THE NIDS MEDICAL ADVISORY BOARD PRESENTS:
A DRAFT PROPOSAL
OF ITS NEURO-IMMUNOLOGY HYPOTHESIS STATEMENT CONCERNING AUTISM
Clinical
Hypothesis - Immune "Dysfunction / Dysregulation" - A Reason for Childhood Neuro-Cognitive
Dysfunction:
Autism, as
classically defined, is a devastating disorder that often robs children of their
ability to communicate and thrive in society. It is characterized by primary
alterations in social interactions and receptive/expressive language, and is
often accompanied by symptoms including ritualistic behaviors and a lack of
imaginative play.
Additionally,
many “autistic” children exhibit a craving for sensory (vestibular) stimulation
that often manifests itself in self-stimulatory behaviors (e.g., spinning and
hand-flapping).
By definition,
autism has an early onset before 30 months of age (which has now been extended
to 36 months under the DSM- IV guidelines), while disorders appearing later in
life have been thought to be symptomatically and medically different from
“autistic” conditions. However, publications over the last 13 years have cast
some doubt on this assumption, and it has been noted in the literature that
there is no firm evidence that similar or identical syndromes might not develop
in older children.1
From an
epidemiological standpoint, autism has migrated from a rare disorder to one that
is now ten (10) to twenty (20) times more likely to be diagnosed. Ten years ago, “autism” occurred in 1-3
per 10,000 births. Now, current estimates suggest an incidence rate of 20 – 40
per 10,000 births. In fact, “cluster groups” throughout the world are currently
being analyzed due to even higher incidence rates. It is also worth noting that
other neuro-cognitive conditions such as “quiet” ADHD and “mixed” ADHD have
received a renewed focus and attention among children and adolescents due to
their perceived increase in incidence rates. Although a portion of these
increases can likely be attributed to better and earlier recognition by the
medical community and parents, the NIDS Board believes that this increase must
prompt a change in how we approach these children.
Specifically, we
must begin to consider that these are not congenital, brain-damaged conditions
but instead are medical disease processes acquired early in life.
In accordance
with this premise, recent discussions have focused on the differentiation
between “congenital autism” (including “classic” Kanner autism) and another form
related to neurologic and medical disorders such as tuberous sclerosis,
phenylketonuria, congenital rubella, and Down’s syndrome. However, a third form
has emerged which is being referred to as “acquired or regressive autism”
(perhaps the largest sub-group of these children). For purposes of this
hypothesis statement, “acquired autism” is a condition in which the child
develops normally for the first 12 to 18 months of life and then regresses into
the increasingly wide spectrum of “autistic” disorders.
These children
challenge the previous belief that 70% to 80% of autistic children are mentally
retarded. They crawl, sit up, walk, and usually attain “normal” motor milestones
on schedule. Until the age of symptom onset, they are affectionate and appear to
have above average intelligence.
Children with
acquired autism may begin to develop some speech but then, without warning,
cease to progress, and begin to regress. Suddenly, these children become
withdrawn. They vacillate between being quiet and hyperactive. Often
self-stimulatory behaviors (i.e. arm flapping, rocking, spinning, or head
banging) may develop.
Over time, some
manifest symptoms that are both similar and atypical of children previously
diagnosed as having congenital autism. The authors propose that many of these
children with acquired autism fall into the medical category of N.I.D.S.
(Neuro-Immune Dysfunction Syndromes), and need to be viewed as suffering from an
auto-immune medical illness that is potentially treatable.
The
Past:
Unfortunately, without the tools or the technology to accurately
investigate the human brain, the label of “autism” evolved as a set of symptoms
in a young, dysfunctional child. In its most severe form (“classic autism”),
effective speech was absent and clinicians often saw symptoms of repetitive,
highly unusual, aggressive and sometimes self-injurious behavior. Those
afflicted had extremely abnormal ways of relating to people, objects, or events.
