A Causal Theory of Autism: Is fever suppression involved in the etiology of autism and neurodevelopmental disorders?
by Anthony R. Torres, M.D.
Copyrighted and submitted for publication 1/15/03
http://www.rollingdigital.com/autism/BMC_fever.html
Is fever suppression involved in the etiology of autism and neurodevelopmental
disorders?
— Abstract —
Background
There appears to be a significant increase in the prevalence rate of autism.
Reasons for the increase are unknown, however, there is a substantial body of
evidence that suggests the etiology involves infections of the pregnant mother
or of a young child. Most infections result in fever that is routinely
controlled with antipyretics such as acetaminophen. The blocking of fever
inhibits processes that evolved over millions of years to protect against
microbial attack. Immune mechanisms in the central nervous system are part of
this protective process.
Hypothesis
The blockage of fever with antipyretics interferes with normal immunological
development in the brain leading to neurodevelopmental disorders such as autism
in certain genetically and immunologically disposed individuals.
Testing the hypothesis
Epidemiological studies to determine associations between the use of anti-pyretics
and neurodevelopmental disorders should be undertaken. Biochemical tests will
involve the examination of fluids/serum by mass spectrometry and the
determination of cytokine/chemokine levels in serum and cell culture fluids
after stimulation with fever inducing molecules from bacteria, viruses and
yeast. Postmortem brain can be examined by immunohistochemistry to determine
altered levels of chemokines/cytokines and other proteins.
Implications of the hypothesis
1) The use of antipyretics during pregnancy or in young children may be reserved
for more severe fevers. 2) The perplexing genetic findings in autism may be
better understood by categorizing genes along functional pathways. 3) New
treatments based on immune, cell, pharmacological or even heat therapies may be
developed.
— Hypothesis—
Background
According to epidemiological studies, autism, a neurodevelopmental disorder,
is increasing in the pediatric population [1]. In 1966 the prevalence rate was
4-5/10,000 births [2], while two recent studies show prevalence rates of
14.9/10,000 [1] and 34/10,000 [3]. This apparent increase raises concerns about
an autism epidemic.
In 1943, Kanner [4] described autism as a neurodevelopmental disorder with
impairments in social interactions, restricted stereotyped interests, and
abnormalities in verbal and nonverbal behavior. Little is known about the
etiology, and the diagnosis of autism is done by behavioral criteria as no
biomarkers have yet been identified. There is a strong familial component to
autism [5], and etiologies based on infectious [6], autoimmune [7,8,9,10], and
cytokine factors [11,12] have been proposed.
About 40% of parents with autistic children report that their seemingly normal
children experienced developmental regression after being vaccinated. However,
the theory of vaccines or adjuvants being involved in the etiology [13] has
little support as epidemiological studies have failed to show an association
with the measles, mumps, and rubella (MMR) vaccine [14,15,16] and autism.
It has been reported that 43% of mothers with an autistic child experience upper
respiratory tract, influenza-like, urinary, or vaginal infections during
pregnancy compared to only 26% of control mothers [9]. This suggests that
certain cases of autism may be a sequela of pathogenic infections, especially
those of a viral origin [17,18,19].
There is no overt pathological lesion in autism, however, subtle abnormalities
in the cerebellum, hippocampal fields CA1-CA4, entorhinal cortex, amygdala,
behavioral differences and imbalances in cytokines and brain growth factors
suggest that abnormal brain development is important in the pathogenesis
[20,21,22].
Pathological infections, including vaccinations, commonly result in fever. For
example, 50-60% of young children develop fever after receiving the MMR vaccine
[23]. Fever is defined as an increase in the normal set point of body
temperature. During the rising phase of fever, normal body temperature is below
the new set point and the body, being hypothermic, uses several heat conserving
and heat generating physiological reflexes, as well behavioral responses, to
raise body temperature. The breaking of fever results in a variety of
heat-losing reflexes and behavioral responses to lower body temperature.
There are two related fever pathways. The intraperitoneal injection of
lipopolysaccharide (LPS), a potent pyrogen, results in the production of various
cytokines from organs in the viscera. A signal from IL-1$ is thought to initiate
afferent information traveling from the vagus nerve to the hypothalamus to
increase hypothalamic IL-1$. This in turn causes an increase in hypothalamic
IL-6, which raises the thermoregulatory set point. This pathway is mediated via
prostaglandins that can be blocked by cyclooxygenase inhibitors (antipyretics).
The second fever pathway, also initiated in the hypothalamus by afferent signals
from the vagus nerve, is mediated by locally produced macrophage inflammatory
protein-1 (MIP-1), a chemokine. MIP-1 appears to act directly on the anterior
hypothalamus via a non-prostaglandin mechanism [24].
Fever is metabolically expensive: every 1oC rise in temperature increases the
metabolic rate approximately 10% [25]. It stands to reason that a defense
mechanism that evolved over millions of years and is so costly in terms of
energy must be important. Numerous studies have shown that fever enhances the
immune response by increasing mobility and activity of white cells, stimulating
the production of interferon, causing the activation of T-lymphocytes, and
indirectly reducing plasma iron concentrations [24,25,27,28]. Antiviral and
antibacterial properties of interferon are also increased at febrile
temperatures [29,30]. A decreased morbidity and mortality rate has been
associated with fever in a variety of infections [31,32,33,34,35]. Newborn
animals infected with a variety of viruses have a higher survival rate when
febrile [36]. The use of antipyretics to suppress fever results in an increased
mortality rate in bacterially infected rabbits [37] and an increase in influenza
virus production in ferrets [38]. Brain hyperthermia markedly exacerbates
neuronal injury [39]. There is anecdotal evidence that children with autism show
behavioral improvement when febrile (D. Odell, personal communications, 2003).
