Lukuisia tutkimuksia joissa osoitetaan borrelia-bakteerin voivan aiheuttaa kroonisen infektion.
http://lymekick.com/chroniclyme.pdf
The Case For Chronic Infection: Evidential persistence of Borrelia
species post antibiotic exposure in vivo and in vitro.
Michael D. Parent & Erica Falkingham
Introduction Summary:
There is an abundance of evidence demonstrating that Borrelia Burgdorferi, the causative agent
of Lyme Disease, and related pathogenic species, can persist within specific body tissues and cells
of various mammals despite adequate antibiotic therapy: ponies [93.5, 111.5], non-human
primates [50, 86], dogs [65.5, 70, 80, 81, 82, 84], mice [44, 62, 88, 100, 107, 108, 110, 114], and
humans [all others]. There is also abundant evidence that Borrelia Burgdorferi has evolved in a
manner similar to other bacteria that evade the immune system via pleomorphic modification, in
other words, the bacteria can change its shape beyond the conventional spirochetal form [45, 55,
61, 64, 90, 105, 109, 113]. L-forms, and cystic Borrelia have been identified in a number of studies
[45, 68, 77, 87, 105, 109, 112, 113]. When these "forms" are exposed to the typical antibiotics,
such as Penicillin family antibiotics or Doxycycline, they are unaffected. When the antibiotic is
removed from the environment, the bacterium will alter its form once more, morphing back into
a spiral form, allowing ongoing mobility [45, 68, 87, 90, 105, 109].
I have taken the time to "bold" the conclusions and various other aspects that clearly indicate a
deviation from the point of view given by a number of physicians and researchers who deny the
possibility of ongoing chronic infection within the human host. The current guidelines issued by
the Infectious Disease Society Of America (IDSA) are consistently used to dismiss further
discussion regarding the subject of persistence. The guidelines are titled: ?The Clinical
Assessment, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis,
and Babesiosis? Clinical Infectious Diseases 2006; 43:1089?134.
Patients who receive a diagnosis of Lyme Disease, either based on clinical observation and/or
objective indicators often improve with antibiotic therapy [1, 4, 18, 19, 26, 33, 66].
However, if they have been undiagnosed and untreated for Lyme Disease for a long period of
time, it often takes longer to see progress in symptom reduction [15, 66, 73, 93, 105]. The U.S.
National Institute Of Health funded a number of randomized double-blind placebo-controlled
trials (RCT) regarding the long term treatment of Lyme Disease. However, these RCT's were 3
months in duration or less. Patients with documented medical records indicating Chronic Lyme
Disease or a Lyme-Like Illness who have been untreated often do not see improvement until after 4-6 months of treatment, and even still, the improvements are modest initially in many patients
and may require an ongoing open ended treatment regimen with antibiotics [66, 93].
It is well understood and agreed upon universally that the more time Borrelia Burdorferi has had
to disseminate into various ligaments, bones, collagen, muscles, and other tissues, then the higher
the probability of ongoing complications or symptoms post-antibiotic therapy. Presently, studies
indicate that antibiotics can not access many of the areas that Borrelia Burgdorferi disseminates
to unless the bacterium itself leaves the safe haven of a Fibroblast skin cell [11, 22, 23, 24, 25, 29,
35, 52, 64, 70, 72, 80, 81, 84, 94], or synovial tissue cells and fluid [1, 7, 9, 31, 34, 37, 42, 60, 61, 69,
70, 71, 102].
Introductory Conclusion:
Therefore, we have studies demonstrating abundant persistence. We have National Institute Of
Health funded studies that do not treat patients long enough to confirm whether the treatment
really is effective or not. The short term studies we do have contradict other studies as well as
those based on clinical reports from health care providers treating these patients with antibiotics
beyond the currently accepted time frame. It is unwise for the IDSA to claim that long-term
antibiotic therapy doesn't work when you've only performed a study for 3 months, when the vast
majority of the patients in the study have had the infection for many years and require at least 3-6
months of oral antibiotic before clinical improvements are seen. IV antibiotics may demonstrate
minor to moderate symptomatic improvement after 1- 3 months, but if that treatment is only
given for 3 months and then discontinued, then it will be equally ineffective and the symptoms
will return to pre-treatment levels. Coincidentally, that's exactly what happened in Dr. Brian
Fallon's study. Some symptoms improved, but then returned upon discontinuing therapy.
I have discussed merely one specific possibility for the failure of patients to thrive and improve
during the currently available randomized double-blind placebo-controlled clinical trials (RCT).
Dr. Daniel J. Cameron writes in the Journal Of Medical Hypothesis that a number of limitations
exist within the currently structured (RCTs), that strongly support the position I've laid forth.
