THE NEUROPSYCHIATRIC MANIFESTATIONS OF LYME DISEASE AND OTHER TICK BORNE INFECTIONS Suruchi Chandra, MD Autism Research Institute ACIM June, 2013 Is it a neuropsychiatric illness or infection? Mounting Evidence of the Autism Environment Connection California CDC:1 in 50 US children now has autism. Rising rates of autism Genetic heritability and shared environmental factors among twin pairs with autism. Association of ASD rates with environmental toxins in multiple studies. Causes of ASD Causes are likely unique, individualized and multifactorial. Emerging research is pointing to changes in our environment along with genetic vulnerabilities. Environment includes: Chemical toxins Electromagnetic fields Changes in diet and nutrition Microbiome Infections Prenatal inflammation linked to autism risk The risk of autism among children in the study was increased by 43 percent among mothers with CRP (Creactive protein) levels in the top 20th percentile, and by 80 percent for maternal CRP in the top 10th percentile. Elevated CRP is a signal that the body is undergoing a response to inflammation from, for example, a viral or bacterial infection. Maternal Infection Requiring Hospitalization During Pregnancy and Autism Spectrum Disorders Journal of Autism and Developmental Disorders, Volume 40, Number 12. Maternal immune activation causes age- and regionspecific changes in brain cytokines in offspring throughout development Paula A. Garay et al Brain, Behavior, and Immunity. Possible role of viruses in ASD Association of autism with polyomavirus infection in postmortem brains. Polyviral infections tend to occur more frequently in the brains of autistic patients compared to controls (40% versus 7.7%, respectively; P = .08). J Neurovirol. 2010 Mar;16(2):141-9. Case studies: An 11 year old and 31 year old man developed all the symptoms considered diagnostic of autism after herpes encephalitis. Possible Infectious Contributors to Autism Spectrum Disorders An infectious contributor ideally would be: Chronic Widespread and increasing in prevalence Challenging to diagnose Potentially transmitted during pregnancy or early in life Multisystemic with prominent neurological, immune and gastrointestinal features Potentially a chronic and active infection Resistant to short term antibiotic treatment, although symptoms might temporarily and partially improve with a few weeks of antibiotics Misconceptions about Lyme Disease All patients recall a tick bite or bulls eye rash. Lyme disease is only a concern in Northeastern states. ELISA is a sensitive screening test Only one infectious pathogen is transmitted by the tick bite. A short course of antibiotics resolves all cases of Lyme disease. Lyme disease may present as chronic and complex ‘medically unexplained symptoms.’ Babesiosis: An Underdiagnosed Disease of Children Of the 52 children on Block Island RI tested, 12% were positive for Babesia. Of the 522 adults, 8% tested positive. 25% of the seropositive children and 20% of the seropositive adults reported symptoms compatible with this infection during the previous month. Pediatrics Vol. 89 No. 6 June 1, 1992 pp. 1045 -1048 Is Lyme disease always polymicrobial? The Jigsaw hypothesis. Lyme disease may be due to a tick borne complex. This hypothesis suggests that multiple co-infections are present in the clinical syndrome. In one study of 240 patients diagnosed with Lyme disease, 11% were found to have evidence of concurrent Babesia infection. Owen, DC. Med Hypotheses. 