Preventable Cases of Autism: Relationship Between Chronic Infectious Diseases and Neurological Outcome

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Robert C Bransfield† There is evidence that chronic infections and the immune reactions associated with them may contribute to causing autism spectrum disorders. These infections include Babesia, Bartonella, Borrelia burgdorferi, Ehrlichia, Human herpesvirus-6, Chlamydia pneumoniae and Mycoplasma (in particular Mycoplasma fermentans). Maternal immune reactions to infections appear to adversely affect fetal brain development and possible pathophysiological mechanisms include both inflammatory cytokines, such as IL-6, and maternal autoantibodies to fetal neural tissue of the same kilodalton mass as those seen with B. burgdorferi and some other chronic infections. The timing of the infection and immune response is critical in determining the pathophysiology. It is advisable to evaluate women who are pregnant or planning on becoming pregnant for chronic infections, especially if they demonstrate symptoms of an infection or a systemic illness with persistent inflammatory symptoms. The mother and the newborn should be treated when indicated.

Family case report effective antimicrobial treatment for the mater This article includes brief clinical summa nal grandmother or the mother before or during ries and single photon emission tomography pregnancy or by treating the children at an early (SPECT) scans of a mother and her three chil point in development (Figures 2–4). dren who have all been diagnosed with autism The mother had a diagnosis of chronic spectrum disorders (ASDs). The 48-year-old fatigue syndrome, multiple sclerosis, depres mother had previously been diagnosed with sion and possible congenital Lyme disease. She chronic fatigue syndrome, possible multiple had an acute episode of mononucleosis while sclerosis and depression (Figure 1). Three of pregnant with the son. The SPECT scan dem her four children had ASD. Subsequently, she onstrates an extensive hypoperfusion pattern, and the three children were diagnosed with a predominantly in the cerebral cortices and number of chronic infections and were treated much of the frontal lobes, with a lesser degree in with different degrees of effectiveness. The the temporal lobes and a small degree of hypo presence of Borrelia burgdorferi was confirmed perfusion in the cerebellum. The hypoperfusion by testing from IGeneX Labs, CA, USA, and is moderately extensive and is likely associated †Author for correspondence the presence of the viral infections were con with toxic, inflammatory and infectious pro Psychiatry Riverview Medical firmed at Medical Diagnostic Laboratories, NJ, cesses. There is hyperperfusion of the basal Center, 225 Hwy, 35 Red Bank, USA. The 23-year-old daughter was treated ganglia, which is associated with anxiety and NJ 07701, USA Tel.: +1 732 741 3263 extensively with antibiotics, subsequently mood dysregulation (Figure 1). Laboratory testing became pregnant and gave birth to a normal was positive for B. burgdorferi, Babesia duncani, Fax: +1 732 741 5308 [email protected] healthy infant with an Apgar score of 10 and Bartonella henselae, Mycoplasma fermentans, normal developmental milestones (Figure 2). Human herpesvirus (HHV)-6, Epstein–Barr Retrospectively, the maternal grandmother virus (EBV), high antistreptolysin-O titer and Keywords had cognitive impairments and Asperger’s gamma streptococci in stool. traits. She was positive for B. burgdorferi (the The 26-year-old son is low functioning with autism • autism spectrum causative agent of Lyme disease) by ELISA and autism since 2 years of age and has also been disorders • Bartonella • Borrelia burgdorferi • Chlamydia western blot. There was B. burgdorferi present diagnosed with grand mal seizures, move pneumoniae • infections • Lyme in her heart tissue upon autopsy confirmed by ment disorder, ataxia, hypotonia, megacolon, • Mycoplasma • tick-borne microscopy and polymerase chain reactivity possible mitochondrial disorder, mild hyper and she died from multiple myeloma, which gammaglobulenmia and syncope. There are was considered to have had a possible infec some motion artifacts; however, significant part of tious etiology. This case raises the question of hypoperfusion pattern is both focal as well as whether ASD could have been prevented by generalized. The SPECT scan demonstrates

B. burgdorferi, B. duncani, B. henselae, M. fer- Multi-threshold volume report SPECT with Chang AC mentans, HHV-6, EBV and high-streptococcal Study ID: corrected baseline volume masked ID: brain Patient sex: female; age: 48 years Acq. date: 20/6/2007 titers; the stool was positive for Citrobacter freundii, Klebsiella pneumoniae and gamma Threshold = 60% Threshold = 60% streptococci (Figure 3). The 23-year-old daughter was diagnosed with Asperger’s syndrome, obsessive compul sive disorder, generalized anxiety, social anxiety disorder, depression, post-traumatic stress dis order from an autoaccident, possible narcolepsy, R L L R tremors, cardiac disease, myocardial infarction, osteopenia and arthritis with psuedo rhematoid nodules since 5 years of age. The SPECT scan demonstrates an extensive hyperperfusion pat tern in the cerebral cortices, temporal lobes and Anterior Posterior cerebellum and hypoperufsion of the frontal Threshold = 60% Threshold = 60% lobes and is likely associated with toxic, inflam matory and infectious processes. Laboratory testing was positive for B. burgdorferi, Anaplasma phagocytophilum, M. fermentans, Haemophilus, HHV‑6, EBV, elevated streptococcal titers; stool was positive for toxoplasmosis, cornybacteria and gamma streptococci (Figure 2). The 20-year-old daughter was diagnosed R LL R with ASD since 14 months, petit mal seizure disorder, hypotonia, perceptual impairments and anxiety. The SPECT scan demonstrates a seizure focus with hyperperfusion in the right cerebellar hemisphere. There is extensive hypo perfusion in the frontal lobes, temporal lobes and to a lesser degree to the occipital lobes and Vertex Underside slightly to the cerebellum. There is hyperper Underside tilt = -10 degrees Vertex tilt - 10 degrees © Segami Corporation fusion in the right cerebellar hemisphere. The hypoperfusion is likely associated with neuro Figure 1. 48-year-old mother diagnosed with chronic fatigue syndrome and inflammatory, neuroimmunological, infectious multiple chronic infections. Acq.: Acquisition; Chang AC: Chang’s single iteration method for attenuation and toxic substance exposure. Laboratory test compensation; SPECT: Single photon emission computed tomography. ing was positive for B. burgdorferi, B. henselae, M. fermentans, HHV-6; the stool was positive a focal pattern throughout the cerebral cor for Parvovirus B-19, K. pneumoniae, C. freundii tex bilaterally and the cerebellar hemispheres, and gamma streptococci (Figure 4). which demonstrate atrophy on MRI. There is mild hyperperfusion of the basal ganglia and a Defining autism & autism focally intense hypeperfusion area in the deep spectrum disorders white matter of the temporal lobe. There is a Autism is a group of disorders with proposed hyperperfusion pattern involving the tempo differing causes but common symptoms, which ral lobes and cerebellar hemispheres. The focal include impaired social interaction, impaired decrease is more suggestive of etiologies that communication, stereotyped or repetitive inter would include hypoxic, neuroimmune, trau ests or behaviors that may involve developmental matic factors, infectious and inflammatory arrest, slowing or even regression, most com processes. There is a hyperperfusion pattern of monly apparent by 14–24 months of age [1,2]. the basal ganglia, which may be associated with ASD is a broader term that includes autism an element of anxiety, whereas the focal intense disorder, Asperger’s disorder, Rett’s disorder, areas can be associated with present interictal childhood disintegrative disorder and per seizure focus and are clinically significant as the vasive developmental disorder not otherwise present dose of anticonvulsant is not controlling specified [1]. ASD may frequently be comor this area. Laboratory testing was positive for bid with seizure disorders, mental retardation

