immunization Within the Previous 7 Days 

 

Total Cases

DPT Within
7 Days (No.)

 

Powerb

Category

(No.)

Cases

Control

RR (95% CI)a

50%

80%

All cases

1,167

39

38

2.3 (1.4-3.9)

1.7

2.1

All except infantile spasms

904

30

23

3.3 (1.7-6.5)

2.0

2.6

Seizures

515

18

12

3.3 (1.4-8.2)

2.5

3.7

Encephalopathy

389

12

11

3.1 (1.0-10.5)

3.4

5.7

All except infantile spasms and viral

773

28

23

3.0 (1.5-6.0)

2.0

2.7

Seizure and encephalopathy in previously normal children

770

26

?

3.0 (1.5-6.2)

2.1

2.8

Previously normal; died or neurologically impaired at age 12 months

241

7

3c

4.7 (1.1-28.0)

6.0

12.8

a RR (95% CI), Estimated relative risk (95 percent confidence interval).

b "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.

c From Madge et al. (1990).

SOURCE: Miller et al. (1988). 

Because of concern about the side effects of DPT vaccine at the time of the study, it is possible that children with an acute neurologic illness that occurred in close proximity to immunization would be more likely to be hospitalized or reported to the study investigators and/or included in the final case group than would children with events that did not occur in close proximity to immunization. Miller and colleagues (1988) demonstrated that it would require on the order of 30 percent underreporting of non-vaccineassociated cases (about 400 cases) to obtain a result that showed no significant association of serious acute neurologic events with DPT immunization. It is unlikely that underreporting of this magnitude occurred, since participating physicians were sent cards each month to remind them to report cases, selective review of hospital discharge records as part of the study did not reveal substantial underreporting, the overall incidence rate of encephalopathy (7 per 100,000 children) was similar to that reported by others, and the rates of all serious neurologic disease did not vary markedly within the 16

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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study regions: 11 to 24 events per 100,000 for all regions and between 14 and 18 events per 100,000 for 11 of the 16 regions (Alderslade et al., 1981).

The selective inclusion of less serious events that occurred in close proximity to immunization would overestimate the true relative risk. However, there is evidence that this did not occur, since the ratio of less serious events (seizures) to the more serious encephalopathies was 1.2 in both vaccine-associated and non-vaccine-associated cases (Miller et al., 1988). The decision to include cases of viral encephalitis and Reye syndrome has been faulted on the grounds that they are unlikely to be caused by immunization. The risk of acute neurologic illness remains essentially unchanged when viral cases are excluded (Miller et al., 1988) (Table 4-3). In a separate analysis of the 37 cases of Reye syndrome, investigators reported that only one of these cases occurred within 7 days of DPT immunization (Bellman, 1983). Therefore, the effect of including these cases would be negligible.

(2) Determination of Onset of Illness Because the onset of some of the neurologic events studied may occur over several days or weeks, an exact date of onset may be difficult to determine. Two study investigators together decided on the date of onset on the basis of all available evidence accumulated on each case without reference to previous immunizations (Alderslade et al., 1981). However, investigators may have been aware of the dates of immunizations, and parents' or physicians' recall of the onset of illness may have been influenced by a recent immunization. The effect of such "recall bias" would be to elevate the risk estimates in the early postimmunization period. There are several lines of evidence that suggest that this type of bias was not a major problem. By using an alternate date unlikely to be influenced by recall bias—the date of hospital admission—similar results were obtained. For infantile spasms, which had the greatest disparity between onset and admission dates, there was only a modest increased relative risk in the early postimmunization period, which was followed by a compensatory decline, so that there was no cumulative increase in cases over the 28 days following immunization. In contrast, for other serious neurologic events there was no compensatory decline in cases, so there was a cumulative increase in cases over the 28 days following immunization (Miller et al., 1988).  Finally, an increase in serious neurologic events was found in the 7 to 14 days following measles immunization, the period of time that corresponds to the time of peak fever incidence following administration of this vaccine (Alderslade et al., 1981). Thus, recall bias probably did not influence determination of the onset date for cases occurring in close proximity to measles immunization.