2006;67(4):860-4. Epub 2006 Jun 30. ISRN Immunology Volume 2012 (2012) Development of immune response to Lyme borreliosis from tick bite Both the IgM and IgG immune response showed an undulatory distribution with antibodies coming and going in untreated patients over weeks Late stage neuropsychiatric symptoms of Lyme disease • • • • • • • • • • • • Cognitive Problems Lyme disease can Depression attack the CNS in the form Mood Swings of neuroborreliosis without involving other systems. Psychosis Violent behaviors/irritability OCD Anxiety/Panic Attacks Sleep disorders Seizures ADHD-like symptoms Autism-like behavior Chronic Fatigue Syndrome/Fibromyalgia Joksovic , P et al. Current Psychiatry, December 2011. ‘Medically Unexplained Symptoms’ Chronic Lyme Disease may present as: Chronic Fatigue Fibromyalgia Somatoform Disorders These terms are descriptors of symptoms and do not explain the underlying etiology of the illnesses. Maternal-Fetal Transmission of the Lyme Disease Spirochete, Borrelia burgdorferi “The Lyme disease spirochete may also spread transplancentally to organs of the fetus. The mother in this case developed Lyme disease during the first trimester of pregnancy; spirochetes were seen in the spleen, kidney, and bone marrow of the infant at term. In addition, the infant had several cardiovascular abnormalities. However, no spirochetes were found in his heart and no organ inflammation was seen.” Schlesinger PA, Duray PH, Burke BA, Steere AC, Stillman MT. Ann Intern Med. 1985 Jul;103(1):67-8. Support for this hypothesis includes: Positive reactivity in several studies with autistic spectrum disorder patients for B. burgdorferi (22%, 26% and 20–30%) Multiple cases of mothers with Lyme disease and children with ASD Support for this hypothesis includes: Fetal neurological abnormalities associated with tickborne diseases Improvement in autistic symptoms from antibiotic treatment Similarities between tick-borne diseases and ASD regarding symptoms, immune reactivity, temporal lobe pathology, and brain imaging data. Serologic Markers of Lyme Disease in Children With Autism Serologic testing for Lyme disease was conducted on two populations: 37 children aged 2-18 years who had autism and 27 unaffected siblings None of the children with autism and none of the unaffected controls showed serologic evidence of Lyme disease by the CDC two-tier testing. JAMA. 2013 May 1;309(17):1771-3 The CDC clinical criteria for Lyme Disease which exist for the purpose of monitoring the rate of Lyme disease nationally are quite narrowly defined in order to ensure a high degree of specificity in the diagnosis. These criteria are mainly useful for the early stages and rheumatological presentations of Lyme Disease. The CDC criteria are not very helpful for helping the clinician to detect late stage neurologic Lyme Disease. Emerging Infectious Determinants of Chronic Disease Infectious agents likely determine more neurodevelopmental disorders and other chronic conditions than currently appreciated. The inability to detect an agent does not rule out infectious etiology. Existing tools and methods may not be sensitive enough to link known agents with chronic disease. They may be unable to detect as yet uncharacterized novel or emerging microbes. Diagnostic assays may not access intracellular, sequestered, O'Connor SM, Taylor CE, Hughes JM. or nonreplicating agents. Emerg Infect Dis. 2006 Jul;12(7):1051-7. All five children in the study showed improvement in their autistic symptomology after beginning long term antibiotic treatment for Lyme disease. Common Underlying Pathophysiology Lyme Oxidative stress Mitochondrial dysfunction IDO upregulation Increased kynurenic acid Excitation/ inhibition ratio Microglial activation Gastrointestinal disturbances Immune dysfunction Molecular mimicry Zinc imbalances Autism Tick Borne Illnesses, Hypotonia, and Mitochondrial Dysfunction Dr. Charles Ray Jones, who has treated more than 10,000 children for Lyme disease, finds that hypotonia is present in over 90% of cases of gestational Lyme disease. In Ehrlichia chaffeensis-infected DH82 cells, mitochondria do not incorporate BrdU and transcriptional level of the mitochondrial gene NADPH2 is significantly reduced indicating the inhibition of mitochondrial metabolism. Liu et al. Microbes Infect. 