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(30% mild-to-moderate; 40% serious-to-pro age. Some research attention has been focused found), attention-deficit hyperactivity disorder upon vaccines, toxins, nutrition and other envi (ADHD), gastrointestinal disorders, immune ronmental triggers. Although the cause of some dysregulation, sleep disorders and hearing and cases of ASD is known, the cause of the majority visual impairments, and may be comorbid with of ASDs is still unexplained. Congenital rubella, any psychiatric diagnosis. syphilis and toxoplasmosis have long been asso ciated with causing ASD and other neurological Increased reporting of autism impairments. However, these infections can still spectrum disorders explain only a very limited number of preventa There have been increased reports and an ble cases of ASD and research into other possible increased concern in the media regarding ASD. infectious contributors has been limited. For example, in 1992 only 15,580 children in the US school system were classified with ASD, Can autism be associated with in 2002 this increased to 407,578 and currently, chronic infections? 560,000 in the USA have ASD [3,201,202]. In Historically, acute rubella infections have the UK, researchers at Cambridge University’s been a pathophysiological model for acute Autism Research Centre have estimated that infections contributing to the cause of autism one in 58 children suffer from some form of the and other neurological impairments. A study disorder, compared with previous estimates of conducted after the 1964 rubella outbreak in approximately one in 100 [203]. In 2000, a sur vey of eight states identified regional patterns Multi-threshold report SPECT with Chang AC with one in 150 children in the USA with ASD, Study ID: corrected baseline volume masked ID: brain with the highest rate in New Jersey at 9.9 in Patient sex: female; age: 23 years Acq. date: 20/6/2007 1000 and the lowest rate in West Virginia at Threshold = 60% Threshold = 60% 5.1 in 1000 [204]. Studies in the past 15 years have suggested the prevalence of autism is ris ing and media coverage has indicated the pres ence of an autism epidemic; however, some have questioned whether such an epidemic is fact or R LL R artifact [3–5]. Regardless of whether there is an increased prevalence or just an increase aware ness, it can cost approximately US $3.2 million to care for one autistic person in his or her life time and the prevention of ASD is a high prior Anterior Posterior ity when considering the total financial burden, including lost productivity and the human cost Threshold = 60% Threshold = 60% to families and caregivers [6].

Known causes of autistic spectrum disorders Unlike many other neurological impairments, symptoms of ASD are often not apparent at birth, which increases the difficulty in deter R L L R mining the cause–effect relationships. The known and mostly rare causes of ASD include fragile X syndrome, tuberous sclerosis, cerebral palsy, phenylketonuria, neurofibromatosis, Rett’s syndrome, Rasmussen’s encephalitis, Lennox– Gastaut syndrome, pyruvate dehydrogenase defi ciency, impaired purine metabolism (whereby Vortex Underside uric acid is increased), brain structural anoma Underside tilt = -10 degrees Vertex tilt = 10 degrees © Segami Corporation lies (e.g., cyst), phenylketonuria, Angelman’s syndrome, Landau–Kleffner syndrome, Prader– Figure 2. 23-year-old daughter with autism spectrum disorder and multiple Willi syndrome, Williams syndrome and mul chronic infections. tiple other genetic impairments. In one study, Acq.: Acquisition; Chang AC: Chang’s single iteration method for attenuation ASD has also been associated with older paternal compensation; SPECT: Single photon emission computed tomography.

