2002 RI TBDs Management Plan adopted by commercial interests instead of the stupid State of Rhode Island (LOO, fools)
Foley Hearts Chuck
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Subject: 2002 RI TBDs Management Plan - adopted by commercial
interests and not the State of Rhode Island (LOL, fools)
Date: Feb 29, 2008 8:05 AM
Some of this data I would not includer were I to re-write this. For
example I would
give psychiatry no validity whatsoever.
Nevertheless, you can see the entire report with all the graphics now
on my website.
http://www.actionlyme.org/RI_TBDS_2002.htm
================
RECOMMENDATIONS for RHODE ISLAND’S TBDs COMMISSION, APRIL 2002
A MANAGEMENT PLAN- by Kathleen M. Dickson
TBDs MANAGEMENT OBJECTIVES
1. A statewide physician education program is clearly necessary to
patient management.
2. Improved surveillance for known and new TBDs and the development
of a sentinel
TBDs identification database and DNA ident/sequencing
3. Immediate testing improvement measures via the discontinuation of
the use of
laboratores by RI hospitals and independent physicians, which fail to
report correctly,
or use even the current US recommended stains.
4. The development of a patient/pathology database to identify
cohorts of patients
who would be eligible for neuroprotective regimens such as MMP
inhibition, therapeutic
kynurenines, or whatever is on the horizon in new antibiotic trials,
and blood brain
barrier damage, physical, and cognitive rehabilitation after
resolution of infections,
when or if that becomes possible.
INTRODUCTION
Treatment Failed Before.
That treatment often “fails” in borreliosis is really an incorrect way
to frame
the problem of Chronic Lyme disease. Allen Steere discovered and
published that
persisting spirochetes are responsible for continued Lyme arthritis in
1985 and
1994 (1, 2). Low levels of spirochetal infection driving an
exaggerated immune
response that is not completely suppressed with antibiotics, is the
subject yet
to be understood well enough to be managed adequately.
Some people have more illness symptoms than others, after exposure to
Borrelia burgdorferi
(Bb). Chronic neurologic Lyme exists, or there would not be an outcry
for help with
difficulties with diagnosis and being treated for this chronic
illness. The overwhelming
evidence from of studies of all types of spirochetal infections in all
kinds of
animals (except lizards) is that in some mammals, the infection
persists despite
antibiotic treatment, not primarily due to acquired antibiotic
resistance. In swine
medicine, persistently infected animals are called carriers. Carriers
are culled
from the herd. Chronic Lyme patients tend to receive less severe
special treatment,
but they are deliberately made to become medical and social outcasts.
The state
of Rhode Island now seems to recognize the magnitude of the problem,
and the patients
are appreciative.
In the early years since the discovery of the Dr. Burgdorfer’s
borreliosis, all
participating researchers seemed to agree, based on the evidence, that
persisting
low levels of Bb spirochetes account for a relatively greater immune
response than
other types of infections, in some patients. This was in agreement
with data from
decades earlier on human spirochetal infections. In 1976, in “The
Biology of Parasitic
Spirochetes”, edited by Russell C. Johnson, it was mentioned that
future development
of more effective antimicrobials would address the problem of
relapsing borreliosis
and persisting syphilis. In that text, before the discovery by Dr.
Burgdorfer,
Jay Sanford, MD, of Uniformed Services University Medical School,
Bethesda, Maryland,
stated that:
“There are other aspects of the treatment of the relapsing fever,
syphilis, and
leptospirosis that illustrate similarities and from which therapeutic
principles
may be developed. The ability of borrelia, especially the tick-borne
strains, to
persist in the eye and brain during remission after treatment with
arsenic or with
penicillin or even after apparent cure is well known. The persistence
of treponemes
after treatment of syphilis is a major area which currently requires
additional
study [references].”
In the 1970 comprehensive study of louse-borne relapsing fever,
published by Bryceson
in Quarterly Journal of Medicine, treatment of the borreliosis did not
prevent relapse.
Patients remain infected. Some are symptomatic and some are not.
This was well-established
in the scientific literature before Polly Murray discovered the
syndrome that appeared
to be of infectious etiology, and appeared to be associated with an
arthritis in
Lyme, Connecticut.
Raymond Dattwyler of SUNY Stony Brook found that oral treatment failed
as often
as 50% of the time in patients. At that time, Dr. Dattwyler made the
suggestion
that an intravenous antibiotic with greater CNS penetration, such a
ceftriaxone,
would be necessary for this CNS infection. Ceftriaxone worked best,
but still some
patients did not recover completely or relapsed.
Treatment Failed Again.
It is important to point out the recent work of Mark Klempner, MD,
Tufts, who found
that treating patients with 30 days of ceftriaxone did not appear
alleviate symptoms
more in the drug-treated patients, than in the patients who received
placebo. That
study was seriously flawed. The FIQ was never validated for Lyme
disease. The
attempt at validation showed that Fibromyalgia and Lyme disease were
two different
disorders. Klempner’s “Results” must be given only marginal
consideration, but
within that margin remains the question, what might work better,
faster, to bring
patients greater symptom relief than the current standard of care,
which was used
in this trial?
Among the several important findings that Dr. Klempner did not report
in the July
12, 2001, NEJM- the other data he collected- does hold promise. Just
as there is
a genetic correlate with treatment-resistant Lyme arthritis, Dr.
Klempner found
a genetic correlate with Chronic Lyme disease of the seronegative
kind- the kind
without arthritis as the dominant feature: HLA-DQB1*0602.
Unfortunately, this information
was not published such that other researchers might pursue this
autoimmune correlate.
Roland Martin, of the NIH Multiple Sclerosis study group, had
previously spent many
years studying neuroborreliosis in Germany. There, he discovered
there might be
some T cell autoimmunity in neuroborreliosis patients. Now Dr. Martin
studies T
cell autoimmunity in MS in the US. Dr. Klempner referenced Roland
Martin’s autoimmune-neuroborreliosis
work in: Is it thee or me? --autoimmunity in Lyme disease, (Nat Med.
1999 Dec;5(12):1346-7)
in which he mentions possible cross reactivity of OspA with myelin, as
well as two
other potential cross reactive antigens from borrelia with nerve
cells. That there
were several hundred neurological adverse events associated with rOspA
vaccine appears
to give some credibility to this process. (See www.lyme.org, The Lyme
Disease Foundation).
Although autoimmunity through molecular mimicry is difficult to prove
in vivo, the
two primary haplotypes associated with MS are HLA-DQB1*0602 and HLA-
DRB1*1501.
Roland Martin’s Lyme neuroborreliosis patient from which he extracted
potentially
autoreactive T cells to human nerve tissue had *1501. Klempner seems
to have identified
the other haplotype in Lyme borreliosis patients, who had been
physician-diagnosed
EM- exposure to Borrelia burgdorferi, but who were seronegative
according to the
CDC’s standard (personal communication with Dr. Klempner). That is,
some may have
had some specific bands on a Western Blot, but not 5 of 10.
Klempner’s retreatment study resulted in failure to demonstrate
adequacy of 30 days
of ceftriaxone, which is the standard of care for late Lyme.
Doxycycline for Lyme
disease that has invaded the central nervous system was not
validated. The study
of the comparative efficacy of ceftriaxone and doxycycline was
specifically for
non-CNS Lyme disease (3). Klempner studied the cognitive aspects of
borreliosis
and found neuropsychiatric deficits, referencing Weinstein’s work. So
that there
was a neuropsychiatric component to Chronic Lyme patients’ problems,
means Klempner
should have known doxycycline was not appropriate for this trial. It
would have
better served the public if Klempner reported the positive
pathological findings
in these patients, since this was not a long term treatment study, but
only a trial
of the efficacy of the current standard of care. We might not
consider it a complete
waste of 4.7 million dollars if we could see the real data.
Scientific Integrity and Medical Ethics Failed.
The current standard of care “fails” often, and is the reason why
there is resistance
by insurance companies to pay for continued care. The
reinterpretation of Klempner’s
“results” to the lay media was left to individuals who are often paid
by insurance
companies to perform independent evaluations in which a judgment is
made regarding
the diagnosis as well as the treatment, based on records, and not the
presence of
the patient in what the CDC calls a clinical diagnosis. Some of these
individuals
are hired as expert witnesses for insurance companies who wish to deny
payment for
Lyme disease treatment claims in court cases. This latest round of
reinterpretation
for lay-media consumption echoed previous insurance company-supported
interpretations
of the dynamic of chronic Lyme:
Lyme patients are not sick, it is the anxiety over the possibility of
having Lyme
disease that brings people into a medical office.
It’s not Lyme, it’s your divorce.
Antibiotics are poison.
Women and girls should not be given the diagnosis of Lyme disease
because of their
unnecessary use of healthcare resources.
Perpetuating the notion that there is a chronic Lyme disease incurs
the consideration
of Munchausens’ or Munchausens by Proxy.
I call it Lyme paranoia.
Klempner allegedly found no evidence of Bb DNA in the cerebrospinal
fluid of patients
that he screened out and claimed ineligible for his study of treatment
efficacy
initially. There was at least one patient, who was rejected by
Klempner for eligibility,
due to the presence of Bb DNA in her CSF. Therefore, we have reason
to believe
there may have been others. Low, or no Bb DNA in the CSF of
neuroborreliosis patients
is a common finding, and according to Jorge Benach of Stony Brook, may
be because
the spirochetes are binding to glial cells rather than are free-
floating in fluid
(the flagellum is on the inside, not the outside). Klempner then
resampled the
129 DNA-negative patients, for a total of 740 samples. The alleged
reason he re-performed
this analysis was to look for spirochetal fragments, perhaps released
via the Jarisch-Herxheimer
reaction, but this was not mentioned in the July 12, 2001 NEJM.
Instead, this information
was presented as if it were an assessment of the degree of the
negative finding.
More important than this negative finding, which was to be expected
since this was
fluid and not tissue, is what he did find and reported previously,
matrix-metalloproteinases
(MMPs) in the cerebrospinal fluid. MMPs are recognized as a
neurodegenerative process
marker in other neurodegenerative diseases. We know little else about
what Klempner
found with the 4.7 million dollar grant, because not too much,
apparently, was reported.
What we do know regarding other signs of illness process in
borreliosis patients
was later discussed by Dr. Klempner, verbally, in medical conferences.
Previously, Klempner found that Bb cultured with human foreskin
fibroblasts, resulted
in either intracellular compartmentalization (and/or embedding in
fibroblast outer
membrane) protection of the spirochetes and their subsequent survival
after exposure
to ceftriaxone for 14 days. This is consistent with what has known
about spirochetal
infections of all kinds in all mammals, for decades. An additional
mechanism of
spirochetal survival against adverse conditions, the spheroplast, is a
well-documented
survival mechanism used by free-living spirochetes, as well. In vitro
reports of
efficacies of antimicrobials based on the formation of the Bb
spheroplast as the
“end stage” are therefore invalid.
There is reason to believe there is a genetic tendency to be more
immune-reactive
to Borrelia burgdorferi infection of the CNS, just as there is
proposed in treatment-resistant
Lyme arthritis. Klempner allegedly found it. He did not report it.
There are many other markers of pathological processes that can be
identified in
significant populations of Lyme borreliosis patients. Yet, the
discovery of these
has not led to the development of any formal treatment modality to
address them.
MS is a chronic illness for which the symptoms/effects are treated
without knowing
the cause, as is Lupus and ALS. “Symptoms” is fairly synonymous with
pathophysiological
process signs. It is generally accepted that persons with these other
chronic illnesses,
with their chronic process signs, are not “treated” once, and then
told to please
be on their way to a psychiatrist to address their abnormal emotional
need to have
an illness. They are treated for their illness.
Lyme is the one (political) illness in which there has been no formal
acknowledgement
of these collective chronic process signs in response to low levels of
persisting
spirochetes, much less, in a comprehensive way. There has only been
controversy
over antibiotic “failure”. Throughout this collection are
interspersed examples
of how Lyme disease has been spun, so that the reader will have a
clearer picture
of what patients and Lyme-literate physicians are up against,
politically and socially.
As was seen in the first public hearing in Rhode Island April 8 this
year, this
makes a terrible illness far worse.
Where do we place the fulcrum now, to effect success?
THE SCIENTIFIC METHOD
1. Observation and description of a phenomenon or group of phenomena.
2. Formulation of an hypothesis to explain the phenomena. In physics,
the hypothesis
often takes the form of a causal mechanism or a mathematical
relation.
3. Use of the hypothesis to predict the existence of other phenomena,
or to predict
quantitatively the results of new observations.
4. Performance of experimental tests of the predictions by several
independent experimenters
and properly performed experiments.
The Scientific Method is the reverse of Evidence-Based Medicine.
Evidence-Based
Medicine is where experiments are designed to effect the intended
limited treatment
outcome. The prototype for this Reversed Scientific Method in
practice would be
the Klempner 4.7 million dollar CLD “long term” treatment trial.
Back to basics: What does the data tell us?
One possible consideration for the Rhode Island Legislature is to
simply address
that Chronic Lyme disease is just that: a chronic illness. That then
opens the
door to new treatments, perhaps symptom-based, that are not
antimicrobials, in addition
to antimicrobials. At present, antibiotics are the primary treatment
of Chronic
Lyme, because of political impediments to advancing discovery of
markers of illness
processes and addressing them. If Steere found a genetic link to
treatment-resistant
Lyme arthritis, and Klempner found a genetic link to seronegative
Chronic Neurologic
Lyme, then there is a genetic link to treatment- resistant something,
and it is
not true that Chronic Lyme is a non-entity. Treatment-resistant Lyme
arthritis
is not called “Post-Lyme Arthritis Syndrome”.
The definition of Lyme disease was falsely narrowed to force an
acceptable vaccine
outcome. The vaccine was not recommended for persons with active Lyme
arthritis.
We’ve all now seen how a false standard failed in practice, with a
commercial product:
LymeRIX was pulled off the market due to adverse events in at-risk
populations.
It isn’t possible to completely summarize and index what are the
pathophysiological
signs in burgdorferi borreliosis, with and without coinfections.
These are, formally,
“Emerging Infections”. From one region to another, from one habitat
to another,
it will never be possible to categorize, with any certainty, which
infections should
be tested for upon tick bite. However, starting points in patient
management would
be to 1) point out the problems associated with the present standard
of serodiagnosis,
and 2) summarize some of the analyses that have been performed in the
past, in markers
of pathology, associated with borreliosis. Establishment of protocols
for identifying
associated pathological features, regardless of the probability of
ever identifying
all tick borne infections in any one patient, may at least yield the
identification
of subsets of patients who have signs of pathology which suggest
potential improvement
with a pharmacotherapeutic modality other than antibiotics.
A management plan would be based in making changes to the management
of these infections
and the management of the physiological changes objectively associated
with subjective
symptoms, thereby improving patients’ potential for the greatest
degree of recovery
from symptoms. All observations re-reported here, although
incomplete, are intended
to increase that potential.
-----------
USE OF SERODIAGNOSIS TOOLS & DETERMINING INFECTION PREVALENCE
It is probable that RI has the highest US infection rate of
borreliosis, although
the CDC case reported numbers don’t reflect this. The reasons for
this are that:
1) some areas of RI may have the highest tick density in the world,
according to
Tom Mather at the “Diseases of Summer Conference” at South County
Hospital, RI,
2000, and
2) at least in South County, the primary diagnostic lab, Imugen,
Norwood, MA., uses
none of the CDC’s Dearborn Conference recommended strains of Borrelia
burgdorferi,
and Imugen’s accuracy performance against this CDC criteria was the
lowest reported
performance at the Conference of all the labs that participated, 14%
accurate (4).