(3) Confounding Factors Relative risks could be over- or underestimated if factors (confounding factors) associated with the development of

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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acute neurologic events were also associated with different likelihoods of receipt of DPT vaccine. Children with a history of prior seizures may be more likely both to avoid DPT vaccine and to develop an acute serious neurologic illness. Children with no prior history of seizures were examined separately, and none of the risk estimates changed significantly, except for the RR in the 72-hour to 7-day interval, which increased from 2.1 to 3.2. Socioeconomic status may influence both receipt of vaccine and incidence of neurologic events. An analysis with a broad stratification by socioeconomic status found similar relative risks in both strata.

Since the authors of the NCES were able to estimate the total number of DPT immunizations given to children in the NCES study population, they were able to calculate an attributable risk, that is, the number of excess cases seen in the population receiving DPT vaccine. The calculated attributable risk for acute neurologic illness in the week following DPT immunization in previously normal children was 6.8 per million immunizations.1Because of the relatively small number of case-control sets on which the RR estimate of 3.3 was based, the 95 percent CI around the attributable risk estimate was wide: 2.1 per million to 15.9 per million vaccinations. The attributable risk for encephalopathy alone in previously normal children would be on the order of 2.7 per million immunizations, with a 95 percent CI of 0 to 10.5 per million vaccinations.

The second question the NCES tried to address was whether DPT immunization was associated with permanent neurologic damage in children. Neurologic and developmental status at 12 to 18 months after discharge was assessed directly for those cases considered to be abnormal at the time of discharge and by postal inquiry for all other cases. Neurologic impairment at the time of follow-up was defined on the basis of the results of neurologic examination or developmental assessment. Cases not directly examined were assumed to be normal (Madge et al., 1990; Miller et al., 1988). The analysis of risk was confined to those 241 cases who were apparently neurologically normal prior to the onset of their acute illness and who had died or had a developmental deficit (developmental quotient, <70 in one or more fields) at ages 12 to 18 months and their controls. Of these 241 cases, 7 (2.9 percent) were immunized with DPT vaccine within 7 days compared with 3 of 478 controls (0.6 percent), yielding an RR of 4.7 (95 percent CI = 1.1-28.0) (Madge et al., 1990). Attempts were made to trace all cases and one control per case 10 to 12 years after initial recruitment in the NCES (Madge et al., 1990). The com

1 This and the other attributable risk figures in this paragraph were calculated using the methods of Alderslade et al. (1981, pp. 162-189) applied to the updated relative risk estimates reported in Miller (1988).

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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mittee had available to it a brief report of preliminary results and a general description of the follow-up methods. The report was based on a poster presentation at the Sixth International Symposium on Pertussis in September 1990. Follow-up contact was achieved for 81 percent of cases and 83 percent of controls, and information on neurologic, educational, behavioral, and other functions was obtained from questionnaires submitted to parents, teachers, and physicians. Analyses were confined to children designated as neurologically normal prior to their acute illness, and late dysfunction was defined as death or any degree of reported dysfunction in any developmental or functional area (e.g., neurologic, behavioral, or educational). Results were based on 515 case children, of whom 15 received DPT vaccine within 1 week of their acute illness. The percentage with any dysfunction or death was similar in "vaccine-associated" (~58 percent) and "non-vaccine-associated" cases (~63 percent) (Madge et al., 1990). Among control children, this value was ~20 percent, suggesting that in comparison with controls, children with a history of acute neurologic illness are at greater risk of long-term neurologic problems, regardless of vaccination status. Information was not available to the committee on the criteria used to define each type of dysfunction, the exact methods for evaluating functional and developmental status of cases and controls after 10 to 12 years of follow-up, or whether the assessments were conducted in a masked fashion. Thus, it is unclear what conditions or problems have been included as late outcomes. Given the limited information available, especially regarding the methods used to assess and define late dysfunction, the committee was unable to apply the follow-up data of Madge and colleagues to its assessment of the relation of pertussis vaccine to permanent neurologic damage.

