The prevalence of Lyme disease and associated co-infections in people with a chronic post-concussive syndrome

Abstract

Introduction:
There is increasing awareness that Lyme borreliosis (LB) and traumatic brain injury (TBI) may cause mental health symptoms. TBI and Lyme disease compromise the health and activities of millions of patients per year. The chronic symptoms and disability of TBI and Lyme disease share a similar clinical presentation. We have identified an alarming number of individuals suffering from post-concussion syndrome (PCS) that are refractory to care and that have serologically tested positive for Lyme disease.

Subjects and methods:
A single-center retrospective review of patient charts that were symptomatic a minimum of one year after a TBI that were tested for Lyme disease to ascertain if there was a relationship.

Results:
217 PCS patient records (93 females with a mean age of 34 years, 120 males with a mean age of 40 years and 4 individuals with unknown gender) were included in the review. 38% had a positive Western Blot Igenex IgM. There was a statistically significant relationship of a positive Western Blot Igenex IGM predicting chronic PCS Pearson χ2(1)=6.8866, P=0.009, Fisher's exact score p=0.015 and φ=0.2813 representing a moderate effect size.

Conclusions:
Long term PCS over one year's duration is associated with undiagnosed Lyme disease. There was statistical and substantive significance between individuals with chronic PCS having a positive Western Blot Igenex IgM. Males were more likely to have a positive Western Blot Igenex IgM than females.

Full text

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Psychiatria Danubina, 2019; Vol. 31, Suppl. 3, pp 299–307 Conference paper
© Medicinska naklada - Zagreb, Croatia
THE PREVALENCE OF LYME DISEASE AND ASSOCIATED
CO-INFECTIONS IN PEOPLE WITH A CHRONIC
POST-CONCUSSIVE SYNDROME
Sergio Azzolino1,2, Rashid Zaman3,4,5, Ahmed Hankir2,3,6,7 & Frederick R Carrick1,2,3,8,9
1Department of Neurology, Carrick Institute, Cape Canaveral, FL, USA
2GCSRT, Harvard Medical School, Boston, MA, USA
3Centre for Mental Health Research in association with University of Cambridge (CMHR-CU), Cambridge, UK
4Hertfordshire Partnership University NHS Foundation Trust, UK
5Department of Psychiatry, University of Cambridge, Cambridge, UK
6Department of Psychiatry, Carrick Institute for Graduate Studies, Cape Canaveral, FL, USA
7South London and Maudsley NHS Foundation Trust, London, UK
8Department of Neurology, University of Central Florida College of Medicine, Orlando, FL, USA
9Department of Health Professions Education, MGH Institute of Health Professions, Boston, MA, USA
SUMMARY
Introduction: There is increasing awareness that Lyme borreliosis (LB) and traumatic brain injury (TBI) may cause mental
health symptoms. TBI and Lyme disease compromise the health and activities of millions of patients per year. The chronic symptoms
and disability of TBI and Lyme disease share a similar clinical presentation. We have identified an alarming number of individuals
suffering from post-concussion syndrome (PCS) that are refractory to care and that have serologically tested positive for Lyme
disease.
Subject and methods: A single-center retrospective review of patient charts that were symptomatic a minimum of one year after
a TBI that were tested for Lyme disease to ascertain if there was a relationship.
Results: 217 PCS patient records (93 females with a mean age of 34 years, 120 males with a mean age of 40 years and 4
individuals with unknown gender) were included in the review. 38% had a positive Western Blot Igenex IgM. There was a
statistically significant relationship of a positive Western Blot Igenex IGM predicting chronic PCS Pearson
F