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in the mother or newborn child may contribute Multi-threshold report SPECT with Chang AC towards causing autism, ASD and other neuro Study ID: corrected baseline volume 6.18 masked ID: brain Patient sex: male; age: 26 years Acq. date: 20/6/2007 logical impairments, and we discuss the possible preventative options. Threshold = 60% Threshold = 60% What is the pathophysiology of autistic spectrum disorders? Since monozygotic twins are 70–90% concordant, there are significant genetic pre R LL R disposing factors [9]. Data suggest that autism results from multiple etiologies with both genetic and environmental contributions, which may explain the spectrum of behaviors displayed Anterior Posterior in this disorder [10]. Environmental insults con tributing to ASD may include a complex inter Threshold = 60% Threshold = 60% action with infections, heavy metals, biotoxins, allergens, nutritional excesses/deficits and, pos sibly, vaccines. In addition, physiological and psychological changes associated with chronic unremitting stress contribute to chronic psychi atric symptoms and a chronic immunocompro mised and inflammatory state [11]. Neurological R L L R disease precipitated by an interaction of these environmental insults and susceptibility fac tors often results in a pathogenic interaction that includes inflammation, oxidative stress, mitochondrial dysfunction and excitotoxicity resulting in neuronal dysfunction [12]. In the developing brain, these processes can adversely Underside Vortex affect cell proliferation, migration, differentia tion, synaptogenesis, myelination and apopto Underside tilt = -10 degrees Vertex tilt = 10 degrees © Segami Corporation sis, which can contribute to the development of Figure 3. 26-year-old son diagnosed with autism and multiple autism [13]. chronic infections. Acq.: Acquisition; Chang AC: Chang’s single iteration method for attenuation Theoretical issues: genes & infections compensation; SPECT: Single photon emission computed tomography. Mendel stated that human traits are determined by individual genes that function independently New York City, NY, USA found autism rates of other genes and of environmental influences, much higher than normal in children born while Koch stated that many human diseases to pregnant women infected with rubella [7]. are caused by microbes, which exert their effect A subclinical rubella infection in a vaccinated independently of other microbes, environmen woman has also been reported [8]. Syphilis tal factors and genes. These theories, which has long been a pathophysiological model for advanced science at one point in history, can chronic infections contributing to the cause prevent further progress if they are not revised of neuropsychiatric illnesses including autism. with currently expanding knowledge. Just as the More recently, the role of other chronic, low- theories of Newton were revised by Einstein, grade, relapsing infections has been considered those of Mendel and Koch also need revision. as well. These infections may present with more Yolken revised these theories by stating, “most subtle symptoms and clinical findings and are common human diseases are caused by the more difficult to detect. Since most cases of interaction of environmental insults and suscep autism are still unexplained, and in view of the tibility genes. Many of the susceptibility genes very high human and economic cost of autism, are diverse determinants of human response to insight into every possible contributor or cause environmental factors to infection and preven of autism may assist towards the development tion or treatment of the infections may result of possible preventative strategies. This article in the effective treatment of complex disorders” investigates the evidence that chronic infections (Figure 5) [14].

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A complex disease model that incorporates Diagnostic and Statistical Manuals, the cause multiple variables is needed to explain the causes, of most psychiatric illness is unknown [1]. Since pathophysiology and multiple presentations mental illness often begins early and persists of ASD. throughout life, degenerative disease cannot explain the cause of most psychiatric illness. What are the genes? There is a large body of research documenting A significant number of the genes associated with that infectious disease can cause mental illness. ASD are genes related to the immune system. The same syndrome may be caused by dif For example, a group of genes with known links ferent infections in different individuals, but to natural killer cells, the first to attack viruses, the same infection can cause different syn bacteria and malignancies, are expressed at high dromes in different individuals. For example, levels in the blood of children with autism when obsessive compulsive disorder has been caused compared with children without the disorder [15]. by Streptococcus, Lyme disease, Hong Kong Genes alone do not tell the whole story. Recent and other flu strains, Coxsackievirus, toxoplas increases in chronic diseases such as diabetes, mosis, Mycoplasma and the pandemic flu of childhood asthma, obesity or autism cannot be 1918 [20]. However, many of these infections due to major shifts in the human genome. They have been documented to cause other psychiat must be due to changes in our environment [205]. ric and somatic symptoms. For example, Hajek

What are the Multi-threshold volume report SPECT with Chang AC environmental contributors? Study ID: corrected baseline volume masked ID: brain The geographical patterns seen with ASD also Patient sex: female; age: 20 years Acq. date: 20/6/2007 suggest environmental contributors and many Threshold = 60% Threshold = 60% possible environmental explanations have been proposed. We are witnessing a rapidly chang ing environment that includes globalization and increased exposure to various toxins in the environment. Globalization has resulted in the spread of parasites throughout the world to popu R LL R lations that may have had limited or no exposure or resistance to these organisms and may be quite susceptible to their pathogenic effects. In addition, biotoxins, inorganic toxins and heavy metals can be both toxic and conducive to the proliferation Anterior Posterior of parasites in the environment. Mercury toxicity is one of the toxins proposed to contribute to the Threshold = 60% Threshold = 60% development of ASD. Although controversy sur rounds this issue, recent evidence has been more supportive of this association [16]. Epidemiological studies have reported mixed results. Higher preva lence of autism has been associated with geograph ical regions with higher environmental mercury release, higher precipitation rates and higher R L L R prevalence of Lyme disease [17–19].

Infections causing psychiatric illness The original model for infections causing mental illness was syphilis, an infection with Treponema pallidum pallidum. After the introduction of the Underside polio vaccine, penicillin and other antibiotics, Vortex it was felt the war against infectious diseases Underside tilt = -10 degrees Vertex tilt = 10 degrees © Segami Corporation had been won and infectious causes of chronic illnesses were often not considered. Figure 4. 20-year-old daughter diagnosed with autism spectrum disorder Although psychiatric conditions are well and multiple chronic infections. categorized and defined according to symp Acq.: Acquisition; Chang AC: Chang’s single iteration method for attenuation toms with the American Psychiatric Association compensation; SPECT: Single photon emission computed tomography.