2011 Mar;13(3):232-8. Hijacking mitochondria: bacterial toxins that modulate mitochondrial function It is now clear that bacterial pathogens produce a plethora of proteins known as "toxins" and "effectors" that target a variety of physiological host processes during the course of infection. One of the targets of host targeted bacterial toxins and effectors are the mitochondria. IUBMB Life. 2012 May;64(5):397-401 These studies identify microglia as a previously unappreciated source of inflammatory mediator production following challenge with B. burgdorferi. Chronic neuroinflammation in the frontal cortex of a patient with Lyme neuroborreliosis. First column (A, D and G) immunoreactive microglia forming clumps in the frontal cortex of a patient with Lyme neuroborreliosis. Second column (B, E, H) On frontal sections of the control patient, activated microglia or astrocytes are not visible. JMiklossy et al. Journal of Neuroinflammation 2008 5:40 J Neuroimmunol 2002 Sep;130(1-2):22-31. The Prevalence of Gastrointestinal Problems in Children Across the United States With Autism Spectrum Disorders From Families With Multiple Affected Members Parents reported significantly more GI problems in children with ASD compared with their unaffected siblings. The 2 most common Gl problems in children with ASD were constipation (20%) and chronic diarrhea (19%). Journal of Developmental & Behavioral Pediatrics: Copyright Suruchi Chandra, 2012 June 2011 - Volume 32 - Issue 5 - pp 351-360 Lyme Disease and the Gastrointestinal System Gastrointestinal signs and symptoms are common in the early stages of Lyme disease. Ali Zaidi, 2002) Chronic gastritis, chronic duodenitits, and chronic colitis were found in children and adolescents with Lyme disease and associated with the detection of B burgdorferi DNA in the GI tract despite prior antibiotic treatments. (Fried,2002) Simultaneous Gastrointestinal Infections in Children and Adolescents 81 pediatric patients were assessed for infections associated with abdominal pain, reflux, heartburn, and/or blood in stool. PCR testing of gastrointestinal biopsies from the stomach, duodenum, and/or colon was conducted. 35 had Bartonella spp. 24 had Mycoplasma fermentans 14 had Helicobacter pylori 13 had Borrelia burgdorferi Practical Gastroenterology, November 2004. Tick Borne Illnesses Result in Increased Oxidative Stress Markers and Decreased Reduced Glutathione Lipid peroxidation products, malondialdehyde (MDA), 4hydroxynoneal (4-HNE) were increased about 2-4 fold in the plasma of patients with Lyme. (Luczaj, 2011) Patients with tick borne encephalitis (TBE) had increased generation of oxygen derived free radicals and decreased activity of superoxide dismutase (SOD), glutathione reductase (GSSG-R), glutathione peroxidase (GSH-Px) in CSF. (Pancewicz, 2002) Zinc/Copper Imbalances and Chronic Infections Zinc levels are lower and copper levels are increased in pulmonary tuberculosis and other chronic infections. Zinc and copper levels normalize after antitubercular therapy. Zinc and copper given together was found to be more effective in treating Trypanosoma infection than either zinc or copper alone. The immune response to B. burgdorferi may elicit the production of antibodies capable of damaging or modifying normal host tissues. B. burgdorferi antigens may mimic the thyroid gland and be an environmental trigger of autoimmune thyroid diseases. Antibodies against the OspA epitopes of B. burgdorferi have been shown to cross react with neural tissue. National Institute of Allergy and Infectious Disease. Lyme disease: the role of autoimmune reactivity, retrieved from http://www.niaid.nih.gov/topics/ lymedisease/research/pages/autoimmune.aspx; 2007. Benvenga S, Guarneri F, Vaccaro M, Santarpia L, Trimarchi F. Homologies between proteins of Borrelia burgdorferi and thyroid autoantigens. Thyroid. 2004 Nov;14(11):964-6 Persistence of Borrelia burgdorferi Following Antibiotic Treatment in Mice Antimicrobial Agents and Chemotherapy, May 2008, p. 1728-1736, Vol. 52, No. 5 After antibiotic treatment, mice remained infected with nondividing but infectious spirochetes, especially if treatment was started during the chronic stage of infection. FIG. 1. Immunohistochemical labeling of multiple B. burgdorferi spirochetes (arrows) in ligament tissue of the tibiotarsal joint of a saline solution-treated (control) mouse (A) and of a single spirochete (arrow) in ligament tissue of the tibiotarsal joint of a ceftriaxone-treated mouse (B). Both images are from mice at 4 months after inoculation with B. burgdorferi A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy Patients with well documented Lyme disease, 3 weeks of prior IV antibiotics, and objective memory impairment. Patients received either 10 weeks of treatment with IV ceftriaxone or IV placebo. IV ceftriaxone therapy resulted in short term cognitive improvement but relapse in cognition occurred after the antibiotic was discontinued. Fallon BA et al. Neurology. 