Autor: Palund
Email: monkeypa@dircon.co.uk
Datum: 25.2.1996
Forum: sci.med.diseases.lyme
MANAGING LYME DISEASE
DIAGNOSTIC HINTS AND TREATMENT GUIDELINES
FOR LYME BORRELIOSIS
JOSEPH J. BURRASCANO, JR., M.D.
tenth edition
copyright February, 1995
TABLE OF CONTENTS
INTRODUCTION
DIAGNOSTIC HINTS
ERYTHEMA MIGRANS
DIAGNOSTIC TESTING
DIAGNOSTIC CRITERIA
SYMPTOM CHECKLIST
LYME DISEASE TREATMENT GUIDELINES
GENERAL INFORMATION
TREATMENT INFORMATION
MONITORING OF THERAPY
ANTIBIOTIC CHOICES
TREATMENT CATEGORIES
Prophylaxis
For known tick bites
Early localized disease
Disseminated disease
1. early
2. late
Alternate scheduling of antibiotic treatments
1. pulse therapy
2. combination therapy
Refractory disease
1. responsive to antibiotic therapy
2. non-responsive to antibiotic therapy
ADJUNCTIVE THERAPY
SAFETY
NUTRITIONAL SUPPLEMENTS IN CHRONIC LYME DISEASE
LYME DISEASE REHABILITATION
REHAB THERAPY PRESCRIPTION
MANAGING YEAST INFECTIONS
PATIENT INSTRUCTIONS ON TICK BITE REVENTION AND TICK REMOVAL
APPENDIX
Rationale for treating tick bites
Rationale for treatment recommendations
SUGGESTED READING
INTRODUCTION
The diagnosis and treatment of Lyme Disease is entering a new era,
with the replacement of simplistic approaches with more modern ones
based on better knowledge, more experience, and the application of
common sense. This has resulted in an expansion of syndromes
attributable to Lyme, and new treatment recommendations regarding
both drug and dose. The existence of seronegativity and chronic
persistent infection has been confirmed, as have relapses and
treatment failures. With more careful dosing and more prolonged
treatment durations, chronic symptoms can be eliminated or prevented.
This manuscript is the most detailed clinical guide currently
available. It contains up to date information gathered from the
literature, from scientific meetings, and also from the combined
experiences of clinicians who collectively follow thousands of
patients with Lyme. Because there is no single best diagnostic
test, and no single best drug for treatment, a great deal of
background information is provided and general guidelines are listed
so the treating physician can decide on an individual basis how best
to proceed.
Lyme remains a clinical diagnosis as no currently available test, no
matter the source or type, is definitive in confirming whether an
infection with Borrelia burgdorferi is present, or if so, whether
the infection is active and responsible for the patient's symptoms.
The entire clinical picture must be taken into account, including a
search for the many subtleties that experienced clinicians have
learned to look for.
Treatment remains difficult. It is impossible to know how much
medication will be necessary to control the infection, because
response to therapy is mostly subjective. Also, it cannot be
determined which of the many complaints will improve with further
antibiotics, and which are permanent. There is no test available
that relates to how effective the treatment regimen is, and there is
no test for cure.
Patient diaries that succinctly outline their symptoms over a course
of therapy are vital, and as many objective measures as possible
should be followed, such as temperature graphs, notes from physical
therapists, and physical findings.
The concept of a "therapeutic alliance" between the caregiver and
patient means that the patient must take responsibility for complying
with the recommendations given, maintaining the best possible health
status, reporting promptly any problems or new symptoms, and
especially in realizing that despite all our best efforts, success in
diagnosis and treatment is never assured.
I hope you find the following reading helpful and interesting!
-----
DIAGNOSTIC HINTS
The diagnosis of Lyme Disease is a clinical one, as serologies test
only for the presence of antibodies, and do not serve as a marker of
clinical disease. False negative serologies are common (estimated at
30%) and false positives occur in up to 10% of patients.
Consideration should be given to possible tick exposure, rashes (even
atypical ones), evolution of typical symptoms in a previously
asymptomatic individual, and results of tests for Lyme. A great deal
of effort must be made in ruling out similarly presenting illnesses,
for often Lyme becomes a diagnosis of exclusion. Another very
important factor is response to treatment, presence or absence of
Jarisch Herxheimer-like reactions, and improvement with therapy.
ERYTHEMA MIGRANS
Erythema migrans is diagnostic of Lyme Disease, but may not be present
or may go unnoticed by the patient. It is usually an erythematous,
centrifugally expanding lesion that is raised and warm. Although
painless, sometimes there is mild stinging or pruritus. The EM rash
will begin at least four days after the bite, but may not appear for
several weeks, and may or may not be associated with constitutional
symptoms. Multiple lesions are present less than 10% of the time.
Some lesions have an atypical appearance and skin biopsy specimens may
be helpful. When a vesicular center is seen, this may represent a
mixed infection, involving other organisms besides B. burgdorferi.
DIAGNOSTIC TESTING
When reactive, serologies indicate exposure only and do not directly
indicate whether the spirochete is now currently present. Therefore,
there is no substitute for a detailed, in-depth history. Please refer
to the attached patient questionnaire for guidelines. Have the
patients keep a journal of their symptoms and have them take their
temperature three times a day - morning, late afternoon, and bedtime.
Often you see a late afternoon low grade fever on the order of 99-100
otherwise unnoticed by the patient. Occasionally, late cases of Lyme
are seronegative. Some of these cases (36%) will transiently become
seropositive at the completion of successful therapy.
Because Lyme serologies often give inconsistent results, test at more
than one laboratory using if possible different methods. I recommend
western blotting to confirm serologic results. Some laboratories
report both IgM and IgG titers. However, be aware that clinical
studies have shown that in late disease there may be repeatedly
peaking IgM's and therefore a reactive IgM may not differentiate early
from late disease, but does suggest an active infection.
Western blots are reported by showing which bands are reactive. 41 KD
bands appear the earliest but cross react with T. pallidum and several
other spirochetes. The 22KD, 39KD, 83KD and the 94KD bands are the
most specific but appear later or may not appear at all. The other
specific bands, which corresponds to Osp A and Osp B (31KD and 34KD
respectively) do not always appear and may not be as specific as
those listed above. As a western blot is very difficult for the lab
to interpret objectively, they have fallen out of favor as a primary
diagnostic test. You may need to call the lab to discuss the results
with the test supervisor. You need to see at least the 41KD and
one of these specific bands. 55KD, 60KD, 66KD, and 73KD are
nonspecific and nondiagnostic.
