How Tick-Borne Infections & Lyme Disease Contribute to Autism Spectrum Disorders

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Tick-Borne Infections & Lyme Disease Contributing to Autism Spectrum Disorders
Robert C Bransfield, MD, DFAPA Autism One Conference Chicago, Ill May 25, 2008
Disclosure Statement Robert Bransfield, MD, DFAPA, PC
• Most of my income is paid directly from patients • No insurance, government or other payer contracts that restrict patient care in return for referrals, financial considerations or any other benefit • No Lyme disease financial interests. • Speakers Bureau: Abbott, Astra Zeneca, Forest, GSK, Jazz, Lilly, Pfizer, Sanofi Aventis, Shire, Takeda, UCB. • President Elect International Lyme and Associated Diseases Society
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The association between LYD/TBD and ASD Background Clinical experience Gestational LYD/TBD Laboratory testing of ASD patients for TBD Biochemical similarities Brain imaging similarities Epidemiological findings Pathophysiology Theoretical issues: genes, infections and autism Klüver–Bucy Syndrome, infections and autism Neural networks, neurodevelopment, autism and borreliosis Borreliosis and Borrelia related complex Tick-borne/borreliosis infections and psychiatric illness Immune responses in ASD, Borreliosis and Mycoplasma infections Implications & Response Economic issues Assessment Treatment strategies Further evaluation of the hypothesis Summary
Outline
Autism: A Syndrome of Many Different Etiologies & Comorbidities
• Comorbidity with any DSM Dx • Epilepsy • Mental retardation (30% mild to moderate, 40% serious to profound) • Hearing & visual impairments • Fragile X syndrome & multiple other genetic • Tuberous sclerosis • Cerebral palsey • Phenylketonuria • Neurofibromatosis • Congenital rubella • Rett’s syndrome • Rasmussen’s encephalitis • Lennox-Gastaut syndrome • • • • • • • • • • • • Post infectious Metabolic Pyruvate d hydrogenase deficiency Impaired purine metabolism (uric acid increased) Brain structural—cyst, etc. PKU phenylalanine Angelman’s syndrome Landau-Kleffner syndrome Prader-Willi Williams Multiple other genetic impairments Associated with older paternal age
What Causes Autism?
• “Data suggest that autism results from multiple etiologies with both genetic and environmental contributions, which may explain the spectrum of behaviors seen in this disorder.”*
*Libbey, et al.
The Neurobiology of Autism
• It is becoming clear that the normal trajectory of neurodevelopment is altered in autism, with aberrations in brain growth, neuronal patterning and cortical connectivity. Changes to the structure and function of synapses and dendrites have also been strongly implicated in the pathology of autism by morphological, genetic and animal modeling studies. • Environmental factors are likely to interact with the underlying genetic profile, and foster the clinical heterogeneity seen in autism spectrum disorders. In this review we attempt to link the molecular pathways altered in autism to the neurodevelopmental and clinical changes that characterize the disease. • We focus on signaling molecules such as neurotrophin, Reelin, PTEN and hepatocyte growth factor, neurotransmitters such as serotonin and glutamate, and synaptic proteins such as neurexin, SHANK and neuroligin. • We also discuss evidence implicating oxidative stress, neuroglial activation and neuroimmunity in autism.
Pardo CA, EberhartCG. Brain Pathology. Volume 17 Issue 4 Page 434-447, October 2007
Personal Experience
• Primarily clinical practice • 35 year work with autistic patients • Interest in infectious causes of mental illness for 30+ years. • About 2000+ patients in with infections and other causes of inflammation, especially Lyme/tickborne disease. 1000 data points kept on each patient. Many have progressive systemic illnesses with encephalopathy. • Moderator of Microbes and Mental Illness Internet discussion group (9 years).
• “Whereas Lyme disease and other tickborne diseases are a serious public health threat;…Findings more common in children include autism, Tourette’s syndrome, attention deficit disorder, dyslexia, lethargy, and a decline in grades, tantrums;…”
Bransfield, Fallon, Raxlen, Shepler, Sherr“A Modest Proposal,” Psychiatric News (Newspaper of the APA), Vol. XXXIII, Number 18, September 18, 1998, p. 16.
A controlled study of cognitive deficits in children with chronic Lyme disease
• Twenty children with a history of new-onset cognitive complaints after Lyme disease were compared with 20 matched healthy control subjects. Each child was assessed with measures of cognition and psychopathology. Children with Lyme disease had significantly more cognitive and psychiatric disturbances. Cognitive deficits were still found after controlling for anxiety, depression, and fatigue. Lyme disease in children may be accompanied by long-term neuropsychiatric disturbances, resulting in psychosocial and academic impairments.
The association between tick-borne infections, Lyme borreliosis and autism spectrum disorders
• Tick-borne infections, including Lyme disease contribute to developing autism spectrum disorders (ASD) by direct effects, promoting other infections and immune effects during fetal development and infancy. Combined with other predisposing and contributory factors these infections may provoke immune reactions in susceptible individuals that result in inflammation, molecular mimicry, kynurenine pathway changes, increased quinolinic acid and decreased serotonin, oxidative stress, mitochondrial dysfunction and excitotoxicity that impair the development of the amygdala and other neural structures and neural networks resulting in a partial Klüver–Bucy Syndrome and other deficits resulting in autism spectrum disorders and/or exacerbating ASD from other causes. • Supporting data includes multiple cases of mothers with Lyme disease and children with ASD; fetal neurological abnormalities associated with tick-borne diseases; similarities between tick-borne diseases and ASD regarding symptoms, pathophysiology, immune reactivity, temporal lobe pathology, and brain imaging data; positive reactivity in several studies with ASD patients for Lyme disease (22%, 26% and 20–30%) and 58% for mycoplasma; similar geographic distribution and improvement in autistic symptoms from antibiotic treatment.
Bransfield RC, Wulfman JS, Harvey WT, Usman AI. Medical Hypotheses. 2007
Chronic Bacterial and Viral Infections in Neurodegenerative and Neurobehavioral Diseases
• Often patients with neurodegenerative or neurobehavioral diseases have chronic, neuropathic infections that could be important in disease inception, progression or increasing the types/severities of signs/symptoms. Although controversial, the majority of patients with various neurodegenerative or neurobehavioral conditions, such as amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer’s disease, Parkinson’s disease and autistic spectrum disorders, show evidence of central nervous system and/or systemic bacterial and viral infections. For example, using serology or polymerase chain reaction evidence of Chlamydia pneumoniae, Borrelia burgdorferi, Mycoplasma species, human herpesvirus-1 and -6 and other bacterial and viral infections revealed high infection rates that were not found in control subjects. Although chronic infections were not found in some studies and the specific role of chronic infections in neurological disease pathogenesis has not been determined or is inconclusive, the data suggest that chronic bacterial and/or viral infections could be common features of progressive neurodegenerative and neurobehavioral diseases.
Clinical Experience
Clinical Observations Autism & Lyme/Tick-Borne Disease
• A number of clinicians* and myself have noted an association between autism & Lyme/tick-borne disease. • This association is seen as:
– Infected mothers & children with autistic spectrum disorders (ASD) – Infected infants & ASD or autistic symptoms – Infected children & autistic symptoms
• Lyme/TBD infections in adults often have some symptoms suggestive of ASD:
– – – – – Sound sensitivity & sensory hyperacusis Emotional detachment Mood instability Decline of speech & language Seizures
• More severe symptoms are associated with infections at younger age, coinfections (Bartonella, Babesia & other TBD), genetic vulnerability & lengthy misdiagnosis & under-treatment • Multi-systemic symptoms is a diagnostic clue • Antimicrobial (anti-bacterial & anti-viral) treatment can reverse these symptoms
*Schaller, Corson, Levin, Berenbaum
Opinion of Dr Burrascano
• “It is my contention that Autism is an inflammatory encephalitis cause by a pathogen such as Bartonella or Mycoplasma. I share the view that Bartonella/BLO is a major infection that may eclipse Bb as the ultimate cause of the morbidity in chronic Lyme. Mycoplasma too is a major concern of mine- in reviewing my 7000+ cases, those patients who were relentlessly chronic all, at one point or another in their illness, were PCR + for Mycoplasma.”
BI/TBI & ASD: Similar GI Symptoms
• Kugathasan S. Pediatric inflammatory bowel disease: clinical and therapeutic aspects. Curr Opin Gastroenterol. 2001;17(4):350-5. • Zaidi AS, Singer C. Gastrointestinal and Hepatic Manifestations of Tick-borne Diseases in the United States. Clinical Infect Dis 2002;34:1206-12. • Sherr VT. “Bell’s palsy of the gut” and other GI manifestations of Lyme and associated diseases. Pract Gastroent. 2006:74-91 • Fried MD, Abel M, Pietrucha D, Kuo YH, Bal A. The Spectrum of Gastrointestinal Manifestations in Children and Adolescents with Lyme Disease. JSTD 1999;6. • Fried M. Gastrointestinal manifestations of Lyme disease. Program and abstracts of the 14th Int Sc Conf Lyme Disease and Other TBD; 2001
BI/TBI & ASD Respond to Similar Treatments • Both BI/TBI and ASD respond to similar treatments of psychiatric and cognitive symptoms with psychotropics (including modafinil, stimulants, memantine, mood stabilizers, atypical agents and serotonin reuptake inhibitors), diets, antimicrobials, mitochondrial enhancers, immune modulators, hyperbaric oxygen, glutathione, chelation and allergen elimination.
BI/TBI & ASD Respond to Similar Treatments: References
• Posey DJ, Kem DL, Swiezy NB, Sweeten TL, Wiegand RE, McDougle C. Pilot study of D-cycloserine in subjects with autistic disorder. Am J Psych. 2004;161(11):2115-7. • Sandler RH, Finegold SM, Bolte ER, et al. Short-term benefit from oral vancomycin treatment of regressiveonset autism. J Child Neurol. 2000;15(7):429-35. • Bransfield, RC. Update on the Neuropsychiatric Management of Lyme and Associated Diseases. ILDS Annual Meeting. 2004 • 27. Bransfield RC. Treatment of Autism with LYD/TBI. LIA Conference; 2007 • 28. Erickson CA, Posey DJ, Stingler KA, McDougle CJ. Pharmacotherapy of autism and related disorders. Psychiatric Annals. 37:7
Brain SPECT: Mother with Lyme Disease & 3 ASD Children
• SPECT scans of a mother with TD/BI and her three children with ASD which demonstrate many of the points previously described.
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Mother, 48: There is an extensive hypoperfusion pattern, prominently in the cerebral cortices and much of the frontal lobes, with a lesser degree in the temporal lobes and a small degree hypoperfusion in the cerebellum. The hypoperfusion is moderately extensive and is likely associated with toxic, inflammatory and infectious processes. There is hyperperfusion of the Basal Ganglia, which is associated with anxiety and mood dysregulation. The diagnosis is chronic fatigue syndrome, multiple sclerosis, depression and possible congenital Lyme disease. Lab testing was positive for Borrelia burgdorferi, Babesia WA-1, Bartonella henselae, Mycoplasma fermentans, HHV-6, Epstein Barr virus, high anti-streptolysin o titre and gamma Strep in stool.
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Son, 26: Some motion artifacts, however significant hypoperfusion pattern is both focal as well as generalized. The focal pattern is throughout the cerebral cortex bilaterally and the cerebellar hemispheres (which demonstrate atrophy on MRI) There is mild hyperperfusion of the basal ganglia and a focally intense hypeperfusion area in the deep white matter of the temporal lobe. There is a hyperperfusion pattern involving the temporal lobes and cerebellar hemispheres. The focal decrease is more suggestive of etiologies that would include hypoxic, neuroimmune, traumatic factors, infectious and inflammatory. There is a hyperperfusion pattern of the basal ganglia which may be associated with element of anxiety, whereas the focal intense areas can be associated with present interictal seizure focus and is clinically significant as the present dose of anticonvulsant is not controlling this area. The patient is low functioning with autism spectrum disorder since two years, grand mal seizures, movement disorder, ataxia, hypotonia, megacolon, possible mitochondrial disorder, mild hypergammaglobulenmia and syncope. Lab testing was positive for Borrelia burgdorferi, Babesia WA-1, Bartonella henselae, Mycoplasma fermentans, HHV-6, EBV and high strep titers; stool positive for Citrobacter fundii, Klebsialla p. and gamma Strep.
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Daughter, 23: There is an extensive hyperperfusion pattern in the cerebral cortices, temporal lobes and cerebellum and hypoperufsion of the frontal lobes and is likely associated with toxic, inflammatory and infectious processes. The diagnosis is Asperger’s, obsessive compulsive disorder, generalized anxiety, social anxiety disorder, depression, posttraumatic stress disorder from an auto accident, possible narcolepsy, tremors, cardiac disease, myocardial infarction, osteopenia, arthritis and psuedo rhematoid nodules since 5 years of age. Lab testing was positive for Borrelia burgdorferi, Anaplasma phagocytophilum, Mycoplasma fermentans, Homopholis, HHV-6, EBV, elevated Strep titres; stool was positive for Toxoplasmosis, Cornybacteria and gamma Strep.