3) CDC criteria in practice, finds Lyme disease 14-22% of the time.
In addition,
the disease is at least 10 times underreported (5) due to physicians
neglecting
to make the effort to fill out the report forms. Using Imugen testing
method and
materials puts the identification of potential cases below what it
should be, given
the reluctance of physicians to report 5 of 10 bands to the CDC.
WESTERN BLOT
Reporting forms and use of standard strains from all laboratories
performing serodiagnosis
of Lyme disease in the State of Rhode Island should be reviewed and
approved by
this Commission before being recommended by the State as a competent
evaluating
laboratory, effective immediately.
Laboratories with Western Blot reporting forms which state that “< 5
bands is
Normal” must remove this statement from their report forms
immediately. “Less than
5 bands” is not “normal”. This adds to the diagnostic confusion that
has resulted
in the extensive misdiagnosis of borreliosis patients in RI.
Laboratories that report that 5 IgG CDC Dressler/Steere bands means
past infection
and is not a treatable case must also remove this statement from their
forms. Patients
who present with characteristic symptoms of Lyme disease, the criteria
for diagnosis
as stated by the CDC, would not be having their blood tested if they
and their physician
did not feel there may be a serologically discoverable illness which
required treatment.
EXHIBIT: Imugen Report Form
The 5 of 10 band IgG Dressler/Steere CDC case reporting criteria was
based on a
calculation (6) and does not represent the empirical observation of
what occurs
in a typical infection in non-arthritis prone individuals (65-70% of
the population).
The outer lanes on the neuroborreliosis blots are standards. Graphics
from:
http://alpha1.mpk.med.uni-muenchen.de/bak/nrz-borrelia/miq-lyme/Frame-MiQ-microbiological53.html
MiQ Lyme Borreliose, 12 2000, 5. Microbiological diagnosis
Dressler/Steere CDC IgG criteria more closely approximates the
antibody concentration
found in the arthritis-prone individuals, or those with the HLA-DR4
and DR2 haplotypes
associated with Lyme arthritis and antibodies to OspA and OspB, as
reported by Allen
Steere (7).
The antibody concentration response difference between an arthritis-
prone individual
and a neuroborreliosis-prone individual could be as high as 4-5 times
(8). Where
labs report “< 5 bands is Normal”, patients are being misdiagnosed,
which is
a medical negligence liability.
At the CDC’s Dearborn Serodiagnosis Conference, October 1994, some
labs qualified
the Dressler/Steere IgG criteria in the field and only found
borreliosis patients
responding with 5 of the Dressler/Steere antigens 14 to 22% of the
time (4,9).
The CDC’s case reporting criteria is known to be only 30% accurate, by
CDC’s own
admission (10). This happens to match the prevalence of HLA-DR4, or
the haplotype
associated with the high antibody expression in resistant Lyme
arthritis- 30- 35%.
IgG and IgM
Approximately 30 antigens of Borrelia burgdorferi can be detected via
antibody determination;
not all are specific to Bb, but in the presence of other Bb specific
antigens, some
of these markers may be associated with a resultant neuroautoimmune
disorder, such
as the heat shock proteins, glycolipids, and phospholipids. That is,
more than
just outer surface lipoproteins, flagellin, and the few antigens of
unknown function,
such as P30, identified with Dearborn IgG criteria, are immunogenic.
Other diagnostic
markers in pathological response must be considered for diagnosis and
addressed
in patients because of suspected cross-reactivity.
With rOspA vaccine now off the market, of course, OspA (31 kD) and
OspB (34 kD)
can be put back into the serodiagnostic criteria and there will be no
use for an
OspA-less strain used in Western Blotting, such as what Imugen has
been using for
the past two years.
Before using an OspA-less strain, Imugen was diagnosing antibodies to
US Bb strain
G39/40, and a strain from Germany. At the Dearborn Conference, the
CDC’s Barbara
Johnson recommended not using G39/40, because of insufficient antigen
expression.
Oddly, this was the strain, from which Dressler/Steere, the CDC’s
current reference
for IgG positive antibody criteria, was derived.
In addition to using a non-recommended strain, Imugen was using strain
FRG (Federal
Republic of Germany) to test US patients until they dropped it for the
OspA-less
strain. It would seem prudent to that US patients be tested with
local US strains,
due to strain variation and antigenic variation from environmental
pressures (host
species range and selection). A non-systematic review of RI patients’
blot reports
from Imugen showed that in every patient (except one who was known to
have been
infected in Germany), there are fewer positive bands generated from
the German strain
than the G39/40. Low passage 2591 is best, due to its higher
expression of OspC
than B31, or 297, the other two of the three Dearborn recommended
strains. OspC
is associated with neurotropism (11, 12, 13) and is thought to be the
dominant antigen
in a mammalian host (37C), switching from OspA dominance in the tick,
with exposure
to warm blood. Neuroborreliosis is the more disabling, and the more
common treatment-resistant
Lyme illness, therefore using a low OspC-expressing strain would not
be helpful.
OspA and OspB are encoded on same plasmid. Multiple in vitro
cultures, or high-passage
without exposure to a mammalian host, results in plasmid loss; loss of
plasmid encoded
infectivity and virulence. Strains that have dropped plasmids are not
only, therefore,
not rare, but demonstrating low in vitro passage is still a
requirement for laboratory
performance criteria. The strain neurovirulent strain N40 was
developed by passing
back and forth between mouse brains and in vitro. It wouldn’t be hard
to imagine
developing a strain with mouse joint affinity (G39/40?).
Two other specific antigens may be added to the Dressler/Steere 10, in
addition
to OspA and Osp B: P37 (4, 14) and 35kD, a portion of which went into
the “C6 ELISA”
(15).
It was well known before the 1980s that the borreliae behave
immunologically like
the trypanosomes, and this was noted by Allen Steere in 1986 (16,
17). This is
the reason to expand the Western Blot IgM and IgG reporting, and why
the LymeRIX
vaccine was not qualified properly. Dressler/Steere IgG, the criteria
for CDC case
reporting and qualifying the vaccine, is characteristic of the 30-35%
of the population
who are Lyme arthritis-presenters- the HLA-DR4 types.
Why these arthritis patients continue to present with the same antigen-
stimulated
antibodies is unknown, although genotype-associated binding affinities
of HLA antigen-presenting
molecules and antigen have also been associated in a negative way.
Patients with
HLA-DQ1*0602 tend not to have Type I diabetes. One theory is that
whatever is the
antigen from a possible viral infection that initiates autoimmune
diabetes, simply
flops out of this *0602 presenting molecule and doesn’t continue to
stimulate.
Donald Wiley (Harvard- now deceased) attempted to show how myelin
could “fit” into
the typical class II antigen-presenting molecules of MS patients.
Some believe a chronic infection in a knee joint is due to persisting
organisms,
which is what Allen Steere discovered by repeated DNA sampling of the
synovium in
chronic Lyme arthritis patients in 1994. Bb DNA was found in the
synovium for up
to 7 years, the time limit of the study, in one patient. The CDC’s
IgM criteria
were of Engstrom. These included OspC, 41, or 39. SmithKline Beecham
also agreed
this continued infection might be the possible reason for treatment-
unresponsive
Lyme arthritis, rather than being autoimmune driven, during the
January 31, 2001
FDA vaccine meeting. This is worth mentioning, because one may then
imply from
Steere’s work and the vaccine manufacturer’s, that Bb persists in
neuroborreliosis.
Expanding or changing IgM antibodies implies persisting infection and
always did,
since the Burgdorfer spirochete has similarities in pathogenesis to
trypanosomes
and relapsing fever borreliae. Steere reported recently that the
continued presence
of IgM over time was not associated with a disease state, which is
consistent with
the concept of asymptomatic infection. The presence of IgM in
asymptomatic infection
does not make the presence of IgM antibodies long after the illness,
not a marker
of illness (17). Prior to that, Steere perceived the persistence of
IgM implied
the persistence of the infection (18). The criteria of Engstrom for
IgM are inadequate
for diagnosis at any stage of the illness. Any single specific band,
in the presence
of symptoms, is as diagnostic as its assigned specificity.
Not everyone who is infected is symptomatic. Steere found in 1986
that the ratio
of infected asymptomatics to infected symptomatics was 1:1 (19). The
problem associated
with that came to the surface during the vaccine trial, when the
vaccine was “effective
at preventing asymptomatic infection.” Many people have this observed
this differently-
the vaccine seemed to be finding the asymptomatic previously exposed
patients, and
making them symptomatic. There were 11% more “Unconfirmed Lyme” in
the vaccine
group, than the placebo group the first year of the trial. Once the
vaccine was
on the market, it appeared that mostly patients who had known they
Lyme disease
before, and had improved, were becoming ill again after receiving the
vaccine.
The second year of the trial, the numbers were equal. Again, only the
HLA-DR4 presenters
had a 72% chance of being CDC seropositive in IgG (6).
In empirical exercise, in the field, excluding what Imugen found
(14%), CDC IgG
criteria of Dressler/Steere was accurate 22% of the time. The vaccine
was 78% effective.
Clearly, those data balance out nicely. If CDC came up with a
standard that was
only 10% accurate for a random sampling of all human HLA Class II
genotypes, perhaps
the vaccine would have been marketed as 90% effective. There would
probably also
have been an even greater shift in the increase of “Unconfirmed
Lyme” (less than
5 bands) in the vaccine group over the placebo group, than the 11%
demonstrated,
and reported, in the LymeRIX trial results.
For every infected symptomatic patient, another remains infected but
asymptomatic.
Whether asymptomatic cases should be treated, is controversial, and
likely to not
be entertained by this Commission, given the magnitude of numbers of
patients who
are currently very ill and not being treated in any way. However,
whether this
represents a risk for reactivation due to life stresses such as
surgery, accident,
or vaccination, should remain a consideration and patients and
physicians should
be thus advised.
Continued careful review of data on immune dysregulation caused by the
burgdorferi
lipoproteins, especially as concerns intentions for another Osp-based
vaccine trial
will be necessary. Another vaccine trial should not go forward until
the CDC’s
serodiagnostic standard reflects acceptable accuracy of >95% across
all human
Class II genotypes represented in the US.
Therefore:
IgM or IgG should be one of more of at least 14. The percent
specificities of these
bands average in the 90s. The 41kD flagellar antigen is non-specific,
but more
specific in the absence of periodontal disease or syphilis.
18 kDa, 21 kDa (OspC) *, 28 kDa, 30 kDa, 31kDa (OspA), 34kDa
(OspB), 35 kDa,
37kDa, 39 kDa (BmpA), 41 kDa (Fla), 45 kDa, 58 kDa (not GroEL),
66 kDa, and
93 kDa.
In addition to these:
55kD:
Feng S, Barthold SW, Telford SR 3rd, Fikrig E., P55, an immunogenic
but nonprotective
55-kilodalton Borrelia burgdorferi protein in murine Lyme disease.,
Infect Immun.
1996 Jan;64(1):363-5. PMID: 8557366
Feng S, Das S, Lam T, Flavell RA, Fikrig E., A 55-kilodalton antigen
encoded by
a gene on a Borrelia burgdorferi 49-kilobase plasmid is recognized by
antibodies
in sera from patients with Lyme disease. Infect Immun. 1995 Sep;63(9):
3459-66. PMID:
7642278
3-5kD Glycolipid
Oschmann P, Wellensiek HJ, Zhong W, Dorndorf W, Pflughaupt KW.
Relationship between the Borrelia burgdorferi specific immune response
and different
stages and syndromes in neuroborreliosis. Infection. 1997 Sep-Oct;
25(5):292-7.
PMID: 9334864
“Antibodies against certain proteins and the glycolipid of B.
burgdorferi seem to
have a prognostic value as to the development of more severe disease
or transition
to stage III.”
Honarvar N, Schaible UE, Galanos C, Wallich R, Simon MM., A 14,000 MW
lipoprotein
and a glycolipid-like structure of Borrelia burgdorferi induce
proliferation and
immunoglobulin production in mouse B cells at high frequencies.,
Immunology. 1994
Jul;82(3):389-96., PMID: 7959873
Eiffert H, Lotter H, Jarecki-Khan K, Thomssen R., Identification of an
immunoreactive
non-proteinaleous component in Borrelia burgdorferi., Med Microbiol
Immunol (Berl).
1991;180(5):229-37. PMID: 1722277
14kD:
Honarvar N, Schaible UE, Galanos C, Wallich R, Simon MM., A 14,000 MW
lipoprotein
and a glycolipid-like structure of Borrelia burgdorferi induce
proliferation and
immunoglobulin production in mouse B cells at high frequencies.,
Immunology. 1994
Jul;82(3):389-96., PMID: 7959873
OspE is ~19kD
OspF is ~29kD
OspD is ~28kD, Fikrig, Yale University.
These are all surface exposed lipoproteins associated with virulence,
but because
of their proximity to other antigens in migration through a Western
Blot, they cannot
be detected and are less useful. It was necessary to have a vaccine
trial, therefore,
progress in serodiagnosis stagnated. Not all borrelial spirochete
strains and species
will have exact analogs to these molecules and therefore local (RI)
strain sonicates
must accompany CDC strains in blot preparation. Better tests than the
Western Blot
are 2 dimensional blots and antigen-antibody decomplexing before
assay. However,
the gel-based electrophoresis-transfer method could stand development
to increase
sensitivity and separation, using perhaps capillary electrophoresis
(CE).
CE methods and instrumentation are capable of assaying immune
complexes.
There are yet many other antigens, some of which are not lipoproteins
(10-, 13-,
33-, 57-, 94- kD etc).
To look at the problems with serodiagnosis another way, according to
Alan Barbour
in:
Antigenic Variation in Vector-Borne Pathogens, Emerging Infections, a
CDC pub, Vol
6, No. 5
Alan G. Barbour* and Blanca I. Restrepo, *University of California
Irvine, Irvine,
California; and †Corporación para Investigaciones Biológicas,
Medellín, Colombia
“Several pathogens of humans and domestic animals depend on
hematophagous arthropods
to transmit them from one vertebrate reservoir host to another and
maintain them
in an environment. These pathogens use antigenic variation to prolong
their circulation
in the blood and thus increase the likelihood of transmission. By
convergent evolution,
bacterial and protozoal vector-borne pathogens have acquired similar
genetic mechanisms
for successful antigenic variation. Borrelia
spp. and Anaplasma marginale (among bacteria) and African
trypanosomes, Plasmodium
falciparum, and Babesia bovis (among parasites) are examples of
pathogens using
these mechanisms. Antigenic variation poses a challenge in the
development of vaccines
against vector-borne pathogens.”
It therefore also poses a challenge in serodiagnosis. At least an
attempt to find
local strains to test local patients using better separation methods
with greater
sensitivity is clearly the direction to start in, to identify Lyme
patients so that
they can be treated appropriately. It most certainly doesn’t help to
be testing
RI patients with a strain from West Germany, as Imugen did for several
years (personal
communication with Victor Berardi, Imugen). That the CDC remained
stagnant on this
issue was because they sponsored the serodiagnostic criteria for the
vaccine manufacturers.
The CDC therefore had to continue to support their criteria. With the
vaccine off
the market, CDC no longer has to support the Dressler/Steere and
Engstrom criteria.
Coinfection with at least an Erhlichia results in a diminution of
antibody response.