2008 Mar 25;70(13):992-1003. Several granules along Borrelia after 24 h of incubation with ceftriaxone at the middle and end regions. Kersten et al. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, May 1995, p. 1127–1133 Possible Contributors to Autism Spectrum Disorders GI Dysfunction Toxins Microbes Immune Dysfunction Nutrition Genetics Effects are complex and bi-directional ASD Hormones History of Borrelia First description of a case of probable Lyme disease appeared in the writings of Reverend Dr. John Walker in 1764 Borrelia DNA has been found in an infected Ixodes ricinus tick from Germany dating back to 1884 Recent autopsy of a 5,300 year old mummy found DNA sequence of Borrelia Autism: modern day illness It is unlikely that autism is simply related to an infection Modern day changes have likely contributed to the development of these disorders: Exposome Changes in microbiotica Dietary and nutrition changes Body’s Terrain Water/Hydration status Nutritional Status Environmental Toxins including metals Electromagnetic pollution Stress Negative emotions Overuse of medications Lack of movement and exercise Lack of sunlight Poor tissue oxygenation Tissue acid-base imbalance Are we weaker than ever before and more prone to chronic infections? Biomedical and Integrative Approach to ASD Dietary changes Nutritional supplementation Methylation support Reduce exposure to toxins Detoxification Mitochondrial support HPA axis support Address GI symptoms and dysbosis Mitochondrial Dysfunction in Autism JAMA. 2010;304(21):2389-2396 50-80% of children with autism had one or more biomarkers for mitochondrial dysfunction. The cells of children with autism were exposed to higher levels of oxidative stress. Half the children had mtDNA over replication, indicating an effort to overcome some form of damage or dysfunction. Holistic Model for Treatment of Mitochondrial Dysfunction Avoid toxins that may interfere with function Avoid medicines that interfere with mitochondrial function Use herbs that protect and support mitochondria Individualized mitochondrial cocktail High ORAC/antioxidant foods Reduce excess consumption of omega 6 oils Treat any chronic bacterial issues and infections Copyright Suruchi Chandra, 2012 Children with ASD have altered gut microbiota Desulfovibrio species and Bacteroides vulgatus were present in significantly higher numbers in stools of severely autistic children. (Finegold SM, 2010) Lower relative abundances of Bifidobacteria species and the mucolytic bacterium Akkermansia muciniphila were found in children with autism. (Wang L, 2011) Sutterella species were found in ileal mucosal biopsy specimens from patients diagnosed with ASD but not in control children with GI symptoms. (Williams BL, 2012) Copyright Suruchi Chandra, 2012 Modern practices that have established a potential influence on microbial diversity: Caesarian delivery Formula feeding Refined foods, rarely fermented, and often grown with antibiotics Refrigeration Chlorinated water Widespread antimicrobial use Gut microbiota At least 500 different species of bacteria Probiotics have only a few species Functions: Nutrient extraction immune system development defense against pathogens Normal gut microbiota modulates brain development and behavior Results suggest that the microbial colonization process initiates signaling mechanism that affect neuronal circuits involved in motor control and anxiety behavior. Proc Natl Acad Sci 2011, February 15. Microbiota and Short-Course Antibiotic Challenge Six healthy study volunteers received oral amoxicillin (1.5 g/day) for 5 days. The fecal microbiota showed a major shift in dominant species after just 24 hours of antibiotic treatment. After 4 days of treatment, the average similarity to pre-treatment microbiota was 74%. After 60 days, the average similarity to the pre-treatment microbiota was 89%. In one subject, there were significant changes even at 2 months after treatment. J Clin Microbiol. 