Recurrent Seizures After Diphtheria,

and Pertussis Vaccine Immunization

Tetanus,

Onset Less Than 24 Hours After Vaccination

Jerome V.

Murphy, MD; Larrie D. Sarff, MD; Kathleen M. Marquardt, RN, MS

\s=b\ Twenty-two patients with recurrent

seizures that started less than 24 hours
after immunization with diphtheria, tetanus, and pertussis (DTP) vaccine were
retrospectively studied. The initial seizure generally occurred after one of the
first three DTP vaccine immunizations,
and followed that immunization by less
than 12 hours. Two of the 22 patients
were siblings. Eight patients had additional immunizations with DTP vaccine
and four had immediate worsening of
their seizures. Of the 22 patients, only
one was seizure free and stopped taking
anticonvulsants. Three patients exhibited normal development, and 11 had
severe developmental delays. Based on
these observations, we reviewed current
contraindications for immunization with
pertussis vaccine.

(AJDC 1984;138:908-911)

"Deports describing adverse neu

rologic reactions following immu
nizations with pertussis vaccine have
appeared since 1933, when the vaccine
was first introduced.1 In 1948 Byers
and Moll reported the first series of 15
patients with convulsions beginning
less than 24 hours after the injection of
For editorial comment
904.
see

prophylactic pertussis vaccine.2 Since

then, similar observations have been
reported by other authors.34 Accord
ing to these reports, neurologic symp
toms generally occur within 24 hours
of the immunization, and follow one of
the first three immunizations.
Mild neurologic reactions, without

From Milwaukee Pediatric Neurology (Dr

Murphy and Ms Marquardt), and the Department
of Pediatrics, Medical College of Wisconsin, Milwaukee (Drs Murphy and Sarff).
Reprint requests to Milwaukee Pediatric Neurology, 2040 W Wisconsin Ave, Milwaukee, WI
53233 (Dr Murphy).

sequelae, occur more frequently after

a diphtheria, tetanus, and pertussis
(DTP) immunization than after a diph

theria and tetanus vaccination alone.5

In one series, the risk of a seizure
within 24 hours of a DTP vaccination
was 1:1,750 immunizations. (The con
trol population receiving DT immu
nization was too small to determine the
specific risk from the pertussis compo
nent of the vaccine.) These seizures do
not recur, and some of them may be
benign febrile seizures.6
The risk of a more serious neurologic
reaction following a pertussis immu
nization is small. The National Child
hood Encephalopathy Study (NCES)
in Great Britain reported the risk of
neurologic abnormality, starting in the
week after a DTP immunization and
persisting for at least one year, to be
1:310,000.' This study excluded all chil
dren whose initial seizures were less
than 30 minutes in duration. The per
manent

encephalopathies frequently

have seizures as their initial manifes

tations. In light of this outcome, these
were probably not benign febrile sei
zures.

That the neurologic reactions cited

relate to the pertussis component of
the vaccine, rather than the diphtheria
or

tetanus

components,

seems

likely.

In the report by Byers and Moll in

1948,12 of 15 patients had been immu
nized with pertussis vaccine alone and
three had received pertussis vaccine in
combination with other vaccines.2 The
NCES did describe neurologic adver
sity after diphtheria and tetanus and
DTP immunizations. A statistical as
sociation was present only after immu
nization with the DTP vaccine.7
Realizing that there might be an
association between immunization