Ticks in CT are infected with an Erhlichia 50% of the time
(Magnarelli, NIH Rare
Diseases Conference, 1996). Coinfections can be the reason for
seronegativity and
the reason patients should be routinely tested for coinfections when
Lyme is suspected.
Local strains must be employed for testing local patients.
Identifying local strains
for serodiagnosis in RI is a project for which the State should
request NIH funding.
The goal for a RI Public Health TBDs management program is to identify
Bb infected
patients and not to narrow disease definitions to qualify patented
biological methods
and materials, such as what occurred with the Wampole PreVue ELISA,
the C6 ELISA,
or the LymeRIX vaccine.
ELISAs
A screening test, such as a Lyme ELISA, is completely unacceptable to
identify human
cases of Lyme borreliosis, at the recommended concentrations of test
kit antigens
(20) and serum dilution.
Patients who are Western Blot positive are often ELISA negative (21).
All false
positives ever claimed to occur in Lyme borreliosis, have been
identified via ELISA.
False positive ELISAs allegedly occur in Rheumatoid arthritis, Lupus
and syphilis
(22). It is impossible to have a false positive with a Western Blot,
since a specific
band is a specific band, and specificity assignments are high with the
CDC’s chosen
antigens for US patients. That a person may have a negative ELISA and
still have
many Bb specific bands via Western Blot, demonstrates how much less
sensitive the
ELISA is, than is claimed. It is claimed to be more sensitive than a
Western Blot,
but less accurate. It is less sensitive than a blot and therefore is
the exact
opposite of a screening test.
The newest ELISA, yet to be on the market, will include several
partial-recombinant
OspCs, and similar specific antigens, so it will be more specific than
flagellin-based
ELISAs (20). The concept of this new ELISA is acceptable, but if this
test is used,
it seems that a trial of doubling the sample concentration may make up
for current
lack of sensitivity. Hopefully someone will have the funding to
compare this new
ELISA, with adequate dilution, to a Western Blot from a low passage
2591 strain.
In lieu of the possible qualification of this new ELISA, as described
above, the
ELISA should be dropped altogether as a screening test. Screening
tests are acceptable
for livestock, not people.
LYME-LIKE ILLNESS
Not all Bb antigens are detectable by Western Blot, and borreliae
other than burgdorferi
are in the continental United States and cause a Lyme-like illness.
B. lonestari
is transmitted via the Lone Star tick and Master’s disease is a Lyme-
like illness
transferred by the Lone Star tick. There is fair diversity of
borreliae in the
US that is non-sensu stricto. It hasn’t been ruled out that they
cause an illness
similar to relapsing fever or Lyme borreliosis, and neither has there
been any attempt
by the CDC to change serodiagnostics to reflect these new
discoveries. Of 60 or
more Bb sensu lato strains and several newly discovered species of
borreliae found
in Lyme endemic areas, “Lyme disease” so far, can only be detected by
a few of the
antigens from 3 strains of Bb sensu stricto (23). If persons are
infected by non-sensu
stricto strains, or non-burgdorferi species, the CDC currently has no
design to
recognize them.
The following abstract pertains to RI, as well as NY and CT:
Glen A. Scoles; Michele Papero; Lorenza Beati; Durland Fish
Source: Vector Borne and Zoonotic Diseases Volume: 1 Number: 1
Page: 21 --
34
DOI: 10.1089/153036601750137624 Publisher: Mary Ann Liebert, Inc.
“Abstract: A species of Borrelia spirochetes previously unknown from
North America
has been found to be transmitted by Ixodes scapularis ticks. Infected
ticks are
positive for Borrelia spp. by DFA test but negative for Borrelia
burgdorferi by
polymerase chain reaction (PCR) using species-specific primers for 16S
rDNA, outer
surface protein A, outer surface protein C, and flagellin genes. A
1,347-bp portion
of 16S rDNA was amplified from a pool of infected nymphs, sequenced,
and compared
with the homologous fragment from 26 other species of Borrelia. The
analysis showed
4.6% pairwise difference from B. burgdorferi, with the closest
relative being Borrelia
miyamotoi (99.3% similarity) reported from Ixodes persulcatus in
Japan. Phylogenetic
analysis showed the unknown Borrelia to cluster with relapsing fever
group spirochetes
rather than with Lyme disease spirochetes. A 764-bp fragment of the
flagellin gene
was also compared with the homologous fragment from 24 other Borrelia
species. The
flagellin sequence of B. burgdorferi was 19.5% different from the
unknown Borrelia
and showed 98.6% similarity with B. miyamotoi. A pair of PCR primers
specifically
designed to amplify a 219-bp fragment of the flagellin gene from this
spirochete
was used to survey field-collected I. scapularis nymphs from five
northeastern states
(Connecticut, Rhode Island, New York, New Jersey, and Maryland).
Positive results
were obtained in 1.9-2.5% of 712 nymphs sampled from four states but
in none of
162 ticks collected from Maryland. Transovarial transmission was
demonstrated by
PCR of larval progeny from infected females with filial infection
rates ranging
from 6% to 73%. Transstadial passage occurred from larvae through
adults. Vertebrate
infection was demonstrated by feeding infected nymphs on Peromyscus
leucopus mice
and recovering the organism from uninfected xenodiagnostic larvae fed
7-21 days
later. Considering the frequency of contact between I. scapularis and
humans, further
work is needed to determine the potential public health significance
of yet another
zoonotic agent transmitted by this tick species.”
As mentioned in the previous section, some coinfections inhibit
antibody response.
Pachner AR, et al, Detection of active infection in nonhuman primates
with Lyme
neuroborreliosis: comparison of PCR, culture, and a bioassay. J. Clin
Microbiol.
1998 Nov;36(11):3243-7. PMID: 9774573:
“The presence of specific anti-B. burgdorferi antibody in the CSF is
the most widely
used assay for Lyme neuroborreliosis. In the immunocompetent NHPs in
our study it
was a very successful assay for detection of CNS invasion. However, it
is frequently
false negative, especially early in the course of the infection or if
there is transient
immunosuppression. Transient suppression of the anti-B. burgdorferi
immune response
in humans could occur in instances of coinfection, i.e., simultaneous
transmission
via the tick of pathogen other than B. burgdorferi. Coinfection of
ixodid ticks
has been demonstrated for a number of pathogens, including the agent
of human granulocytic
ehrlichiosis (16), babesiosis (25), and tick-borne encephalitis virus,
as well as
for a newly described virus (23) and bacterium (22). In a recent study
from an endemic
area of New Jersey, 18% of infected ticks were infected with more than
one readily
identifiable pathogen (25); this number is likely an underestimate,
since many tick-borne
agents have not yet been identified. Infections, even subclinical
ones, with a variety
of pathogens have been demonstrated to suppress the expected host
immune response
(2). Thus, mild immunosuppression as accomplished in this study was
designed to
mimic conditions in the human host which allow B. burgdorferi in the
natural state
to gain a firm foothold in the CNS in the 10 to 15% of B. burgdorferi-
infected patients
who develop clinically symptomatic nervous system disease.”
22. Schwarzova, K., and I. Ciznar. 1996. Spirochetal non-Borrelia
microorganisms
isolated from Ixodes ricinus. Folia Microbiol. 41:175-180.
The bioassay used in the study above was the mouse infectivity test,
such as is
used in syphilis. This is a better method than PCR, since PCR can be
limited by
inadequate primers.
There appears to be intent to use what is left over of rOspA (LymeRIX)
to sterilize
ticks with Bb ss OspA-bearing spirochetes in their gut, via adding
rOspA to some
kind of wild mouse food. We don’t know what effect this might have on
shifting
the spirochete populations away from those expressing antigen with
which we are
are familiar. Getting rid of ticks is more important that getting rid
of Bb ss,
because of the known and unknown coinfections.
----------
SURVEILLANCE, LONG TERM GOALS
IMPROVE METHODS OF DETECTION OF ILLNESS
IMPROVE SURVEILLANCE FOR ALL TBDs
Any new strains and species of Borreliae identified in RI and the
three CDC recommended
strains of Bb ss, together should be used in Western Blotting in Rhode
Island’s
own university and hospital labs, as is done in Europe.
WB is not a complicated procedure and should be performed in all
hospital labs until
faster, more sensitive antigen/antibody assay, instrumentation and
methods, are
developed and put into widespread use.
The health management goal is to be able to identify a borreliosis
patient while
still in the early, acute, flu-like infection stage, and before
borreliae are distributed
to the nervous system (“Quantitative immunohistochemical analysis
demonstrated infection
of spirochetes in kidney interstitium and brain as soon as 2 days
postinoculation”-
Bergstrom, et al, Infect Immun 2001 Sep;69(9):5832-9). This means we
should target
diagnosis turnaround-time of less than 12 hours, i.e., same-day
testing and results.
The technology is available, but one cannot put that level of
technological sensitivity
into a test kit, such as an ELISA test kit. There has been commercial
pressure
to keep testing poor, sloppy, slow, and therefore undeniably harmful
to TBDs patients.
It is claimed that antibody response is low in early Bb-infected
patients, but that
hasn’t been proven to only be a function the host’s response. It may
be a function
of method sensitivity or that antibodies require decomplexing before
assay.
Funding will be necessary to accommodate local vector/host low passage
antigen facility.
Since RI is a sentinel state, and as the Massachusetts islands are
sentinel islands
for CDC’s TBDs surveillance, it is imperative that RI institute
measures to identify
new TBDs. Coastal islands and states are monitored in the US and
Europe, because
many TBDs make their way into new habitats via sea birds (24).
Several objective scientific methods and evidence for pathology, in
addition to
specific markers of infection with borrelia in borreliosis patients
have been developed
and discovered. These analyses should be routinely employed in
diagnosis and differential
diagnosis in patients who are both seronegative and seropositive by
the RI local
(sl and ss; all) and CDC’s Bb (ss) antibody criteria. Better
separation methods
besides gel electrophoresis with solid polymer blot substrate, might
accommodate
these.
ERHLICHIOSIS- An example of the current state of the art, just with
monocytic:
The Division of Microbiology and Infectious Diseases, NIAID with
support from the
Office of Rare Diseases convened a workshop on "Human Ehrlichiosis" on
September 5, 1996.
Human infections with Ehrlichia chaffeensis: clinical, pathological,
and immunologic
aspects.
David H. Walker, M.D., Department of Pathology, The University of
Texas Medical
Branch at Galveston, Galveston, TX 77555-0609.
“The spectrum of syndromes and distribution of severity of human
monocytic ehrlichiosis
(HME) is incompletely defined. Two prospective active surveillance
studies suggest
the contradictory views that HME is usually either asymptomatic or
requires hospitalization.
The largest series reporting 237 passively collected cases includes
62% hospitalized
patients, a median duration of illness of 23 days, and a systemic
disease often
with gastrointestinal, hepatic, neurologic, and hematopoietic
involvement. Bone
marrow hyperplasia, granulomas, and erythrophagocytosis, multifocal
hepatocellular
necrosis, perivascular lymphohistiocytic infiltrates, and meningitis
are known pathologic
lesions. The pathology of HME has yet to be investigated adequately.
Pathologic
study of fatal cases suggests that HME can occur as an opportunistic
infection or
conversely can induce immunosuppression. The spectrum of syndromes
and distribution
of severity of human monocytic ehrlichiosis (HME) is incompletely
defined. Two prospective
active surveillance studies suggest the contradictory views that HME
is usually
either asymptomatic or requires hospitalization. The largest series
reporting 237
passively collected cases includes 62% hospitalized patients, a median
duration
of illness of 23 days, and a systemic disease often with
gastrointestinal, hepatic,
neurologic, and hematopoietic involvement. Bone marrow hyperplasia,
granulomas,
and erythrophagocytosis, multifocal hepatocellular necrosis,
perivascular lymphohistiocytic
infiltrates, and meningitis are known pathologic lesions. The
pathology of HME has
yet to be investigated adequately. Pathologic study of fatal cases
suggests that
HME can occur as an opportunistic infection or conversely can induce
immunosuppression.
A serious flaw in our current state of knowledge is the laboratory
basis for the
diagnosis of HME, which is overwhelmingly serologic. A small fraction
of cases
have been documented by Ehrlichia chaffeensis- specific PCR. Only
three isolates
of E. chaffeensis have been established, all from cases of human
illness. Each isolate
differs from the others genetically and antigenically. Ehrlichia canis
was isolated
from a healthy seropositive person. It is quite likely that all of the
Ehrlichia
species capable of causing human infection have not yet been
discovered. The genetic
and antigenic diversity of E. chaffeensis itself is incompletely known
as are their
potential strain-determined pathogenicity. The ehrlichical virulence
factors have
yet to be identified as well as the host factors that determine host
resistance
and the severity of illness. Likewise, the mechanisms of immunity, or
indeed the
existence of protective immunity to E. chaffeensis, have yet to be
established.
There are serious deficiencies in each of the animal models of
ehrlichiosis, particularly
for the investigation of immune mechanisms against E. chaffeensis. The
problems
with the models include distant genetic relationship of E. chaffeensis
with the
E. risticii-E. sennetsu genogroup, lack of characterization of some
models for the
target cells and pathologic lesions, unrealistic route of inoculation
(certainly
not via tick-bite transmission), and lack of quantitation of the
ehrlichical inoculum
and the time course of the organ infectivity titers. HME poses
substantial challenges
in diagnosis, pathogenesis, and immunity. Research, optimally
collaborative, interactive,
and multidisciplinary, holds the answers.”
BABESIOSIS
Persistent parasitemia after acute babesiosis., N Engl J Med 1998
Jul 16;339(3):160-5,
Krause PJ, Spielman A, Telford SR 3rd, Sikand VK, McKay K,
Christianson D, Pollack
RJ, Brassard P, Magera J, Ryan R, Persing DH., Department of
Pediatrics, Connecticut
Children's Medical Center and University of Connecticut School of
Medicine,
Hartford 06106, USA.
“BACKGROUND: Babesiosis, a zoonosis caused by the protozoan Babesia
microti, is
usually not treated when the symptoms are mild, because the
parasitemia appears
to be transient. However, the microscopical methods used to diagnose
this infection
are insensitive, and few infected people have been followed
longitudinally. We compared
the duration of parasitemia in people who had received specific
antibabesial therapy
with that in silently infected people who had not been treated.
METHODS: Forty-six
babesia-infected subjects were identified from 1991 through 1996 in a
prospective,
community-based study designed to detect episodes of illness and of
seroconversion
among the residents of southeastern Connecticut and Block Island,
Rhode Island.
Subjects with acute babesial illness were monitored every 3 months for
up to 27
months by means of thin blood smears, Bab. microti polymerase-chain-
reaction assays,
serologic tests, and questionnaires. RESULTS: Babesial DNA persisted
in the blood
for a mean of 82 days in 24 infected subjects without specific
symptoms who received
no specific therapy. Babesial DNA persisted for 16 days in 22 acutely
ill subjects
who received clindamycin and quinine therapy (P=0.03), of whom 9 had
side effects
from the treatment. Among the subjects who did not receive specific
therapy, symptoms
of babesiosis persisted for a mean of 114 days in five subjects with
babesial DNA
present for 3 or more months and for only 15 days in seven others in
whom the DNA
was detectable for less than 3 months (P<0.05); one subject had
recrudescent
disease after two years. CONCLUSIONS: When left untreated, silent
babesial infection
may persist for months or even years. Although treatment with
clindamycin and quinine
reduces the duration of parasitemia, infection may still persist and
recrudesce
and side effects are common. Improved treatments are needed.” PMID:
9664092
The anecdotal evidence is that mortality from babesiosis is high in
Rhode Island.