Med Hypotheses. 2009 Jun;72(6):688-91. Epub 2009 Mar 5. Insufficient evidence to deny
antibiotic treatment to chronic Lyme disease patients. First Medical Associates, Medicine, 175
Main Street, Mount Kisco, NY 10549, USA.
Cameron@LymeProject.com
"Evidence for the hypothesis: There are eight limitations that support the hypothesis: (1) the
power of the evidence is inadequate to draw definite conclusions, (2) the evidence is too
heterogeneous to make strong recommendations, (3) the risk to an individual of facing a
long-term debilitating illness has not been considered, (4) the risk to society of a growing
chronically ill population has not been considered, (5) treatment delay has not been considered as
a confounder, (6) co-infections have not been considered as a confounder, (7) the design of RCTs did not address the range of treatment options in an actual practice, and (8) the findings cannot
be generalized to actual practice. Implications of the hypothesis: This hypothesis suggests that
physicians should consider the limitations of the evidence before denying antibiotic treatment for
Chronic Lyme Disease (CLD). Physicians who deny antibiotic treatment to CLD patients might
inform their patients that there are some clinicians who disagree with that position, and then
offer to refer them for a second opinion to a doctor who could potentially present a different
point of view. The hypothesis also suggests that health care insurers should consider the
limitations of the evidence before adopting policies that routinely deny antibiotic treatment for
CLD patients and should expand coverage of CLD to include clinical discretion for specific
clinical situations."
There is more than enough information to justify at least a neutral position in respect to whether
Borrelia Burgdorferi and related infectious species persist in human beings despite the Infectious
Disease Society Of America's recommendations. Due to this uncertainty, treating physicians can
not conclusively deny that persistence in human beings may be more problematic than assumed.
The scientific studies available on Lyme Disease contradict each other to a significant degree.
Many study authors state in no uncertain terms that the discussion of Lyme Disease is a closed
case. I disagree. The evidence disagrees. The Chief Medical Officer in the United Kingdom
echoed the sentiments of the IDSA in 2009 stating: "There is no biological evidence of
symptomatic chronic Lyme disease amongst those who have received the recommended
treatment regimen." - CMO, Autum 2009, Issue 49, pg. 4. The IDSA states: "To date, there is no
convincing biologic evidence for the existence of symptomatic chronic B. burgdorferi infection
among patients after receipt of recommended treatment regimens for Lyme disease." - Clin Infect
Dis 2006 Nov 1;43(9):1089-134
Skepticism is the heart of science. Cynicism is the death of reason.
The following studies are organized by year, page, and study title within the Study table index.
3
Study Table Index:
Year Page Study Title
1986 18 Ann Intern Med. 1986 Jun;104,6:798-800. Borrelia burgdorferi in
joint fluid in chronic Lyme arthritis. Snydman DR, Schenkein DP,
Berardi VP, Lastavica CC, Pariser KM.
1986 18 J Am Acad Dermatol. 1986 Sep;15,3:459-63.Treating erythema
chronicum migrans of Lyme disease. Berger BW.
1987 18 Arthritis Rheum. 1987 Apr;30,4:448-50.Failure of tetracycline
therapy in early Lyme disease. Dattwyler RJ, Halperin JJ.
1987 19 Arthritis Rheum. 1987 Jun;30,6:705-8. Lyme meningoencephalitis:
report of a severe, penicillin-re sistant case. Diringer MN, Halperin
JJ, Dattwyler RJ.
1988 19 Pediatr Infect Dis J. 1988 Apr;7,4:286-9. Borrelia burgdorferi in a
newborn despite oral penicillin for Lyme borreliosis during
pregnancy. Weber K, Bratzke HJ, Neubert U, Wilske B, Duray PH.
1988 19 Ann N Y Acad Sci. 1988;539:346-51. Treatment of erythema
chronicum migrans of Lyme disease. Berger BW. Department of
Dermatology, New York University School of Medicine, New York
10016.
1988 20 Arthritis Rheum. 1988 Apr;31,4:487-95. Spirochetal antigens and
lymphoid cell surface markers in Lyme synovitis. Comparison with
rheumatoid synovium and tonsillar lymphoid tissue. Steere AC,
Duray PH, Butcher EC.
1988 20 AMA. 1988 May 13;259,18:2737-9 Fatal adult respiratory distress
syndrome in a patient with Lyme disease. Kirsch M, Ruben FL,
Steere AC, Duray PH, Norden CW, Winkelstein A.