2005 Nov;43(11):5588-92. Resilience of the dominant human fecal microbiota upon short-course antibiotic challenge. Send to: •Abstract Abstract ab 2 0 s trac (text) t Pathways involved in bidirectional communication between the gut microbiota and the brain. John F. Cryan & Timothy G. Dinan Nature Reviews Neuroscience 13, 701712 (October 2012) Disruption of the gut microbiome as a risk factor for microbial infections. We suggest that modern lifestyle advances may be depleting specific microbes that enhance immunity against pathogens. Validation of the notion that absence of beneficial microbes is a risk factor for infectious disease may have broad implications for future medical practices. Curr Opin Microbiol. 2013 Apr 15. Microbiome and environmental toxins Tissue content of mercury in rats given methylmercuric chloride orally: influence of intestinal flora. Antibiotics-treated rats given labeled metyhlmercuric chloride orally had significantly more mercury in their tissues, especially in kidney, brain, lung, blood, and skeletal muscle, and also excreted less mercury in the feces than conventional rats. Biodegradation of chlorpyrifos by lactic acid bacteria during kimchi fermentation. Arch Environ Health. 1980 May-Jun;35(3):155-60. J Agric Food Chem. 2009 Mar 11;57(5):1882-9 Impairment of innate immune killing mechanisms by bacteriostatic antibiotics In essence, certain drugs may be functioning at odds with our immune system rather than in synergy to achieve bacterial killing. Certain pharmaceutical therapies could allow bacteria to persist longer in host tissue environments where innate immune responses are normally summoned. The FASEB Journal. Online January 10, 2007, Treatment of Dysbosis We are still in the infancy stages of treatment, Over 1000 human associated microorganisms have been identified in the human microbiota. Probiotics usually contain only a few different species. Preserve and restore natural diversity Avoid unnecessary antibiotics and antibiotic treated meat Probiotics Prebiotics/fibers Fermented foods Reduce Stress Dietary Changes Target possible pathogenic biofilm formation Copyright Suruchi Chandra, 2012 Treatment of Dysbosis Possible future treatments: Herbs to balance and restore gut microbiota – need studies to better understand and support use. Human probiotics Fecal transplant Identification and targeted treatments for Desulfovibrio species Copyright Suruchi Chandra, 2012 Treatment in the setting of an uncertain diagnosis Many cases of chronic neurologic Lyme will not have confirmatory testing Patient may have an infection that has not yet been identified Herbal antimicrobials are a better option in the setting of an uncertain diagnosis Long Term Antibiotic Use in Tick Borne Illnesses May: Promotes dysbosis and fungal overgrowth in the GI system Affect behavior and brain development Decrease natural immunity in GI system Contribute to the development of antibiotic resistant bacteria Promote cyst or round body formation Become another toxic burden on an already taxed liver Not be effective against microbes that exist in biofilm formation. Herbal Protocol Treatments for Tick Borne Illnesses Stephen Buhner Core Protocol: Andrographis, Cat’ Claw, Japanese Knotweed, Astragalus, and Similax Byron White Dr. William Lee Cowden Nutramedix herbs: Cumanda, Banderol, Samento, Lakato, Houttuynia, Enula, Mora, and Quina In Vitro Effectiveness of Samento and Banderol Herbal Extracts on the Different Morphological Forms of Borrelia Burgdorferi Control Samento (1:300 dilution) Banderol (1:300 dilution) The cells inside the colonies are >90% dead. In Vitro Effectiveness of Samento and Banderol Herbal Extracts on the Different Morphological Forms of Borrelia Burgdorferi Samento + Banderol (1:300 dilution) Doxycyline Hottuyniae Herba protects rat primary cortical cells from amyloid beta induced neurotoxicity via regulation of calcium influx and mitochondria – Mediated apoptosis. Houttuyniae Herba water extract inhibited the amyloid beta induced elevation of intracellular calcium level, reactive oxygen species overproduction, mitochondrial membrane potential disruption, and caspase 3 activation. Hum Ex Tocicol. 