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suggested that a pregnant woman’s exposure to Most current disease models influenza directly increases her child’s risk of developing schizophrenia [206]. Infants born to Acute infection Fairly well understood Well-defined diagnostic mothers exposed to the flu only during the first Acute toxic exposure pathophysiology signs and symptoms trimester had a sevenfold greater risk of develop Genetic defect ing schizophrenia [25]. More recent studies have Trauma Cancer also demonstrated an association between schizo

Degenerative disease phrenia and antibodies to Toxoplasma gondii [26], Chlamydophila [27] and Herpes simplex virus 2 [28]. Model for complex disease with multiple variables Prenatal exposures to certain infections are immunogenic. Inflammatory cytokines can play a key role in the link between prenatal exposure Complex and multiple Complex and multiple Complex and contributors: genetic pathophysiological processes multiple clinical to infection and the risk for schizophrenia by and environmental presentation with significantly reducing dendrite development and multiple signs (e.g., infections, complexity of developing cortical neurons [29]. and symptoms toxins and deficiencies) In addition, it appears prenatal exposure to cer tain infections can also induce maternal autoan Figure 5. Disease models. tibodies that cross-react with proteins in the developing fetal brain, resulting in aberrant fetal demonstrated the same infection, B. burgdorferi, neurodevelopment [30]. can be associated with many different psychiatric diagnoses [21]. Some infections result in residual Infectious link with autism injury and are no longer present, while others spectrum disorder may persist in a chronic relapsing and remitting As aforementioned, T. pallidum pallidum (syphi state. Chronic persistent infections are more lis), rubella and Toxoplasma gondii have been commonly viral, venereal and zoonotic vector- recognized for causing congenital neurological borne. The WHO defines zoonotic diseases as symptoms. Although rubella and syphilis are infections that are naturally transmitted between well-understood models for causing ASD, these vertebrate animals and man (Box 1). two infections are relatively uncommon now and the significant incidence of ASD cannot be Infections & the developing fetus explained. An association between infections dur Infections associated with pregnancy may be ing fetal development and in infancy with autism, transplacental, perinatal or postpartum. In addi ASD and autistic symptoms in children has been tion, infections in the mother may indirectly noted by a multiple clinicians and parents and affect the developing fetus through immune- in the medical literature. A closer review of more mediated effects even when the fetus is not recent research has expanded the list of infections actually infected. Adverse effects from infections associated with causing ASD. A number of infec upon the fetus include fetal death, prematurity, tions have been associated with causing symp intrauterine growth retardation, congenital dis toms of ASD or Klüver–Bucy syndrome, which ease and also developmental abnormalities that is associated with ASD, including rubella [10,31], may not be apparent at birth. It has been recently Herpes simplex virus [32,33], Herpes virus fam recognized that prenatal exposed to maternal ily [10], Borna (animal models) [10,34], varicella [25],

cystitis, pyelonephritis, diarrhea, coughs and/or Cytomegalovirus [35–37], Mycoplasma pneumo- vaginal yeast infections resulted in an increased niae [38], M. fermentans, Mycoplasma genetalium, risk for epilepsy in childhood [22]. Mycoplasma hominis, HHV-6, Chlamydia pneu- In evaluating the association between infec moniae [39–41], Shigella [42], syphilis [25], neuro tions and schizophrenia, a review of over cysticercosis [43], malaria [44], toxoplasmosis [36,45], 250 studies in different geographical regions have Blastocystis [46,47], Rubeola [48,49], B. burgdorferi demonstrated that the incidence of schizophrenia and other tick-borne diseases [19], unknown [50] of people born in the winter or spring is 5–8% and yet unrecognized infections (Box 2) [51]. higher than average. It was initially hypothesized that viruses, which are more prevalent during the Acute versus chronic infections fall, may be causative [23]. Polio and several flu Infections adversely impacting the developing epidemics have been associated with an increased nervous system may be either acute or chronic and incidence of schizophrenia [24]. Since the 1950s, persistent and may cause neurological impair more than a dozen epidemiological studies have ments through a number of pathophysiological

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processes. The acute infections are more readily have adaptive mechanisms to evade elimination recognized and are treated more aggressively, by the immune system [52]. Physicians are trained while chronic persistent infections are more to recognize and treat the acute symptoms of easily overlooked and less effectively treated. acute infectious diseases; however chronic The chronic infections may be associated with infections associated with chronic symptoms biofilms that are created by multiple organisms may be more significant in causing persistent interacting in a manner that perpetuates their immune reactions and psychiatric symptoms. survival in the host, and stealth pathogens that Most commonly, these infections may have an

Box 1. Some microbes associated with Box 1. Some microbes associated with mental symptoms & mental illness. mental symptoms & mental illness Spirochetes (cont.). • Borrelia afzelii (Lyme disease in the UK and Prion the rest of Europe) • Variant Creutzfeldt–Jakob • Borrelia burgdorferi sensu stricto (Lyme Viruses disease in the USA, UK and rest of Europe) • Borna virus • Borrelia garinii (Lyme disease in the UK and • Coltivirus (Colorado tick fever) rest of Europe) • Coxsackievirus • Borrelia hermsii (relapsing fever) • Cytomegalovirus • Borrelia turicatae (relapsing fever) • Enterovirus • Leptospira (Leptospirosis) • Flaviviridae virus (Japanese B encephalitis) • Treponema pallidum pallidum (syphilis) • Hepatitis C virus Bacteria • Herpes virus family • Anaplasmas phagocytophilum (human • Human endogenous retroviruses granulocytic ehrlichiosis) • Human herpesvirus 4 or Epstein–Barr virus • Bartonella henselae (cat scratch fever) • HIV • Bartonella quintana (trench fever) • Influenza A virus subtype H3N2 • Bartonella rochalimae (bartonellosis) (Hong Kong flu) • Chlamydophilia pneumoniae (chlamydia) • Influenza virus • Chlamydophila psittaci (chlamydia) • Pandemic influenza of 1918 • Coxiella burnetti (Q-fever and post-Q fever • Papopavirus fatigue syndrome) • Paramyxovirus (measles virus) • Ehrlichia chaffeensis (human monocytic ehrlichiosis) • Parvo B19 • Francisella tularensis (rabit fever or tularemia) • Poliovirus • Haemophilus influenzae (haemophilus) • Rabies virus • Listeria • Rubella • Meningococcus (meningococcal meningitis) • Toga virus • Mycoplasma fermentans • Varicella zoster virus (chicken pox) • Mycoplasma pneumoniae • Viral meningitis • Mycobacterium tuberculosis (tuberculosis) • West Nile virus Protozoa • Rickettsia akari (rickettsialpox) • Plasmodium (malaria) • Rickettsia rickettsii (rocky mountain spotted fever) • Babesia microti (babesiosis) • Rickettsia species (eastern tick-borne • Babesia duncani (babesiosis) rickettsiosis) • Other Babesia species (babesiosis) • Shigella (shigellosis) • Toxoplasma gondii (toxoplasmosis) • Streptococcus pneumoniae or pneumococcus Parasites (pneumonia) • Blastocystis (blastocystosis) • Streptococcus (pediatric autoimmune diseases • Taenia solium (neurocysticercosis associated with Streptococcus, Sydenham’s or cysticercosis) chorea and St Vitus dance) Fungal Yeast • Cryptocococcus • Candida albicans (candidiasis) • Coccidiomycosis • Candida dubliniensis • Histomycosis