1988 20 J Infect Dis. 1988 Oct;158,4:905-6. Cultivation of Borrelia
burgdorferi from joint fluid three months after treatment of facial
palsy due to Lyme borreliosis. Schmidli J, Hunziker T, Moesli P,
Schaad UB.
Year Page Study Title
4
1988 21 N Engl J Med. 1988 Dec 1;319,22:1441-6. Comment in: N Engl J Med.
1989 May 11;320,19:1279-80.Seronegative Lyme disease.
Dissociation of specific T- and B-lymphocyte responses to Borrelia
burgdorferi. Dattwyler RJ, Volkman DJ, Luft BJ, Halperin JJ,
Thomas J, Golightly MG.
1989 21 Am J Clin Pathol. 1989 Jan;91,1:95 7. Spirochetes in the spleen of a
patient with chronic Lyme disease. Cimmino MA, Azzolini A, Tobia
F, Pesce CM Istituto Scientifico di Medicina Interna, Università di
Genova, Italy.
1989 22 Conn Med. 1989 Jun;53,6:335-7. Treatment of Lyme disease. Schoen
RT.
1989 22 Infection. 1989 Jul-Aug;17,4:216-7. High-dose intravenous
penicillin G does not prevent further progression in early
neurological manifestation of Lyme borreliosis. Kohler J, Schneider
H, Vogt A.
1989 22 Dtsch Med Wochenschr. 1989 Oct 20;114,42:1602-6.
Neuro-borreliosis or intervertebral disk prolapse? [Article in
German] Dieterle L, Kubina FG, Staudacher T, Büdingen HJ.
1989 23 Infection. 1989 Nov-Dec;17,6:355-9.Survival of Borrelia
burgdorferi in antibiotically treated patients with Lyme
borreliosis. Preac-Mursic V, Weber K, Pfister HW, Wilske B, Gross
B, Baumann A, Prokop J. Neurologische Klinik Grosshadern,
München, FR Germany.
1990 23 Acta Trop. 1990 Dec;48, 2:89-94.Clinical implications of delayed
growth of the Lyme borreliosis spirochete, Borrelia burgdorferi.
MacDonald AB, Berger BW, Schwan TG.
Department of Pathology, Southampton Hospital, New York 11968.
1991 24 Infect Immun. 1991 Feb;59,2:671-8. Intracellular localization of
Borrelia burgdorferi within human endothelial cells. Ma Y,
Sturrock A, Weis JJ.
1991 24 1991: Journal of Infectious Diseases, Feb;163,2:311-8 Randomized
comparison of ceftriaxone and cefotaxime in Lyme
neuroborreliosis. Pfister HW, Preac-Mursic V, Wilske B, Schielke E,
SÃrgel F, Einhäupl KM.
Year Page Study Title
5
1991 25 Medicine, Baltimore. 1991 Mar;70,2:83-90. Lyme disease: clinical
features, classification, and epidemiology in the upper midwest.
Agger W, Case KL, Bryant GL, Callister SM.
1991 25 N Engl J Med. 1991 Apr 18;324(16):1137. Chronic neurologic
manifestations of Lyme disease. Logigian EL, Kaplan RF, Steere AC.
Department of Neurology, Tufts University School of Medicine,
Boston, MA 02111.
1991 26 Arthritis Rheum. 1991 Aug;34,8:1056-60. Treatment of refractory
chronic Lyme arthritis with arthroscopic synovectomy. Schoen RT,
Aversa JM, Rahn DW, Steere AC.
1992 26 Clin Exp Rheumatol. 1992 Jul-Aug;10,4:387-90. Molecular detection
of persistent Borrelia burgdorferi in a man with dermatomyositis.
Fraser DD, Kong LI, Miller FW.
1992 27 J Infect Dis. 1992 Aug;166,2:440-4.Fibroblasts protect the Lyme
disease spirochete, Borrelia burgdorferi, from ceftriaxone in vitro.
Georgilis K, Peacocke M, Klempner MS. Department of Medicine,
New England Medical Center, Boston, Massachusetts.
1993 27 J Am Acad Dermatol. 1993 Feb;28,2 Pt 2:312-4. Recurrent erythema
migrans despite extended antibiotic treatment with minocycline in
a patient with persisting Borrelia burgdorferi infection. Liegner
KB, Shapiro JR, Ramsay D, Halperin AJ, Hogrefe W, Kong L.
1993 27 J Infect Dis. 1993 May;167,5:1074-81.Invasion of human skin
fibroblasts by the Lyme disease spirochete, Borrelia burgdorferi.
Klempner MS, Noring R, Rogers RA.