Spinal taps are not routinely recommended, as a negative tap does not
rule out Lyme. A recent study has shown that antibodies to Bb ca be
detected in the CSF in only 20% of patients with late disease.
Therefore, spinal taps are performed in patients with pronounced
neurological manifestations, especially if they are seronegative or
are still significantly symptomatic after completion of treatment.
When done, the goal is to rule out other conditions, determine if Bb
antigens are present, and to determine whether Lyme antibodies are
being locally produced in the central nervous system. This is done by
comparing simultaneously drawn serum and CSF Lyme titres and relating
them to the IgG index. It is especially important to look for
elevated protein and mononuclear cells, which would dictate the need
for more aggressive therapy, as well as the opening pressure, which
can be elevated and add to headaches, especially in children.
The bottom line is that the diagnosis of Lyme is still a clinical one,
as no test currently available is 100% accurate. It is important to
note that the CDC's published reporting criteria are for surveillance
only, not for diagnosis. Therefore, a workable set of diagnostic
criteria were developed with the input of dozens of front line
physicians. The resultant document has proven to be extremely useful
not only to the clinician, but it also can help clarify the diagnosis
for third party payers and hospital utilization review committees.
The format consists of a point system that is simple, clear cut, and
amenable to revision and additions as newer testing technologies
appear. The entire document is reproduced below.
-----
LYME DISEASE DIAGNOSTIC CRITERIA RELATIVE VALUE
Tick exposure in an endemic region 1
Historical facts and evolution of symptoms consistent with Lyme 2
Systemic symptoms/signs consistent with Lyme
Disease (other potential diagnoses excluded)
Single system, e.g., monarthritis 1
Two or more systems, e.g., monarthritis
and facial palsy 3
Erythema Migrans 5
Acrodermatitis Chronica Atrophicans, biopsy confirmed 5
Seropositivity 2
Seroconversion (paired sera) 3
Tissue Microscopy - silver stain 3
Tissue Microscopy - monoclonal immunofluorescence 4
Culture Positivity 4
Borrelia Antigen Recovery (when validated) 3
Borrelia DNA Recovery (when validated) 3
-----
DIAGNOSIS
Definite Lyme Borreliosis 5
Probable Lyme Borreliosis 4
Possible Lyme Borreliosis 3
I suggest that when using these criteria, you state "possible, probable
or definite Lyme Borreliosis based upon the following criteria," then
list the criteria.
-----
SYMPTOM CHECK LIST
This is not meant to be used as a diagnostic tool, but is provided to
streamline the office interview.
NAME_______________________________________DATE__________________
RISK PROFILE (PLEASE CHECK)
Tick infested area__ Frequent outdoor activities__ Hiking__
Fishing__ Camping__ Gardening__ Hunting__ Ticks noted on pets__
Do you remember being bitten by a tick?.......No__ Yes__ when________
Do you remember having the "bull's eye rash"? No__ Yes__
Any other rash?..............................................No__ Yes__
Have you had any of the following? CIRCLE ALL YES ANSWERS
1. Unexplained fevers, sweats, chills, or flushing
2. Unexplained weight change (loss or gain)
3. Fatigue, tiredness
4. Unexplained hair loss
5. Swollen glands
6. Sore throat
7. Testicular pain/pelvic pain
8. Unexplained menstrual irregularity
9. Unexplained milk production; breast pain
10. Irritable bladder or bladder dysfunction
11. Sexual dysfunction or loss of libido
12. Upset stomach
13. Change in bowel function (constipation, diarrhea)
14. Chest pain or rib soreness
15. Shortness of breath, cough
16. Heart palpitations, pulse skips, heart block
17. Any history of a heart murmur or valve prolapse?
18. Joint pain or swelling
list joints_________________________________________________
19. Stiffness of the joints, neck, or back
20. Muscle pain or cramps
21. Twitching of the face or other muscles
22. Headache
23. Neck creaks and cracks, neck stiffness
24. Tingling, numbness, burning or stabbing sensations
25. Facial paralysis (Bell's Palsy)
26. Eyes/Vision: double, blurry, pain, increased floaters
27. Ears/Hearing: buzzing, ringing, ear pain
28. Increased motion sickness, vertigo
29. Lightheadedness, wooziness, poor balance, difficulty walking
30. Tremor
31. Confusion, difficulty in thinking
32. Difficulty with concentration or reading
33. Forgetfulness, poor short term memory
34. Disorientation: getting lost, going to wrong places
35. Difficulty with speech or writing
36. Mood swings, irritability, depression
37. Disturbed sleep too much, too little, early awakening
38. Exaggerated symptoms or worse hangover from alcohol
-----
LYME DISEASE TREATMENT GUIDELINES
GENERAL INFORMATION
Because the Lyme spirochete is rapidly distributed to all parts of the
body, including the CNS once it enters the bloodstream, the antibiotic
chosen must be able to penetrate all tissues in adequate concentrations
to be bacteriocidal to the organism, even in the earliest stages of
infection.
As the spirochete has a very long generation time (12 to 24 hours in
vitro and possibly much longer in living systems) and may have periods
of dormancy, during which time antibiotics will not kill the organism,
treatment may have to be continued for a long period of time to
eradicate all the active symptoms and to prevent a relapse, especially
in late infections.
I have found conclusively that the duration of treatment is just as
important as the choice of antibiotic. If treatment is discontinued
before all symptoms of active infection have cleared, the patient will
remain ill and possibly relapse further. All patients respond
differently and therapy must be individualized.
Vegetative endocarditis has been associated with Borrelia burgdorferi,
but the vegetations may be too small to detect with echocardiography.
Keep this in mind when evaluating patients with murmurs, as this may
explain why some patients seem to continually relapse after even long
courses of antibiotics. In addition, repeated treatment failures
should alert the clinician to the possible existence of an otherwise
not apparent immune deficiency, and a workup for this then may be
advised.
There is now evidence that B. burgdorferi can remain viable within
cells, such as macrophages, endothelial cells, neurons, and
fibroblasts, and also evade the effects of antibiotics in vitro by
sequestering in intracellular niches. In addition, Bb secretes a
glycoprotein that can coat and encapsulate the organism, (an "Slayer").
This may impair immune recognition and block antibiotic penetration.
Because this glycoprotein binds host IgM, it is possible that
Borrelial antigens are hidden by host protein, and in theory at least,
this will interfere with immune recognition, and thus affect
spirochetal clearance and possibly be another cause of seronegativity.