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have instinctively evoked fear. For example, Box 2. Infections associated with they would approach a snake, even after being autism spectrum disorders or attacked by it (placidity). Patients with trauma Klüver-Bucy syndrome. to the temporal lobes may demonstrate some • Babesia features of this syndrome, including other tem • Bartonella poral lobe symptoms, such as memory disorders, • Blastocystis flattened emotions, bulimia, communication • Bornavirus (animal model) impairments and visual agnosia. • Borrelia burgdorferi and other Other major anatomical structures associ tick-borne diseases ated with autism include the cerebral cortex, • Chlamydia pneunomiae hippocampus, basal ganglion, corpus callosum, • Cytomegalovirus brain stem and cerebellum. On a microscopic • Ehrlichia level, loss of Purkinje cells in the cerebellum are • Herpes simplex virus also involved in cases of ASD. • Human herpesvirus-6 • Herpes virus family Infection or immune reaction • Mycoplasma fermentans to infection? • Mycoplasma genitalium The placenta is considered to prevent most • Mycoplasma hominis viruses, bacteria and parasites from entering • Mycoplasma pneumoniae the developing fetus. There are known excep • Plasmodium (malaria) tions such as rubella, syphilis and B. burgdorferi. • Rubella Many infections, such as influenza, are localized to the nasal passages and airways and do not • Rubeola appear to cross the placenta. Therefore, these • Shigella infections most likely affect the fetus by evok • Taenia solium (neurocysticercosis) ing a reaction in the mother’s immune system or • Toxoplasma gondii (toxoplasmosis) possibly the fetus’s or infant’s immune system. • Treponema pallidum pallidum (syphilis) Inflammatory signals are propagated across • Varicella the intact or ruptured blood–brain barrier to • Unknown viral and other infectious the CNS by proinflammatory cytokines, prosta glandins or lipopolysaccharides. These changes adverse effect upon the fetus by causing an aber can then trigger microglia to release cytokines, rant immune reaction that has an adverse effect oxygen free radicals and trophic factors, which upon the developing fetus. can adversely influence dendritic length and spine density, dopaminergic cells, neurogenesis, Infections & neuroanatomy glial proliferation, white matter functioning, One hypothesis to explain autism is the amy emotional stability and cognition [55]. Infections gdala theory of autism, which states there is a that cause immunological events in early fetal network of neural regions that comprise the life can adversely affect these brain develop social brain and this includes the amygdalae. mental processes and predispose the developing Since the childhood psychiatric condition nervous system to undergo additional failures of autism involves deficits in perceiving and in subsequent cell migration, target selection, responding to social cues, it is hypothesized and synapse maturation and pruning that may that autism may be caused by an amygdala eventually lead to multiple brain and behavioral abnormality and the Klüver–Bucy syndrome abnormalities that become apparent later in is an experimental model that partially repli life [56]. cates autism [53,54]. Klüver and Bucy removed the temporal lobes bilaterally in rhesus mon Animal models of maternal keys, which resulted in them developing visual immune reactions agnosia (inability to recognize objects or faces), Maternal immune reactions in pregnant emotional changes, hypermetamorphosis (a rodents result in offspring with gene expres desire to explore everything), oral tenden sion, histology and behavioral abnormalities cies, hypersexualism and flattened emotions with similarities to schizophrenia and autism. (placidity). The monkeys became emotionally One study demonstrated that IL-6 mediated dulled with less expressive facial expressions. these effects. A maternal injection of this They were also less fearful of things that would cytokine in early pregnancy resulted in deficits