1993 28 Infection. 1993 Mar-Apr;21,2:83-8. Azithromycin versus doxycycli
ne for treatment of erythema migrans: clinical and microbiological
findings. Strle F, Preac-Mursic V, Cimperman J, Ruzic E, Maraspin
V, Jereb M.
1993 29 J Neurol. 1993 May;240,5:278-83. Borrelia burgdorferi myositis:
report of eight patients. Reimers CD, de Koning J, Neubert U,
Preac-Mursic V, Koster JG, Müller-Felber W, Pongratz DE, Duray
PH.
Year Page Study Title
6
1993 30 Arthritis Rheum. 1993 Nov;36,11:1621 6. Persistence of Borrelia
burgdorferi in ligamentous tissue from a patient with chronic
Lyme borreliosis. Häupl T, Hahn G, Rittig M, Krause A, Schoerner
C, Schönherr U, Kalden JR, Burmester GR.
1993 30 J Clin Neuroophthalmol. 1993 Sep;13,3:155-61; discussion 162. 59:
First isolation of Borrelia burgdorferi from an iris biopsy.
Preac-Mursic V, Pfister HW, Spiegel H, Burk R, Wilske B, Reinhardt
S, Böhmer R.
1993 31 Cent Eur J Public Health. 1993 Dec;1,2:81-5. Electron microscopy
and the polymerase chain reaction of spirochetes from the blood of
patients with Lyme disease. Hulínská D, Krausová M, Janovská D,
Rohácová H, Hancil J, Mailer H.
1993 32 Neurology. 1993 Dec;43,12:2705-7. Stroke due to Lyme disease. Reik
L Jr. Department of Neurology, University of Connecticut Health
Center, Farmington 06030-1845.
1994 32 N Engl J Med. 1994 Jan 27; 330,4:282-3.Detection of Borrelia
burgdorferi DNA by polymerase chain reaction in synovial fluid
from patients with Lyme arthritis. Nocton JJ, Dressler F, Rutledge
BJ, Rys PN, Persing DH, Steere AC.
1994 33 J Clin Microbiol. 1994 Mar;32,3:715-20.Isolation of Borrelia
burgdorferi from biopsy specimens taken from healthy-looking
skin of patients with Lyme borreliosis. Kuiper H, van Dam AP,
Spanjaard L, de Jongh BM, Widjojokusumo A, Ramselaar TC, Cairo
I, Vos K, Dankert J. Department of Medical Microbiology, Academic
Medical Centre, University Hospital, University of Amsterdam, The
Netherlands.
1994 33 J Rheumatol. 1994 Mar;21,3:454-61. Lyme disease: an infectious and
postinfectious syndrome.Asch ES, Bujak DI, Weiss M, Peterson MG,
Weinstein A.
1994 34 Ann Intern Med. 1994 Mar 15;120,6:487-9. The persistence of
spirochetal nucleic acids in active Lyme arthritis. Bradley JF,
Johnson RC, Goodman JL.
1994 34 Ann Intern Med. 1994 Oct 15;121,8:560-7.The long-term clinical
outcomes of Lyme disease. A population-based retrospective
cohort study. Shadick NA, Phillips CB, Logigian EL, Steere AC,
Kaplan RF, Berardi VP, Duray PH, Larson MG, Wright EA, Ginsburg
KS, Katz JN, Liang MH.
7
1994 35 Infect. 1994 Nov;29,3:255-61.Treatment of late Lyme borreliosis.
Wahlberg P, Granlund H, Nyman D, Panelius J, Seppälä I.
1994 36 Late complaints after erythema migrans Herta Klade, MD and
Elizabeth Aberer, MD. JSTD 1994; 1:52-56.
1994 36 Borrelia burgdorferi - Seek and ye shall find. Expanding the
envelope Kenneth Liegner, MD. JSTD 1994; 1:79-81.
1994 37 Psychiatric aspects of Lyme disease in children and adolescents: A
community epidemiologic study in Westchester, New York Brian
A. Fallon, MD, MPH; Hector Bird, MD; Christina Hoven, DrPH;
Daniel Cameron, MD, MPH; Michael R. Liebowitz, MD; and David
Shaffer, MD. JSTD 1994; 1:98-100.
1994 37 Persistence of Borrelia burgdorferi despite antibiotic treatment
Michael A. Patmas, MD. JSTD 1994; 1:101.
1994 38 J Infect Dis. 1994 Nov;170,5:1312-6 Comment in: J Infect Dis. 1995
May;171,5:1379-80. Fate of Borrelia burgdorferi DNA in tissues of
infected mice after antibiotic treatment. Malawista SE, Barthold
SW, Persing DH. Department of Internal Medicine, Yale University
School of Medicine, New Haven, Connecticut.