The analyses relating to permanent neurologic damage have also received intense scrutiny (Griffith, 1989; MacRae, 1988; Marcuse and Wentz, 1990; Miller et al., 1989; Stuart-Smith, 1988; Wentz and Marcuse, 1991). The two major problems are (1) the number and composition of cases on which the estimates were based and (2) the nature of the relationship between an episode of acute neurologic illness and subsequent demonstration of neurologic or developmental abnormalities.

Cases Since the RR estimate of 4.7 for permanent neurologic damage is based on a very small number, that is, seven cases, it is particularly vulnerable to the effects of chance, error, or bias (Miller et al., 1988). Of the seven cases, there were two deaths, one associated with Reye syndrome and one with an overwhelming viral infection. Of the remaining five cases, the acute event was a seizure in two cases (one with a major and one with a minor delay in development) and encephalopathy in three cases (one a case of viral encephalitis associated with major impairments and the two others associated with a major and a minor developmental delay, respectively)

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

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(Alderslade et al., 1981). It has been suggested that if cases with other etiologies for their illness were eliminated from the analysis, the results would no longer be statistically significant.  However, it is not sound practice epidemiologically to eliminate any of these cases and recalculate relative risks without similarly evaluating the non-vaccine-associated cases; this has not been done. It is clear, however, that the risk estimates are very fragile and could be very sensitive to the reclassification of two or three cases. In addition, if results for seizures and encephalopathies were calculated separately, it is likely that neither result would be statistically significant.

Relationship Between Acute Event and Follow-up Results It is important to consider whether acute neurologic events are a necessary cause of later observed neurologic impairment or whether, at least at times, these events are markers of children who have an underlying neurologic abnormality. It is well recognized that seizures with fever are more likely to occur in children with underlying neurologic abnormalities than in neurologically normal children. In a group of 96 children followed for febrile seizures or epilepsy by Livingston (1972), about 10 percent of those with a history of febrile seizures were noted to have a recurrent febrile seizure within 24 hours of initial pertussis immunization (none of whom subsequently developed epilepsy), and of 284 patients with epilepsy and frequent seizures, a few had a temporary increase in severity or frequency of seizures following pertussis immunization, but no apparent permanent effects were noted (Livingston, 1972). Other data also indicate that children with a personal or family history of convulsions are more likely to experience a febrile seizure following DPT immunization (Livengood et al., 1989; Stetler et al., 1985a,b).

The NCPP (Niswander and Gordon, 1972), a large longitudinal study, attempted to follow closely approximately 54,000 children from birth to age 7 years. In this population, 1,706 children developed febrile convulsions, 518 developed afebrile seizures, and 233 developed epilepsy by age 7 years. Two studies in which children's intellectual performance both before and after the onset of their seizure disorders and at age 7 years was compared with that of a sibling with no seizures demonstrated that neither febrile (Ellenberg and Nelson, 1978) nor afebrile (Ellenberg et al., 1986) seizures cause intellectual deterioration in children. For febrile seizures, developmental regression was associated only with neurologic and developmental status prior to the onset of seizures and not the number of seizures, presence of focal features, or the duration of the seizure (14 children had seizures of longer than 1 hour). About 22 percent of children with febrile seizures were neurologically abnormal or were suspected to be neurologically abnormal prior to the first febrile seizure (Nelson and Ellenberg, 1976). Most of

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

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these children did not have obvious malformations, but they were judged to be suspect because of lags in development. The prevalence of epilepsy at age 7 years was 5 per 1,000 in children with no febrile seizures, 11 per 1,000 in those previously normal with simple febrile seizures, 17 per 1,000 in those previously normal with complex febrile seizures (lasting longer than 15 minutes, focal features, or more than 1 in 24 hours), and 28 and 92 per 1,000 in those previously abnormal or suspect with simple and complex febrile seizures, respectively. Thus, children who were judged to be previously abnormal or suspect were more likely to have febrile seizures and to develop epilepsy following either simple or complex febrile seizures.

