Neurological adverse events associated with vaccination
Sucheep Piyasirisilpa and Thiravat Hemachudhab
Public tolerance to adverse reactions is minimal. Several
reporting systems have been established to monitor adverse
events following immunization. The present review summarizes
data on neurologic complications following vaccination, and
provides evidence that indicates whether they were directly
associated with the vaccines. These complications include
autism (measles vaccine), multiple sclerosis (hepatitis B
vaccine), meningoencephalitis (Japanese encephalitis vaccine),
Guillain±Barre syndrome and giant cell arteritis (influenza
vaccine), and reactions after exposure to animal rabies vaccine.
Seizures and hypotonic/hyporesponsive episodes following
pertussis vaccination and potential risks associated with
varicella vaccination, as well as vaccine-associated paralytic
poliomyelitis following oral poliovirus vaccination, are also
described. In addition, claims that complications are caused by
adjuvants, preservatives and contaminants [i.e. macrophagic
myofasciitis (aluminium), neurotoxicity (thimerosal), and new
variant Creutzfeldt±Jakob disease (bovine-derived materials)]
are discussed. Curr Opin Neurol 15:333±338. # 2002 Lippincott Williams &
Wilkins.
a
Division of Neurology, Department of Medicine, Faculty of Medicine, Chiang Mai
University, Chiang Mai, and bDivision of Neurology, Department of Medicine, Faculty
of Medicine, Chulalongkorn University, Bangkok, Thailand
Correspondence to Dr Sucheep Piyasirisilp, Division of Neurology, Department of
Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
Tel: +665 394 5482; fax: + 665 394 5481; e-mail: spiyasir@mail.med.cmu.ac.th
Current Opinion in Neurology 2002, 15:333±338
Abbreviations
BSE bovine spongiform encephalopathy
DTP diphtheria, tetanus toxoids and whole-cell pertussis vaccine
DTaP diphtheria, tetanus toxoids and acellular pertussis vaccine
HBV hepatitis B virus
HHE hypotonic/hyporesponsive episodes
IPV inactivated poliovirus vaccine
MMR measles, mumps and rubella vaccine
OPV oral poliovirus vaccine
# 2002 Lippincott Williams & Wilkins
1350-7540
Introduction
Vaccines are generally given to healthy persons to
prevent diseases. At present, 25 vaccines are licensed
and about seven candidate vaccines have undergone
phase 3 clinical trials [1 .]. Although all vaccines are
rigorously tested before they are licensed, no vaccine is
perfectly safe. Furthermore, adverse effects have to be
considered whether they are attributed to the vaccines or
merely coincidences; consideration must also be given to
whether the risks outweigh the bene®ts. When any
suspected adverse reactions are reported with vaccines,
the following criteria are used to assess a causal
relationship [2 .]: strength of the association, consistency,
speci®city, temporal association, dose±response effect,
biological plausibility, coherence, experimental evi-
dence, and analogy to other biologic systems. Risk±
bene®t analyses determine whether a particular vaccine
is cost-effective. For instance, post-measles-vaccination
encephalopathy occurs in approximately 1 in a million
recipients, whereas the incidence of encephalomyelitis
after measles infection is much higher (approximately 1
per 1000) [1 .].
The present review provides an update on progress in
the adverse central nervous system events that are
associated with vaccines. Only major studies that showed
evidence to substantiate such associations are considered
here. Other well recognized adverse reactions are
described elsewhere [3,4 .].
Complications with currently available
vaccines
Currently available vaccines have been monitored for
their safety. Because vaccines are administered to
healthy persons (in particular to infants), public tolerance
to adverse reactions is low.
Measles vaccine and autism
Autistic spectrum disorder is a complex developmental
disorder that is characterized by qualitative de®cits in
social interaction and communication, and restricted,
repetitive and stereotyped patterns of behaviours,
activities and interests [2 .]. Attention to the possible
relation between the measles, mumps and rubella
vaccine (MMR) and autistic spectrum disorder was
prompted by a case series of 12 children with chronic
enterocolitis [5]. Of those children, 10 had autistic
spectrum disorder. Eight of the 12 children were
vaccinated with MMR. Measles nucleocapsid antigen
has also been found in the intestinal wall of patients with
in¯ammatory bowel disease [6]. Furthermore, Kawashi-
333
334 Inflammatory diseases
ma et al. [7] detected and sequenced vaccine strains of
measles virus in three out of nine children with autistic
enterocolitis.