1995 39 Antimicrob Agents Chemother. 1995 May;39,5:1127-33. Effects of
penicillin, ceftriaxone, and doxycycline on morphology of Borrelia
burgdorferi. Kersten A, Poitschek C, Rauch S, Aberer E.
1995 40 Persistent PCR positivity in a patient being treated for Lyme
disease. Kornelia Keszler, MD and Richard C. Tilton, PhD. JSTD
1995; 2:57-58.
1995 40 Neuroborreliosis in Texas Audrey Stein Goldings, MD. JSTD 1995;
2:59-61.
1995 40 Vartiovaara I. 1995 Living with Lyme. Lancet, 345:842-4 A Finnish
physician ?s account of his experiences that beginning with a tick
bite in Vancouver in 1987.
Year Page Study Title
1995 40 J Neuropsychiatry Clin Neurosci. 1995 Summer;7,3:345-7. Rapidly
progressive frontal-type dementia associated with Lyme disease.
Waniek C, Prohovnik I, Kaufman MA, Dwork AJ.
8
1995 41 Ann Neurol. 1995 Oct;38,4:667-9. Comment in: Ann Neurol. 1995
Oct;38,4:560-2.Neuroborreliosis in the nonhuman primate:
Borrelia burgdorferi persists in the central nervous system.
Pachner AR, Delaney E, O'Neill T.
1995 41 Eur Neurol. 1995;35,2:113-7. Comment in: Eur Neurol.
1996;36,6:394-5. Seronegative chronic relapsing
neuroborreliosis.Lawrence C, Lipton RB, Lowy FD, Coyle PK.
1996 42 Infection. 1996 Jan-Feb;24,1:64-8. Azithromycin and doxycycline
for treatment of Borrelia culture-positive erythema migrans. Strle
F, Maraspin V, Lotric-Furlan S, Ruzi·-Sablji· E, Cimperman J.
1996 42 Infection. 1996 Jan-Feb;24,1:9-16. Erratum in: Infection 1996
Mar-Apr;24,2:169.Kill kinetics of Borrelia burgdorferi and
bacterial findings in relation to the treatment of Lyme borreliosis.
Preac Mursic V, Marget W, Busch U, Pleterski Rigler D, Hagl S. Max
v. Pettenkofer Institut, Ludwig-Maximilians-Universität München,
Germany.
1996 43 Infection. 1996 Jan-Feb;24,1:73-5. Treatment failure in erythema
migrans--a review. Weber K. Dermatologische Privatpraxis,
München, Germany.
1996 43 Infection. 1996 May-Jun;24,3:218-26. Erratum in: Infection 1996
Jul-Aug;24,4:335. Formation and cultivation of Borrelia
burgdorferi spheroplast-L-form variants. Mursic VP, Wanner G,
Reinhardt S, Wilske B, Busch U, Marget W.
1996 44 JAMA. 1996 Jun 5; 275,21, :1657-60. Concurrent Lyme disease and
babesiosis. Evidence for increased severity and duration of illness.
K rause PJ, Telford SR 3rd, Spielman A, Sikand V, Ryan R,
Christianson D, Burke G, Brassard P, Pollack R, Peck J, Persing DH.
1996 44 Antimicrob Agents Chemother. 1996 Jun;40,6:1552-4. Eucaryotic
cells protect Borrelia burgdorferi from the action of penicillin and
ceftriaxone but not from the action of doxycycline and
erythromycin. Brouqui P, Badiaga S, Raoult D. Unité des Rickettsies,
Faculté de Médecine, Centre National de la Recherche Scientifique,
Marseille, France.
Year Page Study Title
9
1996 45 Infection. 1996 Sep-Oct;24,5:347-53.Borrelia burgdorferi DNA in
the urine of treated patients with chronic Lyme disease symptoms.
A PCR study of 97 cases. Bayer ME, Zhang L, Bayer MH. Fox Chase
Cancer Center, Philadelphia, PA 19111, USA.
1996 45 Hum Pathol. 1996 Oct;27,10:1025-34.Ultrastructural demonstration
of spirochetal antigens in synovial fluid and synovial membrane in
chronic Lyme disease: possible factors contributing to persistence
of organisms. Nanagara R, Duray PH, Schumacher HR Jr.
Allergy-Immunology-Rheumatology Division, Department of
Medicine, Faculty of Medicine, KhonKaen University, Thailand.
1996 46 Rheumatol Int. 1996;16,3:125-32.Intracellular persistence of
Borrelia burgdorferi in human synovial cells. Girschick HJ,
Huppertz HI, Rüssmann H, Krenn V, Karch H.
