Download PANDAS, Autism Spectrum Disorders And Involvement Of

PANDAS, Autism Spectrum Disorders and
Involvement of Streptococcus Organisms
David Wolfson, ND, Stephen Olmstead, MD, Dennis Meiss, PhD, Janet Ralston, BS
ABSTRACT: The term “Pediatric Autoimmune Neuropsychiatric
Disorders Associated with Streptococcal infections”, or PANDAS,
was coined in the late 1990s by Susan Swedo and colleagues of the
National Institute of Mental Health. The term refers to a subgroup
of childhood obsessive-compulsive and tic disorders triggered or
exacerbated by group A beta-hemolytic streptococcus (GABHS)
infection. GABHS is believed to elicit production of antibodies that
cross-react with neural tissues and thereby provoke the neurobehavioral
symptoms associated with PANDAS. Similar anti-GABHS
antibodies have been found in a subset of persons with Autism
Spectrum Disorders (ASD) giving rise to concerns that
other streptococcal organisms, including the probiotic species
S. thermophilus, may be capable of provoking an autoimmune
response. A review of the literature reveals no evidence that
S. thermophilus promotes production of cross-reactive antistreptococcal antibodies and no indication that any streptococcal
organism other than GABHS is associated with PANDAS or ASD.
S. thermophilus lacks the virulence factors found in pathogenic
streptococcal species such as GABHS rendering it a benign organism
that has, in fact, demonstrated a variety of health benefits for humans.
THE EVOLUTION OF PANDAS
The belief that neuropsychiatric symptoms might be associated with
streptococcal infection dates back to 1894 when Sir William Osler
described “a certain perseverativeness of behavior” in patients with
Sydenham’s chorea, a movement disorder associated with rheumatic
fever and triggered by infection with GABHS.2 Later observations
that persons with Sydenham’s chorea often manifest symptoms of
obsessive-compulsive disorder, and vice versa,3,4 raised suspicions
that perhaps these and other neurological and neurobehavioral
illnesses have a common streptococcal etiology. Neuroimaging
studies demonstrating basal ganglia dysfunction and findings of
antineural antibodies in both obsessive compulsive disorder and
Sydenham’s chorea supported this hypothesis.2 A pathophysiological
model emerged in which antibodies against GABHS were believed
to cross-react with neural tissue in the basal ganglia leading to
dysfunctional movements, tics, and/or other neuropsychiatric
symptomatology.5 In the mid 1990s, the term PITANDS (Pediatric
Infection-Triggered Autoimmune Neuropsychiatric Disorders) was
introduced to summarize the essential features of a subgroup of
patients with obsessive-compulsive disorders or tics (including
Tourette’s syndrome) whose symptoms were triggered or exacerbated
by bacterial or viral infections.6 Swedo and colleagues later refined
the diagnostic criteria for PITANDS to include only individuals
whose symptoms were temporally associated with GABHS infection,
and grouped these patients under a new acronym, PANDAS.7
AUTISM SPECTRUM DISORDERS AND
AUTOIMMUNITY
ASD is a neurodevelopmental disorder characterized by social
withdrawal, communication deficits, and often repetitive or
restrictive behaviors. While its etiology remains unclear, ASD is
believed to be a heritable disorder in which genetic and environmental
factors combine to produce an array of neurological, immunologic,
and metabolic derangements.8 The possibility of a link between
autism and autoimmunity was first posited in 1971 by researchers at
the Johns Hopkins Hospital who observed symptoms of autism in a
child with primary Addison’s disease and a strong family history of
autoimmunity.9 Since then, a variety of immune abnormalities have
been described in ASD including T- and B-cell dysfunctions,10 a
proinflammatory cytokine pattern,11 and anti-neural antibodies,11
the latter providing the clearest evidence of autoimmune
dysregulation. Autoimmunity in ASD has been attributed to
abnormal antibody response to the measles component of MMR
vaccination, dietary peptides from dairy and wheat, specific bacterial
antigens from Chlamydia pneumoniae and GABHS, and possibly the
ethyl mercury component of thimerosal.11-14 Maternal antibodies
crossing the placental barrier have also been postulated as a source of
autoantibody production in infants.15 The growing number of
reports of autoreactivity in ASD patients has lent support to a model
of autoimmune pathogenesis in which antibodies cross-react with
one or more components of the brain giving rise to dysfunction in
these areas.11
IMPLICATION OF S. THERMOPHILUS IN PANDAS
AND ASD?