Nevertheless, no causal association between autistic
spectrum disorder and MMR was identi®ed in subse-
quent studies. Taylor et al. [8] studied almost 300
patients with autistic spectrum disorder born since 1979
in the UK. There was no sudden increase in cases by
year of birth following the introduction of MMR in 1988,
and there was no temporal association with onset of
autism within 1 or 2 years after MMR vaccination. A
retrospective study of MMR immunization coverage
rates among children born during 1980±1994 in Califor-
nia and of autism caseloads among those children [9]
demonstrated a lack of correlation between trends in
MMR coverage and numbers of autistic spectrum
disorder cases. Another time trend analysis of data
collected from children aged 12 years or younger who
had been diagnosed with autism and were born between
1988 and 1999, and from boys aged 2±5 years born
between 1988 and 1993 in the UK [10 .] found no
correlation between the prevalence of MMR vaccination
and increased risk for autism over time. During the
period from 1988 to 1993, the 4-year risk for diagnosed
autism increased nearly fourfold. In contrast, the
prevalence of MMR vaccination was almost constant,
at approximately 97%. Finally, the US Institution of
Medicine [11] concluded that the available evidence
does not support the hypothesis that MMR causes
autism.
Hepatitis B vaccine and multiple sclerosis
Concerns regarding the safety of vaccination in patients
with multiple sclerosis have been expressed since the
early 1990s. Theoretically, immune stimulation from
vaccination could precipitate the onset of multiple
sclerosis in susceptible persons or could lead to relapses,
perhaps as a result of molecular mimicry between
vaccine antigens and human proteins. Although the
`molecular mimicry hypothesis' is at least plausible, this
hypothesis remains controversial because infection with
wild-type hepatitis B virus (HBV) has not been
identi®ed as a risk factor for multiple sclerosis and there
is no evidence that HBV protein may trigger an attack on
nerve tissue [12].
A well designed, nested, case-control study recently
showed no association between HBV vaccination and
development of multiple sclerosis [13 . .]. The relative
risk for multiple sclerosis for women vaccinated against
HBV within 2 years before the index date as compared
with unvaccinated women was 0.7 (95% con®dence
interval 0.3±1.8), and that for women with exposure to
HBV vaccine at any time before the onset of disease was
0.9 (95% con®dence interval 0.5±1.6). A further case-
crossover study of patients with multiple sclerosis found
no increased risk for relapses after vaccination [14 . .].
The relative risk for relapse associated with exposure to
any vaccination during the previous 2 months before
relapse was 0.7 (95% con®dence interval 0.4±1.3), and
that associated with exposure to HBV vaccination was
0.7 (95% con®dence interval 0.2±2.2).
Japanese encephalitis vaccine and neurological
complications
Approximately 10% of those administered Japanese
encephalitis vaccine reported systemic reactions, such
as fever, headache, malaise and rash [4 .]. Serious adverse
events include hypersensitivity-type reactions and neu-
rological reactions [4 .,15]. A review of postmarketing
data in Japan from 1996 to 1998 [15] revealed 17
neurological disorders after the administration of ap-
proximately 9.4 million doses of Japanese encephalitis
vaccine. Among those, 16 cases had meningitis or
meningoencephalitis, including ®ve probable cases of
acute disseminated encephalomyelitis (0.2 per 100 000
vaccinations). In Denmark, acute disseminated encepha-
lomyelitis following Japanese encephalitis vaccination
occurred more frequently, at approximately 1 in 50 000±
75 000 vaccinees [16]. In contrast, no serious neurological
events were reported in the USA after the administration
of more than 813 000 doses of Japanese encephalitis
vaccine between 1993 and 1998 [15].
Influenza vaccine, Guillain±Barre syndrome and giant
cell arteritis
The association between the swine in¯uenza vaccination
and onset of Guillain±Barre syndrome after an immuni-
zation campaign during the period 1976±1977 was
notable because of the high relative risks, ranging from
4.0 to 7.6 [17]. During the 1992±1993 and 1993±1994
seasons, concerns regarding vaccine-associated Guillain±
Barre syndrome were expressed again, when the US
Centers for Disease Control and Prevention reported an
increased incidence of this complication, without in-
dicating the number of people at risk. Hence, Lasky et
al. [17] undertook an investigation and found that there
was no increase in risk for Guillain±Barre syndrome
associated with in¯uenza vaccination (relative risk 1.7,
95% con®dence interval 1.0±2.8; P = 0.04). Interestingly,
another neurological complication recently claimed to be
associated with in¯uenza vaccination is giant cell arteritis
[18,19].