1996 47 Antimicrob Agents Chemother. 1996 Nov;40 11 :2632-6.In vivo
activities of ceftriaxone and vancomycin against Borrelia spp in the
mouse brain and other sites. Kazragis RJ, Dever LL, Jorgensen JH,
Barbour AG.
1996 47 Brain. 1996 Dec;119, Pt 6:2143-54. Inflammatory brain changes in
Lyme borreliosis. A report on three patients and review of
literature. Oksi J, Kalimo H, Marttila RJ, Marjamäki M, Sonninen P,
Nikoskelainen J, Viljanen MK.
1996 48 Am J Dermatopathol. 1996 Dec;18,6:571-9. Heterogeneity of
Borrelia burgdorferi in the skin. Aberer E, Kersten A, Klade H,
Poitschek C, Jurecka W.
1997 48 328: Semin Neurol. 1997 Mar;17,1:25-30.Peripheral nervous system
Lyme borreliosis. Logigian EL.
1997 49 J Clin Microbiol. 1997 January; 35(1): 111?116. Persistence of
Borrelia burgdorferi in experimentally infected dogs after
antibiotic treatment. R K Straubinger, B A Summers, Y F Chang,
and M J Appel Institute for Animal Health, College of Veterinary
Medicine, Cornell University, Ithaca, New York 14853, USA.
rks4@cornell.edu
1997 49 Clin Infect Dis. 1997 Jul;25 Suppl 1:S52-6. Tetracycline therapy for
chronic Lyme disease. Donta ST.
Year Page Study Title
10
1997 50 Clin Infect Dis. 1997 Jul;25 Suppl 1:S64-70.Why is chronic Lyme
borreliosis chronic? Aberer E, Koszik F, Silberer M.
1997 51 American College of Rheumatology, Vol 40,9, Branigan P; Rao J;
1997 PCR evidence for Borrelia burgdorferi DNA in synovium in
absence of positive serology. Suppl, Rao J; Gerard H; Sept, p.S270
Hudson A; Williams W; Arayssi T; Pando J; Bayer M; Rothfuss S;
.PCR evidence for Borrelia has been identified in synovial biopsies of
patients with clinical pictures that had not initially suggested Lyme
disease. Clayburne G; Sieck M; Schumacher HR.
1997 51 Journal of Spirochetal & Tick-borne Diseases, Vol. 4, No. 1/2 Two
lessons from the canine model of Lyme Disease: migration of
Borrelia burgdorferi in tissues and persistence after antibiotic
treatment. Straubinger RK; 1997 Straubinger AF; Jacobson RH;
Chang Y; Summer BA;
1998 51 Ann Rheum Dis. 1998 Feb;57,2:118-21.Detection of Borrelia
burgdorferi by polymerase chain reaction in synovial membrane,
but not in synovial fluid from patients with persisting Lyme
arthritis after antibiotic therapy. Priem S, Burmester GR, Kamradt
T, Wolbart K, Rittig MG, Krause A.
1998 52 Med J Aust. 1998 May 18;168,10:500-2. Comment in: Med J Aust.
1998 May 18;168,10:479-80. Culture-positive Lyme borreliosis.
Hudson BJ, Stewart M, Lennox VA, Fukunaga M, Yabuki M,
Macorison H, Kitchener-Smith J.
1998 52 Acta Clin Belg. 1998 Jun;53,3:178-83.Lyme borreliosis--a review of
the late stages and treatment of four cases. Petrovic M, Vogelaers D,
Van Renterghem L, Carton D, De Reuck J, Afs chrift M. Department
of Internal Medicine, University Hospital Ghent, Belgium.
1998 53 Eur J Clin Microbiol Infect Dis. 1998 Oct;17,10:715-9.Comparison of
oral cefixime and intravenous ceftriaxone followed by oral
amoxicillin in disseminated Lyme borreliosis. Oksi J, Nikoskelainen
J, Viljanen MK. Department of Medicine, Turku University Central
Hospital, Finland.
Year Page Study Title
11
1998 53 Neurology. 1998 Nov;51,5:1489-91. Comment in: Neurology. 1999
Sep 11;53,4:895-6. Clinical and serologic follow-up in patients with
neuroborreliosis. Treib J, Fernandez A, Haass A, Grauer MT, Holzer
G, Woessner R.
1998 54 Infection. 1998 Nov-Dec; 26,6:364-7.A proposal for the reliable
culture of Borrelia burgdorferi from patients with chronic Lyme
disease, even from those previously aggressively treated. Phillips
SE, Mattman LH, Hulínská D, Moayad H. Greenwich Hospital, CT
06830, USA.