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in the adult offspring. By contrast, coadmin demonstrated as association with autism and istration with an anti-IL-6 antibody normal 37 and 73 kDa maternal antibodies on western ized gene expression and behavior in the adult blot testing of the serum of mothers of autistic offspring [57]. children [64]. A second study demonstrated an In a mouse model, respiratory infection association with 36, 39 and 61 kDa maternal with influenza virus leads to behavioral abnor antibodies on western blot testing of serum malities in the adult offspring. These behav from mothers with autistic children [65]. A third iors are consistent with abnormalities seen in study of serum from mothers who subsequently schizophrenia and autism, including deficits in gave birth to autistic children measured mater social interaction. The adult offspring display nal autoantibody reactivity by western blot to neuropathology in the cortex and hippocam fetal brain tissue. Reactivity to a band at 39 kDa pus similar to that found in schizophrenia and a was more common among mothers of children localized deficit in Purkinje cells that resembles with autism (7%) compared with the control that in autism. The cause of these abnormali mothers and control subjects and simultane ties was the maternal response to viral infec ous reactivity to bands at 39 and 73 kDa was tion, since treatment of uninfected, pregnant found only in mothers of children with early mice with the double-stranded ribonucleic acid onset autism [66]. Therefore, the 36, 37, 39, 61 polyinosinic-polycytidylic acid (which evoked and/or 73 kDa bands on western blot testing an antiviral-like immune response) also caused may be associated with something that pro the same deficits and Purkinje cell changes in vokes am immune reaction and contributes the offspring. Similar Purkinje cells losses have to causing autism. In addition, reactivity of been observed in post-mortem brains of people the 37 kDa band is associated with three spe with autism [58]. cies of Mycoplasma [67–69]. The 73 kDa band The timing of infection is crucial for some is associated with C. pneumonia, Streptococcus infections. When pregnant mice are injected pneumoniae and Mycoplasma [70–72]. Both the with flu virus on embryonic day 9, there are 37 and the 73 kDa bands are associated with significant changes in more than 200 genes of B. henselae and Bartonella quintana [73]. The the cerebellum [59]. By contrast, injecting the 36 and 37 kDa bands may represent the same mice on embryonic day 18 generates significant antibody and is a marker for Lyme neurobor alterations in gene expression in the frontal, reliosis [74]. The 37 and 39 kDa antibodies are hippocampal and cerebellar cortices of the fetal highly specific for B. burgdorferi infections. A brain [60]. When mice are injected on embryonic 60 or 62 kDa antibody is found in Lyme bor day 16, it affects the expression of genes involved reliosis and 73 kDa proteins of B. burgdorferi in the production of myelin and these associated are dominant immunogens and expressed in all genes may be more significant with autism strains of B. burgdorferi [75]. [61,206]. Brain developmental processes (i.e., cell proliferation, migration, differentiation, synap Other pathophysiological findings togenesis, myelination and apoptosis) occur at Most neurological diseases are associated with vulnerable periods during development of the a gene–environment interaction. Parasites nervous system and are sensitive to environmen may adversely affect the host by a number of tal insults, and changes in these processes can mechanisms, including cell penetration, toxin contribute to autism [61]. release and incorporation of parasite genes into the host genome. The host response may then Could maternal antibodies to infections contribute to the pathophysiology by a number cause autism spectrum disorders? of processes that may include cytokine release, Rhesus monkeys gestationally exposed to IgG antibodies, inflammation and other cellular class antibodies from mothers of children with responses. This, in turn, results in patho ASD consistently demonstrated increased logical cascade that includes oxidative stress, whole-body stereotypes and were also hyper inflammation, excitotoxicity and mitochon active compared with controls [62]. Another drial dysfunction resulting in neural dysfunc study demonstrated that the sera of mothers tion [76]. Chronic intracellular infections (e.g., of autistic children exposed to prenatal rat Mycoplasma, Borrelia and Chlamydia) cause brain proteins presented specific patterns of increased oxidative stress by their release of reactivity in immunoblotting when compared reactive oxygen species and stimulation of with controls [63]. Three studies analyzed IgG reactive oxygen species in mitochondria. This antibodies associated with autism. One study causes increased oxidation of mitochondrial

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lipid membranes and proteins and loss of mito Chronic infections associated with chondrial function. The same process is seen autism spectrum disorder in adults who acquire these chronic infections; A number of chronic infections have been asso however, the consequences are different upon ciated with ASD (Box 3). However, what infec a fully developed brain [40]. tions may be the most significant at this point Altered tryptophan metabolism is seen with in time? The author and colleagues previously chronic infections that adversely affect the CNS. described an association between ASD and Lyme Inflammation and proinflammatory cytokines disease and other tick-borne diseases including result in increased indoleamine 2,3-dioxygen Mycoplasma, Bartonella, Ehrlichia and Babesia. ase, which increases the levels of neurotoxins, Nicholson has demonstrated an association quinolinic acid and 3-hydroxykynurenine and between ASD and M. fermentans, M. genetal- decreases the levels of serotonin and kynurenic ium, M. hominis, HHV-6 and C. pneumoniae. acid, which is neuroprotective [77–79]. He also noted an association between Gulf war Changes in lymphocytes are noted in both syndrome and ASD in the children of these vet ASD and chronic infections. Changes in erans associated with mycoplasma infections [40]. populations of natural killer cells are noted in the The association between ASD and M. fermen- blood of autistic children when compared with tans appears to be particularly significant. children without the disorder and these changes There are a number of reports and citations of are noted in changes in gene expression associated maternal transmission of Lyme disease and asso with these cells [80]. Invasion and cytopathic kill ciated adverse events [88–95]. Gardner reviewed ing of human lymphocytes and reduced natural 263 cases of congenital and gestational Lyme killer cells subsets have been noted in chronic borreliosis in the literature. A total of 66 of the infectious diseases [81,82]. 263 were associated with adverse outcomes and A number of metabolic changes are noted 15% of the 263 cases had neurological malforma in both autism and chronic infections. These tions [96]. Jones et al. performed a comprehensive include disorders of the oxidoreductive system case history review on the charts of 102 gesta in cerebrospinal fluid and serum, increases of tional cases of B. burgdorferi and other tick-borne superoxide dismutase, increased glutathione disease infections. Of these cases, 9% had been peroxidase activity, decreased glutathione levels, diagnosed with autism and 56% with ADHD. increased concentration of serum malondial Psychiatric symptoms included irritability or dehyde, alterations in homocysteine or methio mood swings (54%), anger or rage (23%), anxi nine metabolism, and impaired methylation and ety (21%), depression (13%), emotional (13%), sulfation (Figure 6) [83–87]. obessive compulsive disorder (11%) and suicidal thoughts (7%). Neurological symptoms included headache (50%), vertigo (30%), developmental Box 3. Chronic infections associated delays (18%), tic disorders (14%), seizure dis with autism spectrum disorder. orders (11%), involuntary athetoid movements • Babesia (9%) and hypotonia (7%). Sensory sensitivity • Bartonella symptoms included photophobia (43%), hypera • Blastocystis cuity (36%), motion sickness (9%) and other • Borrelia burgdorferi (tactile, taste or smell; 23%). Cognitive symp • Chlamydia pneumoniae toms included poor memory (39%), cognitive • Cytomegalovirus impairments (27%), speech delays (21%), read • Ehrlichia ing/writing (19%), articulation (17%), auditory/ • Herpes simplex virus visual processing (13%), word selectivity (12%) • Herpes virus family and dyslexia (18%). GI symptoms were common • Human herpesvirus-6 and included gastroesophageal reflux disease • Mycoplasma fermentans (27%), abdominal pain (29%), diarrhea or con • Mycoplasma genetalium stipation (32%) and nausea (23%) [19,97]. Four independent studies demonstrated significant • Mycoplasma hominis reactivity of ASD patients for Lyme disease on • Mycoplasma pneumoniae western blot testing, another study demonstrated • Plasmodium a high incidence of autism and hyperactivity in • Taenia solium over 300 gestational Lyme disease patients with • Toxoplasma gondii the mothers reporting difficult pregnancies and • Treponema pallidum pallidum frequent miscarriages, and similarities were