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Daughter, 20: there is extensive hypoperfusion in the frontal lobes, temporal lobes and to a lesser degree to the occipital lobes and slightly to the cerebellum. There is hyperperufsion in the right cerebellar hemisphere. The hypoperfusion is likely associated with neuroinflammatory, neuroimmunological, infectious and toxic substance exposure. There is a seizure focus with hyperperfusion in the right cerebellar hemisphere. The diagnosis is autism spectrum disorder since 14 months, petit mal seizure disorder, hypotonia, perceptual impairments, and anxiety. Lab testing was positive for Borrelia burgdorferi, Bartonella henselae, Mycoplasma fermentans, HHV-6; stool positive for Parvo/B-19, Klebsiella, p., Citrobacter f. and gamma Strep.
Gestational Tick-Borne Infections/Borreliosis Infections
Maternal Fetal Issues
• Antibodies
– From mother – From fetal immune response to intrauterine infection
• Pregnancy and the Maternal Immune System
– Down regulated
• Teratogenic Issues in the Developing Fetus
– Rubella infection model for intrauterine infections
Mac Donald
Harvey, WT; Salvato, P: ‘Lyme Disease’: Ancient Engine of an Unrecognized Borreliosis Pandemic?
Medical Hypotheses (2003) 60(5), 742-759; Elsevier Science Ltd.
U n H inf um ec an ted s
Congenital Transfer
d te ec s nf an ni m U Hu
Sexual Transfer
ArthropodVectored Zoonotic Lyme Disease
Humans Infected With Borrelia burgdorferi
NonarthropodVectored Zoonotic Borreliosis
Figure 1. Revised model of human Borrelia burgdorferi infection
Maternal Transmission of LYD
• • • • • • • • • • • • • • Schlesinger PA, Duray PH, Burke BA, Steere AC, Stillman MT. Maternal-fetal transmission of the LYD spirochete, B. burgdorferi. Ann Intern Med. 1985;103(1):67-8. Lampert F. Infantile multisystem inflammatory disease: another case of a new syndrome. Eur J Pediatr. 1986;144(6):593-6. Lavoie PE, Lattner BP, Duray PH, et al. Culture positive, seronegative, transplacental Lyme borreliosis infant mortality. Arthritis Rheum.1987; 3:S50. MacDonald AB. Gestational Lyme borreliosis. Implications for the fetus. Rheum Dis Clin North Am. 1989;15(4):657-77. Markowitz LE, Steere AC, Benach JL, Slade JD, Broome CV. Lyme disease during pregnancy. JAMA. 1986;255(24):3394-6. Nadal D, Hunziker UA, Bucher HU, Hitzig WH, Duc G. Infants born to mothers with antibodies against Borrelia burgdorferi at delivery. Eur J Pediatr. 1989;148(5):426-7. Hercogova et al. Could borrelia found in the placenta influence the fetus? Study of 19 women with EM during pregnancy. 6th Int Conf Lyme Borreliosis.1994 Gardner T. Lyme disease In Infec Dis Fetus and Newborn Infant. Saunders, 1995 Gardner T. Lyme disease. 66 Pregnancies complicates by Lyme Borreliosis. Infec Dis Fetus and Newborn Infant. Saunders, 2000. Jones CR, Smith H, Gibb E, Johnson L. Gestational Lyme Disease Case studies of 102 Live Births. Lyme Times. 2005;Summer:34-6. Harvey, WT; Salvato, P: ‘Lyme Disease’: Ancient Engine of an Unrecognized Borreliosis Pandemic? Medical Hypotheses (2003) 60(5), 742-59. Bach G. Sexual Transmission of Lyme Disease. Microbes and Mental Illness Symp; Am Psych Assn Inst Psych Services. 2000 Jones, CR. Lyme Disease and Autism. LIA Conf;2007 Schmidt BL, Aberer E, Stockenhuber C, Klade H, Breier F, Luger A. Detection of Borrelia burgdorferi DNA by polymerase chain reaction in the urine and breast milk of patients with Lyme borreliosis. Diagn Microbiol Infect Dis. 1995;21(3):121-8.
Perinatal Transmission of the Agent of Human Granulocytic Ehrlichiosis
• We describe a case of Human Granulocytic Ehrlichiosis that developed in a pregnant woman near term and was transmitted perinatally to her infant. • (Hawaii has a high incidence of Ehrlichiosis)
Horowitz HW et al. NEJM. Volume 339 Number 6. p
Laboratory testing of ASD patients for tick-borne diseases
Testing ASD Patients for TBI
• • Vojdani tested Autism samples from different clinics in Northern CA, NY, NJ and CT. 22% of (12/54) tested IgG and IgM positive for Bbsl by Immunosciences Lab (Note: in this sample the Western Blot (WB) test used CDC surveillance criteria and did not include the full complement of Bbsl specific bands. A LIAF study tested the blood of 19 children with an ASD diagnoses plus an indication of immune dysfunction and five normal controls. Patients were not screened for BI before study entry. WB and IFA IgG and IgM were performed by IgeneX Laboratory. A result was considered Bbsl positive for exposure if there was reactivity of one or more Bbsl specific bands. 26% of the ASD children were positive compared to 0 controls. Levine tested nine consecutive ASD patients in Connecticut in 2003 and all nine tested positive for Bbsl with WB by IGeneX Laboratory criteria. Nicolson tested 48 ASD patients with forensic PCR and Southern Blot confirmation. 20–30% (depending upon the lab) were positive for Bbsl. 58% were positive for Mycoplasma species while 5% of 45 age matched controls were positive for Mycoplasma (Odds ratio = 13.8) with 35% M. fermentans vs. 0% control, 33% M. pneumoniae vs. 5% control, 10% M. homonis vs. 0% control, 2% M. penetrans vs. 0% control and 25% were M. fermentans and other species. Also 8% were positive for C. pneumoniae vs. 2% of controls (Odds ratio = 5.6) and 29% were positive for Human Herpes Virus-6 (HHV-6) vs. 8% of controls. 6.5% of healthy family members were positive for Mycoplasma and 8% were positive for HHV-6 (P < 0.001) [18]. He also reported WB positive BI patients had a 68% coinfection rate with Mycoplasma (M. Fermentans was 70%), Bartonella, Ehrlichia, and Babesia.
• •
Gestational BI/TBI & Austism
• Jones et al. performed a comprehensive case history review on the charts of 102 gestational BI/TBI cases. • 9% had been diagnosed with autism and 56% with attention deficit disorder. Psychiatric symptoms included irritability or mood swings (54%), anger or rage (23%), anxiety (21%), depression (13%), emotional (13%), OCD (11%) and suicidal thoughts (7%). Neurological symptoms included headache (50%), vertigo (30%), developmental delays (18%), tic disorders (14%), seizure disorders (11%), involuntary athetoid movements (9%) and hypotonia (7%). Sensory sensitivity symptoms included photophobia (43%), hyperacuity (36%), motion sickness (9%) and other (tactile, taste or smell) (23%). Cognitive symptoms included poor memory (39%), cognitive impairments (27%), speech delays (21%), reading/writing (19%), articulation (17%), auditory/visual processing (13%), word selectivity (12%), and dyslexia (18%). GI symptoms were common and included GERD (27%), abdominal pain (29%), diarrhea or constipation (32%), and nausea (23%). As a control, 66 mothers with Lyme disease who were treated with antibiotics prior to conception and during the entire pregnancy; all gave birth to normal healthy infants.
Jones CR, Smith H, Gibb E, Johnson L. Gestational Lyme Disease Case studies of 102 Live Births. Lyme Times 2005:34–6. Summer.
Biochemical Similarities
Biochemical Similarities
• Testing patients with autism and BI/TBI also reveals biochemical similarities. Disorders of an oxidoreductive system in CSF and serum, increases of superoxide dismutase, increased glutathione peroxidase activity, increased concentration of serum malondialdehyde and decreased glutathione have been detected in neuroborreliosis and BI. • In autism, several studies have suggested alterations in the activities of antioxidant enzymes such as superoxide dismutase and glutathione peroxidase, altered glutathione levels and homocysteine/methionine metabolism, increased malondialdehyde levels and reduced glutathione. • Impaired methylation & sulfation in both ASD & BI/TBI
Biochemical Similarities: References
• Pancewicz SA, Skrzydlewska E, Hermanowska-Szpakowicz T, Stankiewicz A, Kondrusik M. Evaluation of oxidoreductive potential of patients with neuroborreliosis. Przegl Epidemiol. 2002;56(3):425-33. • Pancewicz SA, Skrzydlewska E, Hermanowska-Szpakowicz T, Zajkowska JM, Kondrusik M. Role of reactive oxygen species (ROS) in patients with erythema migrans, an early manifestation of Lyme borreliosis. Med Sci Monit. 2001;7(6):1230-5. • Chauhan A, Chauhan V. Oxidative stress in autism. Pathophysiol. 2006;13(3):171-81. • Chauhan A, Chauhan V, Brown WT, Cohen I. Oxidative stress in autism: increased lipid peroxidation and reduced serum levels of ceruloplasmin and transferrin--the antioxidant proteins. Life Sci. 2004;75(21):2539-49 • James SJ, Cutler P, Melnyk S, Jernigan S, Janak L, Gaylor DW, Neubrander JA. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr. 2004;80(6):1611-7.
Brain Imaging Tick-Borne Diseases/Borreliosis and Autism
Brain Imaging Similarities
• Both BI/TBI and ASD patients demonstrate significant temporal lobe dysfunction. In autism the cerebral cortex, hippocampus, and amygdala showed trends toward being disproportionately smaller in the developing autistic brain. In addition smaller amygdala volume correlates with impairments in nonverbal social impairment in autistic patients. Infectious encephalopathies associated with autistic symptoms have demonstrated lesions of the temporal lobes. PET scanning of neuroborreliosis patients demonstrates the most striking finding was hypometabolism, which correlates with decreased activity, in the temporal lobes in 74% patients. • Both BI/TBI and ASD demonstrate predominately white matter encephalopathy. Regional cerebral blood flow suggests that Lyme encephalopathy may primarily affect cerebral white matter. • Disruption of white matter tracts between regions implicated in social functioning may contribute to impaired social cognition in autism. • Both ASD and BI/TBI patients demonstrate sensory hyperacusis and this clinical observation is supported by brain imaging of patients with BI that demonstrates increased thalamus activity and increased activity in auditory and visual areas of cortex.
Maternal infection and white matter toxicity
• Studies examining maternal infection as a risk factor for neurological disorders in the offspring have suggested that altered maternal immune status during pregnancy can be considered as an adverse event in prenatal development. Infection occurring in the mother during the gestational period has been implicated in multiple neurological effects. The current manuscript will consider the issue of immune/inflammatory conditions during prenatal development where adverse outcomes have been linked to maternal systemic infection. The discussions will focus primary on white matter and oligodendrocytes as they have been identified as target processes. This white matter damage occurs in very early preterm infants and in various other human diseases currently being examined for a linkage to maternal or early developmental immune status. The intent is to draw attention to the impact of altered immune status during pregnancy on the offspring for the consideration of such contributing factors to the general assessment of developmental neurotoxicology.
Harry GJ, Cindy L, Brunssen SH. Neurotoxicology. 2006 Sep;27(5):658-70.
Brain Imaging Similarities References
• • • • • • • • • • • • • Herbert MR, Ziegler DA, Deutsch CK, et al. Dissociations of cerebral cortex, subcort and cerebral white matter volumes in autistic boys. Brain. 2003;126(5):1182-92. Nacewicz BM, Dalton KM, Johnstone T, et al. Amygdala volume and nonverbal social impairment in adolescent and adult males with autism. Arch Gen Psych. 2006;63(12):1417-28 DeLong GR, Bean SC, Brown FR 3rd. Acquired reversible autistic syndrome in acute encephalopathic illness in children. Arch Neurol. 1981;38(3):191-4. Newberg A, Hassan A, Alavi A. Cerebral metabolic changes associated with Lyme disease. Nucl Med Commun. 2002;23(8):773-7. Fallon BA, Keilp J, Prohovnik I, Heertum RV, Mann JJ. Regional cerebral blood flow and cognitive deficits in chronic Lyme disease. J Neuropsychiatry Clin Neurosci. 2003;15(3):326-32. Morgen K, Martin R, Stone RD, et al. A. FLAIR and magnetization transfer imaging of patients with posttreatment Lyme disease syndrome. Neurol. 2001;57(11):1980-5. Steinbach JP, Melms A, Skalej M, Dichgans J. Delayed resolution of white matter changes following therapy of B burgdorferi encephalitis. Neurol. 2005;64(4):758-9. Belman AL, Coyle PK, Roque C, Cantos E. MRI findings in children infected by Borrelia burgdorferi. Pediatr Neurol. 1992;8(6):428-31. Fernandez RE, Rothberg M, Ferencz G, Wujack D. Lyme disease of the CNS: MR imaging findings in 14 cases. AJNR Am J Neuroradiol. 1990;11(3):479-81. Logigian EL, Johnson KA, Kijewski MF, et al. Reversible cerebral hypoperfusion in Lyme encephalopathy. Neurol. 1997;49(6):1661-70. Barnea-Goraly N, Kwon H, Menon V, Eliez S, Lotspeich L, Reiss AL. White matter structure in autism: preliminary evidence from diffusion tensor imaging. Biol Psych. 2004;55(3):323-6. Chung MK, Dalton KM, Alexander AL, Davidson RJ. Less white matter concentration in autism: 2D voxelbased morphometry. Neuroimage. 2004;23(1):242-51. Moeller, JR. Functional Neuroimaging findings in Chronic LYD; Research as a Tool to Solve Medical Controversies. Lyme and TBD Research Cen Columbia Univ. 2007
Epidemiological Findings: Lyme Disease/Tick-Borne Disease and Autism
Number of Lyme disease cases according to the CDC
BI/TBI Epidemiology
• Acute BI/TBI is more endemic in humid temperate locations with ecosystems that support populations of ticks and other hosts that carry the infectious agents. These locations are more commonly the Northeast; coastal regions; areas near the Mississippi River, the Mississippi tributaries, the Great Lakes region and the lake region of the upper Mid West. These endemic regions also coincide with the Atlantic, Mississippi and Pacific migratory bird flyways and migratory birds have been found to disseminate infected ticks. Veterinary data is helpful in this analysis (www.dogsandticks.com).