1998 54 Klin Monatsbl Augenheilkd. 1998 Dec;213,6:351-4. Pars plana
vitrectomy in Borrelia burgdorferi endophthalmitis [Article in
German] Meier P, Blatz R, Gau M, Spencker FB, Wiedemann P.
1999 55 Ann Med. 1999 Jun; 3,3:225-32. Borrelia burgdorferi detected by
culture and PCR in clinical relapse of disseminated Lyme
borreliosis. Oksi J, Marjamäki M, Nikoskelainen J, Viljanen MK.
1999 55 Zentralbl Bakteriol. 1999 Jul;289,3:301-18. Persistence of Borrelia
garinii and Borrelia afzelii in patients with Lyme arthritis.
Hulínská D, Votýpka J, Valeso vá M.
2000 56 J Infect Dis. 2000 Mar;181,3:1069-81. Status of Borrelia burgdorferi
infection after antibiotic treatment and the effects of
corticosteroids: An experimental study. Straubinger RK,
Straubinger AF, Summers BA, Jacobson RH.
2000 57 J Clin Microbiol. 2000 Jun; 38,6, :2191-9. PCR-Based quantification
of Borrelia burgdorferi organisms in canine tissues over a 500-Day
postinfection period. Straubinger RK. James A. Baker Institute for
Animal Health, College of Veterinary Medicine, Cornell University,
Ithaca, New York 14853, USA.
rks4@cornell.edu
2001 59 Br J Dermatol. 2001 Feb;144,2:387-92. Is olation and polymerase
chain reaction typing of Borrelia afzelii from a skin lesion in a
seronegative patient with generalized ulcerating bullous lichen
sclerosus et atrophicus. Breier F, Khanakah G, Stanek G, Kunz G,
Aberer E, Schmidt B, Tappeiner G.
Year Page Study Title
12
2001 59 Epidemiol Mikrobiol Imunol. 2001 Feb;50,1:10-6.Persistence of
Borrelia burgdorferi sensu lato in patients with Lyme borreliosis
[Article in Czech] Honegr K, Hulínská D, Dostál V, Gebouský P,
Hanková E, Horácek J, Vyslouzil L, Havlasová J. Infekcní klinika,
Fakultní nemocnice, Hradec Králové.
2001 60 Ann Neurol. 2001 Sep;50,3, :330-8.Central and peripheral nervous
system infection, immunity, and inflammation in the NHP model
of Lyme borreliosis. Pachner AR, Cadavid D, Shu G, Dail D, Pachner
S, Hodzic E, Barthold SW. Department of Neurosciences,
UMDNJ-New Jersey Medical School, Newark 07103, USA.
pachner@umdnj.edu
2002 60 Wien Klin Wochenschr. 2002 Jul 31;114,13-14:574-9. Cystic forms of
Borrelia burgdorferi sensu lato: induction, development, and the
role of RpoS. Murgia R, Piazzetta C, Cinco M.
2002 61 Acta Neurol Scand. 2002 Oct;106(4):205-8. Chronic symptoms are
common in patients with neuroborreliosis -- a questionnaire
follow-up study. Vrethem M, Hellblom L, Widlund M, Ahl M,
Danielsson O, Ernerudh J, Forsberg P.
2002 62 J Infect Dis. 2002 Nov 15;186,10:1430-7. Epub 2002 Oct 23.
Detection of attenuated, noninfectious spirochetes in Borrelia
burgdorferi-infected mice after antibiotic treatment. Bockenstedt
LK, Mao J, Hodzic E, Barthold SW, Fish D.
2002 62 Antimicrob Agents Chemother. 2002 Nov;46,11:3637-40.
Erythromycin resistance in Borrelia burgdorferi. Terekhova D,
Sartakova ML, Wormser GP, Schwartz I, Cabello FC.
2002 63 Przegl Epidemiol. 2002;56 Suppl 1:57-67.New aspects of the
pathogenesis of lyme disease [Article in Polish] Zajkowska JM,
Hermanowska-Szpakowicz T. Klinika Chorób Zaka·nych i
Neuroinfekcji AM w Bia ymstoku.
2003 63 Neurology. 2003 Jun 24;60,12:1923-30. Comment in: Neurology.
2003 Jun 24;60,12:1888-9.Study and treatment of post Lyme di
sease, STOP-LD: a randomized double masked clinical trial. Krupp
LB, Hyman LG, Grimson R, Coyle PK, Melville P, Ahnn S, Dattwyler
R, Chandler B.
Year Page Study Title
13
2003 64 Med Sci Monit. 2003 Nov;9,11:PI136-42. Macrolide therapy of
chronic Lyme Disease. Donta ST.