Parents noticed that something was “not right,” often within the first three to
six months of life. These children typically did not smile and often resisted
affection.
Most researchers and clinicians did not look for “medical” answers to
autism because they believed it was a disorder that was medically untreatable.
Without the technology to understand these children, pediatricians and pediatric
psychologists accepted the concepts of poor parenting, childhood
psychosis/schizophrenia and classified “autism” as a psychological and/or
developmental disorder. Treatment was typically delivered by psychologists and
psychiatrists.
Eventually, it
became well documented that known medical disorders such as tuberous sclerosis,
PKU, congenital rubella, and others could cause autism. However, to date, these
remain rare disorders and a small sub-group of autism.
Given that
researchers are just now beginning to understand the medical origins and
implications of the potential therapies for these children, autism is still
treated primarily by psychologists and educators (with mixed results).
Past Medical
Research:
A review of the existing medical literature relative to autism research
reveals evidence of an emerging medical disease process in these children. For
instance, research indicates that autism can follow infectious disorders
affecting the central nervous system including
encephalitis.2 3 4 5 Multiple studies
have focused on various anatomic locations of suspected dysfunction.6 7 8 9
It is important to note that
emphasis is often put on the medial temporal lobe. Pertinent to this new “model”
of dysfunction, are the multiple published reports of autistic symptoms
developing in association with encephalitis in children. (Ref: 1981 DeLong10,
1986, Gillberg,11 1989,12) Most of these reports site injury to the temporal
lobes as part of their findings. This is consistent with the areas of decreased
function identified on NeuroSPECT scans initially by Dr. Ismael Mena from the
NIDS Board and now by Dr. Bruce Miller and Dr. Fred Mishkin, both of who have
clinical research in progress.
New research
techniques are increasing the rates at which Herpes Simplex Virus (HSV)
sequences are being identified in temporal lobe tissues13,14 (i.e., locales
likely to be substrates for various aspects of autism). In 1975, an article was published in
Cortex15 describing a syndrome similar to autism in adult psychiatry. The
condition involves the loss of emotional significance of objects, the inability
to adapt in social settings, the loss of recognition of the significance of
persons, and the absence of sustained purposeful activity after temporal lobe
damage.
The literature also comments on the cognitive and behavioral deficits
caused by temporal lobe damage in Herpes encephalitis. There are many reports,
particularly in the British literature,16 suggesting a connection to
coxsackie/enteroviruses, while in the United States it has been suggested that
many cases may be linked to the Herpes family of viruses (i.e., EBV, HHV6, HHV7,
CMV, etc.).17 18 19 20 21 Neither theory has been conclusively proven, nor has
the evidence for a contagious disorder been conclusive (although some have
inferred it based upon incidents related to epidemic outbreaks22 23) However,
HSV in humans has long been known to prefer temporal lobe and limbic sites. One
theory focuses on the olfactory nerves as a possible route for infection, but
oral cavities may also provide entry. In 1996, O’Meara et al postulated that:
"Inoculation of murine tooth pulp with HSV selectively infected the mandibular
division of the trigeminal nerve and caused encephalitis predominantly affecting
the temporal cortex and limbic system, a pattern of disease similar to human HSE
[herpes simplex encephalitis]...24."
While other
studies have also implicated the temporal lobes in the pathogenesis of
autism,25,26 a direct association between temporal lobe pathology and autism has
not yet been proven conclusively. In fact, research has found a variety of
lesions in the “autistic” brain, particularly in the cerebellum.27 These
variable findings may be due to the heterogeneity (differences) in the possible
etiologies or time/duration effects within this syndrome.
Although Herpes
virus has a predilection for the temporal lobes,28 the course of autism does not
suggest an acute infection with traditional Herpes viruses. 29 However, delayed
temporal lobe development early in life may produce different symptoms from
those arising from deterioration or destruction of previously normal
lobes.
