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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
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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).
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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
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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
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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.
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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
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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
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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
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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
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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
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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-
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Representative terms from entire chapter:
dpt immunization
Page 114
TABLE 4-7 Study of Neurologic Diseases in
Children (SONIC) Estimated Relative Risks for Pertussis Vaccine
Exposure by Case Class and Exposure Interval, With and Without
Adjustment for Potential Confounders
Matched Setsb
Time Interval
Powerd
Analysis Groupa
(No.)
(days)
RR (95% CI)c
50%
80%
All cases
424
<7
1.1 (0.6-2.0)
1.82
2.35
<14
1.2 (0.8-2.0)
1.67
2.07
<28
0.9 (0.6-1.3)
1.44
1.69
Incident cases
358
<7
1.2 (0.6-2.3)
1.92
2.53
<14
1.2 (0.8-2.0)
1.67
2.07
<28
1.9 (0.6-1.3)
1.44
1.69
Incident cases,
358
<7
1.1 (0.5-2.3)
2.09
2.87
adjustede
<14
1.2 (0.7-2.1)
1.75
2.22
<28
0.9 (0.6-1.5)
1.67
2.07
NCES eligible
100
<7
2.5 (0.7-9.3)
3.72
6.53
casesf
<14
1.8 (0.8-4.4)
2.44
3.59
<28
1.1 (0.5-2.3)
2.09
2.87
NCES eligible
100
<7
3.6 (0.8-15.2)
4.22
7.83
cases, adjustede,f
<14
2.1 (0.8-5.8)
2.76
4.27
<28
1.2 (0.5-2.9)
2.42
3.53
a NCES, National
Childhood Encephalopathy Study.
b Matched
case-comparison study design.
c RR (95% CI),
Estimated relative risk (95 percent confidence interval).
d "Power" denotes
the probability that a statistical test based on a sample of the
same size as the one in the study cited would find a statistically
significant increased risk (with alpha = 0.05), given that the true
RR in the population being studied is the number stated in the
table. The numbers tabulated are the RRs such that the powers are
50 and 80 percent, respectively.
e Incident cases
adjusted for prior seizure, prior major DPT reaction, family
history of seizures, and illness within 30 days.
f NCES eligible
cases, see Chapter 4.
of 864,000 children. Six encephalopathies were
recorded within 2 days, and two (in the SONIC study) were recorded
as occurring within "1 week" of vaccination. Using a "background"
rate of encephalopathy of 78 per 100,000 children per year,2it is
possible to estimate the attributable risk for encephalopathies
following vaccination. If data from all cited studies are included,
the attributable risk estimate is 7.2 per million children. In
these
2 This rate
was calculated from data in the NCES (Alderslade et al., 1981;
Miller et al., 1981), Walker et al. (1988), Griffin et al. (1990),
and SONIC (Gale et al., 1990) studies, with an age adjustment
derived from Beghi et al. (1984). For details, see Appendix D.
Page 115
studies, children received on average three DPT immunizations;
therefore, the estimated attributable risk of encephalopathy is 2.4
per million immunizations. If the studies of Pollock and Morris
(1983) and Strom (1967), which relied on spontaneous reports for
ascertainment, are excluded, the attributable risk estimate is 2.3
per million immunizations. Relying only on the data in controlled
studies of well-defined populations (Gale et al., 1990; Griffin et
al., 1990; Walker et al., 1988), the estimate of the attributable
risk is 3.3 per million immunizations.
In the case of febrile and afebrile seizures, the committee was
able to carry out a meta-analysis of the other studies in defined
populations (Gale et al., 1990; Griffin et al., 1990; Walker et
al., 1988). Three of these studies provide information specifically
on afebrile seizures (Gale et al., 1990; Griffin et al., 1990;
Walker et al., 1988). Using the methods described in Appendix D,
the pooled RR estimate from these studies is 0.6 (95 percent CI =
0.4-1.1), assuming a fixed-effects model, and 0.7 (95 percent CI =
0.3-1.5), under a random-effects model. Thus, even pooling of the
available data provides no evidence of a statistically significant
increase in the risk of afebrile seizures following DPT
vaccination.