with pertussis vaccine and subsequent

neurologic adversity, contraindica
tions to the administration of pertussis
vaccine have been established in sev
eral countries. In Great Britain these
include the following criteria: (1) sei
zures in the patient or his or her imme
diate family; (2) neurologic defects in
the patient; (3) a febrile, particularly
respiratory, illness at the time of im
munization; and (4) a severe reaction to
a preceding dose.8 There are different
suggested contraindications cited in
the Report of the Committee on Infec
tious Diseases of the American Acad
emy of Pediatrics, as follows: (1) a
progressive neurologic disease in the
infant; (2) the presence of convulsions,
focal neurologic signs, encephalitis, or
collapse after a prior pertussis immu
nization; and (3) excessive somno
lence, excessive crying, or a tempera
ture of at least 40.5 C as a reaction to a
prior pertussis immunization.9
We have reviewed data on 22 pa
tients who have had recurrent seizures
beginning less than 24 hours after a
DTP immunization. The goals of this
review are (1) to record the eventual
outcome in these selected patients, (2)
to find any predispositions in these
patients for this neurologic adversity,
(3) to learn if the application of present
contraindications would have pre
cluded the administration of pertussis
vaccine to any of these patients, and (4)
to learn if additional contraindications
need to be considered. In this study,
recurrent seizures were selected as a
sign of a neurologic deficit for their
ease of identification. The first 24
hours after immunization was the time
period chosen in an attempt to limit the
number of coincidental seizure disor
ders beginning early in life.

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SUBJECTS AND METHODS

Eighty questionnaires were sent to fam
ilies with children who were believed to
have illnesses related to a DTP immuniza
tion. These names were obtained from sev
eral sources. Some resulted from direct
inquiries following the television produc
tion "Vaccine Roulette," which featured
one of us (J. V.M.). Three subjects were also
followed up by J.V.M., and names were
submitted by Dissatisfied Parents To
gether. These families were not a random
sample of children who had received DTP
immunizations, but they were families con
taining at least one child whom the parents
or guardians believed had suffered a reac
tion to the pertussis vaccine. The question
naire requested details concerning the rele
vant immunizations, the name of the
manufacturer of the vaccine, the site of the
immunization, the presence of intercurrent
illness, a description of the reaction, the
seizure frequency and treatment (if sei
zures were a factor), the patient outcome,
and the family history of neurologic dis
ease. After the questionnaires were re
viewed, the only patients included in the
study were those who had recurrent sei
zures, with the occurrence of the first sei
zure within 24 hours of an immunization
with DTP vaccine.

RESULTS

Forty-three of the 80 questionnaires

were returned, and only 22 of the re
turned questionnaires met the preced
ing criteria. Thirty-seven families did
not respond, and ten families were
randomly selected to determine if the
nonrespondents included a significant
number of persons who met the study
entry criteria. The nonrespondents
were contacted by telephone and none

of them met the criteria. The reasons

for noninclusion were as follows: sei
zures beginning after the 24-hour pe
riod, absence or lack of seizures as a
suspected reaction, or the absence of
other criteria.
At the time of the pertinent immu
nization, five subjects were 3 months
of age or younger, ten subjects were 4
to 6 months of age, five subjects were 7
to 12 months of age, and two subjects
were 5 and 6 years of age, respectively.
Five subjects lived in Wisconsin, and
the remaining 17 subjects lived in nine
other states and one foreign country.
Medical records from seven subjects
were available for review, and they
revealed only minor discrepancies
from the information reported in the

questionnaire.

The male-female ratio

8:14. The time of follow-up was one
to 28 years (X 9.9 years). Eight of the
22 families could name the manufac
turer of the vaccine and four pharma
ceutical firms were so identified.
Preceding Events
Of the 22 subjects, 13 had a prior
DTP immunization without seizures.
Of these 13 subjects, six had no ad
verse reaction to the earlier immuniza
tion^); five subjects had experienced
fever, irritability, lethargy, and/or
screaming; one subject had a tempera
ture of 40 C, and another subject had a
temperature of 41.1 C. (According to
present recommendations, only the
subject with a temperature of 41.1 C
should have been excluded from fur
ther immunization with pertussis vac
was

cine.9)

One subject in this series was ill at

the time of the immunization preced
ing the first seizure. According to the
family, the symptoms were violent
coughing with vomiting. No medical
records were available for further in
formation on this patient. The pres
ence of whooping cough was ques
tioned by the family, but diagnostic
tests were not performed. This subject
was 6 months old when his seizures
started.