A Rapidly Changing Global Environment Encourages the Proliferation of Parasites, Including Ticks and Tick-Borne Diseases
Is there as association between migratory bird flyways (Atlantic, Pacific & Mississippi), TBD and ASD?
CDC: Lyme Disease --- United States, 2005
Top 15 States for Autism & Lyme Disease vs. Obesity (Control)
• • • • • • • • • • • • • • • Autism 1, Minnesota 2, Oregon 3, Indiana 4, Maine 5, Massachusetts 6, Michigan 7, California 8, Maryland 9, Connecticut 10, Wisconsin 11, Rhode Island 12, New Jersey 13, Pennsylvania 14, Hawaii 15, Virginia • • • • • • • • • • • • • • • • Lyme 1, Delaware 2, Connecticut 3, New Jersey 4, Massachusetts 5, Pennsylvania 6, New York 7, Wisconsin 8, Maryland 9, New Hampshire 10, Maine 11, Minnesota 12, Vermont 13, Rhode Island 14, Virginia 15, West Virginia
• • • • • • • • • • • • • • • • Obesity 1. Mississippi 2. Alabama 3. West Virginia 4. Louisiana 5. Kentucky 6. Tennessee 7. Arkansas 8. Indiana (tie for 8th) 8. South Carolina 10. Texas 11. Michigan 12. Georgia 13. Oklahoma 14. Missouri 15. Alaska
©2006 Lyme disease info.(JRS)
Informal Poll
• An informal poll by a show of hands was conducted at the LIAF Conference. It has been calculated 6.7/1000 8 y/o children have ASD (CDC). In addition, it has been calculated 11/100,000 5-9 y/o children have LYD/year (CDC). According to the Infectious Disease Society of America (IDSA) LYD is easily diagnosed & treated & not chronic, therefore incidence equals prevalence. The statistical probability of comorbid ASD + LYD is 6.7/1000 x 11/100,000 = 7/10,000,000, or approximately 1 in one million. If LYD + ASD are comorbid more than 1/1,000,000 and CDC & IDSA are correct, there is a causal association. As a control group, 18,000 have hemophilia in the US: this number is similar to the approximately 20,000 yearly prevalence of LYD in the US. At the LIA conference the author asked the 200 in attendance how many have seen ASD associated with hemophilia. One attendee raised her hand. The attendees were then asked how many have seen ASD associated with LYD. Half raised their hands. In addition a significant number have seen ASD associated with LYD in 10 or more cases, 6 have seen ASD associated with LYD in 100 or more cases and one physician has seen ASD associated with LYD in 500 or more cases.
Theoretical Issues: Genes, Infections and Autism
Physics, Math & Astrophysics:
Newton to Einstein
• Newton-Universal gravitation and the three laws of motion
• Einstein-Theory of relativity, massenergy equivalence, (E=mc²), nonuniform motion & a new theory of gravitation
Complex Human Diseases
Beyond Koch and Mendel
Mendel-Human traits are determined by individual genes which function independently of other genes and of environmental influences Koch-Many human diseases are caused by microbes which exert their effect independently of other microbes, environmental factors and genes
Yolken
 Most common human diseases are caused by the interaction of environmental insults and susceptibility genes.  Many of the susceptibility genes are diverse determinants of human response to environmental factors to infection.  Informative laboratory methods for complex disorders have to address both genetic and environmental factors.  Prevention or treatment of the infections may result in the effective treatment of complex disorders:  Helicobacter-Peptic Ulcer  HPV-Genital Cancer  Chlamydia-Cardiac Disease?
Yolken
Gene-Environmental Interactions Beyond Koch’s Postulates
Emerging Infectious Determinants of Chronic Diseases
• Evidence now confirms that non-communicable chronic diseases can stem from infectious agents. • Identifying the relationships can affect health across populations, creating opportunities to reduce the impact of chronic disease by preventing or treating infection. • Infectious agents likely determine more cancers, immune-mediated syndromes, neurodevelopmental disorders, and other chronic conditions than currently appreciated. • To capitalize on these opportunities, clinicians, public health practitioners, and policymakers must recognize that many chronic diseases may indeed have infectious origins.
Siobh M. et al (CDC). Emerging Infectious Determinants of Chronic Diseases. Emerging Infectious Diseases. Vol. 12, No. 7
Associations between Chlamydophila infections, schizophrenia and risk of HLA-A10
• Several microbes have been suspected as pathogenetic factors in schizophrenia. We have previously observed increased frequencies of chlamydial infections and of human lymphocyte antigen (HLA)-A10 in independent studies of schizophrenia. • We found chlamydial infection in 40.3% of the schizophrenic patients compared to 6.7% in the controls. The association of schizophrenia with Chlamydiaceae infections was highly significant (P=1.39 10-10, odds ratio (OR)=9.43), especially with Chlamydophila psittaci (P=2.81 10-7, OR=24.39). • Schizophrenic carriers of the HLA-A10 genotype were clearly most often infected with Chlamydophila, especially C. psittaci (P=8.03 10-5, OR=50.00). Chlamydophila infections represent the highest risk factor yet found to be associated with schizophrenia. This risk is even further enhanced in carriers of the HLA-A10 genotype.
Selected Infectious Agents and Risk of Schizophrenia Among U.S. Military Personnel
• The authors found significant associations between increased levels of scaled T. gondii IgG antibodies and schizophrenia for antibodies measured both prior to and after diagnosis.
Maternal Exposure to Herpes Simplex Virus and Risk of Psychosis Among Adult Offspring
• Background: Viral exposure during gestation is thought to be a risk factor for schizophrenia. Previous studies have indicated that prenatal exposure to herpes simplex virus type 2 (HSV-2) may be a risk for the subsequent development of schizophrenia in some populations. In this investigation, we tested a large and diverse population to assess the risk of psychoses among offspring of mothers with serological evidence of HSV-2 infection. Results: Offspring of mothers with serologic evidence of HSV-2 infection were at significantly increased risk for the development of psychoses (odds ratio [OR] = 1.6; 95% confidence interval [CI] = 1.1–2.3). This risk was particularly elevated among women with high rates of sexual activity during pregnancy (OR = 2.6; 95% CI = 1.4–4.6). Conclusions: Maternal exposure to herpes simplex virus type 2 is associated with an increased risk for psychoses among adult offspring. These results are consistent with a general model of risk resulting from enhanced maternal immune activation during pregnancy.
•
•
Stephen L. Buka, Tyrone D. Cannonc, E. Fuller Torrey, Robert H. Yolken. Biological Psychiatry. Volume 63, Issue 8, 15 April 2008, Pages 809-815
Disease Contributors Change with Time
Predisposing Factors Precipitating Factors Perpetuating Factors
Symptom “Intensity”
Threshold
1 Preclinical
2 Onset Course
3 Short-Term
4 Chronic
Adapted from Spielman AJ et al. Psychiatr Clin North Am. Course of Insomnia; 1987;10:541-553.
Schema of Etiologic and Pathogenetic Factors That Have Been Implicated in Cell Death in Parkinson Disease and Possible Neuroprotective Approaches
Schapira, A. H. V. et al. JAMA 2004;291:358-364.
Copyright restrictions may apply.
The Biotoxin Pathway
Capillaries In genetically susceptible people , biotoxin binds to fat -cell receptors, causing continuing, unregulated production of cytokines .
Bo d b ya t ox iot o c qu org in-p xins ires foo anis r odu or c or d, wa ms f ing ins te rom r, a ec t b ir, ite s
High cytokine levels in the capillaries attract white blood cells , leading to restricted blood flow , and lower oxygen levels. Reduced VEGF leads to fatigue, muscle cramps, and shortness of breath (may be over-ridden by replacement with erythropoietin). Immune system symptoms
Biotoxin (HLA susceptible)
Surface (“Toll”) receptor
Fat Cell
Increased Cytokines
(H Bi LA oto su x in s ce pt i ble )
Fat cells then produce more leptin, leading to obesity (which doesn’t respond to exercise and diet ).
Patients with certain HLA genotypes (immunityrelated genes) may develop inappropriate immunity. Most common are antibodies to: -- Myelin basic protein (often from fungal biotoxins; affects nervous-system functions) -- Gliadin (affects digestion) -- Cardiolipins (affects blood clotting ) The “complement” alternative immune pathway may be triggered (detectable as an increase in levels of the proteins C3a C4a). Cytokine-related symptoms High levels of cytokines produce flu -like symptoms: Headaches, muscle aches , fatigue, unstable temperature, difficulty concentrating . High levels of cytokines also result in increased levels of several other immune -response related substances, including TNF, MMP-9, IL-1B, and PAI-1. MMP-9 delivers inflammatory elements from blood to brain, nerve, muscle, lungs, and joints. It combines with PAI-1 in increasing clot formation and arterial blockage. Reduced ADH Reduced MSH can cause the pituitary to produce lower levels of anti-diuretic hormone (ADH), leading to thirst , frequent urination, and susceptibility to shocks from static electricity . Reduced sex hormones Reduced MSH can cause the pituitary to lower its production of sex hormones. Stage 1: Biotoxin effects Stage 2: Cytokine effects Stage 3: Reduced VEGF Stage 4: Immune effects Stage 5: Low MSH Stage 6: Resistant Staph bacteria Stage 7: Pituitary hormone effects
s rea Inc n pti Le ed
dC se rea I nc
es k in yto
Nerve cell
Biotoxins have direct effects, including impairment of nerve cell function. One result is poor performance on contrast sensitivity test .
Excessive cytokine levels can damage leptin receptors in the hypothalamus.
Leptin receptor Hypothalamus VIP AVP
Damaged leptin receptors lead to reduced production by the hypothalamus of MSH, a hormone with many functions.
In most people, biotoxins are either removed from the blood by the liver or attacked by the immune system, broken down, and excreted harmlessly. In people who don’t have the right immune-system genes, however, biotoxins can remain in the body indefinitely.
© G. Alexander 2004
in t ox A Bio t HL le) b (no ept i sc su
Removal from the body
Sleep disturbance Production of melatonin is reduced, leading to light , nonrestorative sleep. Chronic pain Endorphin production is suppressed. This can lead to chronic, sometimes unusual, pain. Gastrointestinal problems Lack of MSH can cause malabsorption in the gut, resulting in diarrhea. This is sometimes called “leaky gut” and resembles (but is not) celiac disease . Patients must avoid gluten, whey, and amylose.
Reduced MSH
Prolonged illness White blood cells lose regulation of cytokine response, so that recovery from other illnesses , including infectious diseases , may be slowed.
Resistant Staph bacteria Colonies of Staph bacteria with resistance to multiple antibiotics may develop in mucous membranes. The bacteria produce substances that aggravate both the high cytokine levels and low MSH levels .
Changes in cortisol and ACTH levels The pituitary may produce elevated levels of cortisol and ACTH in early stages of illness , then drop to excessively low levels later . (Patients should avoid steroids such as prednisone, which can lower levels of ACTH.)
Rev. 10, 12-12-05
Heavy Metal Toxicity
Summarizing the Theories
• Most commonly human diseases are caused by the interaction of environmental insults and susceptibility genes. Many of the susceptibility genes respond to environmental factors and infection. Environmental insults contributing to ASD may include a complex interaction with infections, heavy metals, biotoxins, allergens, nutritional excesses/deficits and possibly vaccines resulting in a pathogenic interaction that includes inflammation, oxidative stress, mitochondrial dysfunction and excitotoxicity resulting in neuronal dysfunction.