Of those children in the NCES study with an acute serious neurologic event (encephalopathy or seizure) within 7 days of DPT immunization who were judged to be neurologically normal prior to immunization, seven were neurologically impaired or had died at the 12-month follow-up evaluation. Estimates of permanent neurologic damage following DPT immunization have been based on data for these seven children, five of whose acute event was classified as encephalopathy and two of whose event was classified as seizure. Although these children were presumed to be normal at the time of immunization, no prevaccine neurologic testing was performed. Available evidence, such as that from the NCPP (Ellenberg and Nelson, 1978; Ellenberg et al., 1986; Nelson and Ellenberg, 1976) and from the studies of Livengood et al. (1989), Livingston (1972), and Stetler et al. (1985a,b) reviewed above, suggests that seizures do not produce neurologic impairment but, rather, may be markers of those children with underlying neurologic disease. For the two children with seizures, it is therefore possible that DPT immunization caused the seizure but unlikely that it caused the subsequently diagnosed neurologic impairment. Of the remaining five children with encephalopathy, three had evidence of other conditions (one of Reye syndrome, two of viral encephalitis) known to produce neurologic damage or death.

Other Controlled Studies in Humans

The onset of neurologic disorders in children was examined in Denmark in two different eras, corresponding to changes in the schedule and type of vaccination (Jacobsen et al., 1988; Shields et al., 1988). Before 1970, DPT vaccine was administered at ages 5, 6, 7, and 15 months. Since 1970, monovalent pertussis vaccine is given at ages 5 and 9 weeks and 10 months. All records of children age 7 years or less hospitalized in seven counties in Denmark (serving about 50 percent of the population) with a diagnosis of convulsive disorder, CNS infection, or encephalopathy were reviewed for two time periods: 1967 to 1968 and 1972 to 1973. The age-specific distribution of the time of onset of the first febrile seizure was similar in the two time periods until age 10 months, when there was a significant increase in

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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the second time period, which corresponded to the recommended age of the third pertussis immunization. Following this, the age-specific distributions were again similar until 16 months, when there was an increase in the first time period corresponding to the third DPT immunization. The two distributions were found to be significantly different with p = 0.004.

On the basis of these data, the authors calculated that approximately 5.4 percent of first febrile seizures occurred in association with pertussis immunization. It is noteworthy that a shift in the distribution of febrile seizures was not observed for those less than age 10 months, suggesting that febrile seizures following administration of DPT vaccine occur during the ages when children are most likely to experience these seizures related to other febrile events (American Academy of Pediatrics, 1980; Hirtz and Nelson, 1983; Nelson and Ellenberg, 1978).

No similar correlations were observed in the distributions of the times of onset of epilepsy.  The power of the test to detect such an effect was reasonably high. For instance, if 10 percent of all cases of epilepsy first occurring in the age range under study were due to DPT immunizations, the test would have 50 percent power to detect an increased relative risk. If 15 percent of cases were caused by the vaccine, the power would be 80 percent.

Walker and colleagues (1988) conducted a case-cohort study in a population of 26,600 children born in Group Health Cooperative hospitals from 1972 through 1983 with normal birth weights and no congenital disorders or perinatal events that might predispose them to seizure disorders. New neurologic disorders without an obvious predisposing cause (e.g., trauma) occurring from ages 30 days to 6 years were identified through inpatient hospital records and pharmacy records. There were 5 cases identified with encephalopathy (clinical diagnosis) and 231 cases with one or more seizures. Fifty-five of these cases had at least one afebrile seizure, and the remaining 176 cases had only febrile seizures. The timing of DPT immunization for case children and a random sample of 262 control children matched to cases was obtained through a review of outpatient records. It was estimated that the study population received a total of 106,000 doses of DPT vaccine.

None of the five cases of encephalopathies (Table 4-4) occurred in the first 30 days following DPT immunization. Using the period 30 or more days following DPT immunization as the reference period, the authors identified one, one, and four afebrile seizures in the 0 to 3, 4 to 7, and 8 to 29 days after DPT vaccination, respectively, compared with 1.1, 0.9, and 3.1 expected cases, respectively (Table 4-5). The RRs for these periods were 1.0, 1.2, and 1.5, respectively, but none were significantly elevated. The powers of these tests were low, however. For the first two periods, RRs of over 9.2 would have been needed to achieve 50 percent power. The age-

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

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TABLE 4-4 Summary of Controlled Studies on DPT Immunization and Encephalopathy

 

All Encephalopathy

Encephalopathy Within 7 Days of DPT

         

Powerb

Reference

Design

Years

Age

No. Child-Years (No. Children)

No. DPT

No.