Animal rabies vaccine and human skin infection
Oral vaccination of wild animals with feed that contains
recombinant vaccinia/rabies glycoprotein virus is widely
used to control rabies in Europe and in the USA [20 .].
Although this vaccine virus is highly attenuated, in
theory adverse events (including in the central nervous
system) may occur, particularly in immunocompromised
 Neurological events and vaccination Piyasirisilp and Hemachudha 335
persons, pregnant women and patients with an exfolia-
tive skin condition [21]. Thus far there has been only
one reliable documented case of human skin infection
with vaccinia/rabies glycoprotein virus following trans-
dermal exposure in an immunocompetent patient [20 .].
Improved vaccines to address complications
Since 1990, improved vaccines have become available
for protection against pertussis, Haemophilus in¯uenzae
type b, pneumococcal disease and typhoid [4 .]. Serious
adverse events have been described for pertussis
vaccine.
Pertussis vaccine and seizures and
hypotonic/hyporesponsive episodes
Vaccination with diphtheria, tetanus toxoids and whole-
cell pertussis vaccine (DTP) has been associated with
increased risks for seizures and hypotonic/hyporespon-
sive episodes (HHEs) [22 . .,23]. In 1991 the Vaccine
Safety Datalink project ± a population-based study of
adverse reactions after childhood immunization initiated
by the US Centers for Disease Control and Prevention
± collected data from more than 600 000 children.
Barlow et al. [22 . .] analysed this cohort to study the
associations between vaccinations and risks for ®rst and
subsequent seizures and neurodevelopmental disability.
That study showed that DTP vaccination was signi®-
cantly associated with febrile seizures only on the day
of vaccination (relative risk 5.7, 95% con®dence interval
2.0±16.4). This was also the case for MMR, with an
increased risk for febrile seizures 8±14 days after
vaccination (relative risk 2.8, 95% con®dence interval
1.4±5.5). Neither DTP nor MMR was associated with
an increased risk for nonfebrile seizures. Children with
febrile seizures after vaccination were found to be at no
greater risk for subsequent seizures or neurodevelop-
mental disorders. Those ®ndings are consistent with
earlier reports [24,25].
The newly licensed diphtheria, tetanus toxoids and
acellular pertussis vaccine (DTaP) has been developed
to replace DTP. Acellular vaccines are composed one
or more puri®ed proteins from Bordetella pertussis [4 .].
After the use of millions of doses of DTaP, adverse
reactions, such as fever, prolonged crying and injec-
tion site reactions, were much less common [26]. In a
murine model, the administration of whole-cell
vaccine induced production of the proin¯ammatory
cytokine interleukin-1b in the hippocampus and
hypothalamus [27 .]. This was not observed in the
case of acellular vaccine. Seizure-like behavioural
changes and increased production of interleukin-1b
were noted when active pertussis toxin and lipopoly-
saccharide (which are present in the whole-cell
vaccine) were injected in mice. However, acellular
vaccine did not cause seizures in mice, probably
because of the induction of the anti-in¯ammatory
cytokine interleukin-10.
HHE is an adverse reaction that usually occurs after
immunization with DTP and is less common with DTaP
or HBV vaccine [23,28]. It is characterized by sudden
onset of pallor, hypotonia and unresponsiveness within
48 h after immunization. The median age of onset of
HHE is 4 months, ranging from 1 to 107 months [23].
Generally, it is a benign, self-limited and nonrecurrent
event. Nonetheless, a few patients with HHE developed
autism and complex partial epilepsy that were not
known to be associated with immunization [23]. No
recurrence of HHE was found after subsequent admin-
istration of DTP or DTaP [23,29,30]. Therefore, the
Advisory Committee for Immunization Practices [31]
considers HHE a precaution against further pertussis
vaccination.
New vaccines to address complications
New vaccines have become available for varicella, Lyme
disease, and hepatitis A virus and rotavirus infections
[4 .]. Potential harms in varicella vaccination have been
identi®ed.
Varicella vaccine and potential risks
Although varicella is a benign disease, serious complica-
tions or death may occur. Neurological complications
following varicella or zoster include myelitis, ventriculitis
and meningitis, Reye's syndrome, and large-vessel and
small-vessel encephalitis in immunocompetent and im-
munode®cient patients, respectively [32]. Despite the
fact that live-attenuated varicella vaccine has been
licensed in the USA for use in healthy children since
1995 [33 .], there is a concern that the vaccine may not be
safe. Vazquez et al. [34 .] conducted a case-control study of
330 children with potential chickenpox and 500 matched
control individuals in Connecticut, and found high
effectiveness of the varicella vaccine. Adverse reactions
included fever, mild local reactions and varicella-like rash
[33 .]. Immunization with a higher concentration of virus
did not result in a greater frequency of adverse events. A
second dose of vaccine caused fewer reactions. No serious
adverse reactions were reported.