Being a Borrelia, antigenic shifts are thought to occur on a regular
basis. Similarly, cyclic periods of spirochetemia are seen in animal
models. Clinically, it has been observed that cycles of symptoms will
occur every four weeks. If the antibiotics are working, over time
these flares will lessen in severity and duration. The very
occurrence of ongoing monthly cycles indicates that living organisms
are still present and that antibiotics should be continued. Therefore,
therapy is designed to bracket at least one whole generation cycle,
hence the minimum duration recommended for established infections,
even early ones, is six weeks.
With I.V. antibiotics, it is common for symptoms to flare at the fourth
week, then every four weeks until the Borrelia are no longer active.
In those with longstanding highly symptomatic disease, this reaction
can be very severe, similar to a serum sickness reaction. This can be
associated with transient leucopenia and/or elevations in liver
enzymes. You must follow these patients closely, and decrease the
dose temporarily or interrupt treatment for one to three days, then
resume carefully with a lower dose initially. It is important to
expect this reaction, and quickly cut the dose, for if you are able
to continue therapy and get the patients through this rough time, and
continue I.V. medications, then they dramatically improve.
Those whose treatment is stopped and not restarted at this point
usually need retreatment in the future due to ongoing or recurrent
symptoms. Those patients on I.V. therapy who do have a reaction at
the fourth week will need to continue parenteral antibiotics for
several months, for when this reaction, which will occur every four
weeks, finally lessens in severity, then oral or IM medications can
be substituted. Indeed, it is just this observation that guides the
clinician in determining the endpoint of I.V. treatment.
There are three things that will predict treatment failure regardless
of which regimen is chosen: Non-compliance, alcohol use on a regular
basis, and failure of the patient to obtain proper rest. Advise them
to take a break when (or ideally before) the inevitable mid
afternoon fatigue sets in.
All patients must keep a carefully detailed daily diary of their
symptoms to help us judge the effects of treatment, the presence of
the classic four week cycle, and treatment endpoint. Remember, there
currently is no test that will tell you when all the Borrelia have
been eradicated, so clinical follow-up assumes a major role in Lyme
Disease care.
TREATMENT INFORMATION
There is no universally effective antibiotic for treating Lyme Disease.
The choice of medication used, and the dosage prescribed will vary for
different people based on multiple factors. These include age,
weight, blood levels achieved, gastrointestinal function, and patient
tolerance. Doses found to be effective clinically are often higher
than those recommended in older texts. This due to deep tissue
penetration by Bb, presence in the CNS including the eye, within
tendons, and because very few of the many strains of this organism
now known to exist have been studied for antibiotic susceptibility. In
addition, all animal studies to date have only addressed early disease
in models which behave differently than human hosts.
For the background and rationale for the following recommendations,
please refer to the suggested reading list and the appendix at the end
of this document.
There are four types of antibiotics in general use for Lyme treatment.
The tetracyclines, including doxycycline and minocycline, are
bacteriostatic at doses commonly prescribed, and treatment failures in
early and late disease are becoming more apparent. Tetracycline
itself does not penetrate into the CSF as well as doxycycline and
minocycline and its use is not advised in any case. Doxycycline can
be very effective only if high blood levels are achieved either by
high oral doses (300 to 600 mg daily) or by parenteral administration.
Penicillins are bacteriocidal. As would be expected in managing an
infection with a gram negative organism such as B. burgdorferi,
amoxicillin has been shown to be more effective than oral penicillin
V. Because of its short half life and need for high levels,
amoxicillin is usually administered along with probenecid. However,
perhaps because B. burgdorferi has been demonstrated to possess a
slowly acting beta lactamase, treatment failures in disseminated
disease do occur. In addition, blood levels are extremely variable
and should be tested.
Cephalosporins are useful but must be of advanced generation: first
generation drugs are not effective, and second generation drugs are
comparable to amoxicillin and doxycycline both in-vitro and in-vivo.
Third generation agents are currently the most effective of the
cephalosporins because of their very low MBC's (0.06 for ceftriaxone)
and because of excellent tissue penetration. Also, cephalosporins
have been shown to be effective in penicillin and tetracycline
failures. Cefuroxime axetil (Ceftin), a second generation agent, is
also effective against staph and thus is useful in treating atypical
erythema migrans that may represent a mixed infection, containing
some of the more common skin pathogens in addition to Bb. Because
these agents are difficult to tolerate due to G.I. side effects and are
costly, they are not used as first line drugs.
Erythromycin has been shown to be almost ineffective when used alone.
The advanced macrolides (they are classified as azalides) such as
azithromycin and clarithromycin have impressively low MBCs, but can
be difficult to tolerate due to poor GI tolerance at the high doses
needed, and their excessive tendency to promote yeast overgrowth.
When choosing a third generation cephalosporin, there are several
points to remember: cefotaxime (Claforan) and ceftriaxone (Rocephin)
both have demonstrated activity in-vitro, in-vivo, and in clinical
studies. Ceftriaxone is administered once daily (an advantage for
home therapy), but has 95% biliary excretion and can crystallize in
the biliary tree with resultant colic and possible cholecystitis.
GI excretion results in a large impact on gut flora. Cefotaxime,
which must be given at least every twelve, and preferably every eight
hours, is less convenient, but as it has only 5% biliary excretion,
it never causes biliary concretions, and may have less impact on
gut flora. Biliary and superinfection problems with ceftriaxone
can be lessened if this drug is given in interrupted courses, such
as five days in a row each week.
Other agents with demonstrated in-vitro efficacy have been used
successfully in treating Lyme patients and are discussed further
below.
MONITORING OF THERAPY
With parenteral therapy, CBC and chem/liver panels are done at least
every two weeks and during symptom flares, with urinalysis and
prothrombin time monitored monthly. Drug levels are done until the
most acceptable dose is achieved and then at any time major changes in
the treatment regimen occur.
-----
ANTIBIOTIC CHOICES
ORAL THERAPY: Always check blood levels and adjust dose to achieve a
peak level in the mid-teens and a trough greater than three
Amoxicillin
Adults: 1g q8h plus probenecid 500mg q8h.
Pregnancy: 1g q6h.
Children: 50 mg/kg/day divided into q8h doses.
Doxycycline
Adults: 100 mg tid with food.
Note: doxycycline is only effective at high blood levels.
Not for children or in pregnancy.
If levels are too low at tolerated doses, parenteral therapy will
be needed.
Cefuroxime axetil, an oral alternative that may be effective in
amoxicillin and doxycycline failures. Useful in EM rashes
co-infected with common skin pathogens.
Adults and pregnancy: 1g q12h.
Children: 125 to 500 mg q12h based on weight.
Tetracycline
poor response and not recommended.