Incidence/ 100,000

No.

Odds Ratio (95% CI)a

50%

80%

Alderslade et al., 1981; Miller et al., 1988

Matched case-control

July 1976- June 1979

2-35 months

-5.4 million

-2.2 million

389

7

12

3.1 (1.0-10.5)

3.4

5.7

Walker et al., 1988

Matched case-cohort

1972-1983

30 days-6 years

~100,000 (26,000)

~106,000

5

5

0

   

Griffin et al., 1990

Cohort

1974-1984

29 days-3 years

~60,562
(38,171)

107,000

2

3

0

   

Gale et al., 1990

Matched case-control

1987-1988

1-24 months

218,000 (equivalent to a cohort of 109,000)

~368,878

22

10

2

4.0 (0.4-44.1)

11.0

30.8

a 95% CI, 95 percent confidence interval.

b ''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.

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

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TABLE 4-5 Summary of Controlled Studies on DPT Immunization and Afebrile Seizures 

 

No. of Cases in Interval

Time Interval (days)

 

Powerb

Reference

Design

   

RR (95% CI)a

50%

80%

Walker et 

Matched

1

0-3

1.0 (0.1-9.7)

9.7

25.7

al., 1988

case-cohort

1

4-7

1.3 (0.1-12.0)

9.2

23.9

   

4

8-29

1.5 (0.4-5.5)

3.7

6.4

Griffin et

Cohort

1

0-3

1.3 (0.2-9.7)

7.5

17.7

al., 1990

 

2

4-7

2.2 (0.5-9.9)

4.5

8.6

   

1

8-14

0.6 (0.1-4.9)

8.2

20.1

   

3

15-29

0.9 (0.3-3.1)

3.4

5.9

Gale et al.,

Matched 

?

<7

0.5 (0.2-1.5)

3.0

4.8

1990

case-control

14

<14

0.8 (0.4-1.5)

1.9

2.5

 

(SONIC)c

25

<28

0.6 (0.3-1.1)

1.8

2.4

a RR (95% CI), Estimated relative risk (95 percent confidence interval).

b "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.

c SONIC, Study of Neurologic Illness in Children.  

adjusted incidence of identified febrile seizures in the immediate postimmunization period was 3.7 times (95 percent CI = 1.4-10.0) that in the period 30 or more days after immunization (Table 4-6). In concert with this result, the power of this test was higher than that for afebrile seizures. An RR of 2.7 for febrile seizures had 50 percent power and an RR of 4.1 had 80 percent power.

This study thus demonstrated no increase in afebrile seizures or encephalopathies in the early postimmunization period. However, the study examined only seizures serious enough to warrant either admission to a hospital or the use of anticonvulsant medications, and it had limited power to study encephalopathies or permanent neurologic damage. Febrile seizures were reported to be 3.7 times greater in the early postimmunization period, but no other details about this estimate were presented.

Griffin and colleagues (1990) linked computerized immunization files available for four Tennessee counties from 1974 through 1984 to Tennessee birth certificates and to Tennessee Medicaid files, which contain information on Medicaid enrollment, diagnoses associated with all medical encounters, and records of all filled prescriptions. They studied a cohort of children born in Tennessee who were enrolled in the Medicaid program and

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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TABLE 4-6 Summary of Controlled Studies on DPT Immunization and Febrile Seizuresa 

 

No. of Cases 

Time Interval

 

Powerc

Reference

Design

in Interval

(days)

RR (95% CI)b

50%

80%

Walker et al., 1988

Matched case-cohort

?