(1)=6.8866, P=0.009,
Fisher’s exact score p=0.015 and
I
=0.2813 representing a moderate effect size.
Conclusions: Long term PCS over one year’s duration is associated with undiagnosed Lyme disease. There was statistical and
substantive significance between individuals with chronic PCS having a positive Western Blot Igenex IgM. Males were more likely to
have a positive Western Blot Igenex IgM than females.
Key words: Lyme disease - traumatic brain injury - post-concussion syndrome - mental illness
* * * * *
INTRODUCTION
Traumatic brain injuries (TBI) and Lyme disease
compromise the health and activities of millions of
patients per year. The chronic symptoms and disability
of TBI and Lyme disease share a similar clinical pre-
sentation. Lyme disease causes immune and metabolic
effects that result in a gradually developing spectrum of
neuropsychiatric symptoms, usually presenting with
significant comorbidity which may include develop-
mental disorders, autism spectrum disorders, schizoaf-
fective disorders, bipolar disorder, depression, anxiety
disorders (panic disorder, social anxiety disorder, gene-
ralized anxiety disorder, posttraumatic stress disorder,
intrusive symptoms), eating disorders, decreased libido,
sleep disorders, addiction, opioid addiction, cognitive
impairments, dementia, seizure disorders, suicide, vio-
lence, depersonalization, dissociative episodes, dereali-
zation and other impairments (Bransfield 2018).
Moreover, current evidence suggests a link between
sports-related concussion and depression symptoms in
elite athletes (Rice et al. 2018) and students who expe-
rience a concussion may be at increased risk for poor
mental health outcomes, including suicide attempts
(Yang et al. 2019). Our specialist TBI clinic has appre-
ciated an alarming incidence of Lyme disease in patients
suffering from a post-concussion syndrome (PCS) se-
condary to TBI. Furthermore, we have witnessed a dra-
matic improvement in function and reduction in dis-
ability following treatment of these patients. TBI,
according to the World Health Organization, will sur-
pass many diseases as the major cause of death and
disability by the year 2020. With an estimated 10
million people affected annually by TBI, the burden of
mortality and morbidity that this condition imposes on
society makes TBI a pressing public health and medical
problem (Hyder et al. 2007). TBIs are categorized into
mild, moderate and severe based on clinical factors such
as the severity of the injury, and loss of consciousness.
Eighty to ninety percent of TBIs are classified as mild
and labeled concussions. Despite many concussions
healing relatively quickly, a number of these patients
are refractory to treatment and have persistent disabling
symptoms referred to as PCS. Furthermore, according to