Family History
The 22 subjects had 48 siblings. One
sibling pair was included in this series.
Both brothers, who were previously
normal, had recurrent seizures start
ing within 24 hours of their first DTP
vaccination (at ages 3 and 4 months,
respectively), and both had severe
neurologic impairment afterward.
Both boys had been examined by sev
eral university-based pediatrie neu
rologists, and no other specific causes
for their neurologic handicaps were
discovered.
Thirty-six of the remaining siblings
of the other 20 subjects were immu
nized with DTP vaccine. Six siblings
had fevers (<40.0 C) and none experi
enced seizures.
No seizures, including febrile sei
zures, were reported in any of the
first-degree relatives of these 22 pa
tients. Three families had more distant
relatives with seizures; the rela
tionships were uncle, aunt, and cousin.

A
that

Type of Seizure
description of the initial seizure

was sufficient for classification

available from 19 of the 22 ques
tionnaires. Eleven of these 19 subjects
had generalized seizures, of which nine
were tonic-clonic and two were pro
longed absence. Eight of these 19 sub
jects had unilateral tonic or clonic sei
zures, which became secondarily
generalized in one patient. In five of
the 19 subjects the initial seizure
lasted one hour. In no subject did in
fantile myoclonic spasms occur ini
was

tially.

At this

follow-up, ten of these 22

experiencing gener
alized tonic or clonic seizures, eight
were having mixed seizures, three
were having partial complex seizures,
and one subject was seizure free. Two
of the 22 subjects had had infantile
subjects

were

spasms that started some time after

the original seizure. Only one of the 22
subjects no longer received anticonvulsants, six were receiving only one
anticonvulsant daily, and the remain
ing 15 patients received at least two
anticonvulsants daily. Of the 21 sub

jects receiving anticonvulsants,

two

seizure free for more than two

years, and the remaining 19 subjects
had seizures at least every four
months. Eight subjects were having
daily seizures at the time of follow-up.
Relation to DTP
Subjects in this series had their first
seizure after the DTP immunization,
as follows: nine after the first, four
after the second, eight after the third,
none after the fourth, and two after
the fifth. The shortest interval be
tween the DTP immunization and the
seizure was one hour, and 16 (73%) of
these 22 patients had their first sei
zure less than 12 hours after their
immunization. Fever accompanied the
seizure in 14 subjects and this was
specifically recorded in eight subjects;
the distribution of temperatures was
as follows: 38.3 C, one patient; 38.9
C, one patient; 39.4 C, two patients;
40.0 C, two patients; and 41.1 C, two
were

patients.
Eight subjects in this series

were

reimmunized with DTP vaccine

despite their prior reaction. Of these
eight patients, four had no immediate

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adverse reaction, two had repeated

seizures with good recovery, and two
had repeated seizures with deteriora
tion of the seizures and further regres
sion in their development.

Follow-up
All of the subjects were followed up

for at least one year from the onset of

their seizures. No predisposing
chronic illnesses were discovered, save
for one subject who had tuberous scle
rosis diagnosed subsequently. Objec
tive developmental assessment was
available for 15 of the 22 subjects. Four
of the 15 subjects had normal develop
ments; one subject was a self-suffi
cient college graduate, another sub
ject was a high school graduate with
known learning disabilities, the third
subject was 5V2 years old and in a
normal kindergarten, and the fourth
subject was 4V2 years old and showed
normal skills on the Denver Develop
mental Screening Test. This child is
the only subject who was seizure free
and who did not take anticonvulsant
drugs. Eleven of these 15 subjects
showed significant developmental
delays that were assessed by various
tools. Using either the Wechsler Intel
ligence Scale for Children or the Stanford-Binet Intelligence Scale, six chil
dren had respective full-scale scores of
66, 52, 39, 32, 30, and less than 20. The
development of two children was as
sessed using the Bayley Scales of In
fant Development; at 26 months of age
one child scored at the 12-month-old
level; at 37 months of age the other
child scored at the 22-month-old level.
Using the Learning Accomplishment
Profile, one child (4 years of age) was
determined to have the cognitive, so
cial-emotional, and motor skills of a 7to 8-month-old child. One child (15
years of age) had the estimated grossmotor, language, visuomotor, and finemotor skills of a 4- to 5-year-old child,
according to his pediatrie neurologist.
The last of the 15 subjects was ex
amined by a school psychologist at 28
months of age. The subject had finemotor, cognitive, and self-help skills
appropriate for 6 to 15 months of age,
and the gross-motor skills appropriate
for a 21-month-old child. Formal devel
opmental assessments were not avail
able for the remaining seven subjects.