2012 Jul; 31 (7) 689-709. Anti-inflammatory activity of Mirtraphylline isolated from Uncaria tomentosa bark. Mitraphlline inhibited around 50% of the release of interleukins 1 alpha, 1 beta, 17, and TNF-alpha. This activity was similar to dexamethasone. It also reduced almost 40% of the production of interleukin 4 (IL-4) while the corticoid did not. J Ethnpharmacol. 2012 Oct 11;143 (3): 801-4. Protective activity of the Uncaria tomentosa extract on human erythrocytes in oxidative stress induced by 2,4-dichlorophenol (2,4DCP) and catechol Food Chem Toxicol. 2011 Sep; 49 (9):2202-11 Neuroprotective effects of aqueous extracts of Uncaria tomentosa: Insights from 6-OHDA induced cell damaged transgenic Caenorhabditis elegegans model. Neurochem Int. 2013 Mar14;62 (7):940-947 Case Studies Case 1 9 year old boy with history of PDD Presents with Poor focus Impulsivity Fatigue Anxiety Low tone Delays in fine motor skills Treatment History IVIG IV EDTA/DMPS HBOT 40 Leucovorin 50 mg Fluoxetine Memantine Neuro feedback therapy Mother’s History Mother had history of: Multiple tick bites as an adolescent Chronic fatigue Fibromyalgia ‘Foggy thinking’ Chronic depression After her son’s visit she took 4 drops of Banderol and had a herxheimer reaction Treatment Stopped Leucovorin, Namenda, and IVIG Started a vitamin, mineral, and herbal based protocol After two months, mother reported that he was ‘doing better than ever.’ Started Lakato herbal and 10 days later experienced poor focus, hyperactivity, and school difficulties. Stopped the Lakato and within one week was back to his baseline. Mother’s Test Results Advanced Laboratory Polyclonal Borrelia Culture Result: Growth Positive Growth of spirochetes in the blood which stained positive via immunohistochemical method using polyclonal antibody for Borrelia species. Borrelia and co-infection testing was done when patient was experiencing a herxheimer reaction while on Lakato IGENEX Panel: Lyme IgM WB IGENEX Negative CDC/NYS Negative Lyme IgG WB IGENEX Positive CDC/NYS Negative Ehrlichia chaffeensis IgM 20 Positive IgG <40 Negative Babesia duncani IgM 80 Positive IgG <40 Negative Case 2 8 year old boy with history of Asperger's and possible bipolar disorder Treated with risperidone and fluoxetine Genova ONE test results all within normal range With minerals, vitamins, and adaptogenic support came off medications. Case 2 Started Cumanda Developed auditory hallucinations Became aggressive Started hitting his own head Borrelia and co-infection testing was done after patient had been on Cumanda. IGENEX Panel: Lyme IgM WB IGENEX Negative CDC/NYS Negative Lyme IgG WB IGENEX positive CDC/NYS Negative Babesia duncani IgM <20 Negative IgG 80 Positive Bartonella henselae IgM 20 Positive IgG <40 Negative Treatment N acetyl cysteine cream Treatment with less broad spectrum antimicrobials including herbs for possible parasitic infection After 9 months of antimicrobial treatment, teachers and mother felt he was indistinguishable from other children Still struggles under stressful situations Conclusion All of these infections are emerging diseases. We still have much to learn about them. Consider Lyme disease and the associated co-infections in the differential of any severe or atypical psychiatric disease. Lyme disease is a clinical diagnosis. Serologies can be used to support a diagnosis. For late stage Lyme disease, consider a treatment approach that is multi-faceted and addresses all forms of Borrelia, co-infections, and secondary complications of the infection.