Sergio Azzolino, Rashid Zaman, Ahmed Hankir & Frederick R Carrick: THE PREVALENCE OF LYME DISEASE
AND ASSOCIATED CO-INFECTIONS IN PEOPLE WITH A CHRONIC POST-CONCUSSIVE SYNDROME
Psychiatria Danubina, 2019; Vol. 31, Suppl. 3, pp 299-307
S300
the Centers for Disease Control and Prevention (CDC),
Lyme disease is the most commonly reported vector-
borne illness and the fifth most common disease in the
National Notifiable Diseases Surveillance System, ma-
king it a significant public health concern (Younger et
al. 2016). The Neurological manifestations of Lyme di-
sease, called Neuroborreliosis, are reported in up to 15%
of patients with Lyme disease (Rice et al. 2018, Yang et
al. 2019) with symptoms similar to those of PCS. Des-
pite numerous studies and increased awareness of con-
cussions, there continues to be a paucity of understan-
ding regarding why some patients recover and others
remain symptomatic. Our clinical team attends TBI,
PCS and Lyme patients that are referred to us from
around the globe. We have identified an alarming num-
ber of individuals suffering from PCS that are refractory
to care and that have serologically tested positive for
Lyme disease. As a consequence, we were interested in
testing PCS patients for Lyme disease that had no
history of or testing for Lyme disease.
Research Question
We desired to investigate the prevalence of Lyme
disease and co-infections in our PCS patients that
remained symptomatic over one year after a TBI. We
searched a variety of databases for randomized controlled
trials of PCS and Lyme Disease up until January 2018
without success. Our search included Cochrane Injuries
Group's specialized register, Cochrane Depression, An-
xiety and Neurosis Group's specialized register, Cochrane
Central Register of Controlled Trials, MEDLINE,
PsycINFO, EMBASE, CINAHL, AMED, ERIC, and
PsycBITE. Because of the lack of research in this area,
we decided to perform a retrospective chart review of
our patients that were symptomatic a minimum of one
year after a TBI that we also had tested for Lyme
disease to ascertain if there was a relationship.
Hypothesis
Based on our experience and clinical observations,
we hypothesized that a significant percentage of patients
with PCS symptomatology that are symptomatic after 1
year from the date of injury might continue to be
symptomatic due to ongoing undiagnosed and untreated
Lyme disease or associated co-infection.
SUBJECTS AND METHODS
The study was a single-center retrospective review
of patient charts performed at our clinical facility in San
Francisco, California. All charts were anonymized ensu-
ring patient confidentiality appropriate to the Decla-
ration of Helsinki and approved by the Carrick Institute
for Graduate Studies Institutional Review Board. We
reviewed the complete history of current complaints,
past history, social history, surgical and medication
history, social history, review of symptoms and family
history to identify all inclusionary and exclusionary
factors. Each record that was accepted in our review met
the study criteria for inclusion and was not disqualified
by any of the exclusionary criteria.
Inclusion criteria
All participants had at least one PCS symptom (e.g.,
headache, irritability, dizziness, vertigo, difficulty
concentrating) for more than 12 months in combi-
nation with a negative brain computed tomography
(CT) or magnetic resonance imaging (MRI) scan.
All participants had undergone testing for Lyme
disease at our facility that included IgG Western
Blot and IgM Western Blot.
Exclusion criteria
Patients that previously tested serologically positive
for Lyme and /or co-infection.
Patients that have had  2 weeks of antibiotics since
the date of injury.
Patients with other diagnosed primary neurological
illness such as seizure disorder, or multiple sclerosis.
Post-stroke syndrome.
Statistical Analysis
The statistical analysis was performed using STATA
14 (College Station, Texas). Linear and Logistic re-
gression models and correlations were fitted to identify
any laboratory predictors of TBI and effect size was
identified by Eta Squared and Cohen d calculations.
RESULTS
Our review identified 217 PCS patient records that
met our criterion (93 females with a mean age of 34
years, 120 males with a mean age of 40 years and 4
individuals with unknown gender). The normality of the
distributions of data was verified using Kolmogorov-
Smirnov with Lilliefors Significance Correction and
Shapiro-Wilk tests of normality. A linear regression
model including all laboratory tests and including males
and females revealed a high statistically significant
predictor of PCS if the patient had a positive Western
Blot Igenex IgM test (P<0.0001). We removed the
subjects that had unknown values for TBI and Western
Blot Igenex IgM from the analysis to consider only
those subjects with data for both of these variables. This
reduced the sample from 217 to 87 subjects (18 without
a history of TBI and 69 with a history of TBI). Of the
remaining subjects with a history of TBI, 37.68% had a
positive Western Blot Igenex IgM while 62.32% did
not. For those remaining patients without a history of
TBI, 72.22% had a positive Western Blot Igenex IgM,
and 27.78% had a negative Western Blot Igenex IgM.
An examination of the relationship between a history of