Potential harms may occur as a result of varicella
vaccination. First, there is a theoretical risk of transmis-
sion of attenuated virus from vaccinees to others. At
present, no epidemiological study has con®rmed any
transmission of vaccine virus following varicella vaccina-
tion [33 .]. Only case reports of transmission have been
published [35,36]. Another theoretical risk, predicted by
mathematical models, is a shift in varicella cases to an
older age group, resulting in more severe disease [33 .].
Also, increased zoster in adults may appear more often as
a result of widespread vaccination in children. However,
336 Inflammatory diseases
there are insuf®cient data at present to support those
models.
Changes in immunization strategies to
address complications
New and improved vaccines become available, but
vaccine recommendations and schedules have also been
modi®ed and changed.
Poliomyelitis vaccine and vaccine-associated paralytic
poliomyelitis
The global poliomyelitis eradication campaign is
moving into its ®nal stages. Three World Health
Organization regions (i.e. the Americas, Western Paci®c
and European regions) have eliminated or nearly
eliminated poliovirus [4 .]. The remaining major foci
of poliovirus transmission are in southern Asia and in
Africa [4 .]. These achievements have primarily been
based on the use of oral (live-attenuated) poliovirus
vaccine (OPV). Immunization with OPV is painless and
produces optimal intestinal immunity. Furthermore, the
attenuated virus shed in faeces can immunize unvacci-
nated persons in the community, leading to herd
immunity. However, in the polio-free countries, such as
Brazil, cases of poliomyelitis were all attributable to
vaccine, with an estimated risk of 1 in 2.4 million for
the ®rst dose and 1 in 13 million for the total number
of OPV doses [37]. Cases of vaccine-associated paralytic
poliomyelitis were also reported in the Dominican
Republic and in Haiti [38]. The US Centers for
Disease Control and Prevention sequenced the virus
from those victims and found that virus reverted to the
virulent wild-type form. This was the ®rst reliable
report that attenuated poliovirus may have reverted and
spread contagiously.
Because there is a risk, albeit minimal, for vaccine-
associated paralytic poliomyelitis and because a highly
improved inactivated poliovirus vaccine (IPV) has been
developed, this vaccine has begun to replace OPV. Four
doses of IPV have been recommended for routine
childhood immunization in the USA since January
2000 [4 .]. Denmark, Israel and one province of Canada
have used sequential schedules of IPV followed by OPV
[4 .]. In the USA, OPV may be used only in certain
circumstances, such as for mass vaccination campaigns
during outbreaks, for naõÈve children who will travel
within 4 weeks to an endemic area, and for children of
parents who do not accept IPV [4 .].
In developing regions, routine immunization with IPV
may not be practical because of its higher cost and the
requirement for injection. Therefore, OPV is still in use,
particularly in areas endemic for polio. Some countries,
such as Oman, combine the advantages of both OPV and
IPV by adding a supplemental dose of IPV to the routine
®ve doses of OPV. This is to boost immunity against
type 3 poliovirus, which is usually suboptimal in infants
in many developing countries [39].
Complications caused by adjuvant,
preservative, or contaminants
Not only may the antigen in the vaccine itself cause
adverse effects, but also any substances in the vaccine
may cause complications.
Aluminium and macrophagic myofasciitis
Aluminium is widely added to vaccine formulations for
diphtheria, tetanus, hepatitis A and B viruses, and
anthrax [4 .,40,41 . .]. Recently, macrophagic myofasciitis
± a new type of in¯ammatory myopathy ± was
described [42]. Patients with macrophagic myofasciitis
had diffuse steroid-responsive arthromyalgias and
chronic fatigue. Some patients also had demyelinating
central nervous system disorders, such as sensorimotor
symptoms, pyramidal signs, cerebellar signs, visual loss,
cognitive and behavioural disorders, and bladder
dysfunction [43 .]. Deltoid muscle biopsy from those
patients showed granular periodic acid±Schiff reagent-
positive macrophage in®ltration intermingled with
lymphocytes [41 . .]. Intracytoplasmic inclusions contain-
ing aluminium hydroxide were detected in macro-
phages from some patients. These macrophagic
myofasciitis lesions were exclusively detected in the
deltoid muscle, a common site of vaccine injection. All
patients in that series had received vaccines against
hepatitis B virus (86%), hepatitis A virus (19%) or
tetanus toxoid (58%) within the preceding 3±96
months, leading to the hypothesis that aluminium
hydroxide in the vaccine may induce an abnormal
in¯ammatory response [41 . .]. This concept has ignited
a public debate over the safety of aluminium. However,
aluminium may not be removed from vaccines because
any effort to replace aluminium with another adjuvant
will be costly and time consuming [40].