Combining data from the same three studies on febrile seizures
yields a pooled RR of 1.8 (95 percent CI = 1.2-2.7), assuming a
fixed-effects model, and 1.9 (95 percent CI = 1.0-3.3), under a
random-effects model. Thus, regardless of the kind of statistical
model assumed, the pooled data from these three studies indicate an
increased relative risk for febrile seizures following DPT
immunization.
Evidence from Studies in Animals
The same limitations that apply to the use of animal models to
gain understanding of pathogenesis and immunity in human whooping
cough (see Chapter 3) pertain to their use for the study of
pertussis vaccine-induced encephalopathy. Superficial understanding
of the effects on the human brain of various putative virulence
factors and of pertussis vaccine makes it impossible to interpret
previous results in animals with any certainty. Unless the basic
nature of the postulated vaccine-induced encephalopathy in humans
is understood, preferably at the molecular and cellular levels, it
is not possible to determine whatever abnormalities produced in an
animal represent a valid "model."
Retrospective analysis of work that has been done to date yields
little useful information. Mice die from an apparent toxemia after
intraperitoneal inoculation of large numbers of viable B.
pertussis organisms (Pittman, 1970; Proom, 1947). The reasons
for death are not understood, as is the case for most infectious
diseases. Intracerebral inoculation of viable B. pertussis
organisms in mice induces an encephalopathy (Cameron, 1988), which
is not
Page 116
surprising. Any relationship of this encephalopathy to the
cerebral effects of injecting a vaccine at an extracerebral site is
speculative. Amiel (1976) and Bergman and colleagues (1978) found
changes in the permeability of the cerebral vasculature of rodents
given pertussis vaccine, but it has not been clear how this might
relate to encephalopathy in rodents or humans.
Steinman and colleagues (1982) have proposed a mouse model for
pertussis vaccine-induced encephalopathy that is linked to the
genetic locus H-2. In this model, animals with a certain H-2 type
that had been given a large number of heat-killed B.
pertussis organisms 2 days earlier died within 30 minutes to 2
hours after injection of bovine serum albumin. Postmortem
examination of the brain revealed diffuse vascular congestion and
parenchymal hemorrhage, which the authors believed resembles the
findings in human cases in whom death occurred quickly after
immunization. The model raises interesting questions regarding
possible genetic control and a role for immediate hypersensitivity
in postulated vaccine-induced encephalopathy, but the relationship
of these variables to the proposed response in humans is
speculative. Moreover, it is not clear whether these pathologic
changes represent a primary encephalopathy or the agonal effects of
shock, hypovolemia, and the like.
Presumably, the vaccine lots that have been suspected of causing
irreversible encephalopathy in children have passed the
intracerebral mouse protection test or the intranasal mouse
protection test for vaccine potency and the mouse weight gain test
for toxicity. Therefore, the capacity to cause serious
encephalopathy in mice, if present, has been missed. The endpoint
of the intracerebral mouse protection test is death from active
infection within 14 days. The interval between injection of vaccine
and intracerebral injection of viable organisms, a matter of a few
weeks, might not be sufficient for detection of late neurologic
effects. More importantly, neurologic sequelae that might relate to
changes in memory, learning ability, emotional control, and the
like might not be obvious in mice. Similar considerations apply to
the mouse weight gain test, which is carried out for up to 7 days
and which focuses on weight gain as an endpoint. In summary, it is
not evident that the studies in animals completed to date provide
information useful to understanding the possible relation of
encephalopathy to pertussis immunization in children.
Aluminum Salts
The possibility has been raised that the aluminum salts
regularly present in DPT vaccines might play a role in the
occurrence of encephalopathy following DPT immunization (see
Appendix E for discussion). There are no data bearing on this
possible mechanism.