Reports of Neurologie Adversities Following

Pertussis Immunizations

Study
Patient
Characteristics

Byers and
Moll,2 1948

Kulenkampff
et al,3 1974

15

36
23/13
1

No.

Female/male, No.
With prior seizures, No.

3/12
0

Aicardi and

Present

Chevrie,4 1975

Study

20

22

93

12/8

52/41

14/8
0*

45

73

Total

With first-degree
relatives with

seizures, No.
12 hr after
immunization, %

Reacting
With

good

recovery, %

Patients with

80
8

27

11

prior seizures were excluded by admission

COMMENT

criteria.

explanations. One patient had symp

suggestive of a pertussis infec

toms

Our data indicate that patients with

starting imme
diately after a DTP immunization have
a poor prognosis for normal develop
ment. This poor outcome is probably
biased because of the method of pa
tient selection. Prospectively collected
data would be more valuable, but given
the rarity of such events, such a collec
tion could be difficult to perform. (In
the British study, the risk for a perma
nent encephalopathy was 1:310,000 im
munizations, but the 95% confidence
limits were wide.7) Until a controlled
study on recurrent seizures after DTP
immunization is available, knowledge
about the outcome of patients similar
to those described has to be based on
uncontrolled data.
Care must be taken to avoid overinterpretation of our data. There are
inherent biases secondary to the
method of collection. Questionnaires
were mailed to parents who suspected
that their child had had an adverse
reaction to pertussis vaccine, and the
rate of return of the questionnaires
was low (54%). This favors the report
ing of severe reactions. The long delay
from the initial seizure to the report in
many subjects, while permitting pro
longed follow-up, did limit the accu
racy of some of the collected data. The
lack of control subjects makes it diffi
cult to ascribe a causal relationship to
pertussis vaccine. Nevertheless, we
believe that certain observations can
be made.
In our series, alternate causes for
the seizure must be considered. Two
patients' conditions may have had such
recurrent seizures

tion at the time of her immunization

and the other patient subsequently
showed signs of tuberous sclerosis. In
the remaining 20 subjects, no alter
nate cause was apparent that could
explain the seizures, but extensive in
vestigations were not completed on all

patients.

The types of seizures occurring in

these subjects are not unusual. The
most common initial seizure was gen
eralized tonic-clonic. In this, and in
one other series,10 infantile spasms
were never the initial seizure. It there
fore seems likely that if infantile
spasms occur immediately after a per
tussis immunization, they are coinci
dental to, rather than secondary to,
that immunization.
How pertussis vaccine relates causatively to the recurrent seizures, if it
does, is unknown. Several theoretical
causes deserve consideration. A faulty
batch of vaccine may be able to produce
this adversity, but this seems unlikely,
considering the lack of clustering of
cases in time or geography. A previ
ously suggested cause is that some
seizures after DTP immunizations are
benign febrile seizures.6 The absence
of a family history of febrile seizures in
these 22 subjects, the frequent pres
ence of a permanent neurologic handi
cap, and the lack of a recognized fever
at the time of the first seizure in most
of these subjects indicate that this
population did not represent benign
febrile seizures.
A third cause is the presence of some
unusual host factor. The presence of
two siblings with identical difficulties