In summary, although not conclusive, past research further strengthens
the linkage of the temporal lobe and “autistic” symptoms. Boucher and Warrington
noted similarities between behavioral deficits reported in animals with
hippocampal lesions and autistic behavior.30 Medial temporal lobe damage on
pneumoencephalograms was reported in a subset of autistic children.31 Damasio
and Mauer proposed that “the syndrome results from dysfunction in a system of
bilateral neural structures that includes the ring of mesolimbic cortex located
in the mesial frontal and temporal lobes, the neostriatum, and the anterior and
medial nuclear groups of the thalamus. At least two other studies have also
implicated the temporal lobes in the pathogenesis of autism.32,33
The
Present:
With new and more precise tools and technology available to us now, the
medical anatomy of “autism” is gaining definition after years of conflicting
findings. Currently, EEG abnormalities34, immune markers, and NeuroSPECT
findings support the concept of a medical disease process occurring in these
children’s brains. For example, it is generally recognized that an EEG finding
of “slow” waves or “abnormal” brain wave activity is often consistent with the
idea of an underlying and unknown “encephalopathy/encephalitis.”
In addition,
recent work with the NeuroSPECT strengthens the connection of blood flow
abnormalities and neuro- dysfunctional states, particularly in situations in
which patients appear to have immune and/or possible viral etiologies. NeuroSPECT scans capture blood flow
through specific areas of the brain. Blood flow correlates with
function/activity.35,36 As noted, NeuroSPECT scans on children with autism have
shown a decrease in blood flow in the temporal and parietal areas, which is
consistent with past reports of temporal lobe dysfunction in such
children.
Neurological models of the brain correlate right temporal lobe areas with
social skills and left temporal lobe areas with speech and auditory dysfunction,
all of which are compromised in autistic children. It should also be noted that
there is no good explanation for our finding of increased blood flow in the
frontal lobes of a group of these children, which is more consistent with ADD
and Hyperactivity. Further research
is required relative to this finding.
Also, the Board
has been monitoring the emerging body of evidence related to the immune system
and its interactive messengers: interleukins and cytokines. It appears that a
dysregulated immune system state, whether triggered by a virus, genetic
disposition, intrauterine, prenatal, neonatal stress or trauma, may account for
the cognitive processing and other deficits seen in some children with autism.
This concept is supported by the lack of consistent neurological/anatomical
abnormalities and metabolic abnormalities in these children. We now know that
neuro- polypeptides called cytokines can and do restrict brain blood flow under
certain conditions. In these children, we may be looking at an immune system
continually sending out signals to restrict brain blood flow. Whether this
continues as an “auto-immune” reaction (whereby the immune system continues this
pathway with no active reason to do so) or is due to the presence of a
retro-viral or other viral process is open to further research. However, the
concept of an immune-related disease process in a large number of these children
appears unquestionable at this point in time.
Futhermore, many
autistic children have major allergies or intolerances to many chemicals and
foods. While occasionally these reactions may turn into urticaria or asthma, the
effect in the majority of these children is the worsening of autistic-like
behavior. Family history often reveals eczema, migraines (especially in mothers)
hay fever, asthma, and histories of other disorders, which are often
immune-mediated. These external symptoms may well prove to be signs of a
“hyper-reactive” / stressed / dysfunctional immune system underlying the
biochemistry of these children.
Many anecdotal
reports of successful therapies for autistic children (e.g., gammaglobulin,
allergy-free diets) can most likely be explained through the concept of
regulating a dysfunctional immune system and/or altering metabolic sensitivities
and dysfunction.
Examples of
autism’s probable connection to immune dysfunctional states are:
Extensive
clinical work over the last four to five years further supports the Board’s
hypothesis that we are facing an immune-mediated disease state affecting the
central nervous system (CNS) in these children. The literature is replete with
articles connecting immune system abnormalities to autism, ADD, ADHD, CFS and
CFIDS. Among the main examples are:
Multiple
researchers have found evidence that autoimmunity is a possible mechanism to
explain autistic symptoms.37 38 39 40,41 An increased incidence of two or more
miscarriages and infertility42 as well as pre-eclampsia43 and bleeding during
pregnancy44 have been shown to occur in mothers of autistic children. There are
also multiple studies in the obstetrical literature connecting these events to
immune autoantibody production.