Erythromycin
poor response and not recommended.
Chloramphenicol
not recommended as not proven and potentially toxic.
Poorly studied but anecdotaly effective alternatives:
Azithromycin
Adults: 500 to 1000 mg/d.
Adolescents: 250 to 500 mg/d.
Cannot be used in pregnancy or in younger children.
Clarithromycin
Adults: 250 to 500 mg q6h
Cannot be used in pregnancy or in younger children.
Augmentin
Cannot exceed three tablets daily due to the clavulanate, thus is
given with amoxicillin.
PARENTERAL THERAPY
Ceftriaxone
Risk of biliary sludging can be minimized with intermittent breaks in
therapy (ie: infuse five days in a row per week).
Adults and pregnancy: 2g q24h. for large body habitus, dose up to
4g daily
Children: 75 mg/kg/day up to 2g/day
Cefotaxime
Comparable efficacy to ceftriaxone; no biliary complications.
Adults and pregnancy: 2g q8h; may dose as high as 12g daily
Children: 90 to 180 mg/kg/day dosed q6h (preferred) or q8h, not
to exceed 12 g daily
Doxycycline
Requires central line as is caustic.
Surprisingly effective, probably because blood levels are higher
when given parenterally
Always measure blood levels
Adults: 300 mg q24h and adjust based on levels
Cannot be used in pregnancy or in younger children.
Penicillin G
IV penicillin G is minimally effective and not recommended.
Benzathine penicillin
Surprisingly effective IM alternative to oral therapy.
May need to begin at lower doses as strong, prolonged (6 or more
week) Herxheimer like reactions have been observed.
Adults: 1.2 million U once to twice weekly.
Adolescents: 300,000 to 1.2 million U weekly.
Should not be used in pregnancy.
Poorly studied but anecdotaly effective:
Vancomycin
Observed to be one of the best drugs in treating Lyme, but potential
toxicity limits its use. It is a perfect candidate for pulse
therapy to minimize these concerns. Must check levels.
Imipenim
Similar in efficacy to cefotaxime. Must be given q6 to q8 hours.
Cefuroxime
Not demonstrably better than ceftriaxone or cefotaxime
Ampicillin IV
More effective than penicillin G. Must be given q6 hours.
-----
TREATMENT CATEGORIES
PROPHYLAXIS of high risk groups - education and preventive measures.
Antibiotics are not given.
TICK BITES
Embedded Deer Tick With No Signs or Symptoms of Lyme (see appendix):
Decide to treat based on the type of tick, whether it came from an
endemic area and percent infected, how it was removed, and length of
attachment (nymphs: at least one day; adults: anecdotaly, as little
as four hours). The risk of transmission is greater if the tick is
engorged, or of it was removed improperly allowing the tick's contents
to spill into the bite wound. High risk bites are treated as follows:
1) Adults: Oral therapy for 14 days.
2) Pregnancy: Amoxicillin 1000 mg q6h for 6 weeks.
Alternative: Cefuroxime axetil 1000 mg q12h for 6 weeks.
3) Young Children: Oral therapy for 14 days.
Erythromycin: poor alternative with documented treatment failures.
EARLY LOCALIZED
Single erythema migrans with no constitutional symptoms:
1) Adults: oral therapy for 6 weeks.
2) Pregnancy: 1st and 2nd trimesters: I.V X 21 days then oral X 6
weeks 3rd trimester: Amoxicillin 1000 mg q6h X 6 weeks.
3) Children: oral therapy for 6 weeks.
DISSEMINATED DISEASE
Multiple lesions, constitutional symptoms, lymphadenopathy, or any
other manifestations of dissemination.
EARLY DISSEMINATED
Milder symptoms present for less than one year and not complicated
by immune deficiency or prior steroid treatment:
1) Adults: oral therapy until no active disease for 4 weeks (4-6
months typical)
2) Pregnancy: As in localized disease, but duration as above. Some
experienced clinicians treat throughout pregnancy.
3) Children: Oral therapy with duration based upon clinical response.
PARENTERAL ALTERNATIVES for more ill patients and those unresponsive
to or intolerant of oral medications:
1) Adults and children: IV therapy for 6 weeks or until clearly
improved. Follow with oral therapy or IM benzathine penicillin
until no active disease for 8 weeks.
2) Pregnancy: IV then oral therapy as above.
LATE DISSEMINATED present greater than one year, more severely ill
patients, and those with prior significant steroid therapy or any
other cause of impaired immunity.
1) Adults and pregnancy: extended IV therapy (6 to 10 or more
weeks), then oral or IM to same endpoint.
2) Children: IV therapy for 6 or more weeks, then oral or IM follow
up as above.
-----
ALTERNATE SCHEDULING OF ANTIBIOTIC TREATMENT
PULSE THERAPY
This consists of administering antibiotics (usually parenteral ones)
two to three days in a row per week. This allows for several
advantages:
Dosages are doubled (ie: cefotaxime, 12 g daily), increasing efficacy
More toxic medications can be used with safety (ie: vancomycin)
IV access may be easier
More agreeable lifestyle for the patient
May be effective when conventional, daily regimens have failed.
Note that this type of treatment is expected to continue for a minimum
of ten weeks, and often must continue beyond twenty weeks. The
enhanced efficacy of this regimen is presumably based on the fact that
it takes 24 to 48 hours of continuous bacteriocidal antibiotic levels
to kill the spirochete, yet it will take longer than the four to five
days between pulses for the spirochetes to recover. As with all Lyme
treatments, specific dosing and scheduling must be tailored to the
individual patient's clinical picture based upon the treating
physician's best clinical judgement.
COMBINATION THERAPY
This consists of using two or more dissimilar antibiotics
simultaneously for antibiotic synergism and to better compensate for
differing killing profiles and sites of action of the individual
medications. A typical combination is the use of a cell wall agent
plus a protein inhibitor (ie: amoxicillin plus clarithromycin). Note
that GI intolerance and yeast superinfections are the biggest
drawbacks to this type of treatment. However, these complications
can often be prevented or easily treated, and the clinically observed
benefits of this type of regimen clearly have outweighed these
problems in selected patients.
-----
REFRACTORY DISEASE
PERSISTENT SIGNS & SYMPTOMS THAT RESPOND TO ANTIBIOTIC THERAPY
Patients in this group improve on antibiotics yet relapse repeatedly
when medications are discontinued. Some patients in this category
have been proven, in peer reviewed medical literature, to have
persistent infection. The treating physician may decide on chronic
therapy in order to avoid clinical deterioration. Recommend you
confirm blood levels, and study immune competence. This includes T-
and B- cell function and counts, NK cell cytotoxic assays, complement
levels, neutrophil function, and vaccine responsiveness.