Klüver–Bucy Syndrome, Infections and Autism
http://www.athealth.com
Limbic System
• The limbic system is the mammalian brain • The creation & evolution of the limbic system parallels the creation & evolution of the family
The Amygdala Theory of Autism
• There is a network of neural regions that comprise the "social brain", which includes the amygdala • Since the childhood psychiatric condition of autism involves deficits in "social intelligence", it is plausible that autism may be caused by an amygdala abnormality • This includes reference to the Klüver-Bucy syndrome
Baron-Cohen S, et. Al. Neurosci Biobehav Rev. 2000 May;24(3):355-64.
• The syndrome is named for Heinrich Klüver and Paul Bucy, who removed the temporal lobe bilaterally in rhesus monkeys in an attempt to determine its function. This caused the monkeys to develop visual agnosia, emotional changes, altered sexual behavior, hypermetamorphosis and oral tendencies. • Though the monkeys could see, they were unable to recognize even previously familiar objects, or their use. They would examine their world with their mouths instead of their eyes ("oral tendencies") and developed a desire to explore everything ("hypermetamorphosis"). • Their overt sexual behavior increased dramatically ("hypersexualism"), and the monkeys indulged in indiscriminate sexual behavior including masturbation, heterosexual acts and homosexual acts. • Emotionally, the monkeys became dulled, and their facial expressions and vocalizations became far less expressive. They were also less fearful of things that would have instinctively panicked them in their natural state, such as humans or snakes. Even after being attacked by a snake, they would willingly approach it again. This aspect of change was termed "placidity". • People with bilateral lesions in their temporal lobes show similar behaviors. They may display oral or tactile exploratory behavior (socially inappropriate licking or touching); hypersexuality; bulimia; memory disorders; flattened emotions (placidity); and an inability to
Klüver-Bucy Syndrome
• Studies are reviewed that support the hypothesis that infantile autism results from a neuropathology of the temporal lobes of the brain. First, there are parallels between symptoms noted in autism and those found in the Kluver-Bucy and amnesic syndromes. Second, there is a similarity between developmental dysphasia and autism. Third, the formation of cross-modal associations may be deficient in autistic children, a symptom resembling aspects of Geschwind's disconnection syndromes. Finally, a large number of organic factors have been associated with the development of autism, some of these having specific implications for temporal lobe involvement. It is concluded that the main autistic symptoms are most consistent with a neurological model involving bilateral dysfunction of the temporal lobes. Individual differences in the extent of bilateral involvement and/or other coexistent neuropathologies could contribute to the heterogeneity of the autistic population. Hetzler BE, Griffin JL. J Autism Dev Disord. 1981 Sep;11(3):317-30.
Infantile Autism and the Temporal Lobes of the Brain
Autism, the superior temporal sulcus and social perception
– Based on recent brain-imaging results, our hypothesis is that abnormalities in the superior temporal sulcus (STS) are highly implicated in ASD. STS abnormalities are characterized by decreased gray matter concentration, rest hypoperfusion and abnormal activation during social tasks. STS anatomical and functional anomalies occurring during early brain development could constitute the first step in the cascade of neural dysfunction underlying ASD. We will focus this review on the STS, which has been highly implicated in social cognition. We will review recent data on the contribution of the STS to normal social cognition and review brain-imaging data implicating this area in ASD.
Zibovicius M et al. Trends Neurosci. 2006 Jul;29(7):359-66. Epub 2006 Jun 27.
Amygdala volume and nonverbal social impairment in adolescent and adult males with autism
• In study 1, individuals with autism who had small amygdalae were slowest to distinguish emotional from neutral expressions (P=.02) and showed least fixation of eye regions (P=.04). These same individuals were most socially impaired in early childhood, as reported on the Autism Diagnostic Interview-Revised (P<.04). • Study 2 showed smaller amygdalae in individuals with autism than in control subjects (P=.03) and group differences in the relation between amygdala volume and age. Study 2 also replicated findings of more gaze avoidance and childhood impairment in participants with autism with the smallest amygdalae. Across the combined sample, severity of social deficits interacted with age to predict different patterns of amygdala development in autism (P=.047). • CONCLUSIONS: These findings best support a model of amygdala hyperactivity that could explain most volumetric findings in autism. Further psychophysiological and histopathological studies are indicated to confirm these findings
Nacewicz, et. al. Arch Gen Psychiatry. 2006 Dec;63(12):1417-28
Medline Cited Infectious Causes of Autism
• Rubella, • Herpes simplex • Mycoplasma pneumoniae • Shigella • Neurocysticercosis • Unknown • Various viral infection • Borna • HHV-6 • Chlamydia • • • • • • • • Herpes virus family Malaria Blastocystis Cytomegalovirus Syphilis Varicella Toxoplasmosis Yet unrecognized infectious • Tick-Borne/Lyme
Microbes that Can Cause Mental Symptoms
• • • • • • Syphilis Malaria Toxoplasmosis Candidiasis Other spirochetes 1. Borrelia burgdorferi sensu stricto(USA,UK,Europe) 2. Borrelia garinii (UK, Europe) 3. Borrelia afzelii (UK, Europe) "CHRONIC LYME DISEASE" or "NEW LYME DISEASE" is a combination of LYME DISEASE and one or more of the following Coinfections: Relapsing Fever caused by the spirochetes: - Borrelia hermsii - Borrelia turicatae Mycoplasmas: - Mycoplasma fermentans - Mycoplasma pneumoniae Babesiosis: - Babesia microti - Babesia WA and other Babesia species - Chlamydia pneumoniae Rickettsial Diseases: - Rocky Mountain Spotted Fever - Coxiella burnetti (Q-Fever and "PostQ Fever Fatigue Syndrome") - Colorado Tick Fever - Eastern tick-borne Rickettsiosis - Rickettsialpox - Tularemia (rabbit fever) - Ehrlichiosis (caused by Ehrlichia, and rickettsia-like bacteria) •- Anaplasmas (related to the genera Rickettsia and Ehrlichia) - Hepatitis-C Bartonellosis: - Bartonella henselae (cat scratch fever), Bartonella rochalimae - Bartonella quintana (trench fever) - Viral Meningitis Candida dubliniensis Asfarviridae, Reoviridae, Rhabdoviridae, Orthomyxoviridae, Bunyaviridae, Flaviviridae & Arenaviridae family viruses (38+ species Streptococcus Japanese B encephalitis HHV-1 HHV-2 Borna virus Epstein-Barr virus Pandemic Influenza of 1918 Hong Kong flu Coxackie virus Pneumococcus Haemophilus Meningococcus Leptospira Mycobacterium tuberculosis Cytomegalovirus Enterovirus HIV • • • • • • • • • • • • • • • • • • • • • • • • • • • • Pandemic Influenza of 1918 Influenza virus Measles Papovirus Poliovirus Rabies Toga virus Toxoplasmosis Cryptococcus Coccidiomycosis Histoplasmosis Cysticercosis Rubella, Herpes simplex Mycoplasma pneumoniae Shigella Neurocysticercosis Unknown Various viral infection Borna Herpes virus family Malaria Blastocystis Cytomegalovirus Syphilis Varicella Toxoplasmosis Yet unrecognized infectious
•
Infections, Klüver-Bucy & Autism I
• • • • • • • • • • Baron-Cohen S, Ring HA, Bullmore ET, Wheelwright S, Ashwin C, Williams SC. The amygdala theory of autism. Neurosci Biobehav Rev. 2000;24(3):355-64. Hetzler BE, Griffin JL. Infantile autism and the temporal lobe of the brain. J Autism Dev Disord. 1981;11(3):317-30. Libbey JE, Sweeten TL, McMahon WM, Fujinami RS. Autistic disorder and viral infections. J Neurovirol. 2005;11(1):1-10 Stubbs EG, Crawford ML. Depressed lymphocyte responsiveness in autistic children. J Autism Child Schizophr. 1977;7(1):49-55. De Tiege X, De Laet C, Mazoin N, et. al. Postinfectious immune-mediated encephalitis after pediatric herpes simplex encephalitis. Brain Dev. 2005;27(4):304-7. DeLong GR, Bean SC, Brown FR 3rd. Acquired reversible autistic syndrome in acute encephalopathic illness in children. Arch Neurol. 1981;38(3):191-4. Libbey JE, Sweeten TL, McMahon WM, Fujinami RS. Autistic disorder and viral infections. J Neurovirol. 2005;11(1):1-10 Lancaster K, Dietz DM, Moran TH, Pletnikov MV.Abnormal social behaviors in young and adult rats neonatally infected with Borna disease virus. Behav Brain Res. 2007;176(1):141-8. Stubbs EG, Crawford ML. Depressed lymphocyte responsiveness in autistic children. J Autism Child Schizophr. 1977;7(1):49-55.
• • • • • • • • •
Infections, Klüver-Bucy & Autism II
Markowitz PI. Autism in a Child with Congenital Cytomegalovirus Infection. J Autism Dev Disord. 1983;13(3) Stubbs EG, Ash E, Williams CPS. Autism and Congenital Cytomegalovirus. J Autism Dev Disord. 1984;14(2). Auvichayapat N, Auvichayapat P, Watanatorn J, Thamaroj J, Jitpimolmard S. Kluver-Bucy syndrome after mycoplasmal bronchitis. Epilepsy Behav. 2005;8(1):320-2. Guedalia JS, Zlotogorski Z, Goren A, Steinberg A. A reversible case of Klüver-Bucy syndrome in association with shigellosis. J Child Neurol. 1993;8(4):313-5. Stubbs EG, Crawford ML. Depressed lymphocyte responsiveness in autistic children. J Autism Child Schizophr. 1977;7(1):49-55. Patel R, Jha S, Yadav RK. Pleomorphism of the clinical manifestations of neurocysticercosis. Trans R Soc Trop Med Hyg. 2006;100(2):134-41. Mankoski RE, Collins M, Ndosi NK, Mgalla EH, Sarwatt VV, Folstein SE. Etiologies of autism in a case-series from Tanzania. J Autism Dev Disord. 2006;36(8):1039-51 Thong YH. Reptilian behavioural patterns in childhood autism. Med Hypotheses. 1984;13(4):399-405. Boorom KF. Is this recently characterized gastrointestinal pathogen responsible for rising rates of inflammatory bowel disease (IBD) and IBD associated autism in Europe and the United States in the 1990s? Med Hypotheses. 2007;69(3):652-9.
Infections, Klüver-Bucy & Autism III
• • • • • • • • • • Singh VK and Jensen RL. Elevated levels of measles antibodies in children with autism. Pediatric Neurol. 2003;28:292-294. Singh VK. Autism, vaccines, and immune reactions. Accessed 8-3-07. http:// vacinfo.org/vijendra_singh.htm Halsey NA, Hyman SL. Measles-mumps-rubella vaccine and ASD: report from the New Challenges in Childhood Immunizations Conf. Pediatrics. 2001;107(5):E84 Bransfield RC, Wulfman JS, Harvey WT, Usman AI. The association between tickborne infections, Lyme borreliosis and autism spectrum disorders Medical Hypotheses. 2007 Nicolson GL, Gan R, Nicolson NL, et al. Evidence for Mycoplasma, Chlamydia pneunomiae and HHV-6 Co-infections in the blood of patients with Autism Spectrum Disorders. J Neuroscience Res. 2007;85:1143-48. Takahashi H, Arai S, Tanaka-Taya K, et al. Autism and infection/immunization episodes in Japan. Jpn J Infect Dis. 2001;54:78-79. Yamashita Y, Fujimoto C, Nakajima E, et al. Possible association between congenital cytomegalovirus infection and autistic disorder. J Autism Dev Disord. 2003;33:355-59. Rosen NJ, Yoshida CK, Croen LA. Infection in the first 2 years of life and autism spectrum disorders. Pediatrics. 2007;119:61-9. Nicolson GL, Berns P, Gan R, et al. Chronic mycoplasmal infections in Gulf War veterans’ children and autism patients. Med Veritas. 2005;2:383-87. Nicolson GL. Chronic Bacterial and Viral Infections in Neurodegenerative and Neurobehavioral Diseases. Laboratory Medicine 2008. In Press
Neural Networks, Neurodevelopment, Autism and Borreliosis
The neurodevelopmental impact of prenatal infections at different times of pregnancy: the earlier the worse?
• Infection associated immunological events in early fetal life can have adverse effects on cell proliferation and differentiation; predispose the developing nervous system to undergo additional failures in subsequent cell migration, target selection, and synapse maturation, eventually leading to multiple brain and behavioral abnormalities apparent later in life.
Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models
• Brain developmental processes (i.e. cell proliferation, migration, differentiation, synaptogenesis, myelination, and apoptosis) occur at vulnerable periods during the development of the nervous system and are sensitive to environmental insults that can contribute to autism.
Rice D, Barone S. Environ Health Perspect 2000;108(3):511–33.
Immune Reactions to LYD Disrupt Nerve Fibers
• Younger has demonstrated on biopsies that small nerve fiber disruption can occur in Lyme vaccine recipients and BI/TBI patients who subsequently may heal in response to anti-infective treatment
Younger D. Small nerve fiber disruption in OspA vaccine recipients. Am Acad Neurol. Meeting 2007.
