Transcript Chandra- LymeDallas June 13

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
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Causes are likely unique, individualized and
multifactorial.
Emerging research is pointing to changes in our
environment along with genetic vulnerabilities.
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Environment includes:
Chemical toxins
Electromagnetic fields
Changes in diet and nutrition
Microbiome
Infections
Prenatal inflammation linked to
autism risk
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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
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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
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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
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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
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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.
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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
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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
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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
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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.
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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
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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
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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?
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Biomedical and Integrative Approach
to ASD
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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
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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:
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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:
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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.
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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
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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.
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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
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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
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Long Term Antibiotic Use in Tick Borne
Illnesses May:
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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
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 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
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Treatment History
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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
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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
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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
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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
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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
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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
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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.