Options for treatment:
- Longer duration, including open ended maintenance therapy
- Increased dose
- Different drug
- Change method of administration (oral to IV)
- Combination or pulse therapy
- Synovetomy
- Supportive therapy as needed
- Search for and treat concurrent illnesses
PERSISTENT SIGNS & SYMPTOMS NOT RESPONSIVE TO ANTIBIOTICS
- Reconsider the diagnosis
- Search for and treat concurrent illnesses
- Supportive therapy based on symptoms.
- NSAIDS and hydroxychloroquine
- Antidepressants, analgesics, and muscle relaxants
- Synovectomy
- Psychiatric/psychometric evaluation
- Long-term follow-up
- Consider retreatment if condition change
ADJUNCTIVE THERAPY
RECOMMENDED in all Lyme patients:
- daily yogurt *and* acidophilus preparations
- multivitamins and B complex 50 mg daily
- Physical therapy and rehabilitation
PRESCRIBE AS NEEDED, especially in more severe cases:
- Psychosocial evaluation and possibly refer for counseling
- NSAIDS and remittive agents
- analgesics and muscle relaxants
- antidepressants
- Immune globulins and other immunotherapy if indicated
- vitamin and nutritional supplements as listed below
- Sinequan (DAW) in low doses (5 to 50 mg daily) reportedly improves
T-cell function
CONTRAINDICATED:
- alcohol use
- excessive caffeine intake
- any avoidable stresses
-----
SAFETY
Nearly a decade of experience in treating thousands of patients with
Lyme has proven that therapy as described above, although intense, is
generally well tolerated. The most common adverse reaction seen is
allergy to probenecid. In addition, yeast superinfections are seen,
but these are generally easily recognized and managed. The induction
of Clostridium difficile toxin production is seen most commonly with
ceftriaxone, but can occur with any of the antibiotic regimens
mentioned in this document. However, regular use of the lactobacillus
preparations seems to be helpful in controlling yeast and antibiotic
related colitis, as the number of cases of C. difficile in Lyme
patients is low when these guidelines are followed.
When using PICC lines (peripherally inserted central catheters), if
ANY line problems arise, it is recommended that the line be pulled
for patient safety. Salvage attempts (urokinase, repairing holes)
are often ineffective and may not be safe.
Please advise all patients who take doxycycline of skin and eye
sensitivity to sunlight and the proper precautions.
Years of experience with chronic antibiotic therapy in other
conditions, including rheumatic fever, acne, recurrent otitis,
recurrent cystitis, COPD, bronchiectasis, and others have not
revealed any consistent dire consequences as a result of such
medication use. Indeed, the consequences of untreated, chronic
persistent infection by B. burgdorferi can be far worse than the
potential consequences of this treatment.
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NUTRITIONAL SUPPLEMENTS IN CHRONIC LYME DISEASE
Studies on patients with chronic Lyme Disease and in those with the
Chronic Fatigue Syndrome have demonstrated that some of the late
symptoms are related to cellular damage and deficiencies in certain
essential nutrients. Double blinded, placebo controlled studies, and
in one case direct assay of biopsy specimens have proven the value of
the supplements listed.
ESSENTIAL FATTY ACIDS
There are two broad classes: GLA and EPA, derived respectively from
plant and fish oils. The plant sources are many, and it is
recommended that more than one source be used: plan the regimen to
include a mixture of these capsules.
Plant Oils: evening primrose oil
black currant seed oil
borage oil
fungal oils (this is not in a capsule - you'll
need to eat mushrooms to get this)
Fish oil: "MAX EPA" (or any similar preparation containing 1,000
mg of EPA)
RECOMMENDATION: four plant oil capsules and four EPA capsules daily.
EPA may result in a fishy taste that often repeats, so try to take
them with the largest meal of the day, or cut the dose. Most patients
report they feel more energy and enhanced clarity of thought fairly
rapidly, within several days, but further improvement continues to
occur over time. Continue for three to four months.
CO-Q 10
This is a vitamin B- like compound essential to function of every
living cell. Deficiencies have been related to poor function of the
heart, limitations of stamina, and poor resistance to infections.
Tissue biopsy studies have resulted in the recommendation that a
patient with chronic Lyme should take between 200 and 300 mg daily,
in two or three equal doses. For proper function, supplemental iron
and vitamin C is required. I recommend one Feosol Capsule and 500 mg
of vitamin C taken together daily and stop after one month.
Improvement in stamina and general well being do not begin for several
weeks, so this should be continued for at least one month before
concluding it is not helping. The body will manufacture its own
Co-Q 10 when the original infection is controlled, but only if
stimulated by aggressive exercise. Therefore, use this supplement
until the patient is feeling well and is exercising regularly.
VITAMIN B
Studies in the 1950s demonstrated the need for supplemental vitamin B
in infections with other Borrelia. I recommend one 50 mg B-complex
capsule daily.
MULTI-VITAMIN
I recommend at least one therapeutic strength multivitamin daily, taken
at bedtime. My current favorite that is generally available is Centrum
Silver.
MAGNESIUM
Magnesium supplementation is often very helpful for the tremors,
twitches, cramps, muscle soreness, heart skips, and weakness. The
best source is magnesium chloride ("Slo-Mag"). DO NOT rely on
"cal-mag", calcium plus magnesium combination tablets as they do not
work. Take two to four Slo-Mag tablets daily. In some extreme cases,
IM or IV magnesium may be necessary.
All of these products are available without a prescription from health
food stores and some pharmacies.
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LYME DISEASE REHABILITATION
Those with longstanding Lyme end up in poor physical condition. Even
with successful treatment of the Lyme infection, they will not return
to normal unless they take an active role in personal rehabilitation.
In late stage disease, many negative effects to the body are occurring:
the muscles are atrophying, and to some degree, the heart muscle also
suffers, as do the joints, tendons, nerves, etc.
Besides these physical effects, chemical changes occur. The per cent
fat content of the body as a whole rises, the cholesterol rises, and
the balance between HDL and LDL becomes less favorable. In at least
80% of the patients, significant weight gain occurs.
To make matters worse, because of the extreme fatigue and body pain,
many Lyme sufferers end up spending inordinate amounts of time in bed,
and get far less exercise than they had before they became ill. This
begins a debilitating downward spiral that can be very difficult to
reverse.
As a result, Lyme patients are stiff, weak, tired, have poor stamina,
and are at increased risk for cardiovascular disease and diabetes.