Because RI is a sentinel state, funding should be sought to improve
indentification
of new variants in persons and in ticks. University and hospital
facilities should
coordinate in granted projects for efficient use of available
resources.
---------
PATIENT MANAGEMENT IN ADDITION TO IMPROVED DETECTION OF LYME EXPOSURE
METHODS AND MARKERS OF PATHOPHYSIOLOGY
QUALIFICATION OF PATIENT PRESENTATION
MARKERS OF PATHOPHYSIOLOGY
The following are some, but not all markers of pathophysiology. They
are noteworthy
because they appear to be related to cognitive changes in borreliosis
patients.
If Lyme disease was just an arthritis, there would be very little
disability.
It is not known whether antiphospholipid or antiglycolipid antibodies
seen in borreliosis
patients are of bacterial origin or the result of neurological damage
and are therefore
autoantibodies. The 5 kD glycolipid is specifically a marker of
borreliosis and
is associated with more severe neurological disease, as are the
antiphospholipid
cases and is suspected in borreliosis patients with anti-brain
antiganglioside antibodies.
Additionally, it has been suggested that possibly autoreactive T
cells, matrix-metalloproteinases
(MMPs), quinolinic acid (QUIN), neopterin, and glial fibrillary acid
protein (GFAp)
in the CSF are signs of ongoing neurological injury. These process-
markers are
addressed in other illnesses, e.g., clinical trials of MMP inhibitors
in MS and,
cyclophosphamide for monoclonal gammopathies and for GFAp in
Alzheimer’s, glatiramer
acetate and neuroborreliosis (which failed). There are other
objectively detectable
signs of pathology in borreliosis patients, such as increased CSF
protein, pleocytosis,
dysregulated cytokines, gadolinium-enhanced MRI imaging which used for
meningitis
detection, and EEG changes.
That these process-markers overlap markers of pathophysiology in other
illnesses,
especially in other illnesses where there is a significant association
to Bb exposure,
such as in ALS and MS, is the objective evidence that borreliosis is
the multi-symptom
disease that subjective reporting first showed. It is not to say that
Lyme causes
MS or ALS. It is to say, symptoms reported by borreliosis patients
have a basis
in reality. A differential diagnosis is made based on other disease-
specific criteria.
At this point in time, there are no single set of lab tests that are
100% accurate
for diagnosing ALS or MS or Lupus or Guillain-Barre. These are also
clinical diagnoses,
as is Lyme. It is important to note that just as the Chronic Lyme
symptom complex
overlaps CFIDS or Fibromyalgia, they also overlap these other diseases
with known
pathophysiology. When these pathophysiologies are looked for in
chronic borreliosis
patients, they are more frequently found, than not when using the best
methods.
To not look for them in a patient, and instead assign a re-diagnosis
of a chronic
borreliosis patient with an illness that has overlapping subjective
symptoms, such
as Fibromyalgia, CFIDS, or “some psychiatric disorder” (Steere, in
NewYork Times
Magazine, Stalking Steere), but without these overlapping objective
signs, is a
medical negligence liability.
Yale University at one time had a Lyme and Lupus Clinic, run by
Rheumatologists,
who looked for things like anticardiolipin antibodies in both diseases
(and found
them). This clinic was spun- off as a biotech firm, and is now known
as L2 Diagnostics.
It was never called the Lupus and Fibromyalgia Clinic, nor is its name
now LF Diagnostics.
The spectrum of illness, and the pathophysiological markers of disease
process in
borreliosis frequently coinfected, say that this not simply an
antibody-antibiotic
dynamic. Currently, chronic borreliosis patients appear to have two
options, long
term antibiotic treatment, or be told their illness has become a non-
disease, in
the absence of proper pathophysiological analyses. Limiting treatment
to X days
of antimicrobials for a simple infection, does not appear to suffice.
Spirochetes,
alone, are not, and never have been, simple infections. Paul Erhlich
used the arsenic-containing
drug Salvarsan to treat syphilis. The fulcrum shift might be to,
politically, legally,
frame spirochetal and other tick borne diseases as chronic illnesses.
That’s what
the following data says to do.
QUINOLINIC ACID
The noted pathologies associated with chronic neuroborreliosis include
quinolinic
acid (QUIN) in the cerebrospinal fluid. Lumbar puncture is a safe and
common procedure
according to Mark Klempner of Tufts (Diseases of Summer Conference,
2001, South
County Hospital). QUIN is a marker of immune activation or
infection. National
Institutes of Mental Health has determined that quinolinic acid, an
excitotoxin/neurotoxin,
comes from macrophages. The precise source of QUIN in
neuroborreliosis patients
is unknown.
QUIN’s excitotoxic properties are related to N-methyl –D-aspartate
(NMDA) NMDA agonism.
QUIN, an intermediate in the tryptophan to dopamine pathway, has
oxidative/foreign
antigen lytic properties. QUIN has been implicated as a dopamine
antagonist and
associated with pathology to GABA bearing neurons and thus seizures
(25, 26). The
known manifestations that possibly correlate with QUIN/NMDA/GABA
pathology in borreliosis
are myoclonus, complex partial seizures (Neurocognitive abnormalities
in children
after classic manifestations of Lyme disease Steere, et al, Pediatr
Infect Dis J.
1998 Mar;17(3):189-96.), sleep disorders, explosive rage reaction
(“Lyme-Rage”),
“a schizophrenia-like disorder”, other manifestations of psychosis and
dementia.
Hypnogogic and other types of hallucinations observed in Lyme
neuroborreliosis are
of the type more commonly associated with delirium.
In acute neuroborreliosis, QUIN levels are in the range of, 325 +/-96
nM, while
in chronic borreliosis encephalopathy, the levels are in the range of,
31 +/4 nM,
or about 50% above normal. The assay was performed with GC and
negative ionization
mass spectrometry.
Neuroactive kynurenines in Lyme borreliosis., Neurology 1992 Jan;
42(1):43-50 ,
Halperin JJ, Heyes MP., Department of Neurology, SUNY, Stony Brook.
“Although neurologic dysfunction occurs frequently in patients with
Lyme borreliosis,
it is rarely possible to demonstrate the causative organism within the
neuraxis.
This discordance could arise if neurologic symptoms were actually due
to soluble
neuromodulators produced in response to infection. Since immune
stimulation is associated
with the production of quinolinic acid (QUIN), an excitotoxin and N-
methyl-D-aspartate
(NMDA) agonist, we measured levels of CSF and serum QUIN, and
lymphokines. Samples
were obtained from 16 patients with CNS Borrelia burgdorferi
infection, eight patients
with Lyme encephalopathy (confusion without intra-CNS inflammation),
and 45 controls.
CSF QUIN was substantially elevated in patients with CNS Lyme and
correlated strongly
with CSF leukocytosis. In patients with encephalopathy, serum QUIN was
elevated
with corresponding increments in CSF QUIN. Lymphokine concentrations
were not consistently
elevated. We conclude that CSF QUIN is significantly elevated in B
burgdorferi infection--dramatically in patients with CNS inflammation,
less in encephalopathy.
The presence of this known agonist of NMDA synaptic function—a
receptor involved
in learning, memory, and synaptic plasticity--may contribute to the
neurologic and
cognitive deficits seen in many Lyme disease patients.” PMID: 1531156
The question remains, do the remaining elevated levels mean an ongoing
contribution
to ongoing encephalopathy?
The state of the art in neuroprotection against QUIN and other
reactive oxygen species
damage is development of synthetic kynurenines and free radical
scavengers.
NEOPTERIN
There was only one citation found on PubMed for neopterin production
in borreliosis.
The full text has not been obtained because this is a foreign journal
and is not
readily available:
It was detected in the cerebrospinal fluid, here:
Neopterin production and tryptophan degradation in acute Lyme
neuroborreliosis
versus late Lyme encephalopathy., Eur J Clin Chem Clin Biochem 1994
Sep;32(9):685-9
Gasse T, Murr C, Meyersbach P, Schmutzhard E, Wachter H, Fuchs D.
Klinik fur Neurologie, Universitat Innsbruck, Austria.
“Fourteen patients with Borrelia burgdorferi infection were
investigated for possible
abnormalities of tryptophan and neopterin metabolism. Four patients (2
were investigated
before therapy, 2 when therapy had been already started) had acute
Lyme neuroborreliosis,
and 10 patients were investigated months to years after an acute
infection. Increased
concentrations of neopterin and of the tryptophan-degradation product,
L-kynurenine,
were detected in the cerebrospinal fluid of patients with acute Lyme
neuroborreliosis;
one patient presented with subnormal tryptophan. Similar but less
marked changes
were seen in the treated patients and in some of the patients with
Lyme encephalopathy.
No such abnormalities were seen in the serum of the patients. The data
indicate
a role of the immune system and particularly of endogenously formed
cytokines, like
interferon-gamma and tumour necrosis factor-alpha, effecting
tryptophan and neopterin
metabolism in patients with acute Lyme neuroborreliosis.” PMID:
7865624
Neopterin and other pterins may be assayed with HPLC.
There is little data available regarding disturbances to brain
function associated
with this marker.
Biochemical changes in cerebrospinal fluid associated with the
neurotoxicaction
of HIV-1, [Article in Spanish] Actas Luso Esp Neurol Psiquiatr Cienc
Afines 1996
Jul-Aug;24(4):209-18, Gomez Alcalde MS, Reyes Martin A., Departamento
de Ciencias
Sanitarias y Medico Sociales de la Facultad de Medicina de Alcala de
Henares.
“The aim of this study is to evaluate the usefulness of different
markers to diagnose
neurologic and psychiatric diseases due to HIV-1 infection Increased
concentration
of quinolenic acid has been implicated in the neurologic deficits and
brain atrophy
that may accompany infection with the HIV-1 virus. CFS concentrations
of quinolenic
acid have been implicated in the pathogenesis of the AIDS dementia
complex. Cytokines
liberation are very altered and this factor may be correlated with
direct toxicity
about central nervous system cells. Also are increased the values of
neopterin.
In the different stages of AIDS, the highest values are obtained in
dementia complex.
Neopterin, tryptofan and kinorenina, in blood and CFS are directly
correlated with
neurologic and
psychiatry sintomatology. The highest values of soluble intercellular
adhesion molecule
1 are found in HIV encephalopathy As well as are important the values,
in CSF and
blood of beta-2-M, Ag HIV, Ac41, tumor necrosis factor-alpha in the
neurologic disease
in HIV-1 infection.”
PMID: 8984853
There may be other pterins associated with a disease process.
MMPs
The matrix-metalloproteinases obviously degrade matrix/connective
tissue. The concern
of Mark Klempner (27) was, “Since MMPs can digest myelin, basic
protein, B. burgdorferi
could promote CNS injury indirectly by inducing the expresion of MMPs
in neural
cells. MMPs also digest at least two proteins of the adult CNS
extracellular matrix:
the aggregating proteoglycan versican and tenascin.” -- Perides G,
Steere AC, Klempner
MS, et al, Matrix metalloproteinases in the cerebrospinal fluid of
patients with
Lyme neuroborreliosis. J Infect Dis. 1998 Feb;177(2):401-8.
There are other reports of identification of MMPs in the CNS of
neuroborreliosis,
and these are not in complete agreement with Mark Klempner’s
findings. The method
above was SDS-PAGE zymography.
The relationship of MMPs to the other markers of CNS degradation in
the CSF of neuroborreliosis
patients is unknown, nor is it known the full extent of behavioral and
cognitive
effects of this active marker alone.
GFAp
Glial fibrillary acidic protein in the CSF of borreliosis patients:
Astroglial and neuronal proteins in cerebrospinal fluid as markers of
CNS involvement
in Lyme neuroborreliosis., Eur J Neurol 1999 Mar;6(2):169-78 ,
Dotevall L, Hagberg
L, Karlsson JE, Rosengren LE., Department of Infectious Diseases,
Goteborg University,
Goteborg, Sweden.
“Is Lyme neuroborreliosis, even in its early phase, a parenchymatous
disorder in
the central nervous system (CNS), and not merely a meningitic process?
We quantified
cerebrospinal fluid (CSF) levels of four nerve and glial cell marker
proteins in
Lyme neuroborreliosis patients with pretreatment durations of 7-240
days. All 23
patients had meningoradiculitis, and six had objective signs of
encephalopathy.
Glial fibrillary acidic protein (GFAp) pretreatment levels in
CSF, and the light subunit of neurofilament protein (NFL) levels were
related to
clinical outcome and declined significantly after treatment (P < 0.001
and P
< 0.01, respectively). NFL was detectable in 11 out of 22 patients,
and pre-
and post-treatment NFL levels were associated with the duration of
neurological
symptoms within 100 days prior to treatment. Neuron-specific enolase
(NSE) concentrations
also decreased after therapy (P < 0.001), while CSF levels of
glial S-100 protein remained unchanged. The pretreatment duration of
disease was
related to postinfectious sequelae. GFAp, NSE and NFL levels in CSF
are unspecific
indicators of astroglial and neuronal involvement in CNS disease. The
findings in
the present study are in agreement with the hypothesis that early and
late stages
of Lyme neuroborreliosis damage the CNS parenchyma. Copyright 1999
Lippincott Williams
& Wilkins.” PMID: 10053229
Increased cerebrospinal fluid levels of glial fibrillary acidic
protein (GFAp) in
Lyme neuroborreliosis., Infection 1996 Mar-Apr;24(2):125-9, Dotevall
L, Rosengren
LE, Hagberg L.
Dept. of Infectious Diseases, Ostra University Hospital, Goteborg
University, Sweden.
“Glial fibrillary acidic protein (GFAp), the main protein constituent
of the intermediate
filaments of astrocytes, was analysed in the cerebrospinal fluid (CSF)
of 20 patients
with Lyme neuroborreliosis as a marker of the astroglial reaction. The
mean GFAp
level before antibiotic treatment in the study group was significantly
elevated
(592 pg/ml +/- 596 [SD]) compared to that in 24 healthy controls (121
+/- 87 [SD])
(p < 0.01). The highest CSF-GFAp levels were seen in
the patients with the most severe disease, but the levels were also
increased in
patients with peripheral paresis, such as facial palsy with no or only
minor encephalitic
symptoms. This implies that the infection was not limited to radix
dorsalis or the
meningeal tissues, but affected the central nervous system as well.
Furthermore,
the astroglial reaction seemed to occur early in Lyme neuroborreliosis
since CSF-GFAp
levels were elevated also in patients with recent (< 3 weeks) onset of
disease.
After antibiotic treatment, the GFAp levels decreased. It is suggested
the CSF-GFAp
concentrations might be useful for monitoring CNS involvement in Lyme
neuroborreliosis.”
PMID: 8740104
GFAp in the CSF is also seen in ALS and Alzheimer’s. Exposure to Bb
in ALS patients
met statistical significance:
“There appears to be a statistically significant association between
ALS and immunoreactivity
to B burgdorferi, at least among men living in hyperendemic areas.”—
Halperin JJ,
Dattwyler, RJ, et al, Immunologic reactivity against Borrelia
burgdorferi in patients
with motor neuron disease. Arch Neurol. 1990 May;47(5):586-94. PMID:
2334308
Robert T. Schoen, Yale Rheumatology, Annals of Internel Medicine, Vol
132, No 8:
"Other peripheral neuropathies and Lyme meningitis are also seen at
this stage.
In late-stage disease, the central nervous system may be involved. A
new diagnostic
test measuring glial
fibrillary acidic protein in cerebrospinal fluid may prove to be a
useful tool for
measuring such involvement (20)."