Oxidative Stress
• “Chronic intracellular infections (Mycoplasma, Borrelia, Chlamydia, etc.) cause increased oxidative stress by their release of ROS and stimulation of ROS in mitochondria. This causes increased oxidation of mitochondrial lipid membranes and proteins and loss of mitochondrial function. We see the same thing in CFS patients who also have these infections, although in fully developed brains we do not, of course, see the autism and other developmental disorders.” Prof. Garth Nicolson
Evidence of toxicity, oxidative stress, and neuronal insult in autism
• This article discusses the evidence for the case that some children with autism may become autistic from neuronal cell death or brain damage sometime after birth as result of insult; and addresses the hypotheses that toxicity and oxidative stress may be a cause of neuronal insult in autism. The article first describes the Purkinje cell loss found in autism, Purkinje cell physiology and vulnerability, and the evidence for postnatal cell loss. Second, the article describes the increased brain volume in autism and how it may be related to the Purkinje cell loss. Third, the evidence for toxicity and oxidative stress is covered and the possible involvement of glutathione is discussed. Finally, the article discusses what may be happening over the course of development and the multiple factors that may interplay and make these children more vulnerable to toxicity, oxidative stress, and neuronal insult.
Kern & Jones. J Toxicol Environ Health B Crit Rev. 2006 Nov-Dec;9(6):485-99
– Oxidative stress is postulated to play a role in cell death in many neurodegenerative diseases. As a model of neonatal neuronal cell death, we have examined the role of oxidative stress in Purkinje cell death in the heterozygous Lurcher mutant (+/Lc). Lurcher is a gain of function mutation in the delta2 glutamate receptor (GluRdelta2) that turns the receptor into a leaky membrane channel, resulting in chronic depolarization of +/Lc Purkinje cells starting around the first week of postnatal development. Virtually, all +/Lc Purkinje cells die by the end of the first postnatal month. To investigate the role of oxidative stress in +/Lc Purkinje cell death, we have examined nitric oxide synthase (NOS) activity and the expression of two markers for oxidative stress, nitrotyrosine and manganese super oxide dismutase (MnSOD), in wild type and +/Lc Purkinje cells at P10, P15, and P25. The results show that NOS activity and immunolabeling for nitrotyrosine and MnSOD are increased in +/Lc Purkinje cells. To determine whether peroxynitrite formation is a prerequisite for +/Lc Purkinje cell death, +/Lc mutants were crossed with an alpha-nNOS knockout mutant (nNOSalpha(-/-)) to reduce the production of NO. Analysis of the double mutants showed that blocking alpha-nNOS expression does not rescue +/Lc Purkinje cells. However, we present evidence for sustained NOS activity and nitrotyrosine formation in the GluRdelta2(+/Lc):nNOS(-/-) double mutant Purkinje cells, which suggests that the failure to rescue GluRdelta2(+/Lc):nNOS(-/-) Purkinje cells may be explained by the induction of alternative nNOS isoforms.
Oxidative stress, nitric oxide, and the mechanisms of cell death in Lurcher Purkinje cells
Major Histocompatibility Complex
• An infection during pregnancy or early development in a genetically predisposed individual may evoke an immune response that that disrupts fetal brain development by altering major histocompatibility complex molecules that impact glia and microgila cells, glutamate functioning and synaptic development and plasticity and contribute to the pathophysiology of autism.
Cerebellar atrophy in temporal lobe epilepsy
– The goal of this work was to determine the presence and degree of cerebellar atrophy in chronic temporal lobe epilepsy – CONCLUSIONS: The presence of cerebellar atrophy is a reflection of the extra-temporal abnormalities that can be observed in localization-related temporal lobe epilepsy, which may be due, at least in part, to factors associated with epilepsy chronicity.
Borreliosis and Borrelia Related Complex
Tick-Borne Pathogens
• Humans have 400 different species of bacteria in their mouth. • What pathogens, known and unknown, can be transmitted from a tick that lives in filth and sucks on the blood of rodents?
POLYMICROBIAL INFECTIONS IN ANIMALS AND HUMANS
Polymicrobial diseases represent the clinical and pathological manifestations induced by the presence of multiple microorganisms. These are serious diseases whose etiologic agents are sometimes difficult to diagnose and difficult to treat. They are often called complex infections, complicated infections, dual infections, mixed infections, secondary infections, coinfections, synergistic infections, concurrent infections, or polymicrobial infections. These diseases in animals and humans are induced by multiple viral infections, multiple bacterial infections, viral and bacterial infections, multiple mycotic and parasitic infections, and opportunistic infections secondary to microbe-induced immunosuppression. There are five common underlying mechanisms of disease pathogenesis. First, physical, physiologic, or metabolic abnormalities and stress predispose the host to polymicrobial disease. Second, one microorganism induces changes in the mucosa that favors the colonization of other microorganisms. Third, microorganisms or their products can trigger proinflammatory cytokines that increase the severity of disease, reactivate latent infections, or favor the colonization of other microorganisms. Fourth, microorganisms share determinants among each other allowing them the collective ability to damage tissue. Finally, one microorganism alters the immune system, which allows the colonization of the host by other microorganisms. Many areas of study in polymicrobial diseases are at their infancy and it is our hope that this Conference will stimulate interest and work in this evolving area.
•
•
LYME DISEASE caused by three types of Spirochete Borrelia bacteria (300 strains): 1. Borrelia burgdorferi sensu stricto(USA,UK,Europe) 2. Borrelia garinii (UK, Europe) 3. Borrelia afzelii (UK, Europe) "CHRONIC LYME DISEASE" or "NEW LYME DISEASE" is a combination of LYME DISEASE and one or more of the following Co-infections: Relapsing Fever caused by the spirochetes: - Borrelia hermsii - Borrelia turicatae Mycoplasmas: - Mycoplasma fermentans - Mycoplasma pneumoniae Babesiosis: - Babesia microti - Babesia WA and other Babesia species - Chlamydia pneumoniae Rickettsial Diseases: - Rocky Mountain Spotted Fever - Coxiella burnetti (Q-Fever and "Post-Q Fever Fatigue Syndrome") - Colorado Tick Fever - Eastern tick-borne Rickettsiosis - Rickettsialpox - Tularemia (rabbit fever) - Ehrlichiosis (caused by Ehrlichia, a rickettsia-like bacteria) - Anaplasmas (related to the genera Rickettsia and Ehrlichia) - Hepatitis-C Bartonellosis: - Bartonella henselae (cat scratch fever) - Bartonella quintana (trench fever) - Viral Meningitis Candida dubliniensis Asfarviridae, Reoviridae, Rhabdoviridae, Orthomyxoviridae, Bunyaviridae, Flaviviridae & Arenaviridae family viruses (38+ species) Sean and Leslee Dudley & Labuda and Nuttall & Nunn
What is Chronic LYD/TBD?
•
• •
Borrelia Pathophysiology
• Invade, penetrate, injure or kill host cells • Indirect injury at a distance (coagulation cascade of proteins, activation of coagulation system, blebs, microthrombi, septic emboli) • Biological amplification-cascade of injury • Reservoir inside of host • Leeching-”saps nutrients” • Toxins • Incorporate gene sequences into host genome • Immune effects—inflammation, immunosupression, molecular mimicry • Herxheimer pathophysiology
Adapted from Mac Donald
Fighting Back: How B burgdorferi Persists
• That spirochetes tend to persist in the human body has been demonstrated in both syphilis, caused by Treponema pallidum, and Lyme disease, caused by Borrelia burgdorferi. What accounts for this ability to evade or suppress an effective immune response? According to Charles Pavia, PhD,[1] of the New York College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, New York, there are at least 6 potential explanations: antigenic variation (this is seen with the Borrelia species that cause tick-borne relapsing fever) or differential expression of antigens (especially the outer surface proteins; with B burgdorferi, only OspC is expressed during mammalian infection) production of an outer protective coat (eg, capsule, as seen with T pallidum) atypical forms (eg, cyst-like variants) incomplete immune response (eg, insufficient antibody , T-cell , or phagocytic response) deranged host immune response (eg, host-, tick-, or spirochete-derived immunosuppressive factors) other evasive factors (eg, motility) Immune Suppression Is there evidence that any of these mechanisms allow B burgdorferi to persist in the human body? As of now, not much. However, there have been a few suggestive studies in animals that support immune suppression as a possible explanation. For instance, a study by Chiao and colleagues[2] showed that B burgdorferi is capable of suppressing the immune response. When sonicated Borrelia were added to lymphocytes, the ability of the lymphocytes to proliferate -- a measure of the immune system's ability to respond to an infectious challenge -was inhibited. A similar study by Giambartolomei and coworkers[3] showed that Borrelia can stimulate interleukin10 (IL-10) production, a downregulator of the immune system. In this series of experiments, heat-killed B burgdorferi caused peripheral blood mononuclear cells of humans and rhesus monkeys to produce this cytokine. Another study, by Keane-Myers and Nickell,[4] found that B burgdorferi could suppress T-cell responses in mice, specifically T-helper cells. Even the tick itself may play a role in immunosuppression. Urioste and colleagues[5] showed that the saliva of Ixodes dammini ticks contains an uncharacterized substance that can suppress the immune response, specifically suppressing lymphocyte proliferation and other markers of immune system activity. Looking at the issue of immune suppression from the other side -- that is, by boosting the immune response with the use of cytokines -- Zeidner and colleagues[6] showed that tumor necrosis factor alpha (TNF-alpha), IL-2, and interferon-gamma could suppress B burgdorferi infection in mice. By contrast, it appears that infection with B burgdorferi can also overstimulate the immune system, and this may explain many of the symptoms of both acute and chronic Lyme disease. For instance, Lim and colleagues[7] showed that CD4+ T cells play a role in the arthritis seen in the hamster model of Lyme disease.
• • • • • • • •
• • •
TBD: Borrelia Burgdorferi, Babesia Cause Immunosupression
• Borrelia burgdorferi-induced tolerance as a model of persistence via immunosuppression. (Diterich et. al. Infect Immun. 2003 Jul;71(7):3979-87) • Immunodepression in Babesia microti infections. (Purvis AC. Parasitology. 1977 Oct;75(2):197-205) • Other tick-borne pathogens may also be immunosupressant
Tick Saliva Causes Immunospression
• Kyckova & Kopecky. Effect of tick saliva on mechanisms of innate immune response against Borrelia afzelii. J Med Entomol. 2006 Nov;43(6):1208-14. • Holden K, Hodzic E, Feng S, Freet KJ, Lefebvre RB, Barthold SW. Coinfection with Anaplasma phagocytophilum alters Borrelia burgdorferi population distribution in C3H/HeN mice. Infect Immun. 2005 Jun;73(6):3440-4. • Hannier S, Liversidge J, Sternberg JM, Bowman AS. Characterization of the B-cell inhibitory protein factor in Ixodes ricinus tick saliva: a potential role in enhanced Borrelia burgdoferi transmission.Immunology. 2004 Nov;113(3):401-8. • Wikel SK. Tick modulation of host immunity: an important factor in pathogen transmission. Int J Parasitol. 1999 Jun;29(6):851-9.
Propensity to excessive proinflammatory response in chronic Lyme borreliosis
• All the clinical manifestations, acute or chronic, are characterized by strong inflammation. Borrelia burgdorferi can induce the production of several proinflammatory and anti-inflammatory cytokines • We conclude that chronic forms of Lyme borreliosis can evolve due to an aberrant innate proinflammatory response.
Kisand et. al. APMIS, Volume 115 Issue 2 Page 134-141 - February 2007
Invasion of human neuronal and glial cells by an infectious strain of Borrelia burgdorferi
• Human infection by Borrelia burgdorferi, the etiological agent for Lyme disease, can result in serious acute and late-term disorders including neuroborreliosis, a degenerative condition of the peripheral and central nervous systems. To examine the mechanisms involved in the cellular pathogenesis of neuroborreliosis, we investigated the ability of B. burgdorferi to attach to and/or invade a panel of human neuroglial and cortical neuronal cells. In all neural cells tested, we observed B. burgdorferi in association with the cell by confocal microscopy. Further analysis by differential immunofluorescent staining of external and internal organisms, and a gentamicin protection assay demonstrated an intracellular localization of B. burgdorferi. A noninfectious strain of B. burgdorferi was attenuated in its ability to associate with these neural cells, suggesting that a specific borrelial factor related to cellular infectivity was responsible for the association. Cytopathic effects were not observed following infection of these cell lines with B. burgdorferi, and internalized spirochetes were found to be viable. Invasion of neural cells by B. burgdorferi provides a putative mechanism for the organism to avoid the host's immune response while potentially causing functional damage to neural cells during infection of the CNS.
Livengood & Gilmore. Microbes Infect. 2006 Nov-Dec;8(14-15):2832-40. Epub 2006 Sep 22.
Lyme Disease: The Quest for Magic Bullets
• Borrelia burgdorferi is one of the most complex bacteria known to man. • Two major clinical hurdles are the absence of a therapeutic endpoint in treating Lyme disease and the presence of tick-borne coinfections that may complicate the course of the illness.