Antibiotic treatment alone cannot correct these effects. Therefore,
it is necessary to include various forms of physical and exercise
therapy, the extent of which depends on an individual patients'
condition.
The earliest phase involves multiple modalities (massage, heat, TENS,
MENS, ultrasound, etc.) and simple range of motion exercises supervised
by a physical therapist. The goal is to relieve discomfort and to
promote better sleep and flexibility. This then evolves into
stretching and mild muscular toning which can lessen joint pain and
increase mobility and stamina. Finally, the program must expand to
include muscular conditioning and strengthening, ideally under the
supervision of a credentialed exercise physiologist. Aerobics are
not recommended until the patient has fully recovered.
Diet also plays an important role. This is the time for the very best
of health habits. I recommend light, low fat food, with high quality
nutritional value, minimal amounts of starch and other simple
carbohydrates, absolute abstention from alcohol, elimination of
caffeine, and if applicable, a serious commitment to weight loss.
Consider recommending books that outline "arthritis diets", as they
can help some patients.
Cessation of smoking is extremely important and must be addressed
immediately.
As Written orders for therapy are required to initiate the program,
an example of the format of a typical prescription for Lyme
rehabilitation follows.
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LYME REHAB-PHYSICAL THERAPY PRESCRIPTION
NAME_____________________________________________________________
D.O.B._____________________________ DATE________________________
Please enroll this patient in a program of therapy to rehabilitate
him/her from the effects of Lyme Disease. Such therapy must be graded,
carefully individualized, and be performed on a one-on-one basis, at
least initially, to ensure the maximal amount of supervision and
guidance. If necessary, begin with classic physical therapy, then
progress when appropriate to a whole body conditioning program.
THERAPEUTIC GOALS (to be achieved in order as the patient's ability
allows):
Physical Therapy:
1. Relieve pain and muscle spasms utilizing multiple modalities as
available and as indicated: massage, heat, ultrasound, TENS,
"micro amp", etc.
2. Increase mobility while protecting damaged and weakened joints,
tendons, and ligaments, to increase range of motion and relieve
stiffness.
Exercise Program:
Begin with a private trainer for careful direction and education.
1. Improve strength and reverse the poor conditioning that results
from Lyme, through a whole-body exercise program ("stretch and
tone", or "body sculpture" classes) no more often than every
other day. Each session should last one hour. If the patient
is unable to continue for the whole hour, then modify the
program to decrease the intensity to allow him/her to do so.
This is what is required to achieve wellness and is the main
focus of rehab. Simply placing the patient on a treadmill or an
exercise bike is not acceptable, nor is a simple walking program.
2. Improve endurance and cardiovascular tone when the patient nearly
recovered from his/her illness, and only after the above have
been satisfactorily accomplished. In no circumstances will high
impact exercises be allowed. This aerobic program is to be done
in addition to, not in place of the strengthening sessions
outlined above.
PATIENT EDUCATION AND MANAGEMENT (to be done during the initial
one-on-one sessions and reinforced at all visits thereafter):
1. Instruct patients on correct exercise technique, including
proper warmup, breathing, joint protection, proper body
positioning during the exercise, and how to cool-down and
stretch afterwards.
2. Please work one muscle group at a time and perform extensive
and extended stretches to each muscle group immediately after
each one is exercised, before moving on to the next muscle group.
3. A careful interview should be performed at the start of each
session to make apparent the effects, both good and bad, from
the prior visit's therapy, and adjust therapy accordingly.
Please feel free to contact my office if you would like to discuss this
client's situation in more detail.
PHYSICIAN'S SIGNATURE____________________________________________
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MANAGING YEAST INFECTIONS
Many patients, especially those with Lyme Disease, Chronic Fatigue
Syndrome, and others with depressed immune systems develop an
overgrowth of yeast. Therefore, it is recommended that on a daily
basis the patient eat a full container of yogurt that contains active
cultures, and take acidophilus, either in capsule, chewable tablet, or
liquid form.Here are some suggestions on how to control yeast:
MOUTH: A tongue with a beige coating, bad breath, and a funny taste
in the mouth are signs of thrush. The patient must brush his/her
tongue whenever they brush their teeth, and use antiseptic mouthwashes
frequently. Because the effectiveness of a mouthwash is related to
how long it is in contact with the germs, it should be kept in the
mouth while brushing. Since yeast germs feed on sugars, have patients
avoid simple carbohydrates, starches, fruits, and juices for at least
two weeks, or until the problem is gone.
If this is not enough, there are many alternatives: A simple tongue
scraper, found in health food stores, is quite effective. Prescription
medications can also be used. "Mycelex" troches are dissolved in the
mouth 3 to 5 times daily. "Nystatin" comes as a tablet, a powder, or
as a liquid that is swished and swallowed 4 times daily, after meals
and at bedtime. The best, however, is the powder, which the patient
mixes with water, to make a suspension (believe it or not, nystatin
liquid and Mycelex contain 25 to 50% sugar!). Systemic antifungals
(Diflucan, Nizoral) may be necessary. Prescription medication must
be used for at least two weeks in full doses, then either stopped, or
in certain circumstances, continued at a lower dose as maintenance
therapy.
The most effective (and drastic) treatment uses "Dakin's Solution" as a
mouth rinse. This is a mixture of Clorox, one teaspoon with four
ounces of water. The mouth is rinsed with this while the tongue,
palate, teeth, gums, and cheeks are brushed. Rinse, and repeat until
the four ounces are used up. I recommend this be done no more than
once a week, and only as a last resort until the thrush is controlled.
Then go back to one of the more conventional treatments listed above.
After using an antiseptic to clean the mouth, immediately eat yogurt,
or liquid or chewable acidophilus, to replenish the beneficial
microbes. Because the germ count after such a cleaning will be
artificially reduced, and because yeast germs are opportunists, they
would be the first to come back. By having the yogurt or acidophilus
then, a more normal oral flora will result and thrush will be better
controlled.
INTESTINAL TRACT: An overgrowth of yeast here will ferment dietary
sugars and starches, forming acids, gas, and a form of alcohol.
Symptoms include gas, heartburn and/or pain in the stomach area,
and because of the alcohol, shortly after a meal there can be
dizziness, lightheadedness, and wooziness. To clear intestinal
yeast, first the tongue and mouth must be cleared so yeast does not
reenter the system with every swallow. Avoid eating excessive sweets,
starches, fruits and juices for two weeks or longer to starve the
germs. Systemic antifungals usually are needed.