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after a DTP immunization is con

sistent with a familial predisposition to
a pertussis vaccine-related seizure
disorder. Support for a familial pre
disposition comes from the work of
Steinman et al." They observed the
induction of myoclonic jerks and death
in BALB/c mice following injection
with pertussis vaccine and bovine se
rum albumin. The reaction was spe
cific for these reagents and only oc
curred in inbred mice with a specific
major histocompatibility zone. The re
action in these mice differs from what
we observed in our subjects, but the
specificity of the reaction for the per
tussis vaccine and the induction of sei
zures seem similar.
It is useful to compare our data with
the data generated from three other
reports (Table). Combining these four
series yields 97 subjects whose neu
rologic disorders appeared shortly
after a pertussis immunization. Fe
male subjects generally predominate.
The small number of subj ects with nor
mal intellectual recovery is common to
all series, and may relate to the retro
spective method of data collection.
Of these 97 subjects (Table), only
seven had first-degree relatives who
had seizures. This incidence does not
differ remarkably from what one
would expect in a group of several
hundred first-degree relatives of these
97 subjects.12 If these subjects had no
excessive number of first-degree rela
tives who had seizures, then one must
question the British recommendation
that first-degree relatives of patients
who had seizures should not receive
pertussis vaccine.8 Based on our data,
we recommend the avoidance of per
tussis vaccine in infants and children
with siblings who have had recurrent
seizures less than 24 hours after an
immunization with pertussis vaccine.
Therefore, the presence of seizures in
first-degree relatives does not pre
clude immunization with pertussis
vaccine, but the presence of recurrent
seizures starting within 24 hours of
pertussis immunization should pre
clude such immunizations in that pa
tient's siblings (this recommendation
is based on a single observation).
As two of our subjects had severe
deterioration in their performance and
seizure control following repeated im-

munization with pertussis vaccine, we

support the recommendation, made in
Great Britain and in the United
States, that pertussis immunization
not be repeated in patients who suffer
a severe reaction.8,9 It should be noted
that the conditions of not all of the
patients who had repeated exposure to
pertussis vaccine deteriorated. Four
patients tolerated repeated DTP im
munization, and another two patients
had only a few repeated seizures. It is
tempting to consider that the four pa
tients who tolerated a repeated DTP
immunization may not have had sei
zures

the number of immunizations, as has

happened in Japan and England, there
follows a disastrous increase in the
number of infants infected with per
tussis.1516 The rarity of neurologic re
actions and the severity of the natural
disease necessitate that as many in
fants as possible be protected against
pertussis infections.
Dissatisfied Parents Together, a national infor
mation-gathering, nonprofit organization, fur
nished the names of families with suspected

adverse reactions. The parents of the children

with seizures assisted in the collection of data.
David Nelson, MD, assisted in the preparation of
the manuscript.

secondary to pertussis vaccine,

but they had seizures coincidental with

a DTP vaccination.
Excluding patients with tempera
tures higher than 40.6 C following an
immunization, as recommended by the
Committee of Infectious Diseases,
would have eliminated one subject in
our series of 22 subjects. Lowering the
temperature to 40.0 C would have
eliminated the association of pertussis
vaccine and a seizure disorder in
another subject. As 1% of patients
receiving DTP immunizations have
temperatures of at least 40 C,13 such a
contraindication could eliminate a sub
stantial number of children from the
completion of their immunization
schedule.
If all of the published contraindica
tions to vaccination with pertussis vac
cine, as well as those already sug
gested, had been applied to this group
of patients, less than half would have
avoided the association of neurologic
adversity with pertussis vaccine. Most
patients at risk for these recurrent
seizures have no recognized sign of
their impending neurologic problem.
Hopefully, the development of a new
acellular vaccine will reduce the num
ber of neurologic complications follow
ing this immunization. A new vaccine,
extensively purified from the superna
tant of the pertussis culture, was re
leased in Japan in 1981 and is presently
being studied."
We in no way intend to militate
against the present recommendations
for immunizations in children. Recur
rent seizures starting within 24 hours
of a pertussis immunization are dis
tinctly rare events.7 When these rare
complications prompt a reduction in

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