Sergio Azzolino, Rashid Zaman, Ahmed Hankir & Frederick R Carrick: THE PREVALENCE OF LYME DISEASE
AND ASSOCIATED CO-INFECTIONS IN PEOPLE WITH A CHRONIC POST-CONCUSSIVE SYNDROME
Psychiatria Danubina, 2019; Vol. 31, Suppl. 3, pp 299-307
S301
TBI and Western Blot Igenex IgM revealed a Pearson
F(1)=6.8866, P=0.009 and a Fisher’s exact score
p=0.015. Iҏ was calculated as 0.2813 representing a mode-
rate effect size. A I with an absolute value from 0.0 to
0.19 is considered weak, from 0.20 to 0.49 is considered
moderate, and from 0.50 and above is considered strong
(Table 1).
Figure 1. ROC of Logistic Model Predicting PCS by
Western Blot/Igenex-IGM
We desired to assess the discrimination of a fitted
logistic model, via the receiver operating characteristic
(ROC) curve in patients with chronic PCS and Western
Blot Igenex-IgM. We plotted the values of sensitivity
against one minus specificity, as the value of the cut-
point was increased from 0 through to 1. A model with
high discrimination ability will have high sensitivity
and specificity simultaneously, leading to a ROC curve
which goes close to the top left corner of the plot. A
model with no discrimination ability will have a ROC
curve that is the 45-degree diagonal line. The area
under the ROC curve (AUC) can range from 1 (perfect
discrimination) to 0.5 (no discrimination). A fitted
logistic model of PCS subjects predicted by Western
Blot Igenex-IgM had good discrimination values
(AUC=0.7232). The Cohen’s d=0.819 representing a
strong effect size (Figure 1).
We analyzed male and female subjects removing
those that had unknown values for TBI and Western
Blot Igenex IgM from the analysis (50 females and 36
males). Of the female subjects with a history of TBI,
36.59% had a positive Western Blot Igenex IgM while
63.41% did not. For those remaining female subjects
without a history of TBI but with PCS like symptoms,
77.78% had a positive Western Blot Igenex IgM, and
22.22% had a negative Western Blot Igenex IgM. An
examination of the relationship between a history of
TBI and Western Blot Igenex IgM in female subjects
revealed a Pearson F(1)=5.0822, P=0.024 and a Fisher’s
exact score p=0.032. I was calculated as 0.3188 repre-
senting a moderate effect size (Table 2).
Table 1. TBI and Western Blot Igenex-IgM History in Subjects with chronic PCS Symptoms
Western Blot/Igenex-IgM for All Subjects
TBI
Negative Positive Total F2IP
Frequency No 5 13 18
F2 contribution 2.40 3.00 5.50
Row percentage 27.78 72.22 100.00
Frequency Yes 43
26 69
F2 contribution 0.60 0.80 1.40
Row percentage 62.32 37.68 100.00
Frequency Total 48 39 87
F2 contribution 3.10 3.80 6.90
Row percentage 55.17 44.83 100.00
6.866 0.2813 0.009
Table 2. TBI and Western Blot Igenex-IgM History in Females with chronic PCS Symptoms
Western Blot/Igenex-IgM for Female Subjects
TBI
Negative Positive Total F2IP
Frequency No 2 7 9
F2 contribution 1.80 2.30 4.20
Row percentage 22.22 77.78 100.00
Frequency Yes 26
15 41
F2 contribution 0.40
0.50 0.90
Row percentage 63.41 36.59 100.00
Frequency Total 28 22 50
F2 contribution 2.20 2.80 5.10
Row percentage 56.00 44.00 100.00
5.0822 0.3188 0.024

Sergio Azzolino, Rashid Zaman, Ahmed Hankir & Frederick R Carrick: THE PREVALENCE OF LYME DISEASE
AND ASSOCIATED CO-INFECTIONS IN PEOPLE WITH A CHRONIC POST-CONCUSSIVE SYNDROME
Psychiatria Danubina, 2019; Vol. 31, Suppl. 3, pp 299-307