Stricker RB, Lautin A, Burrascano JJ. Chemotherapy. 2006 Feb 22;52(2):53-59
Tick-Borne/Borreliosis Infections and Psychiatric Illness
Higher prevalence of antibodies to Borrelia burgdorferi in psychiatric patients than in healthy subjects
• 166 (33%) of the psychiatric patients and 94 (19%) of the healthy comparison subjects were seropositive in at least one of the four assays for Borrelia burgdorferi. • These findings support the hypothesis that there is an association between Borrelia burgdorferi infection and psychiatric morbidity. In countries where this infection is endemic, a proportion of psychiatric inpatients may be suffering from neuropathogenic effects of Borrelia burgdorferi.
Hajek T et al. Am J Psychiatry 2002 Feb;159(2):297-301
BI/TBI & Neuropsychiatric Disorders
• • • • • • • • • Fallon BA, Schwartzberg M, Bransfield R, Zimmerman B, Scotti A, Weber CA, Liebowitz MR. Late-Stage Neuropsychiatric Lyme Borreliosis: Differential Diagnosis and Treatment. Psychosomatics 1995;36:295-300. Adams WV, Rose CD, Eppes SC, Klein JD. Long-term cognitive effects of Lyme disease in children. Appl Neuropsychol 1999;6(1):39-45. Fallon BA, Nields JA. Lyme Disease: A Neuropsychiatric Illness. Am J Psych 1994;151(11):1571-83. Fallon BA, Bird H, Hoven C, Cameron D, Liebowitz MR, Shaffer S. Psychiatric aspects of Lyme disease in children and adolescents: A community epidemiologic study in Westchester, New York. JSTD 1994;1:98-100. Waniek C, Prohovnik I, Kaufman MA, Dwork AJ. Rapidly progressive frontaltype dementia associated with Lyme disease J Neuropsych Clin Neurosci 1995;7(3):345-7. Fallon BA, Kochevar JM, Gaito A, Nields JA. The Underdiagnosis of Neuropsychiatric LYD in Children and Adults. Psych Clinics No Am, 1998; 21:693-703. Bransfield RC. Case Report: LYD and Complex Seizures. JSTD 1999;6:1235. Massei F, Gori L, Macchia P, Maggiore G. The expanded spectrum of bartonellosis in children. Infect Dis Clin North Am. 2005;19(3):691-711 Murakami K, Tsukahara M, Tsuneoka H, et al. Cat scratch disease: analysis
Neuroactive Kynurenines in Lyme Borreliosis
• We conclude that CSF quinolinic acid is significantly elevated in B burgdorferi infection-- dramatically in patients with CNS inflammation, less in encephalopathy. • The presence of this known agonist of NMDA synaptic function--a receptor involved in learning, memory, and synaptic plasticity--may contribute to the neurologic and cognitive deficits seen in many Lyme disease patients.
Halperin JJ, Heyes MP. Neuroactive kynurenines in Lyme borreliosis. Neurology 1992 Jan;42(1):43-50
Proinflammatory Cytokines Increase Indoleamine 2,3-dioxygenase (IDO)
• The IDO enzyme converts tryptophan into kynurenine, because IDO activation leads to reduced levels of tryptophan, the precursor of serotonin (5-HT), and thus to reduced central 5-HT synthesis. • Kynurenine metabolites such as 3-hydroxy-kynurenine (3-OH-KYN) and quinolinic acid (QUIN) have toxic effects on brain function. 3-OH-KYN is able to produce oxidative stress by increasing the production of reactive oxygen species (ROS), and QUIN may produce overstimulation of hippocampal N-methyl-D-aspartate (NMDA) receptors, which leads to apoptosis and hippocampal atrophy. Both ROS overproduction and hippocampal atrophy caused by NMDA overstimulation have been associated with depression.
Wichers MC, Maes M. J Psychiatry Neurosci. 2004 Jan;29(1):11-7.
Tryptophan metabolites and brain disorders
• Tryptophan is metabolised primarily along the kynurenine pathway, of which two components are now known to have marked effects on neurons in the central nervous system. Quinolinic acid is an agonist at the population of glutamate receptors which are sensitive to N-methyl-D-aspartate (NMDA), and kynurenic acid is an antagonist at several glutamate receptors. Consequently quinolinic acid can act as a neurotoxin while kynurenic acid is neuroprotectant. A third kynurenine, 3hydroxykynurenine, can generate free radicals and contribute to, or exacerbate, neuronal damage. Changes in the absolute or relative concentrations of these kynurenines have been implicated in a variety of central nervous system disorders such as the AIDS-dementia complex and Huntington's disease
Stone TW, Mackay GM, Forrest CM, Clark CJ, Darlington LG. Clin Chem Lab Med. 2003 Jul;41(7):852-9
Immune Responses in ASD, Borreliosis and Mycoplasma Infections
Natural Killer Cell CD-57
• Autistic children are known to have many metabolic dysfunctions which are shared by victims of LD, in particular, chronically low counts of CD57 natural-killer (NK) cells.
Gene expression changes in children with autism
– The objective of this study was to identify gene expression differences in blood differences in children with autism (AU) and autism spectrum disorder (ASD) compared to general population controls. Transcriptional profiles were compared with age- and gender-matched, typically developing children from the general population (GP). The AU group was subdivided based on a history of developmental regression (A-R) or a history of early onset (A-E without regression). Total RNA from blood was processed on human Affymetrix microarrays. Thirty-five children with AU (17 with early onset autism and 18 with autism with regression) and 14 ASD children (who did not meet criteria for AU) were compared to 12 GP children. Unpaired t tests (corrected for multiple comparisons with a false discovery rate of 0.05) detected a number of genes that were regulated more than 1.5-fold for AU versus GP (n=55 genes), for A-E versus GP (n=140 genes), for A-R versus GP (n=20 genes), and for A-R versus A-E (n=494 genes). No genes were significantly regulated for ASD versus GP. There were 11 genes shared between the comparisons of all autism subgroups to GP (AU, A-E, and A-R versus GP) and these genes were all expressed in natural killer cells and many belonged to the KEGG natural killer cytotoxicity pathway (p=0.02). A subset of these genes (n=7) was tested with qRT-PCR and all genes were found to be differentially expressed (p<0.05). We conclude that the gene expression data support emerging evidence for abnormalities in peripheral blood leukocytes in autism that could represent a genetic and/or environmental predisposition to the disorder.
•Gregg JP, Sharp FR et al. Genomics. 2008 Jan;91(1):22-9. Epub 2007 Nov 14.
Gene Expression Profile Distinctions In Autistic Children Identified: Genomic analysis could add biological certainty to behavioral diagnosis
• • A group of genes with known links to natural-killer cells -- the first to attack viruses, bacteria and malignancies -- are expressed at high levels in the blood of children with autism when compared to children without the disorder. researchers also found gene expression distinctions in children with early onset and regressive forms of the disorder. "What we found were 11 specific genes with expression levels that were significantly higher in the blood of children with autism when compared to the blood of typically developing children," Those 11 genes are all known to be expressed by natural-killer cells, which are cells in the immune system necessary for mounting a defense against infected cells. There is a pattern of 140 genes differentially expressed in children with the early onset form of the disorder and a pattern of 20 genes differentially expressed in children with the regressive form of the disorder. These separate experiences offers biological evidence that there are at least two types of autism -- early onset and regressive. In addition to being expressed by natural-killer cells, some of the 11 genes found to be expressed at higher levels in children with autism are also expressed by CD8+ T lymphocytes -- cells that target infected cells and, once bound to them, destroy them. "What we are seeing can reflect something in the environment that is triggering the activation of these genes…” "Such an immune response could be caused by exposure to a virus, another infectious agent or even a toxin. Another possibility is that these changes represent a genetic susceptibility factor that predisposes children to autism when they are exposed to some environmental factor.“ "If the natural-killer cells are dysfunctional, this might mean that they cannot rid a pregnant mother, fetus or newborn of an infection, which could contribute to autism."
•
• •
•
Invasion and cytopathic killing of human lymphocytes by spirochetes
• Lyme disease is a persistent low-density spirochetosis caused by Borrelia burgdorferi sensu lato. Although spirochetes causing Lyme disease are highly immunogenic in experimental models, the onset of specific antibody responses to infection is often delayed or undetectable in some patients. The properties and mechanisms mediating such immune avoidance remain obscure. To examine the nature and consequences of interactions between Lyme disease spirochetes and immune effector cells, we coincubated B. burgdorferi with primary and cultured human leukocytes. We found that B. burgdorferi actively attaches to, invades, and kills human B and T lymphocytes. Significant killing began within 1 hour of mixing. Cytopathic effects varied with respect to host cell lineage and the species, viability, and degree of attenuation of the spirochetes. Both spirochetal virulence and lymphocytic susceptibility could be phenotypically selected, thus indicating that both bacterial and host cell factors contribute to such interactions. These results suggest that invasion and lysis of lymphocytes may constitute previously unrecognized factors in Lyme disease and bacterial pathogenesis.
Balanced Inflammation
• Inflammation could have a protective role and promote regeneration of damaged neurons. We do not yet know how to achieve a "balanced" inflammation. Because some novel anti-inflammatory treatment might have detrimental consequences, carefully monitoring disease progress in patients treated with this category of drugs is indispensable • A variety of neurological diseases the initial triggers differ significantly, while the subsequent pathways involving inflammatory processes and causing brain damage share certain pathological mechanisms
Aktas, O. et al. Arch Neurol 2007;64:185-189.
ASD & BI/TBI both have:
• Been associated with a combination of inflammatory and autoimmune pathophysiology. • Elevated TNF and IL-6 & reduced NKC • Antibodies against neural tissue • Microglial activation • Oxidative stress • Greater susceptibility to herpes and other viral infections • HLA-DR4 genotypes frequently
ASD & BI/TBI & Inflammation
• • • • • • • • • • • • • • • Wilner. Elevated TNF Found in CSF of Autistic Children. CNS News. 2007;9:4 Patterson P. International neuroscience conference. 2007. Melbourne. Accessed 8-3-07 http://www.news.com.au/story/0,23599,22079407-2,00.html?from=public_rss Cohly HH, Panja A. Immunological findings in autism. Int Rev Neurobiol. 2005;71:317-41 Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain with autism. Ann Neurol. 2005;57(1):67 Rasley A, Anguita J, Marriott I. Borrelia burgdorferi induces inflammatory mediator production by murine microglia. J. Neuroimmunol. 2002;130(1-2):22-31. Alaedini A, N. Latov N. Antibodies against OspA epitopes of Borrelia burgdorferi cross-react with neural tissue. J. Neuroimmunol. 2005;159:192-5 MacDonald AB. Spirochetal cyst forms in neurodegenerative disorders,..hiding in plain sight. Med Hypotheses. 2006;67(4):819-32 Lee LC, Zachary AA, Leffell MS, Newschaffer CJ, Matteson KJ, Tyler JD, Zimmerman AW. HLA-DR4 in families with autism. Pediatr Neurol. 2006;35(5):303-7. Steere AC, Klitz W, Drouin EE, et al. Antibiotic-refractory Lyme arthritis is associated with HLA-DR molecules that bind a Bb peptide. J Exp Med. 2006;203(4):961 Nicholson G. The Role of Chronic Intracellular Infections in ASD. LIA Conf. 2007 Rawadi, G., Roman-Roman, S, et al., Effects of Mycoplasma fermentans on the Myelomonocytic Lineage: Different Molecular Entities with Cytokine-inducing and Cytocidal Potential. J Immunol. 1996;156(2):670-8 Latov N, Wu AT, Chin RL, Sander HW, Alaedini A, Brannagan TH 3rd. Neuropathy and cognitive impairment following vaccination with the OspA protein of Borrelia burgdorferi. J Peripher Nerv Syst. 2004;9(3):165-7. Scott DW. Mycoplasm: The linking pathogen in neurosystemic dis. Nexus 8-2001 Perry VH, Cunningham C, Holmes C. Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev Immunol. 2007;7(2):161-7 Kern JK, Jones AM. Evidence of toxicity, oxidative stress, and neuronal insult in autism. J Toxicol Environ Health B Crit Rev. 2006;9(6):485-99
Inflammation and Cognitive Deficits I
• • • • • • • • • • • • Wilson CJ, Finch CE, Cohen HJ. Cytokines and cognition-the case for a head-to-toe inflammatory paradigm. J Am Geriatr Soc 2002; 50(12): 2041-2056. Eskandari F, Webster JI, Sternberg EM. Neural immune pathways and their connection to inflammatory diseases. Arthritis Res Ther 2003; 5(6): 251-265. Hopkins SJ. Central system recognition of peripheral inflammation: a neural, hormonal collaboration. Acta Biomed 2007; 78 Suppl 1: 231-247. Watkins LR, Maier SF. Immune regulation of central nervous system functions: from sickness responses to pathological. J Intern Med 2005; 257(2): 139-155. Maier SF, Watkins LR. Immune-to-central nervous system communication and its role in modulating pain and cognition: Implications for cancer and cancer treatment. Brain Behav Immun 2003; 17 Suppl 1: S125-131. Banks WA, Farr SA, Morley JE. Entry of blood-borne cytokines into the central nervous system: effects on cognitive processes. Neuroimmunomodulation 2002-2003; 10(6): 319-327. Viljoen M, Koorts AM. A role for proinflammatory cytokines in the behavioral disturbances and cognitive decline in chronic renal failure patients. Clin Nephrol 2004; 61(3): 227-229. Wolfe F, Michaud K. Fatigue, rheumatoid arthritis, and anti-tumor necrosis factor therapy: an investigation in 24,831 patients. J Rheumatol 2004; 31(11): 2115-2120. Yaffe K, Kanaya A, Lindquist K, Simonsick EM, Harris T, Shorr RI, Tylavsky FA, Newman AB. The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA 2004; 292(18): 2237-2242. Tonelli LH, Postolache TT. Tumor necrosis factor alpha, interleukin-1 beta, interleukin-6 and major histocompatibility complex molecules in the normal brain and after peripheral immune challenge. Neurol Res 2005; 27(7): 679-684. Tonelli LH, Postolache TT, Sternberg EM. Inflammatory genes and neural activity: involvement of immune genes in synaptic function and behavior. Front Biosci 2005; 10: 675-680. Licinio J, Kling MA, Hauser P. Cytokines and brain function: relevance to interferon-alpha-induced mood and cognitive changes. Semin Oncol 1998; 25(1 Suppl 1): 30-38.
