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

Genetic heritability and shared environmental factors among twin pairs with autism.

Association of ASD rates with environmental toxins in multiple studies.

Rising rates of autism

Califo

rnia

CDC:1 in 50 US children now has autism.

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 toxinsElectromagnetic fieldsChanges in diet and nutritionMicrobiomeInfections

Prenatal inflammation linked to autism risk

The risk of autism among children in the study was increased by 43 percent among mothers with CRP (C-reactive 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 DisordersJournal of Autism and Developmental Disorders, Volume 40, Number 12.

Maternal immune activation causes age- and region-specific changes in brain cytokines in offspring throughout developmentPaula 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.

Both the IgM and IgG immune response showed an undulatory distribution with antibodies coming and going in untreated patients over weeks

Development of immune response to Lyme borreliosis from tick bite

Click icon to add picture

ISRN Immunology Volume 2012 (2012)

Late stage neuropsychiatric symptoms of Lyme disease

• Cognitive Problems• Depression• Mood Swings• 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.

Lyme disease canattack the CNS in the form of neuroborreliosis without involving other systems.

‘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 tick-borne diseasesImprovement in autistic symptoms from antibiotic treatmentSimilarities 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, or nonreplicating agents.O'Connor SM, Taylor CE, Hughes JM.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

Oxidative stressMitochondrial dysfunction

IDO upregulationIncreased kynurenic

acid Excitation/ inhibition

ratioMicroglial activation

Gastrointestinal disturbances

Immune dysfunction Molecular mimicry

Zinc imbalances

Lyme

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.

JMiklossy et al. Journal of Neuroinflammation 2008 5:40J Neuroimmunol 2002 Sep;130(1-2):22-31.

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.

Copyright Suruchi Chandra, 2012

The Prevalence of Gastrointestinal Problems in Children Across the United States With Autism Spectrum Disorders From Families With Multiple Affected MembersParents 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: 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), 4-hydroxynoneal (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 anti-tubercular 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 ofautoimmune 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

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

After antibiotic treatment, mice remained infected with nondividing but infectious spirochetes, especially if treatment was started during the chronic stage of infection.

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

ASD

Genetics

Nutrition

GIDysfunct

ion

Toxins

Microbes

Immune Dysfunct

ion

Hormones

Effects are complex and bi-directional

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:

ExposomeChanges in microbioticaDietary 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 imbalanceAre 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.

Copyright Suruchi Chandra, 2012

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)

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 bacteriaProbiotics have only a few species

Functions:Nutrient extractionimmune system developmentdefense against pathogens

Normal gut microbiota modulatesbrain 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.

John F. Cryan & Timothy G. DinanNature Reviews Neuroscience 13, 701-712 (October 2012)

Pathways involved in bidirectional communication between the gut microbiota and the brain.

Display Settings:•Abstract

Send to: Abstract (text)Abstractabstractabstractabstract2020

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,

Copyright Suruchi Chandra, 2012

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

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 inoxidative stress induced by 2,4-dichlorophenol (2,4-DCP) and catecholFood 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 PDDPresents with

Poor focusImpulsivityFatigueAnxietyLow toneDelays 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 adolescentChronic fatigueFibromyalgia‘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: GrowthPositive 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 LakatoIGENEX 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.