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Figure 2. ROC of Logistic Model Predicting TBI by
Western Blot/Igenex for Females
We desired to assess the discrimination of a fitted
logistic model, via the receiver operating characteristic
(ROC) curve in female patients with chronic PCS and
Western Blot Igenex-IgM. We plotted the values of
sensitivity against one minus specificity, as the value of
the cut-off point was increased from 0 through to 1. A
fitted logistic model of PCS subjects predicted by
Western Blot Igenex-IgM had good discrimination
values (AUC=0.7470). The Cohen’s d =0.819 represents
a strong effect size (Figure 2).
Of the male subjects with a history of TBI, 39.29%
had a positive Western Blot Igenex IgM while 60.71%
did not. For those remaining male subjects without a
history of TBI but with chronic PCS like symptoms,
75.00% had a positive Western Blot Igenex IgM, and
25.00% had a negative Western Blot Igenex IgM. An
examination of the relationship between a history of
TBI and a positive Western Blot Igenex IgM in male
subjects revealed a Pearson F(1)=3.1844, P=0.074 and
a Fisher’s exact score of 0.114. I was calculated as
0.2974 representing a moderate effect size (Table 3).
We desired to assess the discrimination of a fitted
logistic model, via the receiver operating characteristic
(ROC) curve in male patients with chronic PCS and
Western Blot Igenex-IgM. We plotted the values of
sensitivity against one minus specificity, as the value
of the cut-off point was increased from 0 through to 1.
Figure 3. ROC of Logistic Model Predicting TBI by
Western Blot/Igenex for Males
A fitted logistic model of PCS subjects predicted by
Western Blot Igenex-IgM had fair discrimination values
(AUC=0.6758) that were less than those calculated for
females, however, the Cohen’s d=1.18 represented a
strong effect size but less than that calculated for
females (Figure 3).
37.68% of the sample of subjects that had suffered a
TBI and had longstanding PCS symptoms had a positive
Western Blot Igenex IgM. Males were more likely to
have a positive Western Blot Igenex IgM (39.29%) than
females (36.59%).
We removed the subjects that had unknown values
for TBI and Western Blot Igenex IgG from the analysis
to consider only those subjects with data for both of
these variables. This reduced the sample from 217 to 87
subjects (18 without a history of TBI and 70 with a
history of TBI). Of the remaining subjects with a history
of TBI, 25.71% had a positive Western Blot Igenex IgG
IgM while 74.29% did not. For those remaining patients
without a history of TBI, 33.33% had a positive
Western Blot Igenex IgG, and 66.67% had a negative
Western Blot Igenex IgG. An examination of the
relationship between a history of TBI and Western Blot
Igenex IgG revealed a Pearson F(1)=0.4190, P=0.517
that was not statistically significant with a Fisher’s exact
score p=0.559. Iҏwas calculated as 0.0690 representing
a weak effect size (Table 4).
Table 3. TBI and Western Blot Igenex-IgM History in Males with chronic PCS Symptoms
Western Blot/Igenex-IgM for Male Subjects
TBI
Negative Positive Total F2IP
Frequency No 2 6 8
F2 contribution 1.20 1.30 2.50
Row percentage 25.00 75.00 100.00
Frequency Yes 17
11 28
F2 contribution 0.30
0.40 0.70
Row percentage 60.71 39.29 100.00
Frequency Total 19 17 36
F2 contribution 1.50 1.70 3.20
Row percentage 52.78 47.22 100.00
3.1844 0.3188 0.074