0-3

3.7 (1.4-10.0)

2.7

4.1

Griffin et

Cohort

6

0-3

1.5 (0.6-3.3)

2.2

3.1

al., 1990

 

4

4-7

0.9 (0.3-2.3)

2.6

3.8

   

6

8-14

0.7 (0.3-1.7)

2.4

3.6

   

19

15-29

1.1 (0.7-1.8)

1.6

2.0

Gale et al.,

Matched

6

<7

1.9 (0.6-5.9)

3.1

5.1

1990

case-control

11

<14

1.8 (0.8-4.4)

2.4

3.6

 

(SONIC)d

13

<28

1.1 (0.5-2.3)

2.1

2.9

a For NCES data, see Table 4-3.

b RR (95% CI), Estimated relative risk (95 percent confidence interval).

c "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.

d SONIC, Study of Neurologic Illness in Children.  

who received at least one DPT immunization through the county clinic system. The first neurologic event after initiation of DPT immunization was ascertained by obtaining medical records of children with diagnoses or prescriptions indicating a possible seizure or new neurologic event. Medical records for review were available for emergency room and hospital admissions and for hospital-based clinics. Other outpatient records were not reviewed, so events that resulted in no medical encounter or those that initiated only an outpatient visit are likely to have been missed.

By using a cohort analysis, the risks of seizures and encephalopathy (NCES definition used) were evaluated following DPT immunization in 38,171 children on Medicaid in Tennessee who received 107,154 DPT immunizations in their first 3 years of life. Only two children with encephalopathy were identified (Table 4-4); the onset of symptoms did not occur within 2 weeks of immunization in either child. There were one, two, one, and three children with afebrile seizures in the intervals 0 to 3, 4 to 7, 8 to 14, and 15 to 29 days, respectively, following DPT immunization compared with 35 in the interval 30 or more days post-DPT vaccination, yielding RR estimates (95 percent CIs given in parentheses) of 1.3 (0.2-9.7), 2.2 (0.59.9), 0.6 (0.1-4.9), and 0.9 (0.3-3.1), respectively (Table 4-5). The power

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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of these tests was relatively low. For the early interval, for instance, the RR would have to be 7.5 to achieve 50 percent power and 17.7 to achieve 80 percent power.

This study demonstrated no significant increase in febrile seizures in the 0 to 3 days following DPT immunization (RR, 1.5); however, the upper bound of the 95 percent CI was 3.3. For febrile seizures, the power was greater than those for afebrile seizures and encephalopathy: 50 percent for an RR of 2.2 and 80 percent for an RR of 3.1.

SONIC was a large case-control investigation of the association between the risk of serious acute neurologic illness and DPT immunization in young children. 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. The primary purpose of SONIC was to evaluate the feasibility of conducting in the United States a study similar to the British NCES but that avoided the methodologic problems for which the NCES had been criticized.

Attempts were made to identify, through active surveillance of hospital and physician records, all eligible cases in the two states. Cases were primarily identified through systematic review of emergency room, outpatient clinic, and inpatient discharge listings for 98 percent of the acute-care hospitals with pediatric beds in the two-state area. The conditions included in SONIC (see below) were similar to those in the NCES. Case definitions were determined by a panel of international experts on neurologic illness in childhood. Excluded were acute neurologic illnesses caused by trauma, poisoning, or bacterial infections of the CNS identified by culture or equivalent measures. Cases included children with the following diagnoses: acute encephalitis or encephalopathy; Reye syndrome; loss of consciousness of unknown etiology; acute paralytic syndromes; infantile spasms; and seizures without fever, all seizures in children ages I to 3 months, afebrile seizure or series of febrile seizures with a duration of approximately 15 minutes or longer, and febrile seizures accompanied by focal neurologic signs. A panel of experts confirmed the diagnoses by review of medical records without knowledge of immunization history.

Two controls per case were selected from the 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. Parents of both cases and controls were interviewed by telephone to obtain information on potential risk factors, including immunization histories. Attempts were made to validate immunization information for all cases and controls by using medical record data.

The major differences in the research designs and procedures for data collection between SONIC and the NCES were that (1) the NCES included only hospitalized cases, whereas SONIC included both hospitalized and outpatient cases; (2) case ascertainment in the NCES relied primarily on

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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reporting from the hospitals, whereas SONIC used an active surveillance system; (3) in the NCES, the reporting physician's diagnosis was assumed to be correct, whereas in SONIC, diagnoses were confirmed by a masked expert panel using uniform, prespecified criteria; and (4) in the NCES, both immunization histories and childrens' previous levels of function were obtained solely from a questionnaire submitted to the local physician, whereas in SONIC, the former were independently verified by study staff and the latter were determined from medical records.