Robert T. Schoen, Yale Rheumatology, Prevention Magazine:
“While it's especially important at this time of year to be aware of
the warning
signs of the disease – a skin rash around the site of a tick bite,
headache, fever,
fatigue and muscle or joint pain – Lyme paranoia, as I call it, is not
warranted.”--
The previous text was excerpted from Prevention magazine, published by
Rodale Press.
Lyme fear prevails more than disease. , The Washington Times,
04-18-1999
GFAp has been assayed by ELISA, Western Blot. This needs further
analytical development.
GFAp has been implicated in disturbance to brain function:
Effects of gliosis on dopamine metabolism in rat striatum., Brain Res
1994 Nov
14;663(2):199-205, Wang J, Lieberman D, Tabubo H, Finberg JP, Oldfield
EH, Bankiewicz
KS., CNS Implantation and Regeneration Unit, NINDS, NIH, Bethesda, MD
20892.
“Neuroimplantation is inevitably accompanied by gliosis. Although
graft-induced
trophic effects on host neurons may be mediated by glial cells, the
effects of gliosis
on dopamine (DA) metabolism remains unclear. To examine these effects,
basic fibroblast
growth factor (bFGF) was directly infused into the striatum of 12 male
rats (250-280
g). One week later, substantial gliosis was demonstrated in the
infused striatum
by immunochemical staining for glial fibrillary acidic
protein (GFAP) and quantified by GFAP Western blot analysis. One week
after bFGF
infusion, extracellular DA and its metabolites were measured by in
vivo microdialysis
using HPLC. Infusion of L-dopa through the dialysis probe resulted in
a 60% reduction
in the L-dopa-induced DA peak in the gliotic striatum compared with
the normal side.
After L-dopa infusion, dihydroxyphenylacetic acid (DOPAC) levels were
similar between
the gliotic and normal striatum. In contrast, homovanillic acid (HVA)
levels were
26% higher in the gliotic striatum. Enzyme assays demonstrated that
aromatic L-amino
acid decarboxylase activity was unchanged in the gliotic striatum, but
both MAO-A
and MAO-B activities increased by 23% and 21%, respectively. These
results suggest
that the reduced striatal DA peak in the gliotic striatum after L-dopa
administration
was due to accelerated DA catabolism through enhanced MAO activity.
The bFGF-induced
striatal gliosis may serve as a model to study neurotransmitter
metabolism in the
gliotic brain caused by disease processes, aging, or tissue grafting.”
PMID: 7874502
Although GFAp is a a sign of reactive gliosis in Alzheimer’s, MS, and
ALS, patients
would much rather be told Chronic Lyme is a real disease rather than
be told it’s
fear, anxiety, and paranoia. It makes more sense for a patient to
work with a medical
practioner towards resolution of symptoms. It’s difficult to find in
Medical Ethics
code anywhere, that validating the patient’s person and the patient’s
complaints
is the first step towards recovery. Perhaps this is because this is
common sense
and therefore not worthy of philosophical analysis.
ANTIPHOSPHOLIPID ANTIBODIES
Antiphospholipid antibody production in neuroborreliosis patients, as
has been identified
by Allen Steere, is positively correlated with neurologic symptoms.
“Sera from 28 patients with Lyme disease were tested for the presence
of anticardiolipin
antibodies (ACLA). Seven serum samples had elevated levels of IgM
ACLA, and 4 had
elevated levels of IgG ACLA. Higher IgM ACLA positivity tended to be
associated
with neurologic disease, and IgM ACLA levels correlated with the
specific IgM response
to the infecting spirochete (P less than 0.01). Absorption
experiments indicated
that ACLA and antispirochete antibodies are largely separate
populations. Thus,
ACLA may occur in patients with Lyme disease, particularly in those
with neurologic
abnormalities, and the production of these antibodies seems to be
linked to the
specific IgM response.”— Anticardiolipin antibodies in Lyme disease
Mackworth-Young
CG, Steere AC, et al, Arthritis Rheum 1988 Aug;31(8):1052-6, PMID:
3408508
The analytical methods used there should also be employed as part of
patient workup,
until further investigations reveal a more sensitive and specific
method. Antiphospholipid-negative
assay results do not exclude the diagnosis of Lupus. Although the
Lupus/MS haplotypes
HLA-DQB1*0602 and *1501 have been identified as possible correlates in
chronic CNS
Lyme disease, it is possible to make a differential diagnosis at least
of Lupus.
The phospholipids found in borrelia are phosphatidylcholine and
phosphatidylglycerol
(28).
Adequate assays for antibodies to these are recommended. The VRDL
used in Lupus
was
not adequate to detect anticardiolipin antibodies in borreliosis and
Steere presented
a more sensitive method: radioimmunoassay (RIA). The differential
diagnosis of
the Antiphospholipid Syndrome, Lupus, and antiphospholipid antibodies
from the borrelioses
may be a considerable challenge. We haven’t run across any recent
developments
from L2 Diagnostics.
Antiphospholipid antibodies are implicated in the neuropsychiatric
symptoms.
ANTIGLYCOLIPIDS
Antibodies to glycolipids can also be determined. Jorge Benach of
SUNY Stony Brook
has found that IgM to borrelial gangliosides may result in autoimmune
response similar
to Guillain Barre, or possible antibody competition for receptors, and
clearly,
the nodes of Ranvier, which are suspected to result in compromise to
nerve conduction.
Although these mechanisms of nerve conduction may be reversible and
temporary, animal
models of Lyme borreliosis, such as in Rhesus macaques, have shown
irreversible
nerve damage via immune cell response. Likeliest, these neurological
lesions are
the result of spirochetal blebbing, or the shedding of antigen and
macrophage activity.
Alan Barbour (UC Irvine) and Stephen Bartold (Yale):
“Many researchers believe that the secret to B. burgdorferi's
infectivity and
inflammatory capacity lies in the interaction of its surface proteins
with the host's
immunological system. Yale researcher Stephen Barthold, a veterinarian
and professor
of comparative medicine who developed the first mouse model of Lyme
disease, studies
the expression of B. burgdorferi surface proteins throughout various
stages of the
spirochete's life cycle. He finds that during the early stages of
infection,
B. burgdorferi avoids immune detection by decreasing its expression of
surface proteins
or cloaking its expressed surface proteins under a layer of slime.
"It's
using some sort of stealth-bomber-type mechanism," he says. Or, using
another
diversionary tactic called blebbing, the spirochete can pinch off bits
of its membrane
in order to release its surface proteins. Explains Barbour: "It's
like
a bacterial Star Wars defense program," in which released surface
proteins
might intercept incoming host antibodies, keeping the spirochete safe
from immunological
attack. “— The Scientist, Vol:10, #14, pg.13, July 8, 1996.
Even when spirochetes are not detected in a borreliosis nerve lesion,
it is suspected
some spirochetal material (blebs) remains:
"Nerve changes. A detailed survey of the central nervous system
lesions was
carried out, which included 50 sampling sites. The lesions observed
are listed
in Table 4. Sensory ganglia of the dorsal root and trigeminal ganglia
of animals
J 831 and K 216 had individual neurons
that immunostained positive with anti-Bb 7.5kD lipoprotein mAb (fig
16). These
neurons were swollen and were undergoing chromatolysis. The dorsal
root ganglia
of the thoracic and cervical regions were especially affected. Nerve
sheath fibrosis
within the spinal cord was limited to
the thoracic segment in animal J 831. Positive staining with anti-Bb
mAb, accompanied
by vacuolization of peripheral nerves, was observed in three of four
animals. This
change occurred as a radiculoneuropathy of the thoracic segment and
peripheral nerves
(Fig 17). Animal L 131 had five peripheral nerves affected. When the
same nerves
were stained for fat, focal vacuolization was observed (Figs 18 and
19). Focal demyelination
of the cervical cord was limited to J 831. Lymphocyte infiltration of
the affected
nerves was mild in extent and confined to perivascular spaces. In
animals L 131
and K 383, Bb could be demonstrated by immunostaining (Fig 20).
“ The pathogenesis of Lyme disease neuropathies is poorly
understood...Sensory ganglia
involvement has previously been described in human borreliosis
(27-28). In our
study,
many of the ganglia positive for Bb by immunstaining were undergoing
necrosis.
This staining was seen in two out of five animals and was not
accompanied by a cellular
infiltrate.
" Nerve tissues with perivascular lymphocyte infiltrate were present
in three
out of five animals. This was the only lesions where extracellular Bb
could be
demonstrated. Peripheral cutaneous nerves were prominantly affected in
the early
phase of borreliosis of rhesus macaques(20, 28-29). Changes of the
nercous system
include the full range of changes observed in neuroborreliosis, which
suggests a
variety of disease mechanisms, including sensitization or mimicry as
suggested
by the vacuolization of peripheral nerves and cytokine-mediated
destruction of nerves
as a result of the infiltrating lymphocytes..." --- Chronic lyme
disease in
the rhesus monkey , Lab Invest 1995 Feb;72(2):146-60, Roberts, ED, et
al.
Experimental immunization with Borrelia burgdorferi induces
development of antibodies
to gangliosides., Infect Immun 1995 Oct;63(10):4130-7, Garcia-Monco
JC, Seidman
RJ, Benach JL., Department of Neurology, Hospital de Galdacano,
Vizcaya, Spain.
“Patients with neuroborreliosis produce antibodies, mostly of the
immunoglobulin
M (IgM) class, to gangliosides, particularly to those with Gal(beta
1-3)GalNac terminal
sequences. Lewis rats were immunized with a nonpathogenic strain of
Borrelia burgdorferi
and with a chloroform-methanol extract (nonprotein) of this organism
(CM) to determine
whether antibodies to B. burgdorferi also recognized gangliosides.
Rats were also
immunized with asialo-GM1 to determine whether the elicited antibodies
recognized
antigens in B. burgdorferi. Rats immunized with B. burgdorferi
produced low levels
of IgM antibodies that cross-reacted with asialo-GM1 and GM1. Rats
immunized with
CM had marked IgM reactivity to asialo-GM1 and GM1. Immunization with
asialo-GM1
resulted in antibodies that cross-reacted with B. burgdorferi
antigens. Although
antibodies to B. burgdorferi were of both the IgM and IgG classes,
those to CM and
to asialo-GM1 and GM1 were predominantly in the IgM fraction.
Reactivity of the
IgM antibodies decreased after adsorption with the heterologous and
the homologous
antigens,
indicating bidirectional cross-reactivity between CM, asialo-GM1, and
GM1 and that
immunization with one produces antibodies to the other. There was no
in vivo deposition
of Ig in peripheral nerves, nor was there nerve pathology as a result
of immunizations,
but IgM antibodies to asialo-GM1 and CM recognized homologous antigens
in the nodes
of Ranvier of peripheral nerves from nonimmunized rats. This
immunization model
suggests that antibodies to
gangliosides in Lyme disease have a microbial origin and are
potentially relevant
in pathogenesis.” PMID: 7558329
Reactivity of neuroborreliosis patients (Lyme disease) to cardiolipin
and gangliosides.
J Neurol Sci 1993 Jul;117(1-2):206-14, Garcia Monco JC, Wheeler CM,
Benach JL,
Furie RA, Lukehart SA, Stanek G, Steere AC., Department of Pathology,
SUNY, Stony
Brook 11794.
“A subset of patients (50%) with neuroborreliosis (Lyme disease)
showed IgG reactivity
to cardiolipin in solid phase ELISA. In addition, a subset of patients
with neuroborreliosis
(29%) and syphilis (59%) had IgM reactivity to gangliosides with a
Gal(beta 1-3)
GalNac terminal sequence (GM1, GD1b, and asialo GM1). Anti-ganglioside
IgM antibodies
were significantly more frequent in these two groups of patients
compared to patients
with cutaneous and articular
Lyme disease, primary antiphospholipid syndrome, systemic lupus
erythematosus and
normal controls. Correlative evidence and adsorption experiments
indicated that
antibodies to cardiolipin had separate specificities from those
directed against
the gangliosides. IgM antibodies to Gal(beta 1-3) GalNac gangliosides
appeared to
have similar specificities since these were positively correlated and
inhibitable
by cross adsorption assays. Given the clinical associations of
patients with neuroborreliosis
and syphilis with IgM reactivity to gangliosides sharing the Gal(beta
1-3) GalNac
terminus, we suggest that these antibodies could represent a response
to injury
in neurological disease or a cross reactive event caused by
spirochetes.” PMID:
8410057
In, Role of the cerebrosides and a galactodiglyceride in the antigenic
cross-reaction
between nerve tissue and treponema., J Immunol. 1972 Jul;109(1):
146-53., Dupouey
P. writes:
“This cross reaction between the GDG [galactodiglyceride] contained in
certain species
of treponema and cerebrosides of the cerebral tissue poses a problem
of pathogenesis,
Similar problems have been discussed in a recent review of the role of
microorganisms
in autoimmune response (13). With regard to this subject it should,
however, be
noted: 1) That the central nervous system is infected in syphilis and
yet T. pallidum
does not seem to contain any GDG (8). 2) That the anti-erebroside and
anti-GDG
studied here are circulating antibodies. Antibodies of this type are
considered
to be proof of, not the agents of, autoimmune response. 3) That
certain infectious
or traumatic diseases liable to liberate cerebral constituents within
the organism
should be able to give rise to anti-cerebroside antibodies which are
therefore GDG.
4) That these anti-GDG antibodies are sometimes encountered at high
titers in human
subjects who are in apparent perfect health.”
Abstract from the same publication:
“Various authors have demonstrated an antigenic identity between
various nervous
tissue and treponema. This report shows that this antigenic diversity
is due to
the presence in the treponema extracts of a galactodiglyceride hapten:
i.e., 2,
3-di-O-acyl-1-O-(b -D-galactopyranosyl)-D-glycerol. This hapten shows
a cross reaction
with the cerebrosides; moreover, the the nervous tissue contains a
lipid which,
on deacylation, liberates a O-(b-D-galactosyl_-1-1’-glycerol (11).
The part palyed
by each of the constituents as well as the possible consequences of
this antigenic
community are discussed.”
It was recognized long ago that anti-nerve antibodies might possibly
be coming from
cross reaction, or they may be coming from degradation of host tissue,
which, upon
injury of some sort, becomes autoantigenic. Thirty years ago,
scientists looked
at these questions in spirochetal illnesses. In 1988 and later,
Steere looked at
anti-nerve antibodies in borreliosis patients and found them. Yet
these markers
of illness are not only not addressed in management of patients --not
only are they
are not routinely looked for-- but the lay media are instead told
patients have
“some psychiatric illness”, there are no adverse outcomes in Lyme
disease, Lyme
is curable, and there is no such thing as Chronic Lyme. The Post-Lyme
syndrome is
“ill-defined”, according to the Infectious Diseases Society of
America: “Clinical
Infectious Diseases 2000;31:1-14, GUIDELINES FROM THE INFECTIOUS
DISEASES SOCIETY
OF AMERICA, Practice Guidelines for the Treatment of Lyme Disease,
Gary P. Wormser,
Robert B. Nadelman, Raymond J. Dattwyler, David T. Dennis, Eugene D.
Shapiro, Allen
C. Steere, Thomas J. Rush, Daniel W. Rahn, Patricia K. Coyle, David H.
Persing,
Durland Fish, and Benjamin J. Luft.”
Many of the above authors are the very people who were involved in the
development
and discovery of methods and markers of chronic illness in Chronic
Lyme disease.