Sergio Azzolino, Rashid Zaman, Ahmed Hankir & Frederick R Carrick: THE PREVALENCE OF LYME DISEASE
AND ASSOCIATED CO-INFECTIONS IN PEOPLE WITH A CHRONIC POST-CONCUSSIVE SYNDROME
Psychiatria Danubina, 2019; Vol. 31, Suppl. 3, pp 299-307
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Table 4. TBI and Western Blot Igenex-IgG History in Subjects with chronic PCS Symptoms
Western Blot/Igenex-IgG for all Subjects
TBI
Negative Positive Total F2IP
Frequency No
12 6 18
F2 contribution 0.10 0.20 0.30
Row percentage 66.67 33.33 100.00
Frequency Yes
52 18 70
F2 contribution 0.00 0.10 0.10
Row percentage 74.29 25.71 100.00
Frequency Total
64 24 88
F2 contribution 0.10 0.30 0.40
Row percentage 72.73 44.00 100.00
0.4190 0.0690 0.517
Table 5. TBI and Western Blot Igenex-IgG History in Females with chronic PCS Symptoms
Western Blot/Igenex-IgG for Female Subjects
TBI
Negative Positive Total F2IP
Frequency No 9 0 9
F2 contribution 0.60 2.00 2.50
Row percentage 100.00 0.00 100.00
Frequency Yes 30
11 41
F2 contribution 0.10 0.40 0.60
Row percentage 73.17 26.83 100.00
Frequency Total 39 11 50
F2 contribution 0.70 2.40 3.10
Row percentage 78.00 22.00 100.00
3.0957 0.2488 0.079
Table 6. TBI and Western Blot Igenex-IgG History in Males with chronic PCS Symptoms
Western Blot/Igenex-IgG for Male Subjects
TBI
Negative Positive Total F2IP
Frequency No 3 5 8
F2 contribution 1.10 2.20 3.30
Row percentage 37.50 62.50 100.00
Frequency Yes 22
729
F2 contribution 0.30
0.60 0.90
Row percentage 75.86 24.14 100.00
Frequency Total 25 12 37
F2 contribution 1.40 2.80 4.20
Row percentage 67.57 32.43 100.00
4.2109 0.2488 0.040
We analyzed male and female subjects removing
those that had unknown values for TBI and Western
Blot Igenex IgG from the analysis (50 females and 36
males). Of the female subjects with a history of TBI,
26.83% had a positive Western Blot Igenex IgG while
73.17% did not. For those remaining female subjects
without a history of TBI but with PCS like symptoms,
none had a positive Western Blot Igenex IgG, and 100%
had a negative Western Blot Igenex IgG. An exa-
mination of the relationship between a history of TBI
and Western Blot Igenex IgG in female subjects
revealed a Pearson F(1)=3.0957, P=0.079 that was not
statistically significant with a Fisher’s exact score
p=0.177. I was calculated as 0.2488 representing a
moderate effect size (Table 5).
Of the male subjects with a history of TBI, 24.14%
had a positive Western Blot Igenex IgG while 75.86%
did not. For those remaining male subjects without a
history of TBI but with PCS like symptoms, 62.50% had
a positive Western Blot Igenex IgG, and 37.50% had a
negative Western Blot Igenex IgG. An examination of the
relationship between a history of TBI and Western Blot
Igenex IgG in female subjects revealed a Pearson
F(1)=4.2109, P=0.040 that was statistically significant
with a Fisher’s exact score p=0.083. I was calculated as
0.3374 representing a moderate effect size (Table 6).