Page 117
Summary
Case reports and case series offer no consistent evidence for a
clinically distinctive pertussis vaccine-induced encephalopathy.
The limited understanding of the underlying disease process and an
inability to diagnose encephalopathy accurately or uniformly,
particularly in infants, also hinder the design, conduct, and
interpretation of human studies. Comparisons of results among
different studies are difficult, since different types of events
are included under the term encephalopathy in different
studies.
The animal models of pertussis vaccine-induced encephalopathy
(e.g., Cameron, 1988; Steinman et al., 1982) do not appear to be
pertinent to human disease (e.g., they require intracerebral
inoculation). In addition, the superficial understanding of the
pathophysiology of encephalopathy, the difficulties of accurately
diagnosing even severe cases, the lack of understanding of
pertussis virulence factors, and the variability in pertussis
vaccine composition across manufacturers and time make it almost
impossible to extrapolate animal findings to humans with any
certainty. There are no data to indicate a mechanism of cerebral
injury.
In light of the considerations listed above and given the
limitations of case reports and animal studies (see Chapter 3), the
studies that could best address the question of the possible
relation between pertussis vaccination and encephalopathy have been
controlled epidemiologic studies. To date, four such studies have
been reported (Alderslade et al., 1981; Gale et al., 1990; Griffin
et al., 1990; Walker et al., 1988). The NCES reported a
statistically significant RR of encephalopathy of 3.1 (associated
with an attributable risk of 2.7 per million immunizations) in the
early postimmunization period. None of the other studies
demonstrated a statistically significant risk. However, the total
number of cases reported in the other three studies was consistent
with the attributable risks found in the NCES.
Data bearing on the question of a possible relation between
pertussis vaccination and chronic neurologic damage are limited to
one controlled study (Alderslade et al., 1981; Miller et al.,
1988), in which the neurologic status of children prior to their
acute illness was not directly measured and the definition and
measurement of late outcomes were not uniformly applied to all
participants. In addition, the total number of children with
chronic conditions on which risk estimates were based was very
small, and estimates of chronic neurologic damage following
specific types of acute illnesses, especially encephalopathy, could
not be calculated.
The results of studies comparing rates of febrile seizures
following DPT versus DT vaccine (Cody et al., 1981; Pollock and
Morris, 1983; Pollock et al., 1984), the ecologic study of Shields
and colleagues (1988) showing a shift in occurrence of febrile
seizures following change in time of DPT immuniza-
Page 118
tion, the NCES results on seizures (80 percent of which were
febrile) (Alderslade et al., 1981), and the findings of three
additional controlled studies on febrile seizures (Gale et al.,
1990; Griffin et al., 1990; Walker et al., 1988) suggest that DPT
vaccine may cause a doubling or tripling of the febrile seizure
rate in the first few days following immunization.
The three controlled studies that directly addressed afebrile
seizures (Gale et al., 1990; Griffin et al., 1990; Walker et al.,
1988) were consistent in showing no relation to DPT vaccination,
although each had limited statistical power to detect risks unless
they were on the order of 2.4 or larger. Only the study of Shields
and colleagues (1988) addressed epilepsy specifically, and it found
no relation between the onset of epilepsy and the timing of DPT
immunization. However, the power of this study was limited.
No animal models for seizures and DPT vaccine have been
developed.
Conclusion
The evidence is consistent with a causal relation between
DPT vaccine and acute encephalopathy,3defined in the controlled studies
reviewed as encephalopathy, encephalitis, or encephalomyelitis. On
the basis of a review of the evidence bearing on this relation, the
committee concludes that the range of excess risk of acute
encephalopathy following DPT immunization is consistent with that
estimated for the NCES: 0.0 to 10.5 per million immunizations.
There is insufficient evidence to indicate a causal relation
between DPT vaccine and permanent neurologic damage.
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