Inflammation and Cognitive Deficits II
• • • • • • • • • • • • Capuron L, Miller AH. Cytokines and psychopathology: lessons from interferon-alpha. Biol Psychiatry 2004; 56(11): 819-824. Owens T, Babcock A. Immune response induction in the central nervous system. Front Biosci 2002; 7: d427-438. Chavarria A, Alcocer-Varela J. Is damage in central nervous system due to inflammation? Autoimmun Rev 2004; 3(4): 251-260. Millward JM, Caruso M, Campbell IL, Gauldie J, Owens T. IFN-gamma-induced chemokines synergize with pertussis toxin to promote T cell entry to the central nervous system. J Immunol 2007; 178(12): 8175-8182. Hagberg H, Mallard C. Effect of inflammation on central nervous system development and vulnerability. Curr Opin Neurol 2005; 18(2): 117-123. Magaki S, Mueller C, Dickson C, Kirsch W. Increased production of inflammatory cytokines in mild cognitive impairment. Exp Gerontol 2007; 42(3): 233-240. Lindberg C, Chromek M, Ahrengart L, Brauner A, Schultzberg M, Garlind A. Soluble interleukin-1 receptor type II, IL-18 and caspase-1 in mild cognitive impairment and severe Alzheimer’s disease. Neurochem Int 2005; 46(7): 551-557. Dik MG, Jonker C, Hack CE, Smit JH, Comijs HC, Eikelenboom P. Serum inflammatory proteins and cognitive decline in older persons. Neurology 2005; 64(8): 1371-1377. Boutin H, LeFeuvre RA, Horai R, Asano M, Iwakura Y, Rothwell NJ. Role of IL-1alpha and IL-1beta in ischemic brain damage. J Neurosci 2001; 21(15): 5528-5534. Zhu Y, Saito K, Murakami Y, Asano M, Iwakura Y, Seishima M. Early increase in mRNA levels of proinflammatory cytokines and their interactions in the mouse hippocampus after transient global ischemia. Neurosci Lett 2006; 393(2-3): 122-126. Sheng WS, Hu S, Ding JM, Chao CC, Peterson PK. Cytokine expression in the mouse brain in response to immune activation by Corynebacterium parvum. Clin Diagn Lab Immunol 2001; 8(2): 446-448. Gelinas DS, McLaurin J. PPAR-alpha expression inversely correlates with inflammatory cytokines IL1beta and TNF-alpha in aging rats. Neurochem Res 2005; 30(11): 1369-1375.
Inflammation and Cognitive Deficits III
• • • • • • • • • • • • • Montalban X, Rio J. Interferons and cognition. J Neurol Sci 2006; 245(1-2): 137-140. Pierson SH, Griffith N. Treatment of cognitive impairment in multiple sclerosis. Behac Neurol 2006; 17(1): 53-67. Magaki S, Mueller C, Dickson C, Kirsch W. Increased production of inflammatory cytokines in mild cognitive impairment. Exp Gerontol 2007; 42(3): 233-240. Wan Y, Xu J, Ma D, Zeng Y, Cibelli M, Maze M. Postoperative impairment of cognitive function in rats: a possible role for cytokine-mediated inflammation in the hippocampus. Anesthesiology 2007; 106(3): 436443. Rafnsson SB, Deary IJ, Smith FB, Whiteman MC, Rumley A, Lowe GD, Fowkes FG. Cognitive decline and markers of inflammation and hemostasis: the Edinburgh Artery Study. J Am Geriatr Soc 2007; 55(5): 700-707. Dehghani F, Conrad A, Kohl A, Korf HW, Hailer NP. Clodronate inhibits the secretion of proinflammatory cytokines and NO by isolated microglial cells and reduces the number of proliferating glial cells in excitotoxically injured organotypic hippocampal slice cultures. Exp Neurol 2004; 189(2): 241-251. Hailer NP, Vogt C, Korf HW, Dehghani F. Interleukin-1beta exacerbates and interleukin-1 receptor antagonist attenuates neuronal injury and microglial activation after excitotoxic damage in organotypic hippocampal slice cultures. Eur J Neurosci 2005; 21(9): 2347-2360. Rothwell N. Interleukin-1 and neuronal injury: mechanisms, modification, and therapeutic potential. Brain Behav Immun 2003; 17(3): 152-157. Simi A, Tsakiri N, Wang P, Rothwell NJ. Interleukin-1 and inflammatory neurodegeneration. Biochem Soc Trans 2007; 35(Pt 5): 1122-1126. Lucas SM, Rothwell NJ, Gibson RM. The role of inflammation in CNS injury and disease. Br J Pharmacol 2006; 147 Suppl 1: S232-240. Clarkson AN, Rahman R, Appleton I. Inflammation and autoimmunity as a central theme in neurodegenerative disorders: fact or fiction? Curr Opin Investig Drugs 2004; 5(7): 706-713. Cunningham C, Wilcockson DC, Campion S, Lunnon K, Perry VH. Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J Neurosci 2005; 25(40): 9275-9284.
Inflammation and Cognitive Deficits IV
• • • • • • • • • • • Perry VH. The influence of systemic inflammation on inflammation in the brain: implications for chronic neurodegenerative disease. Brain Behav Immun 2004; 18(5): 407-413. Schultzberg M, Lindberg C, Aronsson AF, Hijorth E, Spulber SD, Oprica M. Inflammation in the nervous system-physiological and pathophysiological aspects. Physiol Behav 2007; 92(1-2): 121-128. Ehrenreich H, Fischer B, Norra C, Schellenberger F, Stender N, Stiefel M, Siren AL, Paulis W, Nave KA, Gold R, Bartels C. Exploring recombinant human erythropoietin in chronic progressive multiple sclerosis. Brain 2007; 130(Pt 10): 2577-2588. Guerreiro RJ, Santana I, Bras JM, Santiago B, Paiva A, Oliveira C. Peripheral inflammatory cytokines as biomarkers in Alzheiner’s disease and mild cognitive impairment. Neurodegener Dis 2007; 4(6): 406-412. Robinson EK, Seaworth CM, Suliburk JW, Adams SD, Kao LS, Mercer DW. Effect of NOS inhibition on rat gastric matrix metalloproteinase production during endotoxemia. Shock 2006; 25(5): 507-514. Suliburk JW, Helmer KS, Kennison SD, Mercer DW, Robinson EK. Time-dependent aggravation or attenuation of lipopolysaccharide-induced gastric injury by nitric oxide synthase inhibition. J Surg Res 2005; 129(2): 265-271. de la Torre JC, Aliev G. Inhibition of vascular nitric oxide after rat chronic brain hypoperfusion: spatial memory and immunocytochemical changes. J Cereb Blood Flow Metab 2005; 25(6): 663-672. Institoris A, Farkas E, Berczi S, Sule Z, Bari F. Effects of cyclooxygenases (COX) inhibition on memory impairment and hippocampal damage in the early period of cerebral hypoperfusion in rats. Eur J Pharmacol 2007; 574(1): 29-38. Shibata M, Yamasaki N, Miyakawa T, Kalaria RN, Fujita Y, Ohtani R, Ihara M, Takahashi R, Tomimoto H. Selective impairment of working memory in a mouse model of chronic cerebral hypoperfusion. Stroke 2007; 38(10): 2826-2832. Zhou YF, Stabile E, Walker J, Shou M, Baffour R, Yu Z, Rott D, Yancopoulos GD, Rudge JS, Epstein SE. Effects of gene delivery on collateral development in chronic hypoperfusion: diverse effects of angiopoietin-1 versus vascular endothelial growth factor. J Am Coll Cardiol 2004; 44(4): 897-903. Moe CL, Turf E, Oldach D, Bell P, Hutton S, Savitz S, Koltai D, Turf M, Ingsrisawang L, Hart R, Ball JD, Stutts M, McCarter R, Wilson L, Haselow D, Grattan L, Morris JG, Weber DJ. Cohort studies of health effects among people exposed to estuarine waters: North Carolina, Virginia, and Maryland. Environ Health Perspect 2001; 109 Suppl 5: 781-786. Hudnell HK, House D, Schmid J, Koltai D, Stopford W, Wilkins J, Savitz DA, Swinker M, Music S. Human visual function in the North Carolina clinical study on possible estuary-associated syndrome. J Toxicol Environ Health A 2001; 62(8): 575-594.
•
Inflammation and Cognitive Deficits V
• • • • • • • • • • • Qin L, Liu Y, Wang T, Wei SJ, Block ML, Wilson B, Liu B, Hong JS. NADPH oxidase mediates lipopolysaccharide-induced neurotoxicity and proinflammatory gene expression in activated microglia. J Biol Chem 2004; 279(2): 1415-1421. Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong JS, Knapp DJ, Crews FT. Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 2007; 55(5): 453-462. Sparkman NL, Buchanan JB, Heyen JR, Chen J, Beverly JL, Johnson RW. Interleukin-6 faclitates lipopolysaccharide-induced disruption in working memory and expression of other proinflammatory cytokines in hippocampal neuronal cell layers. J Neurosci 2006; 26(42): 10709-10716. Huang Y, Henry CJ, Dantzer R, Johnson RW, Godbout JP. Exaggerated sickness behavior and brain proinflammatory cytokine expression in aged mice in response to intracerebroventricular lipopolysaccharide. Neurobiol Aging 2007; [Ebup ahead of print] Godbout JP, Chen J, Abraham J, Richwine AF, Berg BM, Kelley KW, Johnson RW. Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. FASEB J 2005; 19(10): 1329-1331. Pereira C, Agostinho P, Moreira PI, Cardoso SM, Oliveira CR. Alzheimer’s disease-associated neurotoxic mechanisms and neuroprotective strategies. Curr Drug Targarets CNS Neurol Disord 2005; 4(4): 383403. Ghavami A, Hirst WD, Novak TJ. Selective phosphodiesterase (PDE)-4 inhibitors: a novel approach to treating memory deficit? Drugs R D 2006; 7(2): 63-71. Chen J, Buchanan JB, Sparkman NL, Godbout JP, Freubd GG, Johnson RW. Neuroinflammation and disruption in working memory in aged mice after acute stimulation of the peripheral innate immune system. Brain Behav Immun 2008; 22(3): 301-311. Zhou HR, Harkema JR, Yan D, Pestka JJ. Amplified proinflammatory cytokine expression and toxicity in mice coexposed to lipopolysaccharide and the trichothecene vomitoxin (deoxynivalenol). J Toxicol Environ Health A 1999; 57(2): 115-136. Lang CH, Silvis C, Deshpande N, Nystrom G, Frost RA. Endotoxin stimulates in vivo expression of inflammatory cytokines tumor necrosis factor alpha, interleukin-1beta, -6, and high-mobility-group protein-1 in skeletal muscle. Shock 2003; 19(6): 538-546. Browne SE, Lin L, Mattsson A, Georgievska B, Isacson O. Selective antibody-induced cholinergic cell and synapse loss produce sustained hippocampal and cortical hypometabolism with correlated cognitive deficits. Exp Neurol 2001; 170(1): 36-47.