Sergio Azzolino, Rashid Zaman, Ahmed Hankir & Frederick R Carrick: THE PREVALENCE OF LYME DISEASE
AND ASSOCIATED CO-INFECTIONS IN PEOPLE WITH A CHRONIC POST-CONCUSSIVE SYNDROME
Psychiatria Danubina, 2019; Vol. 31, Suppl. 3, pp 299-307
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TBI and Western Blot Igenex-IgG history in Males
with chronic PCS symptoms are statistically significant
with a moderate effect size, whereas there is no
significant relationship that was found in female
subjects. TBI and Western Blot Igenex-IgM have both
statistical and substantively significant relationships.
DISCUSSION
Traumatic brain injuries are a significant cause of
death and disability among people of all ages affecting
approximately 10 million people worldwide (Yang et al.
2019). According to the US Center for Disease Control
and Prevention (CDC), in 2010 about 2.5 million emer-
gency department (ED) visits, hospitalizations, or deaths
were associated with TBI (https://www.cdc.gov/). Over
the past decade, concussions have been widely discus-
sed concerning contact sports, motor vehicle accidents,
and as the signature injury of soldiers. They also occur
in falls among the elderly and victims of domestic
abuse. Most patients with mild traumatic brain injury
(mTBI) recover rather quickly, but other report
persistent symptoms of PCS, the underlying patho-
physiology of which is mostly unknown (Blennow et
al. 2016). The CDC estimates the annual rate of
concussion to be approximately 1.4–3.8 million. How-
ever, these numbers are likely to be an under-estimate,
because a large number of concussions go unnoticed
and unreported. PCS is a complex disorder characteri-
zed by multiple pathophysiological processes or “poly-
pathology” whose main features are white matter
degradation, neuronal loss, protein misfolding, and
persistent neuroinflammation. Alterations in the neuro-
transmitter and neuroendocrine systems are also wide-
spread (Newcombe et al. 2011, Stocchetti et al. 2016).
The symptoms of PCS include headache, dizziness,
neck pain, exercise intolerance, irritability, anxiety,
insomnia or other sleep problems, cognitive problems
and memory loss, poor concentration, difficulty with
problem-solving, noise and light sensitivity and
affective symptoms. In clinical practice, the symptoms
are often subjective, vague, and non-specific, making
the diagnosis of PCS difficult (Radhakrishnan et al.
2016). Despite emerging new understandings of the
pathophysiology of these injuries, there is relatively
little sound epidemiological data to predict risk factors
for PCS accurately. Numerous studies have documented
risk factors such as age (children and elderly being more
susceptible than adults), female sex, injury-related
litigation, pre-existing stress and premorbid psychiatric
or cognitive conditions (such as learning disabilities)
(Radhakrishnan et al. 2016, Bernard et al. 2016).
Additionally, several genetic polymorphisms involving
brain-derived neurotrophic factor (BDNF) and the
interleukins (IL) have been shown to have a potential
effect on the severity of an axonal injury, inflammation,
blood-brain barrier disruption, neuronal survival, rege-
neration, and plasticity. One of the most documented
allelic variations present in individuals who experience
poor recovery post-TBI is the E4 allele. The apoli-
poprotein E4 allele is the most neurotoxic isoform due
to an induction of neuropathology via proteolytic clea-
vage and reduced growth and branching of neurites
(Davidson et al. 2015). It has long been known that the
production of cytokines is increased in the brain
following contusions, with an expression of IL-6, IL-1b,
and TNF-a by mononuclear cells and IL-1b by astro-
cytes (Rathbone et al. 2015). However, there has been
little reported on the role of systemic infections such as
Lyme disease that present with a similar profile of
symptoms. A relatively inexpensive and widely used
blood test to assess the prevalence of Lyme disease in
PCS would dictate the need for appropriate antimicro-
bial treatment to cure the infection. It is likely that this
intervention, could also alleviate symptoms such as
cognitive disturbances, dizziness, and fatigue. Given the
cost of interventions for PCS, the diagnosis and treat-
ment of co-morbid infections could prove to have a
significant impact on the standard of care of PCS. We
have identified that specific Lyme blood markers are
statistically significant predictors of PCS in our patient
population. We do not know if this correlation is speci-
fic to our clinical population of PCS patients or if there
is a general or global association. Numerous plausible
mechanisms may account for our findings correlating
PCS and LNB that warrant further investigation.
Furthermore, we believe that many of these individuals
suffering from PCS are compromised due to secondary
LNB. Despite numerous theories and much speculation,
our extensive review of the literature reveals that several
questions remain to be answered.
Is there a large subset of the population infected with
the B. Burgdorferi spirochetes that are mostly asymp-
tomatic or is their infection being misdiagnosed given
we know LD to be the "great imitator? It has been well
understood that despite inducing both innate and
adaptive immune responses, B. burgdoferi senso latu
species is one of the few extracellular pathogens that
can cause persistent asymptomatic infection in various
species, especially rodents (Tracy et al. 2017, Bernard et
al. 2018). This mechanism of pathogens surviving with
minimal effects on its host is referred to a reservoir host,
and its persistence can be in part due to a multitude of
factors that requires further study as to its relevance in
humans. Tracy and Bumgarth, (Tracy et al. 2017)
present a detailed overview of eight factors contributing
to persistence of Borrelia burgdorferi in rodent hosts,
some mechanisms of which have already been studied
in humans: Spirochete shape (Charon et al. 2002,
Moriarty et al. 2008) antigenic variation and changes in
gene expression (Rogovskyy et al. 2015, Grimm et al.
2004, Norris et al. 2014) plasminogen binding and
destruction of the extracellular matrix (Coleman et al.
1999) interference with the adaptive immune response,
(Elsner et al. 2015a, Hastey et al. 2012, Elsner et al.
2015b) host-pathogen co-evolution, tick salivary