Preliminary findings from SONIC have been reported recently (Gale et al., 1990) and are shown in Table 4-7. In the population studied, 358 eligible children with incident neurologic illnesses and verified immunizations were identified. Of these, the onset of illness was within 28 days of a previous DPT vaccination for 48 children and within 7 days of a previous DPT vaccination for 14 children. The odds ratio for the occurrence of any of the neurologic illnesses included in SONIC within 7 days of DPT immunization was 1.2 (95 percent CI = 0.6-2.3). Regardless of the definition of the case group (i.e., whether total or only new-onset or NCES-compatible cases were included), whether statistical adjustment was done for potential confounders, or whether the exposure-to-onset interval was <7, <14, or <28 days, no statistically significant increases in risk were observed, although all odds ratios for exposure intervals of <7 days were greater than 1.0. The power of the SONIC study was reasonably high. For the comparison cited above, for instance, the test had 50 percent power for an RR of 1.9 and 80 percent power for an RR of 2.5.

Considering separately the results of analyses of the relationship of DPT immunization within the previous 7 days and the risk of specific types of illnesses, the odds ratio was 4.0 (95 percent CI = 0.4-44.1) for encephalopathy, 0.5 (95 percent CI = 0.2-1.5) for afebrile seizures, and 1.9 (95 percent CI = 0.6-5.9) for complex febrile seizures. Thus, no statistically significant increases or decreases in risk were observed for specific types of neurologic illnesses. However, the study had limited statistical power to detect changes in risk associated with DPT exposure within strata defined by specific types of acute neurologic illnesses. The RRs at which 50 percent power would be achieved for these three outcomes were, respectively, 11.3, 3.0, and 3.1. SONIC was not designed to assess the association of DPT and the risk of long-term neurologic problems and thus did not provide any information on this question.

In all of the preceding studies where encephalopathies were ascertained, it is possible to count the number of DPT-vaccinated children whose experiences subsequent to vaccination were monitored and recorded in the relevant papers. The studies cited in Tables 4-2 and 4-4 (Cody et al., 1981; Gale et al., 1990; Griffin et al., 1990; Long et al., 1990; Pollock and Morris, 1983; Pollock et al., 1984; Strom, 1967; Walker et al., 1988) include a total

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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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.

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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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

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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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.

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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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-

Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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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.

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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Page 102
Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Page 103
Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Page 104
Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Page 105
Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Page 106
Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Page 107
Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Page 108
Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Page 109
Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Page 110
Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Page 111
Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Page 112
Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Page 113
Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Page 114
Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page 115
Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page 116
Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page 117
Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page 118
Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page 119
Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page 120
Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page 121
Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page 122
Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page 123
Suggested Citation:"4 Evidence Concerning Pertussis Vaccines and Central Nervous System Disorders, Including Infantile Spasms, Hypsarrhythmia, Aseptic Meningitis, and Encephalopathy." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
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Page 124
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Adverse Effects of Pertussis and Rubella Vaccines Get This Book
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Parents have come to depend on vaccines to protect their children from a variety of diseases. Some evidence suggests, however, that vaccination against pertussis (whooping cough) and rubella (German measles) is, in a small number of cases, associated with increased risk of serious illness.

This book examines the controversy over the evidence and offers a comprehensively documented assessment of the risk of illness following immunization with vaccines against pertussis and rubella. Based on extensive review of the evidence from epidemiologic studies, case histories, studies in animals, and other sources of information, the book examines:

  • The relation of pertussis vaccines to a number of serious adverse events, including encephalopathy and other central nervous system disorders, sudden infant death syndrome, autism, Guillain-Barre syndrome, learning disabilities, and Reye syndrome.
  • The relation of rubella vaccines to arthritis, various neuropathies, and thrombocytopenic purpura.

The volume, which includes a description of the committee's methods for evaluating evidence and directions for future research, will be important reading for public health officials, pediatricians, researchers, and concerned parents.

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