VAGINAL: An occasional vaginal yeast infection can be controlled with
products such as Monistat cream or suppositories. If it is a
recurrent or ongoing problem, then it often reflects a simultaneous
intestinal infection, reinfecting the genital area with every bowel
movement. Therefore this is treated as above, and preparations such
as Monistat should be used concurrently for two weeks.
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PATIENT INSTRUCTIONS -- BITE PREVENTION AND TICK REMOVAL
HOW TO PROTECT YOURSELF FROM TICK BITES
PROPERTY: Remove wood piles, rock walls, and bird feeders as these
attract tick-carrying small animals and can increase the risk of
acquiring Lyme.
INSECTICIDES: We recommend that you treat your property with a
product called "Damminix". This consists of cardboard tubes
containing cotton balls that have been dipped in insecticide. You
place these tubes around your property in the wooded areas and below
shrubs. Mice, which are a key link in the propagation of Lyme
disease, find the cotton and bring it back to their burrows to be
used as nesting material, with the result being a big decrease in the
number of ticks in the area. Unfortunately, after two years tick
populations may rise again as other small animals that do not gather
cotton become hosts to the ticks. Therefore, Damminix alone is not
recommended. Use this product in conjunction with liquid or granular
insecticides.
LIQUID & GRANULAR PESTICIDES: Products meant for widespread
application include Dursban, Tempo, and sevin. They are available as
a liquid concentrate and as granules. If liquid insecticides are
used, application should be by fogging, not by coarse sprays.
Apply these products in a strip a few feet wide at the perimeter of
your lawn at any areas adjacent to woods and underbrush. Also treat
any ornamental shrubs near the house that may serve as a habitat for
small animals. The best time to apply these products is in late
Spring.
CLOTHING: When wearing long pants, tuck the cuffs into your socks so
any ticks that get on your shoes or socks will crawl on the outside of
your pants and be less likely to bite. Also, wear light colored
clothing so the ticks will be easier to spot. Smooth materials such
as windbreakers are harder for ticks to grab onto and are preferable
to knits, etc.
Tick repellants that contain "permethrin" (Permanone, Permakill) are
meant to be sprayed onto your clothing. When using this product,
spray the clothes before you put them on, and let them dry first.
Do not apply this chemical directly to your skin.
Ticks are very intolerant of being dried out. After being outdoors in
an infested area, place your clothes in the dryer for a few minutes to
kill any ticks that may still be present.
SKIN: Insect repellants that contain "DEET" are somewhat effective when
applied to the arms, legs, and around the neck. Do not use any
repellant over wide areas of the body as they can be absorbed causing
toxicity. Also, it is inadvisable to use a product that contains
more than 50% DEET, and 25% concentrations are preferred. Use
repellants cautiously on small children, as they are more susceptible
to their toxic effects.
Don't forget to check yourself carefully for ticks not only when you
get home but frequently while still outside!
HOW TO REMOVE AN ATTACHED TICK
Using a tweezer (not your fingers!), grasp the tick as close to the
skin as possible and pull straight out. Then apply an antiseptic.
Do not try to irritate them with heat or chemicals, or grasp them by
the body, as this may cause the tick to inject more germs into your
skin. Tape the tick to a card and record the date and location of the
bite and where you were when bitten, then call your physician.
Remember, the sooner the tick is removed, the less likely you are to
get ill.
APPENDIX
RATIONALE FOR TREATING TICK BITES
The Medical Advisory Committee of the Lyme Disease Foundation now
recommends antibiotic prophylactic treatment upon a known tick bite
for:
1. People at higher health risk bitten by an unknown type of tick or
tick capable of transmitting Borrelia burgdorferi, e.g., pregnant
women, babies and young children, and people with serious health
problems, and those who are immunodeficient.
2. Persons bitten in an area endemic for Lyme Borreliosis by an
unidentified tick or tick capable of transmitting B. burgdorferi.
3. Persons bitten by a tick capable of transmitting B. burgdorferi,
where the tick is engorged, or the attachment duration of the tick
is greater than four hours, and/or the tick was improperly removed.
This means when the tick is squeezed between the fingers, irritated
with toxic chemicals in an effort to get it to back out, or disrupted
in such a way that it's contents were allowed to contact the bite
wound. Such practices increase the risk of disease transmission.
4. A patient, when bitten by a known tick, clearly requests oral
prophylaxis and understands the risks. This is a case-by-case decision.
The physician cannot rely on a laboratory test or clinical finding at
the time of the bite to definitely rule in or rule out Lyme Disease
infection, so must use clinical judgement as to whether to use
antibiotic prophylaxis. Testing the tick itself for the presence of
the spirochete, even with PCR technology, is not reliable enough to
guide your decision to treat.
An established infection by B. burgdorferi can have serious, long-
standing or permanent, and painful medical consequences, and be
expensive to treat. Since the likelihood of harm arising from
prophylactically applied spirochetal antibiotics is low, and since
treatment is inexpensive and painless, it follows that the risk
benefit ratio favors tick bite prophylaxis.
It is the Medical Advisory Committee's recommendation that antibiotic
prophylactic treatment for tick bite in many circumstances is not only
justified but warranted. The ultimate decision for treatment on tick
bite should be determined jointly between the physician and patient.
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RATIONALE FOR TREATMENT RECOMMENDATIONS:
When I began treating Lyme Borreliosis (LB) in the mid 1980s, I
recognized that in disseminated disease, the then recommended ten to
fourteen day courses of antibiotics would either result in only a
lessening of the illness, or an initial good outcome followed by a
relapse of symptoms. These patients would then respond again to a
repeat course of antibiotics.
Published studies by Steere and others (1) had, at that time, defined
success as the elimination of the "major" symptoms of Lyme (arthritis,
carditis, and Bell's Palsy) even though they usually resolve over time
without treatment. These same studies go on to report the persistence
of "minor symptoms" of Lyme even after antibiotic therapy, and the
authors call it the "post Lyme syndrome".
In 1987 I participated in a study in which twenty six patients with
active disseminated LB, who were culture positive for Borrelia
burgdorferi (Bb), were treated with ceftriaxone I.V. for fourteen
days, using either two or four grams a day. Although culture negative
at the immediate end of therapy, all patients became culture positive
again within several weeks, which corresponded to the time when their
symptoms recurred. I concluded then that the persistence of symptoms
after this type of therapy in fact represented ongoing infection.
The results of this study were presented in 1989 at the national
meeting of the Lyme Borreliosis Foundation.