Sergio Azzolino, Rashid Zaman, Ahmed Hankir & Frederick R Carrick: THE PREVALENCE OF LYME DISEASE
AND ASSOCIATED CO-INFECTIONS IN PEOPLE WITH A CHRONIC POST-CONCUSSIVE SYNDROME
Psychiatria Danubina, 2019; Vol. 31, Suppl. 3, pp 299-307
S305
protein-mediated immunosuppression (Kotal et al.
2015) adhesions allowing entrance into the vasculature
and tissue (Coburn et al. 2013, Brissette et al. 2014),
and interference with complement via CRASPs, and
BBK32 (Garcia et al. 2016, de Taeye et al. 2013,
Kraiczy et al. 2016, Pietikainen et al. 2010). Bernard,
Pal, et al. Recently reported a discovery of BBA57, a
spirochete surface protein of unknown function that
“orchestrates unique host immune evasion strategies
crucial for early spirochete infection in mammals, sup-
presses host complement-mediated killing and neutro-
phil-derived microbicidal responses, including induc-
tion of antimicrobial peptides, and promotes pathogen
dissemination by regulating type 1 interferon.” (Ber-
nard et al. 2018). Furthermore, earlier studies reported
positive serology in a population at risk, but clinical
disease occurred infrequently (Fahrer et al. 1991,
Zhioua et al. 1998).
Some theorize that the majority of Lyme disease
patients are cured relatively quickly; however, ap-
proximately 10% have prolonged somatic and neuro-
cognitive symptoms, such as fatigue, difficulty in
sleeping, arthralgia, myalgia, memory impairment, and
headache (Cairns 2005) termed Post Lyme disease
syndrome (PLDS) or post-treatment Lyme disease syn-
drome (PTLDS). A recent study conducted at Tulane
University revealed that spirochetes, that can evade the
immune response, were able to infect vital organs such
as the brain and heart, despite a traditional 28-day
course of Doxycycline (Embers et al. 2017). It was
also found that all subjects treated with antibiotics
were found to have some level of infection 7 -12
months post-treatment, and despite testing negative by
antibody tests for Lyme disease, two of 10 subjects
were still infected with Lyme bacteria in heart and
bladder (Embers et al. 2017). Fallon et al. observed
significantly reduced blood flow in certain white
matter areas of the brain, particularly in the posterior
temporal and parietal lobes bilaterally, in patients with
post-LB syndrome compared with healthy subjects,
flow reductions in white matter areas were signifi-
cantly associated with deficits in memory and visuo-
spatial organization. These studies do not explore
whether the patients that have such sequela have had a
history of TBI or PCS (Fallon et al. 2003, Fallon et al.
2009).
The anatomic and physiologic changes witnessed
following a TBI, such as hypoxia, alteration in glucose
metabolism, a significant increase in proinflammatory
cytokines IL-6, IL-1b, and TNF-a by mononuclear
cells and IL-1b by astrocytes to the blood-brain
barrier, maybe allow pre-existing autoreactive T-cells
to transmigrate into the central nervous system
(Pachter et al. 2003). We anticipate that future epide-
miological investigation can determine the likelihood
of patients developing PLDS/PTLDS or PCS secon-
dary to previous exposure of LD or TBI. Understan-
ding such might provide significant impact in under-
standing the pathophysiology of PCS and neuro-
degenerative conditions such as Chronic Traumatic
Encephalopathy (CTE). Hazeldine et al. provide a
comprehensive overview of the underlying mecha-
nisms of systemic immune suppression involving
neutrophils, monocytes, natural killer cells, and T
cells, following TBI (Hazeldine et al. 2015). These
mechanisms substantially increase the risk of infec-
tions. We opine that if a high number of subclinical
infections, asymptomatic, and/or misdiagnosed cases
exist, then compromise of the blood-brain barrier and
immunological suppression as a result of TBI might
explain our observations.
CONCLUSIONS
Our retrospective review of records of patients seen
in our facility suffering from mental health issues and
PCS over one year’s duration is significantly associated
with undiagnosed Lyme disease. We found that there
was statistical and substantive significance between
individuals with chronic PCS who had suffered a TBI
and having a positive Western Blot Igenex-IgM test. We
also found that males who had suffered a TBI and had
chronic PCS also had statistical and substantively
significant relationships with a positive Western Blot
Igenex-IgG. 37.68% of the sample of subjects that had
suffered a TBI and had longstanding PCS symptoms
had a positive Western Blot Igenex IgM. Males were
more likely to have a positive Western Blot Igenex IgM
(39.29%) than females (36.59%). This relationship
demands an adequately designed multi-site randomized
controlled study that might provide insights into the
relationship of undiagnosed Lyme disease complicating
recovery in PCS patients. We suggest that it may be
worthwhile to test for Lyme Disease in PCS patients,
with and without mental health issues even if they have
no history of a known Tick bite.
Limitations
This is a single site review of records that does not
allow generalization to the global population of PCS
patients. Furthermore, due to the lack of standardization
of Lyme disease laboratory testing, it is possible that
differing labs will yield varying results. As a records
review, the report does not have the benefit of a robustly
designed randomized controlled trial.
Acknowledgements:
Our deepest appreciation and thanks to the clinical
and support staff team at the Azzolino Clinic in San
Francisco, California.
Conflict of interest: None to declare.

Sergio Azzolino, Rashid Zaman, Ahmed Hankir & Frederick R Carrick: THE PREVALENCE OF LYME DISEASE
AND ASSOCIATED CO-INFECTIONS IN PEOPLE WITH A CHRONIC POST-CONCUSSIVE SYNDROME
Psychiatria Danubina, 2019; Vol. 31, Suppl. 3, pp 299-307
S306
Contribution of individual authors:
Sergio Azzolino conceived the idea for the study and
contributed to the literature review, statistical
analysis and revised the manuscript.
Rashid Zaman & Ahmed Hankir contributed to the
literature review and revised the manuscript.
Frederick Carrick collected and analysed the data and
contributed to the literature review and revised the
manuscript.
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Correspondence:
Sergio Azzolino, FACFN, DACNB
Department of Neurology, Carrick Institute
Cape Canaveral, FL, USA
E-mail: sergioazzolino@gmail.com