| Chuck 2005-08-27, 11:53 am |
| Well, here are some markers of disease, in case the ID Society doesn't
know how to look for pathology, nor knows anything about lab
techniques, and want to spend all their time being SUCK-UPS to IOM, who
is BigBusinessMedicine. DOT COM
IOM says, "Bend over."
ISDA says "How faaaah bosssss?"
This is old, but the markers of disease are important, See the second
half.
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RECOMMENDATIONS for RHODE ISLAND'S TBDs COMMISSION, APRIL 2002
A MANAGEMENT PLAN
TBDs MANAGEMENT OBJECTIVES
1=2E A statewide physician education program is clearly necessary to
patient management.
2=2E Improved surveillance for known and new TBDs and the development of
a sentinel TBDs identification database and DNA ident/sequencing
3=2E 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=2E 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=2E Observation and description of a phenomenon or group of phenomena.
2=2E 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=2E Use of the hypothesis to predict the existence of other phenomena,
or to predict quantitatively the results of new observations.
4=2E 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.
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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....me/Frame-MiQ-m=
icrobiological53.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 =86Corporaci=F3n para Investigaciones
Biol=F3gicas, Medell=EDn, 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=2E 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=3D0.03), 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 =B5g 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 =B5g 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=2E 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 =3D 0.01; CSF IgG, NBD
1=2E22 +/- 0.64 vs. NIND 0.81 +/- 0.35, P =3D 0.01). Similarly, high serum
IgM antibody titres were also detected in NBD (1.83 +/- 0.72 vs. 1.16
+/- 0.49, P =3D 0.0005) and in MS (1.57 +/- 1.07, P =3D 0.046), whereas
elevated CSF IgM responses were observed only in GBS (2.09 +/- 1.09 vs.
1=2E41 +/- 0.7, P =3D 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
=B7 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
=B7 Disorganized thinking
=B7 Confusion developed over a short period of time
=B7 Fluctuating level of confusion
=B7 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
=B7 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
=B7 Learning Problem
=B7 Dysarthria/Involuntary Movement
=B7 Hypoactivity
=B7 Psychotic
=B7 Euphoric Mood
=B7 Depressed Mood
=B7 Somatic/Sexual Dysfunction
=B7 Hyperactivity
=B7 Addiction
=B7 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 =A9 1995-2000 by
Phillip W. Long, M.D.
Inasmuch as biopsychiatry relies on pharmacological treatment of a
brain disease, primarily within the framew |