Studies have
been done comparing the maternal antibodies of mothers with their autistic
children,45 suggesting an association of abnormal maternal immunity with
autism.
Antibodies reactive with lymphocytes of fathers of autistic children have
also been found.
Multiple
researchers have shown an interaction of maternal antibodies with trophoblast or
embryonic tissue antigens, and a cross-reaction with antigens found on
lymphocytes.46 47 48 49 Researchers
have also shown a significant depression of CD4+T helper cells and their
suppresser-inducer subset50 51 with an increased frequency of the null allele at
the complement C4B locus52 in children with autism. As similar changes have been
known to occur in other autoimmune diseases,53 54 these researchers have
postulated that immune activation of a T-cell subpopulation may be important in
the etiology of the disorder in some children with autism. (Note: Many of the
autistic children evaluated by the Board have shown very high CD4 and CD8
counts, low natural killer (NK) cells, or other “markers” consistent with immune
dysfunction/ dysregulation).
Abnormalities of
Cell Adhesion Molecules (NCAM) 55 have been reported.
Antibodies to
neurofilament axonal proteins (NFAP) have been noted in autistic children 56a
and have been reported in neurotropic slow virus diseases (Kuru and
Creutzfeld-Jacob disease) in adults.56 Other studies57 58 have suggested an
association of an infectious agent (slow virus) in the etiology of these
diseases. This is considered indirect evidence that some cases of autism may
also be associated with the concept of a "slow virus." Anti-central nervous
system serum immunoglobin reactivity has been reported that was specifically
directed against the cerebellum. 56a A small percentage of autistic children
with demonstrable immunologic abnormalities have normalized their autistic
symptoms with intravenous immunoglobulin treatment. 59a 59b This result shows
that immune abnormalities can cause autism in a subset of children and that
“acquired autism” can be effectively treated.
Singh et al.
hypothesized that autoimmunity secondary to a virus infection may best explain
autism in some children.59 Congenital rubella virus60 and congenital
cytomegalovirus61 have been indirectly involved as causative factors in
autism.
Given this support from the medical research literature, the concept of
immune dysregulation as a medical disease process in childhood neuro-cognitive
dysfunction is an emerging reality. This concept could easily account for a
portion of the increase of neuro-cognitive diagnoses over the last ten years.
Whether the etiology of this
dysfunction is related to environmental factors (e.g., ozone layer depletion,
local toxins, etc.), new retro-viruses, stealth, spongiform or other viruses (or
altered viral responses), we now have a medical hypothesis that can facilitate
the definition of clinical sub-groups and lead to the treatment of these
patients without first determining the origin or etiology.
If an infectious
etiology indeed exists, it may be as ordinary as the common cold, or so rare
that we have not yet developed the tools to either identify or study it. Whether
an ongoing agent is present, or the body simply remains in a dysfunctional
state, it seems likely we are confronted with a phenomenon/illness that has
multiple etiologies, multiple origins, and various clinical manifestations. At
this point, they appear linked by an immune dysfunction or possible
viral-mediated state. Genetic predisposition to this syndrome may have a great
deal to do with why certain individuals suffer with these symptoms. However, we
must begin to consider these apparently heterogeneous expressions as linked and
potentially treatable through the common pathway of an immune dysfunctional/CNS
dysregulated state.
For example, in
a recent study62 on Chronic Fatigue Syndrome (CFS), two NIDS Board members
reported a significant diminution of blood flow in both the temporal and, to a
lesser degree, the parietal lobes in children suffering from CFS and Chronic
Fatigue Immune Dysfunction Syndrome (CFIDS).
These findings
are similar to those previously noted in children with acquired autism.