There is little doubt that streptococcal infection can be a causative or
contributory factor in a number of neurological disorders.16,17 By
definition, the onset of symptoms in PANDAS is temporally
associated with streptococcal infection.7 Additionally, serum samples
of autistic patients have been found to produce higher than normal
levels of anti-streptococcal antibodies that cross-react with neural
tissue.13 The etiological role of streptococcal infection in PANDAS
and possibly ASD has led some to question whether non-pathogenic
species of streptococcus, such as the commonly ingested probiotic
organism S. thermophilus, may trigger autoantibody production in
either of these disorders. While this is an understandable concern, it
must be emphasized that GABHS, or Streptococcus pyogenes, is the
only streptococcal organism that has been shown to evince
immunological reactivity in either PANDAS or ASD. A search of the
medical literature reveals no evidence of production of cross-reactive
antibodies in PANDAS or ASD patients exposed to other species
of streptococcus, such as S. thermophilus. In contrast to the
human pathogen GABHS, S. thermophilus is a food-source
organism that ferments dairy products (it is one of the probiotic
organisms commonly used in the culturing of yogurt) and has been
associated with a variety of health benefits in humans.18-21 Though
belonging to the same genus as disease-causing GABHS, an
examination of the genome of S. thermophilus reveals a lack of the
most important genetic determinants of pathogenicity.22 Of note,
one of these determinants, a specific M protein (STM6P) found in
GABHS, to which autistic children have demonstrated immune
reactivity,13 is not present in S. thermophilus.23 Other M proteins
known to evoke antibodies that cross react with human brain tissue,
such as serotypes 5 and 19,16 are also specific to various strains of
GABHS but are not found in S. thermophilus.23 In fact, of the more
than 60 different microbial peptides that to date have been reported
to cross-react with human brain tissue, none derive from
S. thermophilus.16,24,25 Additionally, streptolysin O, a virulence factor
against which the human immune system produces antistreptolysin
O (ASO), is expressed only by pyogenic streptococcal species such as
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GABHS and has never been associated with S. thermophilus.26,27
Therefore, elevated ASO titers should not be considered indicative of
the presence of S. thermophilus in the body. A recent review of the
molecular biology and physiology of S. thermophilus by Hols, et al.
makes clear that S. thermophilus:
• “… has followed an evolutionary path divergent to that of
pathogenic species due to its adaptation to the rather narrow and
well-defined ecological niche, milk.”
• “… has lost many virulence related functions common among
pathogenic streptococci … ”22
Thus all evidence indicates that both PANDAS and ASD are associated
solely with GABHS. No other species of Streptococcus, including
S. thermophilus, has ever been implicated in either of these disorders.
On the contrary, research shows that S. thermophilus along with
other probiotic organisms can actually improve human resistance
against pathogens such as GABHS.18-21 In one study, consumption of
milk cultured with S. thermophilus and other lactic acid bacteria was
found to reduce or eliminate the presence of GABHS and
S. pneumoniae in the nasal cavities of study participants.20
S. thermophilus may also favorably modulate specific aspects of
immune dysfunction in ASD. Studies have found that persons with
ASD exhibit a polarity in Th1/Th2 lymphocyte responses such that
Th2 responses predominate.11,28 This type of imbalance is believed to
predispose to towards allergic (IgE-mediated) and autoimmune
(antineural antibody-mediated) processes that can exacerbate
symptomatology in autism and possibly contribute to its pathogenesis.28
Preliminary research suggests that S. thermophilus may help balance
Th1/Th2 responses. In one study, mice challenged with the
antigenic protein ovalbumin produced significantly more TH1associated IFN-gamma and significantly less TH2-associated IgE
when fed milk fermented with S. thermophilus than when fed nonfermented milk.29 In another study, mesenteric lymph nodes from
colitis-prone mice orally gavaged with S. thermophilus and B. breve
organisms displayed a cytokine secretory profile polarized towards a
TH1 response.30 These studies suggest probiotic organisms like
S. thermophilus may favorably influence immune function and
provide therapeutic benefit in TH2-dominant conditions such as ASD.
SUMMARY
PANDAS is a recently described neurobehavioral disorder characterized
by pediatric onset of obsessive-compulsive disorder and/or tics
following infection with pyogenic group A beta-hemolytic
streptococcus (GABHS). Findings of anti-streptococcal antibodies
capable of cross reacting with neural tissue in some persons with
Autism Spectrum Disorders (ASD) has given rise to concerns that
the probiotic organism S. thermophilus may also trigger production
of antineural antibodies. This concern in unfounded as the onset of
PANDAS or presence of anti-streptococcal antibodies in ASD has
never been associated with streptococcal organisms other than
GABHS. GABHS-associated autoimmune reactions in PANDAS and
ASD appear to be mediated by surface proteins specific to S. pyogenes
and not carried by S. thermophilus. S. thermophilus has a long history
of safe use around the world as a probiotic component of yogurt and
other fermented dairy products and has demonstrated health
benefits for humans. Current evidence indicates there is no basis for
believing S. thermophilus provokes autoimmune reactions as does
GABHS and rather suggests this probiotic organism can protect
against growth of GABHS and other potentially harmful streptococcal
species in humans.
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