It is not known if IgM antibodies to nerve cell components would be
present in the
absence of spirochetes. That condition, 100% spirochete clearance,
has never been
proven in any animal model.
A recent public relations Lyme prevention announcement:
“Once a dog is infected, it is infected for life.” –American Lyme
Disease Foundation,
Somers, New York, PR Newswire, United Business Media, April, 2002
AUTOREACTIVE T CELLS, NEUROLOGICAL
Very little concrete data to support autoreactive T cells in Lyme
borreliosis exists.
However, there remain the genetic correlates in Klempner’s and
Martin’s MHC Class
II antigen-presenting molecules to be explained. Whether Class II
should be considered
alone, and outside the dynamic of Class I and B cell contribution to
the association
of Class II to an autoimmune disease with a known etiology such as a
permanent spirochetal
infection, will probably be played out in the NIH and CDC funding
competition arena.
The data are:
AUDIO TRANSCRIPT: Mark Klempner, Tufts Unibversity. South County
Hospital Diseases
of Summer Conference, July 2001, regarding his treatment study of
borreliosis, reported
July 12, 2001, NEJM.
“Um, There, these patients obviously, are very, very much interested
in that question,
as we are, and I just want to highlight a preliminary piece of data of
where we
think we’re going from here, unpublished*, and not for large, uh,
dissemination,
but here is the preliminary data.
And, that is, that when you look for the possibility of an autoimmune
disease, the
best way to look is to see if there is any genetic clustering in HLA
haplotypes.
The reason for that is the way antigens get presented in the context
of who you
are, that is, your HLA haplotype. And we can talk in some detail
about that. Those
diseases that I think everybody would agree are so called
Autoimmune :lupus, rheumatoid
arthritis, type 1 diabetes, and perhaps MS, have some clear genetic
clustering that
leads us to believe that these are indeed autoimmune diseases,
although we do not
satisfy so-called Koch’s Postulates of autoimmune disease that we’ve
written[?-KMD]
about. And the odds ratio for your having that particular HLA type,
in the case
of R.A, a DR4, or a DQB0602 to protect you from type 1 diabetes, are
on the order
of 3 to 6. One of the ones that is probably highest, of course, is
B27, in patients
with alkyloiding spondolytis and the like. It turns out that if you
look at the
first 51 patients with post-treatment chronic Lyme disease, the
patient population
that participated in our study, there was a very high incidence of
DQB0602 with
an odds ratio of 770%. So it may well be that exposure to THAT
organism with THAT
background of HLA haplotype may lead you to develop chronic symptoms.
That is a
hypothesis that needs to be tested. It would obviously lead to an
entirely new
form and approach to therapy.”
Borrelia burgdorferi--specific and autoreactive T-cell lines from
cerebrospinal
fluid in Lyme radiculomyelitis. Ann Neurol 1988 Oct;24(4):509-16
Martin R, Ortlauf J, Sticht-Groh V, Bogdahn U, Goldmann SF, Mertens
HG.
Department of Neurology, University of Wurzburg, FRG.
In 3 patients with Lyme radiculomyelitis, cellular immune reactions of
cerebrospinal
fluid (CSF) lymphocytes were analyzed. Phenotypic analysis of CSF
cells demonstrated
that the majority were T cells (CD3+) of the helper/inducer subset
(CD4+). These
T cells were directly expanded from the CSF by limiting dilution. A
total of 505
T-cell lines were tested for Borrelia burgdorferi (Bb)-specific
proliferation and
also partly tested for reactivity to a panel of central and peripheral
nervous system
antigens. Proliferative assays revealed 33 of them to be Bb specific,
16 to be specific
for myelin basic protein, 16 to be specific for peripheral myelin, 1
to be specific
for cardiolipin, and 2 to be specific for galactocerebrosides. The
antigen-specific
proliferation was restricted by autologous human leukocyte antigen
(HLA) class II
molecules. The majority of CSF-derived T-cell lines stained positively
for CD3,
CD4, and HLA class II antigens and negatively for CD8 (cytotoxic/
suppressor subset).
One T-cell line provided help for the production of specific IgG by
autologous B
cells and secreted gamma-interferon upon stimulation with Bb antigen
in the presence
of autologous antigen-presenting cells. These data show that in
patients with severe
neurological manifestations of late Lyme disease, not only Bb-specific
T-cell lines
but also T cells reactive to central or peripheral nervous system
autoantigens can
be found.
PMID: 3266455 [PubMed - indexed for MEDLINE]
Identification of candidate T-cell epitopes and molecular mimics in
chronic Lymedisease.,
Nat Med 1999 Dec;5(12):1375-82, Hemmer B, Gran B, Zhao Y, Marques A,
Pascal J,
Tzou A, Kondo T, Cortese I, Bielekova B, Straus SE, McFarland HF,
Houghten R, Simon
R, Pinilla C, Martin R., Neuroimmunology Branch, National Institute of
Neurological
Disorders and Stroke, National Institutes of Health, Building 10, Room
5B-16, 10
Center DR MSC 1400, Bethesda, Maryland 20892-1400, USA.
“Elucidating the cellular immune response to infectious agents is a
prerequisite
for understanding disease pathogenesis and designing effective
vaccines. In the
identification of microbial T-cell epitopes, the availability of
purified or recombinant
bacterial proteins has been a chief limiting factor. In chronic
infectious diseases
such as Lyme disease, immune-mediated damage may add to the effects of
direct infection
by means of molecular mimicry to tissue autoantigens. Here, we
describe a new method
to effectively identify both microbial epitopes and candidate
autoantigens. The
approach combines data acquisition by positional scanning peptide
combinatorial
libraries and biometric data analysis by generation of scoring
matrices. In a patient
with chronic neuroborreliosis, we show that this strategy leads to the
identification
of potentially relevant T-cell targets derived from both Borrelia
burgdorferi and
the host. We also found that the antigen specificity of a single T-
cell clone can
be degenerate and yet the clone can preferentially recognize different
peptides
derived from the same organism, thus demonstrating that flexibility in
T-cell recognition
does not preclude specificity. This approach has potential
applications in the identification
of ligands in infectious diseases, tumors and autoimmune diseases.
“PMID: 10581079
The above patient had HLA-DRB1*1501.
A trial of glatiramer actetate for putative T cell autoimmunity in
Lyme disease
failed:
Mechanisms of immunomodulation by glatiramer acetate., Neurology 2000
Dec 12;55(11):1704-14,
Gran B, Tranquill LR, Chen M, Bielekova B, Zhou W, Dhib-Jalbut S,
Martin R. Cellular
Immunology Section, Neuroimmunology Branch, NINDS, NIH, Bethesda, MD
20892, USA.
OBJECTIVE: To define the mechanism of action of glatiramer acetate
(GA; formerly
known as copolymer-1) as an immunomodulatory treatment for MS.
BACKGROUND: The proposed
mechanisms of action of GA include 1) functional inhibition of myelin-
reactive T
cells by human leukocyte antigen (HLA) blocking, 2) T-cell receptor
(TCR) antagonism,
and 3) induction of T helper 2 (Th2) immunomodulatory cells. In this
report, the
authors examined the effects of GA on the functional activation of
human T-cell
clones (TCC) specific for myelin basic protein (MBP)
and for foreign antigens. Several questions were addressed: Is the
inhibitory effect
of GA specific for autoantigens? Is it mediated by blocking the
interaction between
peptide and HLA molecule? Is GA a partial agonist or TCR antagonist,
or does it
induce anergy? Does it induce Th2 modulatory T cells? METHODS: The
effects of GA
on antigen-induced activation of human TCC specific for MBP, influenza
virus hemagglutinin,
and Borrelia burgdorferi were studied by
proliferation and cytokine measurements, TCR downmodulation, and
anergy assays.
GA-specific TCC were generated in vitro from the peripheral blood of
patients and
healthy controls by limiting dilution. RESULTS: GA more strongly
inhibited the proliferation
of MBP, as compared with foreign antigen-specific TCC; in some MBP-
specific TCC,
the production of Th1-type cytokines was preferentially inhibited. In
addition to
HLA competition, the induction of anergy, but not direct TCR
antagonism, was observed.
Numerous GA-specific TCC were generated
from the peripheral blood of both MS patients and normal controls, and
a fraction
of these showed a Th2 phenotype. CONCLUSIONS: This study confirms a
preferential
inhibitory effect of GA on autoreactive TCC. With respect to cellular
mechanisms,
although HLA competition appears to play the most important role in
functional inhibition
in vitro, a direct effect on the TCR may be involved at least in some
autoreactive
T cells as shown by anergy induction. Although not confirmed at the
clonal level,
it is demonstrated further that GA induces T cells that crossreact
with myelin proteins.
GA-specific, Th2-modulatory cells may play an important role in
mediating the effect
of the drug in vivo. PMID: 11113226
DETECTING MENINGITIS
Gadolinium Contrast MRI was used to look for spirochetal meningitis
the nonhuman
primate model:
Inoculation of nonhuman primates with the N40 strain of Borrelia
burgdorferi leads
to a model of Lyme neuroborreliosis faithful to the human disease.,
Neurology 1995
Jan;45(1):165-72, Pachner AR, Delaney E, O'Neill T, Major E.,
Department of
Neurology, Georgetown University Medical Center, Washington, DC.
“We injected rhesus macaques with a highly infective strain of
Borrelia burgdorferi
to assess whether experimentally inoculated nonhuman primates (NHPs)
could serve
as models of human Lyme neuroborreliosis (LNB). The animals developed
biopsy-confirmed
erythema migrans in the area of the inoculations. ELISA testing of
sera revealed
strong antibody reactivity to B burgdorferi antigens, and Western
blotting showed
that 16-, 22-, 31-, 34-, and 41-kd proteins of the spirochete were
major antigens
recognized by antibody. Culture and polymerase chain reaction (PCR)
testing of serial
CSF specimens revealed that chronic infection of the CNS occurred in
all NHPs injected.
CSF pleocytosis occurred concurrently with CNS infection. Brain MRI
revealed intense
meningeal inflammation in one NHP as manifested by gadolinium uptake
by the dura
at the base of the temporal lobes. All animals had measurable antibody
in the CSF
after invasion. These studies are the first to demonstrate that
experimental LNB
in NHPs is a reliable model faithful to the human disease, with
spirochetal invasion
of the subarachnoid space. This also is the first report of CSF
samples positive
by culture in experimental LNB. Inflammation in the CNS as manifested
by CSF pleocytosis
and MRI findings was also correlated with the presence of spirochetal
DNA detected
by PCR. These data support the hypothesis that the pathogenesis of LNB
is associated
with direct spirochetal invasion, and provide evidence that CNS
involvement is more
common than heretofore thought.” PMID: 7824109
Note that the monkeys only had one of CDC’s specific bands, and if
these were all
IgG, none would have been a reportable case. This is evidence of
faithfulness to
human disease. These monkeys would have been classified as
“Unconfirmed Lyme” in
the SKB LymeRIX trial. “Unconfirmed Lyme” data was not included in
analysis of
safety and efficacy of the vaccine. Less than 5 bands-Lyme data was
simply discarded.
(OspA and B were excluded in CDC’s IgG.)
Gad-MRI has been used in humans to detect spirochetal meningitis.
Contrast enhancement of the cerebrospinal fluid on MRI in two cases of
spirochaetal
meningitis., Good CD, Jager HR., Lysholm Radiological Department,
National Hospital
for Neurology and Neurosurgery, London, UK.,
“We report two patients with meningitis due to spirochaetal infection,
both of whom
showed diffusely enhancing meninges around the brain and spinal cord.
In addition,
there was enhancement of the cerebrospinal fluid after intravenous
administration
of Gd-DTPA.”
PMID: 10929307
It is not known why this is method not used more commonly. It seems
that this might
be more economical and specific than a neuropsychiatric evaluation.
EEG
Changes in electroencephalography, consistent with delirium, were
identified in
Lyme patients:
QEEG and evoked potentials in central nervous system Lyme disease.,
Chabot RJ, Sigal
LH., Clin Electroencephalogr. 1995 Jul;26(3):137-45.
“Quantitative EEG, flash visual evoked potentials, auditory evoked
potentials to
common and rare tones, and median nerve somatosensory evoked
potentials were obtained
from 12 patients with active CNS Lyme disease and from 11 patients
previously treated
for active CNS Lyme disease. Abnormal QEEG and/or EPs were found in
75% of the active
Lyme disease patients and in 54% of the post CNS Lyme disease
patients. Three different
types of neurophysiological abnormality were observed in these
patients including
QEEG slowing, possible signs of cortical hyperexcitability, and focal
patterns indicating
disturbed interhemispheric relationships. In patients tested before
and after treatment
QEEG and EP normalization was associated with clinical improvement.”
PMID: 7554300
Compare to:
The role of catastrophizing in the pain and depression of women with
fibromyalgia
syndrome. Arthritis Rheum 2000 Nov;43(11):2493-500, Hassett AL, Cone
JD, Patella
SJ, Sigal LH.,
Department of Medicine, University of Medicine and Dentistry of New
Jersey-Robert
Wood Johnson Medical School, New Brunswick 08903, USA.
“OBJECTIVE: Although 2 recent studies have found associations between
catastrophizing
and poor medical outcomes in patients with fibromyalgia syndrome
(FMS), neither
assessed these findings in comparison with a similar group of patients
with chronic
pain. Our study examined the complex relationships between depression,
catastrophizing,
and the multidimensional aspects of pain in women with FMS and
compared these relationships
with those in women with rheumatoid arthritis (RA). METHODS: Sixty-
four FMS patients
and 30 RA patients completed
the Coping Strategies Questionnaire (CSQ), the Beck Depression
Inventory II (BDI-II),
and the McGill Pain Questionnaire. RESULTS: Compared with subjects
with RA, FMS
subjects scored significantly higher on the catastrophizing subscale
of the CSQ.
FMS patients also earned higher scores on overall depression and on
the cognitive
subscale of the BDI-II. Furthermore, the
relationship between catastrophizing and depression was significant in
the FMS group
only. Regression analyses revealed that in FMS, catastrophizing as a
measure of
coping predicted patients' perception of pain better than demographic
variables
such as age, duration of illness, and education. CONCLUSION: Cognitive
factors,
such as catastrophizing and depressive self-statements, have a more
pronounced role
in the self-reported pain of patients with FMS than in patients with
RA. Clinically,
this indicates that treating pain and depression in FMS by adding
cognitive therapy
and coping skills components to a comprehensive treatment program may
improve the
outcomes obtained with pharmacologic interventions.” PMID: 11083273
The above two examples show the inconsistent and non-systematic use of
objective
measures, in addition to non-validated-by-physiology subjective
measures, deployed
in service of Managed Care financial goals.
Leonard Sigal: Chapter 8, page 145, Rahn and Evans’ book, “Lyme
Disease, ACP Key
Diseases Series”, 1998
“Lyme Anxiety
Lyme anxiety is common in and near areas endemic for Lyme disease.
There is widespread
concern that Lyme disease is incurable and that this infection can
only be brought
into temporary remission and will continue to flare. With widespread
anxiety about
Lyme disease has come Munchausen syndrome and Munchausen by Proxy in
those concerned
about Lyme disease. The psychologic and financial costs of the
misdiagnosis of
“chronic” Lyme disease are staggering but have not been considered in
most discussions
of the public burden of the mismanagement of Lyme disease.”
DYSREGULATION OF CSF MONOAMINES AND CYTOKINES
Cytokines
IL-6 in the CSF is associated with physical and emotional depression.