Inflammation and Cognitive Deficits VI
• • • • • • • • • • Semmier A, Frisch C, Debeir T, Ramanathan M, Okulla T, Klockgether T, Heneka MT. Long-term cognitive impairment, neuronal loss and reduced cortical cholinergic innervation after recovery from sepsis in a rodent model. Exp Neurol 2007; 204(2): 733-740. Ponomarev ED, Maresz K, Tan Y, Dittel BN. CNS-derived interleukin-4 is essential for the regulation of autoimmune inflammation and induces a state of alternative activation in microglial cells. J Neurosci 2007; 27(40): 10714-10721. Lyons A, Downer EJ, Crotty S, Nolan YM, Mills KH, Lynch MA. CD200 ligand receptor interaction modulates microglial activation in vivo and in vitro: a role for IL-4. J Neurosci 2007: 27(31): 8309-8313. McIntyre RS, Soczynska JK, Woldeyohannes HO, Lewis GF, Leiter LA, MacQueen GM, Miranda A, Fulgosi D, Konarski JZ, Kennedy SH. Thiazolidinediones: a novel treatments for cognitive deficits in mood disorders? Expert Opin Pharmacother 2007; 8(11): 1615-1628. Noble F, Rubira E, Boulanouar M, Palmier B, Plotkine M, Warnet JM, Marchand-Leroux C, Massicot F. Acute systemic inflammation induces central mitochondrial damage and mnesic deficit in adult Swiss mice. Neurosci Lett 2007; 424(2): 106-110. Rosi S, Vazdarjanova A, Ramirez-Amaya V, Worley PF, Barnes CA, Wenk GL. Memantine protects against LPS-induced neuroinflammation, restores behaviorally-induced gene expression and spatial learning in the rat. Neuroscience 2006; 142(4): 1303-1315. Ohta H, Nishikawa H, Kimura H, Anayama H, Miyamoto M. Chronic cerebral hypoperfusion by permanent internal carotid ligation produces learning impairment without brain damage in rats. Neuroscience 1997; 79(14): 1039-1050. De Jong GI, Farkas E, Stienstra CM, Plass JR, Keijser JN, de la Torre JC, Luiten PG. Cerebral hypoperfusion yields capillary damage in the hippocampal CA1 area that correlates with spatial memory impairment. Neuroscience 1999; 91(1): 203-210. Liu J, Jin DZ, Xiao L, Zhu XZ. Paeoniflorin attenuates chronic cerebral hypoperfusion-induced learning dysfunction and brain damage rats. Brain Res 2006; 1089(1): 162-170. Ernst T, Chang L, Arnold S. Increased glial metabolites predict increased working memory network activation in HIV brain injury. Neuroimage 2003; 19(4): 1686-1693.
Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6
• Schizophrenia and autism are thought to result from the interaction between a susceptibility genotype and environmental risk factors. The offspring of women who experience infection while pregnant have an increased risk for these disorders. Maternal immune activation (MIA) in pregnant rodents produces offspring with abnormalities in behavior, histology, and gene expression that are reminiscent of schizophrenia and autism, making MIA a useful model of the disorders. However, the mechanism by which MIA causes long-term behavioral deficits in the offspring is unknown. Here we show that the cytokine interleukin-6 (IL-6) is critical for mediating the behavioral and transcriptional changes in the offspring. A single maternal injection of IL-6 on day 12.5 of mouse pregnancy causes prepulse inhibition (PPI) and latent inhibition (LI) deficits in the adult offspring. Moreover, coadministration of an anti-IL-6 antibody in the poly(I:C) model of MIA prevents the PPI, LI, and exploratory and social deficits caused by poly(I:C) and normalizes the associated changes in gene expression in the brains of adult offspring. Finally, MIA in IL-6 knock-out mice does not result in several of the behavioral changes seen in the offspring of wild-type mice after MIA. The identification of IL-6 as a key intermediary should aid in the molecular dissection of the pathways whereby MIA alters fetal brain development, which can shed new light on the pathophysiological mechanisms that predispose to schizophrenia and autism.
Stephen EP et al. The Journal of Neuroscience, October 3, 2007, 27(40):10695-10702
Stereotypies and hyperactivity in rhesus monkeys exposed to IgG from mothers of children with autism
• Four control rhesus monkeys were exposed to human IgG collected from mothers of multiple typically developing children. Five additional monkeys were untreated controls. • Rhesus monkeys gestationally exposed to IgG class antibodies from mothers of children with ASD consistently demonstrated increased whole-body stereotypies across multiple testing paradigms. These monkeys were also hyperactive compared to controls.
Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6
• Schizophrenia and autism are thought to result from the interaction between a susceptibility genotype and environmental risk factors. The offspring of women who experience infection while pregnant have an increased risk for these disorders. Maternal immune activation (MIA) in pregnant rodents produces offspring with abnormalities in behavior, histology, and gene expression that are reminiscent of schizophrenia and autism, making MIA a useful model of the disorders. However, the mechanism by which MIA causes long-term behavioral deficits in the offspring is unknown. Here we show that the cytokine interleukin-6 (IL-6) is critical for mediating the behavioral and transcriptional changes in the offspring. A single maternal injection of IL-6 on day 12.5 of mouse pregnancy causes prepulse inhibition (PPI) and latent inhibition (LI) deficits in the adult offspring. Moreover, coadministration of an anti-IL-6 antibody in the poly(I:C) model of MIA prevents the PPI, LI, and exploratory and social deficits caused by poly(I:C) and normalizes the associated changes in gene expression in the brains of adult offspring. Finally, MIA in IL-6 knock-out mice does not result in several of the behavioral changes seen in the offspring of wild-type mice after MIA. The identification of IL-6 as a key intermediary should aid in the molecular dissection of the pathways whereby MIA alters fetal brain development, which can shed new light on the pathophysiological mechanisms that predispose to schizophrenia and autism.
Stephen EP et al. The Journal of Neuroscience, October 3, 2007, 27(40):10695-10702
Stereotypies and hyperactivity in rhesus monkeys exposed to IgG from mothers of children with autism
• Rhesus monkeys gestationally exposed to IgG class antibodies from mothers of children with ASD consistently demonstrated increased whole-body stereotypies across multiple testing paradigms. These monkeys were also hyperactive compared to controls.
Autism: Maternally derived antibodies specific for fetal brain proteins
– Autism is a profound disorder of neurodevelopment with poorly understood biological origins. A potential role for maternal autoantibodies in the etiology of some cases of autism has been proposed in previous studies. To investigate this hypothesis, maternal plasma antibodies against human fetal and adult brain proteins were analyzed by western blot in 61 mothers of children with autistic disorder and 102 controls matched for maternal age and birth year (62 mothers of typically developing children (TD) and 40 mothers of children with non-ASD developmental delays (DD)). We observed reactivity to two protein bands at approximately 73 and 37kDa in plasma from 7 of 61 (11.5%) mothers of children with autism (AU) against fetal but not adult brain, which was not noted in either control group (TD; 0/62 p=0.0061 and DD; 0/40 p=0.0401). Further, the presence of reactivity to these two bands was associated with parent report of behavioral regression in AU children when compared to the TD (p=0.0019) and DD (0.0089) groups. Individual reactivity to the 37kDa band was observed significantly more often in the AU population compared with TD (p=0.0086) and DD (p=0.002) mothers, yielding a 5.69-fold odds ratio (95% confidence interval 2.09-15.51) associated with this band. The presence of these antibodies in the plasma of some mothers of children with autism, as well as the differential findings between mothers of children with early onset and regressive autism may suggest an association between the transfer of IgG autoantibodies during early neurodevelopment and the risk of developing of autism in some children.
Braunschweig D et al. Neurotoxicology. 2007 Nov 6 [Epub ahead of print]
Regressive Autism Reactivity: 28% to 37-kDa & 25% to 73-kDa
Table 2 Summary and significant associations of maternal autoantibody reactivity patterns for human fetal brain proteins in autism Prevalence 37 & 73 (kD) 37 (kD) 73 (kD) Total (n = 61) 7 (12%)* 15 (25%)* 10 (17%) Regressive (36) 6 (17%)* 10 (28%)* 9 (25%)* Early onset (25) 1 (4%) 5 (21%) 1 (4%)
Braunschweig D et al. Neurotoxicology. 2007 Nov 6 [Epub ahead of print]
What is associated with 37-kDa & 73-kDa antibodies?
Medline Search for 37 & 73-kDa Antibodies
• 37-kDa – Mycoplasma agalactiae [1] – Mycoplasma gallisepticum [2] – Mycoplasma arthritidis [3] • 73-kDa – Chlamydia [4] – Streptococcus pneumoniae [5] – Mycoplasma conjunctivae [6] • 37-kDa & 73-kDa – Bartonella henselae and Bartonella quintana [7] – Borrelia burgdorferi
[1] Fleury B et al. Infect Immun. 2002 Oct;70(10):5612-21. [2] Gorton TS et al. FEMS Microbiol Lett. 1997 Oct 1;155(1):31-8. [3] Hasebe A et al. Infect Immun. 2007 Apr;75(4):1820-6. [4] Kanamoto Y et al. Microbiol Immunol. 1993;37(6):495-8. [5] Choi IH et al. Microbiol Immunol. 1999;43(8):807-12. [6] Degiorgis MP et al. J Wildl Dis. 2000 Apr;36(2):265-71. [7] Haimerl M et al. J Med Microbiol. 1999 Sep;48(9):849-56.
73-kDa & 37-kDa Amtibodies & LYD
• 73-kDa proteins of Borrelia burgdorferi are dominant immunogens and expressed in all strains of B. burgdorferi. The humoral response to this antigen occurs relatively early during the course of infection.[1] • A 37-kDa protein from Borrelia burgdorferi (the agent of Lyme disease) was identified as a target for immune-mediated resolution of Lyme arthritis. [2] • 37-kDa is a marker for neuroborreliosis. [3]
[1] Luft BJ et al. J Immunol. 1991 Apr 15;146(8):2776-82. [2] Feng S et al. Immun. 2000 Jul;68(7):4169-73. [3] Cinco M et al. Immunol Med Microbiol. 1996 Jun;14(2-3):159-66.
Antibodies against fetal brain in sera of mothers with autistic children
• Serum antibodies in 100 mothers of children with autistic disorder (MCAD) were compared to 100 age-matched mothers with unaffected children (MUC) using as antigenic substrates human and rodent fetal and adult brain tissues, GFAP, and MBP. MCAD had significantly more individuals with Western immunoblot bands at 36 kDa in human fetal and rodent embryonic brain tissue. The density of bands was greater in fetal brain at 61 kDa. • MCAD plus developmental regression had greater reactivity against human fetal brain at 36 and 39 kDa. Data support a possible complex association between genetic/metabolic/environmental factors and the placental transfer of maternal antibodies in autism.
Singer HS et al. Neuroimmunol. 2008 Feb;194(1-2):165-72. Epub 2008 Feb 21.
Residual serologic reactivity in children with resolved Lyme arthritis
• “The 41, 39, and 60 kDa were the most commonly observed reactive bands.”
Rose CD et al. J Rheumatol. 1996 Feb;23(2):367-9.
The antibody response in Lyme disease
• “These polypeptides had molecular weights of 62, 60, 47, 37, 22, 18, and 15 kDa, and were not recognized by control sera.”
Craft JE et al. Yale J Biol Med. 1984 Jul-Aug;57(4):561-5
What is the significance of these bands?
• 39 kDa is highly specific for Lyme disease • 36/37 kDa is a Lyme disease band • 60/62 kDa is a Lyme disease band
The MMR Debate & TBD
• In 1998, Dr. Wakefield "postulated in the Lancet that the vaccine might cause autism." • Patients with TBD often report symptom flares following vaccinations. • Is there an association between vaccines, patients infected with TBD’s & ASD?
Vaccines a risk for pregnant women?
• “Vaccinating a pregnant woman may be risky if her immune response interferes with neuronal growth in her unborn baby’s brain.”
Economic Issues
• It may cost $3.2 million to care for one autistic person in their lifetime and the preliminary data suggests Borreliosis may be a contributor in 20– 30% of ASD, and pathogenic Mycoplasma may be a contributor in 58%. If 20% or 58% of the 560,000 recognized cases of ASD in the US can be prevented or more effectively treated, this could result in a savings of $358 billion to $1 trillion in addition to incalculable human impact of this disease.
Bransfield RC, Wulfman JS, Harvey WT, Usman AI. Medical Hypotheses. 2007
Assessment
• When a patient has been diagnosed with childhood bipolar illness, ADHD, autism and other comorbidity, consider the presence of Tick-borne disease/Lyme disease and perform an adequate evaluation. • Evaluating the possibility of TBI/BI should be considered in the evaluation of autism
Treatment Strategies
• Since ASD is caused by an interaction of genes and environment • Should treatment be focused upon changing:
– Genes? – Environment contributors?
• When TBI/BI is a possibility, consider a course of antibiotic treatment
Antibiotic Treatment
• “In our work with children with LD, we have encountered a few children with autistic-like disorders,” says Dr Fallon. “When they received intensive antibiotic therapy, the autistic syndromes dramatically improved and, in some cases, resolved.”
Further evaluation of the hypothesis
• It is important to research this association further and to address the other environmental contributors that increase the impact of these infections diseases. • Narrow and restrictive opinions on the diagnosis and treatment of Lyme disease may have contributed to the increased incidence of ASD. • It is imperative to research all possible causes, prevent every preventable case and treat every treatable case of ASD.
Summary
• A broad base of research & clinical observations supports the conclusion that Lyme disease, other tick-borne diseases and other infectious diseases are significantly associated with a growing epidemic of autism spectrum disorder. • Now greater attention needs to be focused upon the pathophysiology, prevention, early diagnosis and treatment.
Thanks for Your Attention