Sequestering fever during pregnancy may have effects on the fetus. Goetzl et al.
[40] have shown that the treatment of epidural fever with acetaminophen
significantly decreased maternal and fetal serum IL-6 levels at the time of
birth. This may be significant, as it appears that the fetus is incapable of
producing IL-6 at the time of birth and is dependent on maternal IL-6 [41].
Ozato et al. [42] described the response of cell-surface toll-like receptors (TLRs)
upon binding to microbial pathogens. There are at least 10 TLRs that recognize
ligands from bacteria, viruses, yeast, and nucleic acids from viruses. There is
a high binding specificity of the different TLRs for each microbial structure
referred to as pathogen-associated molecular patterns (PAMPs) [42]. The best
studied is TLR4 that binds LPS from gram-negative bacteria. The ligation of LPS
to cell surface TLR4 initiates a signal cascade that results in the activation
of intracellular nuclear factor kappa beta (NF6B) and the transcription of
numerous genes involved in immune responses. This signaling pathway appears to
be common to all the TLRs whether the PAMPs originate from bacteria, virus, or
yeast. TLR are mainly expressed myeloid lineage cells including macrophages,
granulocytes and dendritic cells.
The central nervous system exhibits a similar immune reaction to pathogenic
infection. The binding of LPS to TLR on microglia cells (brain macrophage) leads
to the expression of cytokines, chemokines, extracellular matrix proteins,
proteolytic enzymes, and complement proteins in the brain parenchyma [43,44].
The release of the many different cytokines and chemokines produced by microglia
cells exert a diversity of actions in neurodevelopment as well as
neurodegeneration [44].
Fever is generally considered harmful by physicians and is treated with
antipyretics as it may lead to febrile seizures, stupor, dehydration, increased
breathing, discomfort, and tachycardia [45]. Home use of antipyretics upon the
first signs of a fever is also common. This approach has lead to the ubiquitous
use of aspirin, acetaminophen, nimesulide, and ibuprofen, which control
temperature by inhibiting prostaglandin synthesis in the hypothalamus. Aspirin
it is not currently used in the pediatric population due to an association with
Reye’s syndrome [46].
Acetaminophen (AP), the most widely used medication, is considered safe when
used at pharmacological doses. High doses of AP can lead to liver failure and
death without proper emergency treatment. Although the hepatotoxic actions of AP
have been extensively researched, there is evidence that it is also an
immunosuppressive agent. Suppression of the delayed hypersensitivity response
and mixed lymphocyte reaction occur in mice fed AP [47]. It has recently been
shown that AP added directly to splenocyte cultures inhibited the in vitro
antibody response without affecting cell viability [48]. Other immune effects
include an impairment of TNF-alpha release [49] and a 10-20-fold increase of
monocyte chemoattractant protein (MCP-1) and chemokine receptor (CCR) from liver
Kupffer cells (macrophages) [50]. These studies suggest that the AP directly
effects immune cells and is not a secondary response to AP-hepatitis.
Presentation of the hypothesis
The premise of this theory is that the blockage of fever with antipyretics
interferes with normal immunological development in the brain, leading to
neurodevelopmental disorders in certain genetically and immunologically disposed
individuals. The effects may occur in utero or at a very young age when the
immune system is rapidly developing.
Testing the hypothesis
The experimental avenues below can be used to test the theory:
1) Epidemiological studies to determine any association between the use
antipyretics and neurodevelopment disorders.
2) Peripheral blood cells from subjects with neurodevelopmental disorders and
controls can be examined in culture for chemokine/cytokine production after
stimulation with bacterial, viral, or yeast PAMPs.
3) An example of infection postulated to progress to neurological abnormalities
goes by the acronym PANDAS for Pediatric Autoimmune Neuropsychiatric Disorders
Associated with Streptococcal infections [51]. This disorder could be examined
as a model for understanding the immune system in autistic subjects.
4) Postmortem brain can be examined by immunohistochemistry to determine altered
expression of chemokine/cytokine, complement, extracellular matrix, and HLA
proteins.
5) Serum samples can be evaluated by analytical methods in an attempt to detect
biomarkers.
6) Animal models can be tested in vivo to determine the neurodevelopmental
effects of fever.
Implications of the hypothesis
Several important changes may result from studies designed to test the theory:
1) The use of antipyretics during pregnancy or in young children may be reserved
for more severe fevers.
2) Many of the perplexing genetic findings in autism may be better understood by
categorizing genes along functional pathways.
3) The discovery of specific immune defects may suggest new therapies for
neurodevelopment disorders. These treatments may be based on immune, cell,
pharmacological or even heat therapies that alter the CNS immune system.
List of abbreviations: Defined in text.
Competing interests: None declared.
Acknowledgements
David Ward at Yale University, Dennis Odell and Virgil Caldwell at Utah State
University for thoughtful comments on the manuscript and Melanie Fillmore for
proofreading.
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Copyright © 2003, A. R. Torres, M.D., Utah State University, All rights
reserved.