Upon the advice of colleagues who for years have been involved in
seminal LB research (2), I then studied the effects of lengthened
duration of treatment. I found a direct correlation between treatment
duration and the ultimate outcome of patients' symptoms. Using
amoxicillin 3g/day plus probenecid 1.5g/day in divided doses, the per
cent success was tabulated for therapies lasting for from one through
six months. Success here is defined as the elimination of all LB
symptoms, both major and minor, without a relapse by three months
after completion of treatment.
The data clearly demonstrated a direct relationship between duration
and success, starting at 17% for one month of therapy, and reaching a
plateau at 67% at five months duration. These data were also
presented at the 1989 meeting mentioned above.
Next, using ceftriaxone, results of therapy were tabulated based on
duration. Even with 45 days of continuous antibiotic, none of the
patients returned to or maintained their well, pre-Lyme state.
However, if oral medications were continued after ceftriaxone, to the
endpoint of being free of signs and symptoms of active disease, then
relapses did not occur. Again, the average duration of antibiotic
treatment necessary to achieve this was at least four months.
Further culture studies involving 74 patients confirmed that the
patients had to be free of signs and symptoms of active Borreliosis
before antibiotics were discontinued in order to be both culture
negative, and not experience a relapse during three months of follow
up.
There are now a growing number of published reports utilizing various
forms of Bb antigen detection that demonstrate the persistence of
infection in antibiotically treated patients (3,4,5,6,7,8), confirming
my earlier work. Even Steere has proposed this as a mechanism for
chronic arthritis in Lyme (9).
Although syphilis perhaps is not a synonymous spirochetosis to Lyme,
similar findings of organism persistence despite presumed adequate
(short course) therapy has been reported in those who later became
immune deficient (10). Indeed, Wassermann in 1936 recommended a
minimum of twenty six weeks of treatment for established infection,
based upon generation-time studies.
I have recently participated in an NIH study utilizing the antigen
detection method of Dorward et al (11). In testing over 130 patients
with Chronic Persistent LB, in whom symptoms of active disease
continued despite even prolonged treatment (indeed, some would
describe as excessive the treatment given to several participants),
Bb could be recovered from blood, CSF, urine, and tears. Indeed,
many of these patients had received months to years of aggressive,
often parenteral therapy for LB. For example, one had received
continual antibiotics for three years, while another was treated for
18 months with repeated courses of parenteral therapy. As a matter
of record, neither one was a patient of mine. These examples clearly
indicate what researchers have recognized as the ability of Bb to
evade host defenses (1,12,13,14,15) even in the presence of
antibiotics (5,6,7,8).
I do not now recommend treatment forever, but I point out the above
results to be able to make several points:
1. There has never been a study in the history of this illness that
even in the simplest way proves that currently recognized
short-course (two to four week) therapy results in a
bacteriologic cure.
2. There has never been a consensus in patients still symptomatic
after short treatment courses as to what constitutes the post
Lyme syndrome, how Bb induces it, and what perpetuates it if
bacteriologic cure is indeed presumed.
3. Patients must be kept on therapy until free of active symptoms or
they either will never recover fully, or suffer a relapse.
4. Extended durations of antibiotic therapy clearly have helped
literally thousands of patients who were not helped by short
courses of treatment.
5. Finally, we have to recognize that in some patients, LB may not be
curable in a strict bacteriologic sense.
Until sensitive and specific antigen detection tests become widely
available, treatment of LB will remain difficult, controversial, and
the subject of much discussion.
J.J. Burrascano, Jr., M.D.
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SUGGESTED READING
1. Steere, A.C. Lyme Disease. N Engl J Med 1989; 321:586-96
2. MacDonald, A.B., Berger, B.W., Schwann, T.G. Clinical
implications of delayed growth of the Lyme Borreliosis spirochete,
Borrelia burgdorferi. Acta Tropica 1991; 48:89-94
3. Cimmino, M.A., Azzolini, A., Tobia, F., Pesce, C.M. Spirochetes
in the spleen of a patient with chronic Lyme Disease. Am J Clin
Pathol 1989; 91:95-97
4. Berger, B.W., Johnson, R.C., Schwann, T.G. Clinical and
microbiologic findings in six patients with erythema migrans of
Lyme Disease. Am J Acad Dermatol 1989; 21:1188-91
5. Kirsch, M. etal. Fatal adult respiratory distress syndrome in a
patient with Lyme Disease. JAMA 1989; 259:2737-39
6. Pfister, H.W., Preac-Mursic, V., Wilske, B. Latent Lyme
neuroborreliosis: Presence of Borrelia burgdorferi in the CSF
without concurrent inflammatory signs. Neurology 1989; 39:1118-20
7. Preac-Mursic, V., Weber, K., Pfister, H.W., Wilske, B. Survival of
Borrelia burgdorferi in antibiotically treated patients with Lyme
Borreliosis. Infection 1989; 17(6):355-359
8. Hassler, D., Riedel, K., Zorn, J., Preac-Mursic, V. Pulsed high
dose cefotaxime therapy in refractory Lyme Borreliosis. Lancet
1991; 338:13
9. Steere, A.C., Dwyer, E., Winchester, R. Association of chronic Lyme
arthritis with HLA-DR4 and HLA-DR2 alleles. NEJM 1990; 323:219-23
10. Musher, D.M. Syphilis, Neurosyphilis, Penicillin, and AIDS. J
Infect Dis 1991; 163:1201-1206
11. Dorward, D.W., Schwan, T.G., Garon, C.F. Immune capture and
detection of Borrelia burgdorferi antigens in urine, blood, or
tissues from infected ticks, mice, dogs, and humans. J Clin
Microbiol 1991; 29(6):1162-70
12. Asbrink, E., Hovmark, A. Successful cultivation of spirochetes
from skin lesions of patients with erythema chronicum migrans
Afzelius and acrodermatitis Chronica atrophicans. Acta Pathol
Microb Immunol Scand 1985; Sect B, 93:161-163
13. Pachner, A.R., Itano, A. Borrelia burgdorferi infection of the
brain: Characterization of the organism and response to
antibiotics and immune sera in the mouse model. Neurology
1990; 40:1535-40
14. MacDonald, A.B. Gestational Lyme Borreliosis. Implications for
the fetus. IN Rheumatic Disease Clinics of North America 1989;
15(4):657-677
15. Logigian, E.L., Kapan, R.F., Steere, A.C. Chronic neurologic
manifestations of Lyme Disease. N Engl J Med 1990; 323:1438-44
16. LaVoie, P.E. Lyme Disease. IN Conn's Current Therapy 1991 pp
101-105
17. Liegner, K.B. Lyme Disease: the Sensible Pursuit of Answers.
J Clin Microbiol 1993; 31(8): 1961-63