Thimerosal and neurotoxicity
Thimerosal ± a derivative of ethylmercury that is used as
a preservative to prevent bacterial contamination ± has
recently been considered to be a potential neurotoxin in
infants. Thimerosal is used in over 30 US-licensed and
currently marketed vaccines, including HBV vaccine
[44 .]. Nearly a decade ago, HBV vaccine was recom-
mended for all infants [45].
The relatively lower body weight of infants led to a
concern that the cumulative exposure to mercury from
infant vaccines might exceed the toxic level. No dose
adjustment was made on the basis of birth weight [46].
Postvaccination mean mercury levels in preterm infants
were signi®cantly higher than those in term infants
[46]. Some childhood vaccines that contain thimerosal
 Neurological events and vaccination Piyasirisilp and Hemachudha 337
are single-antigen HBV vaccines, some DTaP, all DTP
and some Haemophilus in¯uenzae type b vaccines [44 .].
Depending on the particular vaccine formulation and
schedule, an infant may receive a cumulative mercury
dose as high as 187.5 mg during the ®rst 6 months of
life, which exceeds the maximum dose recommended
by guidelines for methylmercury intake [44 .]. Although
the toxicity associated with low-dose exposure to
thimerosal is unknown, evidence indicates that the
toxicities of ethylmercury and methylmercury are
similar [44 .,46]. The toxicity of methylmercury was
identi®ed with the consumption of contaminated ®sh in
Minamata, Japan [44 .]. Delays in motor function and
subtle cognitive de®cits were reported in patients
exposed to methylmercury [44 .].
Although the toxicity of thimerosal is uncertain,
thimerosal has been removed from vaccines since
1999. Thimerosal-free vaccines are available in HBV,
DTaP and H. in¯uenzae type b formulations [44 .].
Physicians may select existing products that do not
contain thimerosal in order to reduce the exposure of
children to mercury. Although preservative-free vac-
cines may be the option in the USA, multidose vials
of vaccines containing thimerosal remain very impor-
tant in immunization programmes of developing
countries. The World Health Organization indicated
that the bene®ts of vaccination and the risk for
bacterial contamination of multidose vials are much
greater than the risks associated with exposure to
thimerosal [44 .].
Bovine-derived materials and new variant
Creutzfeldt±Jakob disease
In 1993 the US Food and Drug Administration
recommended that US manufacturers should not use
materials from animals from countries that have reported
bovine spongiform encephalopathy (BSE) to produce
biological products [47]. At this time, the countries
known to have BSE are the UK, France, the Irish
Republic, Northern Ireland, Switzerland and Oman [48].
(Additional information can be obtained from the US
Food and Drug Administration website [49].) Some
human vaccines currently in use were made from
materials obtained from those countries, but the
potential risk of transmission of the BSE agent by
vaccination has not been con®rmed in humans [48].
However, an accidental infection from an animal vaccine
was suggested as the explanation for outbreaks of scrapie
in Italy in 1997 and 1998 [50]. In July 2000, the US Food
and Drug Administration asked two advisory committees
to consider the potential for human exposure to BSE
agent [48], and concluded that the risk for new variant
Creutzfeldt±Jakob disease posed by these vaccines was
theoretical and remote, and that the bene®ts of
vaccination outweighed the risk for new variant Creutz-
feldt±Jakob disease. As a precautionary measure, the
Administration requested that manufacturers use bovine-
derived materials from BSE-free countries from the year
2001.
Conclusion
Vaccinology is a dynamic subject. Currently available
vaccines have been improved. New vaccines have been
developed. Even the immunization strategy may be
changed once the goal is accomplished. However,
immunization is not without risk, and adverse events
are a further factor to consider. As more data become
available, elaborate analyses of relative bene®ts and risks
will be necessary to evaluate vaccine recommendations.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
. of special interest
.. of outstanding interest
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