The downstream
effect of increased IL-6 in the CNS on neurotransmission needs further
study.
Interleukin-6 is expressed at high levels in the CNS in Lyme
neuroborreliosis.,
Neurology 1997 Jul;49(1):147-52, Pachner AR, Amemiya K, Delaney E,
O'Neill
T, Hughes CA, Zhang WF., Department of Neurology, Georgetown
University School of
Medicine, Washington,
DC 20007, USA.
In patients with Lyme neuroborreliosis, inflammation and symptoms of
fatigue and
malaise occur out of proportion to the relatively low number of
spirochetes present.
Previous studies have identified interleukin-6 (IL-6) as a candidate
molecule for
amplification of CNS inflammation in this disease. We pursued this
possibility by
measuring cytokine gene expression by reverse-transcriptase polymerase
chain reaction
(RT-PCR) in the brain of rhesus macaques actively
infected with Borrelia burgdorferi. Samples of brain tissue were
screened for IL-6
and interferon gamma using RT-PCR-ELISA, a technique that uses RT-PCR,
subsequent
hybridization of the PCR product with a biotinylated probe, and
capture and ELISA
readout of hybridization product. The number of copies in positive
samples was then
quantitated using qRT-PCR-ELISA, in which wild-type cytokine cDNA
competes with
recombinant competitor DNA in the PCR. Elevated
levels of IL-6 cDNA and, to a lesser extent, interferon gamma were
detected in three
of three nonhuman primates with persistent infection with B
burgdorferi, whereas
the brains of three uninfected animals and undetectable levels of gene
expression
of these cytokines. These data support the hypothesis that cytokines
such as IL-6
are important amplification molecules for CNS inflammation in Lyme
neuroborreliosis.PMID:
9222183
IL-10
The following excerpt was taken from the results section of a report
of an experiment
ex vivo. No data was been published as per a search of MEDLINE for
the query parameters:
“borrelia and CSF and IL-10”. It is not known the influence of IL-10
on cognitive
changes. It is suspected that IL-10 plays a role in the persistence
of the spirochete.
OspA appears to exert an effect on IL-10 expression and might play a
role in vaccine
adverse events (Haupl T, Landgraf S, et al, FEMS Immunol Med Microbiol
1997 Sep;19(1):15-23:
“ High induction of IL-10 by L-OspA further suggested a negative
feedback on monocyte
activation by the lipidated form.” Activation of monocytes by three
OspA vaccine
candidates: lipoprotein OspA is a potent stimulator of monokines.).
Modulation of cytokine release in ex vivo-stimulated blood from
borreliosis patients.
Infect Immun 2001 Feb;69(2):687-94, Diterich I, Harter L, Hassler D,
Wendel A, Hartung
T., Biochemical Pharmacology, Department of Biology, University of
Konstanz, D-78457
Konstanz, Germany.
(From the Results Section):
“To compare the patterns of cytokine release induced by LPS and
Borrelia lysate,
the concentrations of endotoxin from four different LPS preparations
were adjusted
to induce the same levels of TNF- release as seen with 10 µg of
protein per ml
of Borrelia lysate. The release of the cytokines TNF- , IFN- , G-CSF,
and IL-10
induced by endotoxins from S. enterica serovar Abortusequi (200 pg/
ml), E. coli
(10 ng/ml), K. pneumoniae (100 pg/ml), and S. enterica serovar
Enteritidis (50 pg/ml)
was uniform in blood from healthy volunteers (Fig. 3), suggesting that
different
endotoxins share a leukocyte activation principle. However, a
pronounced difference
was seen between the four LPS preparations and the Borrelia lysate: at
concentrations
which induced the same TNF- release as 10 µg of protein per ml of
Borrelia lysate,
endotoxins induced much more IFN- than Borrelia lysate did. Instead,
Borrelia lysate
induced a 5- to 10-fold-higher release of the anti-inflammatory
cytokines IL-10
and G-CSF than the LPS preparations did. The lysates from other
Borrelia species,
i.e., B. afzelii and B. garinii, induced the same cytokine pattern as
did those
from B. burgdorferi (data not shown). These findings show that LPS
induces the release
predominantly of the proinflammatory cytokine IFN- while Borrelia
lysate is a stronger
inducer of the anti-inflammatory cytokines IL-10 and G-CSF. Such an
inverse cytokine
induction pattern demonstrates that the immunostimulatory components
of B. burgdorferi
differ from those of endotoxins.”
IL-10 has not been reported found in the CSF of borreliosis patients
in MEDLINE.
This may be a failure of search strategy.
There is other cytokine dysregulation in borreliosis. These were only
a sampling.
It needs to be looked at systematically and probably put into a
database. Different
combinations of TBDs may have different effects. Note that the above
two examples
were controlled studies of infecting monkeys with Bb alone.
Monoamines
Neurotransmitters and their metabolites in the CSF of post-meningitis
patients have
not been extensively studied. Evidence of immune activation such as
quinolinic
acid in HIV and neuroborreliosis and behavioral effects suggest that
there may be
evidence of dysregulation, which can be correlated. MMPs are related
to neurologic
sequelae in childhood meningitis with degree of damage a function of
concentration
dependence. Monoamine dysregulation in the CSF of autistic children
has been studied.
MMR vaccination in childhood has been implicated in the development of
autism, particularly
since many of these children experience normal development until
approximately 18
months of age, the recommended age to administer MMR. This is not to
say that MMR
vaccination results in autism, this is to say, does a strong immune
response from
an immunogen result in permanent or temporary changes to receptor
profiles, neurotransmitters
and their degradants concentration that can be detected in CSF, or
evidence of abnormal
differentiation of brain cells that can be detected via monoamine
assay?
Vaccination effects other than autism, due to MHC capacities, are now
being studied,
but from the reverse standpoint. Scientists are now looking at
targeting vaccines
towards people predisposed to autoimmune disease by HLA
identification.
ANTIBODIES TO HEAT SHOCK PROTEINS
Antibodies to heat shock proteins (sometimes considered part of
“common antigens”)
are considered possible cross-reacting antibodies, since microbial and
mammalian
heat shock proteins are similar. There are times when mammalian heat
shock proteins
are surface-expressed. Bb contains at least 12 heat shock proteins.
This is not
surprising, since it has multiple hosts, including the tick, which
often survives
near zero C temperatures. Bb itself survives freezing, as the
spirochete has been
recovered from frozen banked blood. Lyme patients are prohibited from
donating
blood to the Red Cross.
Heat shock proteins (HSPs) of Bb expressed in humans have apparent
molecular weights
of 60, 62, 72, 74 kilodaltons. P66, one of at least three pore-
forming antigens
of Bb (others: P28, P45) has qualities of heat shock proteins and may
bind heat
shock protein antibodies. HSPs are not always detectable via
antibody. They are
not as immunogenic in some people as they are in others. When they
show up in neurologically
impaired patients, one might expect an MS-like syndrome. HSPs
obviously have less
specificity than Bb-specific lipoproteins, but do not exclude illness
symptoms.
Characterization of the heat shock response and identification of heat
shock protein
antigens of Borrelia burgdorferi., Infect Immun 1990 Jul;58(7):
2186-91, Carreiro
MM, Laux DC, Nelson DR., Department of Microbiology, University of
Rhode Island,
Kingston 02881.
“The heat shock response of Borrelia burgdorferi B31 cells was
characterized with
regard to the heat shock proteins (Hsps) produced. Five to seven Hsps
were detected
by sodium dodecyl sulfate-gel electrophoresis and fluorography of
proteins from
cells labeled with [35S]methionine after shifts from 33 degrees C to
37 or 40 degrees
C or from 20 degrees C to 33, 37, or 40 degrees C. Analysis of
[35S]methionine-labeled
Hsps by two-dimensional electrophoresis and
autoradiography revealed 12 Hsps. Western immunoblot analysis with
antisera to highly
conserved Escherichia coli and Mycobacterium tuberculosis Hsps
revealed a single
72-kilodalton (kDa) protein band that reacted with antibodies to E.
coli DnaK and
with antibodies to the M. tuberculosis 71-kDa Hsp homolog of E. coli
DnaK. Two proteins
with apparent molecular masses of 66 and 60 kDa reacted with
antibodies against
the M. tuberculosis 65-kDa Hsp homolog of E. coli GroEL. Human immune
sera collected
from patients with Lyme disease reacted with both
the 66-kDa Hsp and the 60-kDa Hsp but failed to react with the 72-kDa
Hsp. These
data are discussed with regard to the possibility that host
recognition of highly
conserved epitopes of GroEL homologs of B. burgdorferi may result in
autoimmune
reactions causing arthritis and other pathologies.” PMID: 2194963
Anti-alpha B-crystallin immunoreactivity in inflammatory nervous
system
diseases., J Neurol 2000 Dec;247(12):935-9, Celet B, Akman-Demir G,
Serdaroglu
P, Yentur SP, Tasci B, van Noort JM, Eraksoy M, Saruhan-Direskeneli
G., Department
of Physiology, Istanbul Medical Faculty, Istanbul University,
Istanbul, Turkey.
alpha B-Crystallin, a small heat shock protein, is an immunodominant
antigen with
increased tissue expression in demyelination. To investigate the
humoral response
against alpha B-crystallin, the sera and CSF samples of patients with
multiple sclerosis
(MS), Guillain-Barre syndrome (GBS), neuro-Behcet's disease (NBD) and
other
non-inflammatory neurological diseases (NIND) were screened by enzyme-
linked immunosorbent
assay for anti-alpha B-crystallin IgG and IgM antibodies. Serum and
CSF IgG antibody
responses to alpha B-crystallin were significantly elevated only in
NBD patients
(serum IgG, NBD 1.29 +/- 0.49 vs. NIND 0.95 +/- 0.39, P = 0.01; CSF
IgG, NBD
1.22 +/- 0.64 vs. NIND 0.81 +/- 0.35, P = 0.01). Similarly, high serum
IgM antibody
titres were also detected in NBD (1.83 +/- 0.72 vs. 1.16 +/- 0.49, P =
0.0005)
and in MS (1.57 +/- 1.07, P = 0.046), whereas elevated CSF IgM
responses were
observed only in GBS (2.09 +/- 1.09 vs. 1.41 +/- 0.7, P = 0.007).
Humoral responses
against alpha B-crystallin are increased in NBD and GBS, which may
implicate this
central nervous system antigen in the causation and pathogenesis of
these inflammatory
nervous system
disorders. PMID: 11200685
Molecular mimicry in Lyme disease: monoclonal antibody H9724 to B.
burgdorferi flagellin
specifically detects chaperonin-HSP60., Biochim Biophys Acta 1993 Mar
24;1181(1):97-100
Dai Z, Lackland H, Stein S, Li Q, Radziewicz R, Williams S, Sigal LH.
Center for
Advanced Biotechnology and Medicine, Piscataway, NJ.
“A monoclonal antibody (H9724), specific for the 41-kDa flagellar
protein of the
Lyme disease pathogen Borrelia burgdorferi, cross-reacts with human
axons and detects
one major protein in human neuroblastoma cell extracts. The homologous
cross-reacting
protein has now been isolated from calf adrenal and identified as
chaperonin-HSP60
by N-terminal sequencing.” PMID: 8096152
This citation demonstrates the need for a formal physician education
program in
Rhode Island. In 2000, South County Hospital invited Dr. Sigal to
come and speak
about Fibromyalgia at their Annual “Diseases of Summer” Conference.
Fibromyalgia
is not a disease of summer, nor is it associated with antibodies to
heat shock proteins,
particularly.
The 60-62 kD Bb heat shock protein is not a CDC antigen. That an
antibody to a
heat shock protein from Bb sonicate shows up in a patient with
suspected TBDs implies
simply that: The patient has a heat shock protein antibody that they
are reacting
to, not necessarily from Bb, possibly cross-reactive. The patient may
have neurologic
symptoms, as a consequence.
Some people exposed to bacterial HSPs develop autoimmune disorders.
As a result,
research in vaccines is heading in this direction. It is thought that
exposure
to bacterial HSPs before involution of the thymus may protect against
autoimmune
disease. HSPs as vaccines is a direction of research in development
of vaccines
against MS (a search of the patent database will best reveal the
research). Children
tend to have better outcomes from Bb exposure. Some children with
congenital Lyme
exposure and persisting antibodies have no illness symptoms. They may
have thus
become immune tolerant. Others clearly do not fair as well, as is
seen also in
congenital syphilis.
It makes no sense to make proclaimations whatsoever about Lyme and
long term illness,
or Lyme and pregnancy when in 100 years, we still know so little about
spirochetes.
Again, currently used detection methods and case criteria are not only
poor, but
negligent. The variables are not under control, as we learn from
other autoimmune
diseases.
QUALIFYING PATIENT PRESENTATION
The current state of the art in analysis of the psychological
condition of TBDs
patients is that many of the neuropsychiatric testing instruments
typically employed
have not been validated against the presence of the biophysical
markers of disease
state. Neuroborreliosis patients present with psychiatric symptoms
ranging from
mild depression to psychosis, but essentially fall within the scope of
a mild Delirium,
as described by the Comprehensive Textbook of Psychiatry, 2002. The
following
is an older, but adequate description:
DELIRIUM-Diagnostic Criteria
· Reduced ability to maintain attention to external stimuli and to
appropriately
shift attention to new external stimuli. Thus at least 1 of:
o Questions had to be repeated because attention wandered
o Perseverated answers to previous questions
· Disorganized thinking
· Confusion developed over a short period of time
· Fluctuating level of confusion
· At least 2 out of 6 of:
o Reduced level of consciousness
o Perceptual disturbances
o Disturbance of sleep-wake cycle
o Increased or decreased psychomotor activity
o Disorientation to time, place, or person
o Memory impairment
· Either of the following:
o Evidence that an organic factor initiated and maintained this
confusion
o Confusion cannot be accounted for by any nonorganic mental disorder
Associated Features
· Learning Problem
· Dysarthria/Involuntary Movement
· Hypoactivity
· Psychotic
· Euphoric Mood
· Depressed Mood
· Somatic/Sexual Dysfunction
· Hyperactivity
· Addiction
· Sexually Deviant Behavior
Differential Diagnosis
Schizophrenia; Schizophreniform Disorder; and other psychotic
disorders; Dementia;
Factitious Disorder with Psychological Symptoms.
Internet Mental Health (www.mentalhealth.com) copyright © 1995-2000 by
Phillip W.
Long, M.D.
Inasmuch as biopsychiatry relies on pharmacological treatment of a
brain disease,
primarily within the framework of neurotransmitter imbalance, Lyme as
a brain disease
as not been similarly probed. This is unsurprising, since delirium is
more commonly
associated with an organic problem, such as CNS infection; such as in
Lyme disease.
That Steere suggests Lyme patients have “some psychiatric disorder” is
true, as
shown above. However, the other publicly proclaimed terms of
endearment of Lyme
patients have included “Irrational”, Munchausens, and Paranoia. One
would think
such statements would require proof in the form of demonstrating the
neurotransmitter
imbalance criteria of biopsychiatry, the DSM-IV, and criteria for the
development
of the targeted psychopharmaceuticals.
Stigmatizing Lyme disease in this way also works in reverse. Dr.