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noted between ASD and Lyme disease patients in regard to clinical symptoms, epidemiological Aberrant immune reactions Autism spectrum findings, biochemical findings, brain imaging Infections and/or other immune provocations causing inflammation, disorders studies and pathophysiology [19]. in genetically oxidative stress, mitochondrial Although Lyme disease is considered to be susceptible individual dysfunction and excitotoxicity caused by B. burgdorferi, evidence is slowly resulting in impaired neural development and dysfunction accumulating that Lyme disease is a far more complex condition than borreliosis alone. This hypothesis suggests that it may be more appro Figure 6. Model for infections contributing to autism spectrum disorder. priate to regard Lyme disease as a tick-borne disease complex. Over the recent years, numer are planning to become pregnant for chronic ous different microbes have been found in ticks, low-grade, relapsing infections, especially if they which are known to be zoonotic and can co- appear symptomatic with signs of a systemic infect the human host. The hypothesis suggests illness with persistent inflammatory symp that multiple co-infections are invariably present toms. Regional patterns of infectious diseases in the clinical syndromes associated with Lyme should be considered. A comprehensive general disease and it is suggested that these act synergis history, previous exposure to infectious diseases tically in complex ways. It may be that patterns and a thorough review of systems are indicated of co‑infection and host factors are the main when screening for a possible acute or chronic determinants of the variable clinical features of infectious process. Testing for the microbes dis Lyme disease rather than borrelia types [98,99]. cussed in this article is a consideration, especially when indicated by history, signs and symptoms. Review of research findings Since controversy exists regarding the reliabil In summary, it is challenging to draw conclusions ity of some testing methods, such as the 56% when so many variables exist. The pathophysio sensitivity of the CDC two-tier epidemiology logy through which infections can contribute to criteria for Lyme disease, clinical judgment is causing ASD is not well understood. Since many critical in making a proper assessment [100]. In different types of infections have been described higher-risk cases, the evaluation of the placenta, in the literature as being associated with contrib cord blood and newborn babies for infections uting to ASD, it appears the immune response are recommended. to the infection rather than the infection itself is the more critical process. Different research has Treatment proposed a number of possible mechanisms. It When signs, symptoms and clinical findings also appears that multiple mechanisms may be indicating the presence of chronic infections involved in contributing to the cause of ASD. associated with causing ASD are present, anti Although rubella and malaria are well-docu microbial treatments targeted towards the mented causes of ASD, a significant number of chronic infections are an option with women cases of ASD cannot be explained. More com intending to become pregnant, women who mon or overlooked infections need to be con are pregnant and newborn children. However, sidered as possible contributors. For example, doxycycline should be avoided in pregnant or piroplasms other than malaria, such as Babesia lactating women and newborn babies. Treatment microti and B. duncani, are more prevalent in of children with ASD with antibiotics is an area some geographical areas and need to be consid of potential benefit if there is a clinical impres ered as more likely contributors in those loca sion that active infection is contributory. In one tions. Syphilis is another well established model study, the short-term benefit from oral vanco for congenital disease, but cannot account for mycin treatment of regressive-onset autism was a significant number of current cases of ASD; noted, although this benefit was mostly lost after however B. burgdorferi is a more prevalent spi the antibiotic was discontinued [101]. rochete and may be a significant contributor to Since Lyme disease and syphilis are both causing ASD. spirochetal diseases with many similarities, some suggest that treating pregnant women Patient evaluation suffering from Lyme borreliosis with the same Since information in this area is still evolving, strategy that is used in treating pregnant women rigid guidelines cannot be established regarding with syphilis [96]. Jones studied 66 mothers with assessment and treatment. In view of the current Lyme disease who were treated with antibio findings, it is advisable to evaluate women who tics prior to conception and during the entire

future science group Pediatric Health (2009) 3(2) 135 perspective – Bransfield

pregnancy and found that all gave birth to nor Further research mal healthy infants. However, eight pregnancies Research is needed to better identify chronic per resulted in positive reactivity to B. burgdorferi sistent infections that result in pathological symp and/or B. henselae in placentas, umbilical cords toms; to better clarify the genetic and environ and/or foreskin remnants. Those who were mental contributors and their interaction; to better PCR‑positive were treated successfully with oral define the pathophysiology; to develop screening antibiotics [19,97]. In a study by Maraspin et al., and evaluation protocols for women who are plan 105 pregnant women with Lyme disease were ning to conceive, pregnant women and newborns treated with antibiotics, of these, 88.6% demon and to develop effective treatment strategies. The strated normal pregnancies with healthy infants work at the University of California at Davis, CA, with normal developmental milestones [102]. USA has been opening up new areas of research There are guidelines for the treatment of Lyme and further work needs to be undertaken to and tick‑borne diseases [207]. explain the etiology of the maternal autoantibodies Since there is evidence that immune reactions against fetal neural tissue. Treatment can be anti may contribute to the pathophysiological process, microbial and/or directed towards modifying the it appears advisable for pregnant women to avoid immune response by reducing the inflammatory vaccines, toxins, allergens or other substances cytokines with antibodies against the inflamma known to provoke inflammatory reactions. tory cytokines, plasmaphoresis of the mother to