Based on the
evidence presented herein, the NIDS Board believes that developing a focus on
the inter-relationship of autism, ADD, ADHD, CFS, CFIDS and other
immune-modulated conditions is a key to helping groups of these children in ways
never before possible. If we can address the physiologic part of the dysfunction
in these children (irrespective of its specific etiology), educational therapy,
counseling, study techniques and most/all other current therapies have a far
greater probability of success.
In addition,
research focused on developing and initiating new therapies for autism are
likely to be useful in treating these other inter-related childhood
disorders.
The Future:
As outlined, we
have witnessed the evolution of what is now being recognized and accepted at the
National Institutes of Health (NIH), the Centers for Disease Control (CDC), and
academic institutions world-wide as a “neuro-immune” epiphenomena. Studies are
now confirming the concept of physiologic immune-mediated diseases underlying an
abnormal physiologic state for these patients. This, in turn, creates both
physical and neuro-cognitive deficits and dysfunction, usually of long-term
duration.
The NIDS Board believes that many of the characteristics ascribed to
autistic (and “quiet” ADHD) children overlap with the multiple complaints of
adults afflicted with components of CFS/CFIDS and adult “ADHD”. As previously
noted, all of these groups have reports of various immune abnormalities
including T-cell changes reflected, for example, by increased or decreased
CD4/CD8 cells, increased / decreased NK and B cells, and altered viral titers.
It is this common denominator of immune alterations that gives hope for
potential new therapies in the near future for these children.
However, while
this hypothesis now has support in the literature, there are many important
questions to be answered. How many “autistic” children have evidence of or are
linked to an immune-dysfunctional state or a conclusive viral etiology? Can
these children be viewed and treated differently than the "classic autistic”
child of 20 to 30 years ago? Is their prognosis for recovery significantly
better than the "classic autistic" children from the past?
It is time to
recognize that these children are likely suffering from a medical disease
process and need our clinical and research efforts now! Current treatments need
to be modified and adjusted to account for this finding.
The symptoms of
the “quiet” ADD child (who is likely connected to this phenomenon) is not
consistent with the past training or processes used to “explain” and address the
“hyper” ADD child. It seems likely that the cognitive defects described in
adults and children with CFIDS may be thought of as milder, later-onset form of
“autism”, as they are similar in symptomatology and possible etiologies. The
continued exploration of an immune-dysfunctional epiphenomena, and the potential
etiologies linked to it, is a door we must walk through if we expect to change
the future of this generation of children!
It is the
proposed mission of this Board to accelerate the integration of the above
clinical and research findings to facilitate the employment of new (and perhaps
some older) immune-modulating therapies in the treatment of “acquired autism”,
ADD/ADHD and CFS/CFIDS. We believe that by helping to “regulate” or “normalize”
the immune system, we can restore health to these children. Through our unique
acceleration of clinical knowledge and academic research, there is a chance to
recognize and treat this disease process while these children are still young
and while there is still time to effectively help their cognitive
development.
NIDS Medical
Board Members
Jeffrey Galpin, M.D., a Clinical Associate Professor of Medicine at the
University of Southern California (USC)
Michael
Goldberg, M.D., F.A.A.P., the Director of the NIDS Medical Advisory Board and a
clinical teaching staff member at both UCLA and Cedars-Sinai Hospitals
Nancy Klimas,
M.D., a clinical immunologist affiliated with the University of Miami Medical
Center and the Veterans Administration Hospital
Ismael Mena,
M.D., the Director of the Neuro-Imaging Department of Nuclear Medicine at the
Las Condes Clinic in Santiago, Chile
Audrius Plioplys, M.D., F.R.C.P.C.,
F.A.A.P., C.M.D., is the Director of Child Neurology of the Humana-Michael Reese
Health Plan in Chicago
Bruce Miller, M.D., a UCSF neurologist
specializing in central nervous system dementias and the application of brain
imaging technology
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