Leonard Sigal
has “studied” Fibromyalgia and determined that “catastrophizing” plays
an important
role. Also, he suggests that Lyme patients’ demonstrate “Illness
behavior” (Millar
vs. Kenny and Glenn, SUPERIOR COURT OF NEW JERSEY LAW DIVISION-OCEAN
COUNTY DOCKET
NO. L 2148-94). for which behavior modification is indicated, and
that Lyme disease
patients have Fibromyalgia instead of Lyme disease when they don’t
have 5 of 10
bands. Sigal was also the principle investigator in a vaccine trial,
Connaught’s,
in which the Dressler criteria was also employed, and both trials were
started using
this standard, before the standard was in place (CDC’s Dearborn
Conference).
We fear that such statements about the mental disorder of Lyme
borreliosis might
have an adverse effect on the social consequences to patients with
other mental
illnesses. If illness behavior is mental illness, then mental illness
is illness
behavior, and persons demonstrating signs of mental illness might
receive behavior
modification therapy instead of psychopharmacotherapy, which may only
exacerbate
their mental illness and related suffering. Conversely, anyone with a
new medical
complaint who demonstrates illness behavior might be sent for
psychopharmacotherapy
instead of a proper medical evaluation.
The Evidence-Based Medicine Spin Engine (EBMSE) is a risk to all
populations. Tick
bites are random. It cannot be said otherwise. If next we are to
hear that chronic
Lyme patients had a pre-existing mental illness, via the EBMSE, we
would not be
surprised. The same favor was granted Gulf War Veterans and CFIDS
patients. Fibromyalgia
patients just plain exaggerate, according to Sigal, but how much
closer do these
“studies” bring us to symptom relief? Are we getting what we paid for
as taxpayers?
If we truly want decreased cost of healthcare, we need to stop wasting
money by
spinning diseases, only to have to repeat the studies later because
the empirical
evidence, reality, keeps showing up. Meanwhile, patients linger
miserably in the
MD Pinball Zone, continually driving new medical claims. The burden
of decreasing
healthcare expenses therefore falls on the shoulders of US
government. They must
excise this EBMSE tumor. It can be found originating at the CDC under
the misnomer
“Agency for Healthcare Research and Quality”.
In order to avoid misdiagnosis of TBDs patients based on their
suspected psychiatric
symptoms, RI needs a database of patient/pathological objective
status. Psychological
analyses of suspected TBDS patients are not recommended until the
psychological
testing methods have been validated against the pathophysiology
present. For example,
if 80% of neuroborreliosis patients present with abnormal levels of
matrix-metalloproteinases
and IL-6 in their cerebrospinal fluid, psychiatric instruments such as
the Beck
Depression inventory or MMPIs need to be validated in patients who
have these markers
of pathophysiology. The hazards of misuse of psychological testing
are misdiagnosis
and thus inadequate treatment and prolonged mental and physical
discomfort.
A 4.8 million dollar research program is currently underway at
Columbia to discover
at least the correlates in neurocognitive testing results in known
infected borreliosis
patients, and effects of long term treatment, inasmuch as CDC IgG
criteria could
be valid for current infection (it is not). PCR-positive patients are
also eligible
for enrollment, although these patients are rare. At the conclusion
of that study,
we will at least be certain of some of the elements of the
neurocognitive presentation
of the PCR positive patients, if any such patients are to be found
with Mayo’s Bb
primers. Exposure to Bb, via CDC diagnostic criteria, plus
neurocognitive results
will contribute to a database. We will see what the presence of Lyme
arthritis
IgG antibodies means in Chronic Neurologic Lyme disease to the extent
that the neurocognitive
testing is valid.
Patients with preexisting neuropsychiatric presentation are excluded
from the Columbia
study and therefore this is a realm and patient set for future
discovery. It has
been found by Dr. Klempner of Tufts a high prevalence of HLA-DQB1*0602
patients
in the seronegative Lyme cohort of his 4.7 million dollar retreatment
study of Chronic
Lyme patients. These *0602 patients have a tendency for low immune
competence.
“We demonstrated that HLA-DQB1*0605 was associated with a possible
increased risk
of susceptibility to infection in African Americans and that DQB1*0602
was associated
with a possible increased risk of infection in Caucasians.”-- Achord
AP, et al,
HLA-DQB1 markers associated with human immunodeficiency virus type I
disease progression.
Pathobiology. 1997;65(4):210-5. PMID: 9396045
Since *0602 is associated with Lupus, MS, and narcolepsy as well, it
must be noted
that there are recognized psychiatric manifestations. There may be
infectious etiologies
of mental illnesses. Yale University recently undertook study of the
treatment
of children with a susceptibility to Staphylococcus infection and the
noted resultant
development of Obsessive Compulsive Disorder (Pediatric Autoimmune
Neuropsychiatric
Diseases Disorder Associated With Group A Streptococcal Infection
(PANDAS) and performed
a clinical trial of treating these patients with prophylactic
antibiotics.
Higher prevalence of antibodies to Borrelia burgdorferi in psychiatric
patients
than in healthy subjects., Am J Psychiatry 2002 Feb;159(2):297-301,
Hajek T, Paskova
B, Janovska D, Bahbouh R, Hajek P, Libiger J, Hoschl C., Prague
Psychiatric Center,
Department of Epidemiology, Charles University, Third Faculty of
Medicine, Czech
Republic
“OBJECTIVE: Borrelia burgdorferi infection can affect the CNS and
mimic psychiatric
disorders. It is not known whether Borrelia burgdorferi contributes to
overall psychiatric
morbidity. The authors compared the prevalence of antibodies to
Borrelia burgdorferi
in groups of psychiatric patients and healthy subjects to find out
whether there
is an association between this infection and psychiatric morbidity.
METHOD: Between
1995 and 1999 the authors screened for antibodies to Borrelia
burgdorferi in 926
psychiatric patients consecutively admitted to Prague Psychiatric
Center. They compared
the results of this screening with findings from 884 consecutive
healthy subjects
who took part in an epidemiological survey of antibodies to Borrelia
burgdorferi
in the general population of the Czech Republic. Sera were tested by
means of enzyme-linked
immunosorbent assay. Circulating immune complexes were isolated by
polyethylene
glycol precipitation. To control for potential confounders, the two
groups of patients
and healthy subjects were matched according to gender and age. Results
were obtained
in a sample of 499 matched pairs. RESULTS: Among the matched pairs,
166 (33%) of
the psychiatric patients and 94 (19%) of the healthy comparison
subjects were seropositive
in at least one of the four assays. CONCLUSIONS: These findings
support the hypothesis
that there is an association between Borrelia burgdorferi infection
and psychiatric
morbidity. In countries where this infection is endemic, a proportion
of psychiatric
inpatients may be suffering from neuropathogenic effects of Borrelia
burgdorferi.”
PMID: 11823274
Not only do we want to know if there is an infectious etiology of
psychiatric diseases,
such that they might perhaps be treated and perhaps recover, this is a
place to
mine HLA data for developing concepts in prevention of neurologic
autoimmune diseases.
A characteristic of mental illnesses would be lack of ability to
communicate, or
even the desire, to make medical complaints. This report is clear
evidence that
illness behavior is not mental illness and mental illness is not
illness behavior.
These patients were first in a psychiatric hospital, and then someone
decided to
look to see if they were exposed. These were not patients who went to
went to a
non-psychiatric hospital with hypochondriacal or exaggerated
complaints. Clearly
there is a spectrum in symptom reporting habits in mental illnesses.
Factitious
disorders are uncommon and the current Managed Care contributions to
the understanding
and treatment of Lyme disease would not satisfy the goal of a
factitious disorder
such as Munchausens’: getting medical attention.
Studies such as the one above should be performed in the US, but not
with the CDC’s
HLA-DR4, or Lyme arthritis-related antibody scheme, because there is a
negative
association between rheumatoid arthritis and schizophrenia. There is
a negative
association between HLA-DR4 and schizophrenia:
At issue: schizophrenia and rheumatoid arthritis: the negative
association revisited.,
Schizophr Bull 1999;25(4):625-38, Oken RJ, Schulzer M., New York
State Institute
for Basic Research in Developmental Disabilities, Staten Island, USA.
“A strong negative association between schizophrenia and rheumatoid
arthritis (RA),
implying low comorbidity, has been found in 12 of 14 previous studies,
which we
review. To this literature we add two recently acquired data sets
encompassing 28,953
schizophrenia patients, only 31 of whom had comorbid RA. Integrating
our new data
into those of the previous nine studies, which
stratified their populations according to psychiatric diagnosis, we
obtain a median
frequency of RA in schizophrenia populations of 0.09 percent and a
mean frequency
of 0.66 percent, well below the expected range of 1 percent. These
data robustly
support prior studies. We also present a meta-analysis evaluating the
association
between the two diseases by integrating information derived from nine
data sets,
each furnishing an estimate of the relative risk of RA in
schizophrenia patients
versus that in other psychiatric patients. We find that the estimated
rate of RA
among schizophrenia patients is only 29 percent of the corresponding
rate in other
psychiatric patients. Further, the relative risk of RA in
schizophrenia patients
versus that in the general population is even less than 29 percent and
could be
as low as one-third of this value. We present a new hypothesis
involving the platelet
activating factor system in an effort to account for this negative
association and
review the suggestions of other investigators toward this end.
Finally, we consider
the glutamatergic system dysfunction hypothesis of schizophrenia and
suggest a possible
common pharmacological approach that may ameliorate some of the
symptomatology of
both schizophrenia and RA.” PMID: 10667736
HLA-DR4 and Lyme Arthritis:
Association of treatment-resistant chronic Lyme arthritis with HLA-DR4
and antibody
reactivity to OspA and OspB of Borrelia burgdorferi., Infect Immun
1993 Jul;61(7):2774-9,
Kalish RA, Leong JM, Steere AC, Division of Rheumatology/Immunology,
New England
Medical Center, Tufts University School of Medicine, Boston,
Massachusetts 02111.
“Chronic Lyme arthritis that is unresponsive to antibiotic therapy is
associated
with an increased frequency of the HLA-DR4 specificity. To determine
whether the
immune response to a particular polypeptide of Borrelia burgdorferi
may be associated
with treatment-resistant chronic Lyme arthritis, we correlated the
clinical courses
and HLA-DR specificities of 128 patients with Lyme disease with their
antibody responses
to spirochetal polypeptides. Antibody reactivity was
determined by Western blotting (immunoblotting) with sonicated whole
B. burgdorferi
and recombinant forms of its outer surface proteins, OspA and OspB, as
the antigen
preparations. Of 15 patients monitored for 4 to 12 years, 11 (73%)
developed strong
immunoglobulin G responses to both OspA and OspB near the beginning of
prolonged
episodes of arthritis, from 5 months to 7 years after disease onset.
When single
serum samples from 80 patients with Lyme arthritis, were tested, 57
(71%) showed
antibody reactivity to recombinant Osp proteins; in contrast, none of
43 patients
who had erythema migrans or Lyme meningitis (P < 0.00001) and 1 of 5
patients
who had chronic neuroborreliosis but who never had arthritis (P =
0.03) showed
antibody reactivity to these proteins. Among the 60 antibiotic-treated
patients
with Lyme arthritis, those with the HLA-DR4 specificity and Osp
reactivity had arthritis
for a significantly longer time after treatment than those who lacked
Osp reactivity
(median duration, 9.5 versus 4 months; P = 0.009); a similar trend was
found
for the HLA-DR2 specificity. For other HLA-DR specificities, arthritis
resolved
within a median duration of 2 months in both Osp-reactive and
nonreactive patients.
We conclude
that the combination of the HLA-DR4 specificity and OspA or OspB
reactivity is associated
with chronic arthritis and the lack of a response to antibiotic
therapy.PMID: 7685738
Rheumatoid Arthritis and HLA-DR4
Rheumatoid arthritis (RA)-associated HLA-DR alleles form less stable
complexes with
class II-associated invariant chain peptide than non-RA-associated HLA-
DR alleles.,
J Immunol 2001 Dec 15;167(12):7157-68, Patil NS, Pashine A, Belmares
MP, Liu W,
Kaneshiro B, Rabinowitz J, McConnell H, Mellins ED., Department of
Pediatrics, Stanford
University School of Medicine, Stanford University, Stanford, CA
94305, USA. npa...@genencor.com
“Certain HLA-DR alleles confer strong susceptibility to the autoimmune
disease rheumatoid
arthritis (RA). We compared RA-associated alleles, HLA-DR*0401, HLA-
DR*0404, and
HLA-DR*0405, with closely related, non-RA-associated alleles, HLA-
DR*0402 and HLA-DR*0403,
to determine whether they differ in their interactions with the class
II chaperone,
invariant chain (Ii). Ii binds to class II molecules in the
endoplasmic reticulum,
inhibits binding of other ligands, and directs class II-Ii complexes
to endosomes,
where Ii is degraded to class II-associated Ii peptide (CLIP). To
evaluate the interaction
of Ii and CLIP with these DR4 alleles, we introduced HLA-DR*0401,
*0402, and *0404
alleles into a human B cell line that lacked endogenous HLA-DR or HLA-
DM molecules.
In a similar experiment, we introduced HLA-DR*0403 and *0405 into an
HLA-DM-expressing
B cell line, 8.1.6, and its DM-negative derivative, 9.5.3. Surface
abundance of
DR4-CLIP peptide complexes and their susceptibility to SDS-induced
denaturation
suggested that the different DR4-CLIP complexes had different
stabilities. Pulse-chase
experiments showed CLIP dissociated more rapidly from RA-associated DR
molecules
in B cell lines. In vitro assays using soluble rDR4 molecules showed
that DR-CLIP
complexes of DR*0401 and DR*0404 were less stable than complexes of
DR*0402. Using
CLIP peptide variants, we mapped the reduced CLIP interaction of RA-
associated alleles
to the shared epitope
region. The reduced interaction of RA-associated HLA-DR4 molecules
with CLIP may
contribute to the pathophysiology of autoimmunity in RA.” PMID:
11739539
If autoimmune phenomena are generally thought to occur post-infection,
then Dr.
Klempner has surely found a neuroautoimmune haplotype in great
frequency in the
seronegative borreliosis patients, which, if it had been reported,
would have lent
credibility to patient complaints of chronic illness. Instead, the
public relations’
focus announced, far and wide, that patients should not be given “long
term” antibiotic
treatment. The degree of political ferocity behind these
machinations, is evidenced
by Klempner’s suggestion to NEJM editors, that his “results” be “Early
Released”
in June instead of July, 2001, at the beginning of tick-infection
season. Very
important data regarding the neuroautoimmune association with markers
of pathophysiology
found in Chronic Lyme patients (MMPs and *0602) was not reported last
summer in
the NEJM, but Dr. Klempner mentioned these findings at the South
County Hospital
“Diseases of Summer Conference”, 2001.
The simplest and most economical approach to managing a patient who,
in a Lyme endemic
area, complains of a chronic fatiguing illness, chronic muscular and
perhaps joint
paint, and a memory problem, would be to find out why, using
diagnostic laboratory
analyses. If the patient demonstrates illness behavior, they might
have: Illness?
---
SUMMARY OF RI TBDs MANAGEMENT OBJECTIVES
A statewide physician education program is clearly necessary to
patient management.
Improved surveillance for known and new TBDs, i.e., The development of
a sentinel
TBDs identification database and DNA ident/sequencing.
Immediate testing improvement measures via the discontinuation of the
use of labs
that fail to report correctly or use even the current US recommended
stains.
The development of a patient/pathology database to identify cohorts of
patients
who would be eligible for neuroprotective regimens such as MMP
inhibition, therapeutic
kynurenines, or whatever is on the horizon in new antibiotic trials,
blood brain
barrier, physical, and cognitive rehabilitation after resolution of
infections,
when or if that becomes possible.
===
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