Executive summary • A family with multiple cases of autism spectrum disorders (ASD) associated with chronic infections was described. • There is a significant prevalence of ASD and there are geographical patterns. • Autism spectrum disorders result from multiple etiologies with both genetic and environmental contributions. • Rubella has been associated with causing ASD and now attention has been also focused upon chronic persistent infections. • Infections associated with ASD include Babesia, Bartonella, Blastocystis, Borna virus (animal model), Borrelia burgdorferi and other tick-borne diseases, Chlamydia pneumoniae, Cytomegalovirus, Ehrlichia, Herpes simplex virus, Human herpesvirus-6, Herpes virus family, Mycoplasma fermentans, Mycoplasma genetalium, Mycoplasma hominis, Mycoplasma pneumoniae, Plasmodium (malaria), rubella, Rubeola, Shigella, Taenia solium (neurocysticercosis), Toxoplasma gondii (toxoplasmosis), Treponema pallidum pallidum (syphilis), varicella and other unknown viral and infectious agents. • Chronic infections may be more significant in causing persistent immune reactions and may be associated with biofilms and stealth pathogens. • Autism is associated with the Klüver–Bucy syndrome. • Maternal immune reactions to infections adversely affect fetal brain development. • The timing of the immune response is critical in determining the pathophysiology. • IL-6 is associated with causing ASD. • Based upon three different studies, antibodies that react to the 36, 37, 39, 61 and/or 73 kDa bands on western blot testing are associated with provoking an immune reaction and contribute to causing autism. Reactivity to these bands is also associated with Borrelia burgdorferi and, to a lesser degree, Bartonella henselae, Bartonella quintana, Mycoplasma, C. pneumonia and Streptococcus pneumoniae. • Chronic infections associated with causing ASD include Babesia, Bartonella, Blastocystis, Borrelia burgdorferi, Chlamydia pneumoniae, Cytomegalovirus, Ehrlichia, Human herpesvirus-6 and Mycoplasma (in particular M. fermentans), Plasmodium, T. solium, T. gondaii and T. pallidum pallidum. Coinfections of B. burgdorferi and M. fermentans associated with ASD are frequently observed in clinical settings. • It is advisable to evaluate women who are planning on becoming pregnant for chronic, low-grade, relapsing infections, especially if they appear symptomatic with signs of a systemic infection or illness with persistent inflammatory symptoms. • When chronic infections associated with causing ASD are present, antimicrobial treatments targeted towards the chronic infections are an option with women intending to become pregnant, women who are currently pregnant and newborn babies. • Research is needed to better identify chronic persistent infections; to better clarify the genetic and environmental contributors; to better define the pathophysiology; to develop screening and evaluation protocols for women who are planning to conceive, pregnant women and newborns; and to develop treatment protocols. • Microarrays and other newer diagnostic techniques and effective treatments with antimicrobials and possibly plasmaphoresis may help to further clarify the association between chronic persistent infections and the immune reactions to them that may contribute to these developmental disorders. • This is an opportunity to prevent some cases of ASD that previously could not be prevented.

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eliminate maternal autoantibodies against neural symptoms, and to treat when indicated. Adequate tissue and plasmaphoresis of the child to eliminate evaluations and treatments could help to prevent antibodies against neural tissue. This treatment some cases of ASD and their associated human could be similar to how it is used successfully for and financial costs. pediatric autoimmune diseases associated with streptococcal infections (PANDAS). Future perspective Since this is a complex issue, it is necessary for This is a complex issue that advances a new clinicians and researchers from different back paradigm and future progress requires successful grounds to effectively work together as a team. coordination from clinicians and researchers from The greatest challenge may be to coordinate the many different fields. Persistent immune reactions efforts of those who have something to contribute caused by a hit-and-run infection is a more estab in an effective manner. lished concept, however, chronic and persistent infections triggering a persistent autoimmune Conclusion reaction must also be considered. Since the cause In the presence of genetic susceptible factors there of most cases of ASD is unknown, every possi is evidence that chronic infections and associated ble explanation must be considered and explored. immune reactions contribute to causing autism Microarrays and other newer diagnostic tech spectrum disorders. These infections include niques may be quite useful in identifying known Babesia, Bartonella, B. burgdorferi, Ehrlichia, and still unknown infections, genes, gene expres HHV-6, C. pneumoniae and Mycoplasma (in sions and the immune reactions to them that are particular M. fermentans). Maternal immune contributing to these developmental disorders. We reactions to infections adversely affect fetal brain are living in a global community with increas development and possible pathophysiological ing exposure to toxins and infections. Adequate mechanisms appear to be mediated by both attention to these issues may help to prevent the cytokines and antibodies. Increased levels of catastrophic human and economic impact of ASD. the cytokine IL-6 are associated with causing ASD. There have also been some recent identi Acknowledgements fying maternal antibodies associated with con Robert C Bransfield would like to thank and recognize the tributing to causing ASD. These antibodies are contributions of Jeffrey Wulfmann for assistance with the of the same molecular weight as those seen with patient evaluation section, and Raphael Stricker for B. burgdorferi (Lyme disease) and also B. henselae, assistance regarding cross-antibody reactivity studies. Bartonella quintana, C. pneumoniae, S. pneumoniae and Mycoplasma. It appears a combination Financial & competing interests disclosure of inflammatory and autoimmune processes may The author has no relevant affiliations or financial be involved in the pathophysiology of ASD. The involvement with any organization or entity with a timing of the infection and the immune response financial interest in or financial conflict with the subject is critical in determining the pathophysiological matter or materials discussed in the manuscript. This process. It is advisable to evaluate women who includes employment, consultancies, honoraria, stock are planning on becoming pregnant for chronic, ownership or options, expert testimony, grants or patents low-grade, relapsing infections, especially if received or pending, or royalties. they appear symptomatic with a systemic ill No writing assistance was utilized in the production of ness or infection or with persistent inflammatory this manuscript.

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