2005 65 Vet Microbiol. 2005 May 20;107(3-4):285-94 Antibiotic treatment of
experimentally Borrelia burgdorferi-infected ponies. Chang YF,
Ku YW, Chang CF, Chang CD, McDonough SP, Divers T, Pough M,
Torres A. College of Veterinary Medicine, Cornell University, Ithaca,
NY 14853, USA.
yc42@cornell.edu
2005 65 Int J Antimicrob Agents. 2005 Jun;25,6:474-8. Susceptibility of
Borrelia afzelii strains to antimicrobial agents. Ruzi·-Sablji· E,
Podreka T, Maraspin V, Strle F.
2006 66 Int J Med Microbiol. 2006 May;296 Suppl 40:233-41. Epub 2006 Mar
10.Risk of culture-confirmed borrelial persistence in patients
treated for erythema migrans and possible mechanisms of
resistance. Hunfeld KP, Ruzi·-Sablji· E, Norris DE, Kraiczy P, Strle F.
Institute of Medical Microbiology, University Hospital of Frankfurt,
Paul-Ehrlich Str. 40, D-60596 Frankfurt/Main, Germany.
K.Hunfeld@em.uni-frankfurt.de
2006 67 Eur J Pediatr. 2006 Jun;165,6:420-1. Epub 2006 Mar 4. Persistent
synovitis in two children with Lyme arthritis linked with
HLA-DRB1*1104. Hendrickx G, Demanet C, Vandenplas Y.
Department of Paediatrics, Paediatric Orthopaedic and
Rheumatology Unit, Academisch Ziekenhuis -Vrije Universiteit
Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium.
g.hendrickx@st-anna.nl
2006 67 Int J Immunopathol Pharmacol. 2006 Jul-Sep;19,3:545-9. In vitro
susceptibility of isolates of Borrelia burgdorferi s.l. to
antimicrobial agents. Santino I, Scazzocchio F, Ciceroni L,
Ciarrocchi S, Sessa R, Del Piano M. Department of Public Health
Sciences, La Sapienza University, Rome, Italy.
iolanda.santino@uniroma1.it
2006 68 Microbes Infect. 2006 Nov-Dec; 8,14-15:2832-40. Epub 2006 Sep
22.Invasion of human neuronal and glial cells by an infectious
strain of Borrelia burgdorferi. Livengood JA, Gilmore RD Jr.
Year Page Study Title
14
2007 68 Acta Radiologica, Volume 48, Issue 7 2007 , pages 755 - 762 Brain
Magnetic Resonance Imaging Does Not Contribute to the Diagnosis
of Chronic Neuroborreliosis. Aalto A, Sjöwall J, Davidsson L,
Forsberg P, Smedby O. Division of Radiology, Department of
Medicine and Care, Faculty of Health Sciences, Linköping University,
Linköping, Sweden.
anne.aalto@imv.liu.se
2007 69 Pol Merkur Lekarski. 2007 Apr;22,130:275-9. Related Articles,
Concentrations of pro-inflammatory cytokines IFN-gamma, IL-6,
IL-12 and IL-15 in serum and cerebrospinal fluid in patients with
neuroborreliosis undergoing antibiotic treatment. Article in Polish.
Pancewicz SA, Kondrusik M, Zajkowska J, Grygorczuk S. Akademia
Medyczna w Bialymstoku, Klinika ChorÃ3b Zakaznych i
Neuroinfekcji.20spancewicz@interia.pl
2007 69 J Infect Dis. 2007 May 15;195,10:1489-96. Epub 2007 Apr
6.Anti-tumor necrosis factor-alpha treatment activates Borrelia
burgdorferi spirochetes 4 weeks after ceftriaxone treatment in
C3H/He mice. Yrjänäinen H, Hytönen J, Song XY, Oksi J, Hartiala K,
Viljanen MK. Department of Medical Microbiology, University of
Turku, Turku, 20520, Finland.
heta.yrjanainen@utu.fi
2007 70 Adv Med Sci. 2007;52:174-8. Concentration of TGF-beta1 in the
supernatant of peripheral blood mononuclear cells cultures from
patients with early disseminated and chronic lyme borreliosis.
Grygorczuk S, Chmielewski T, Zajkowska J, Swierzbi·ska R,
Pancewicz S, Kondrusik M, Tylewska-Wierzbanowska S,
Hermanowska-Szpakowicz T. Department of Infectious Diseases and
Neuroinfections, Medical University of Bia·ystok, ul. Zurawia 14,
15-540 Bia·ystok, Poland.
neuroin@amb.edu.pl
2007 71 Rheumatol Int. 2007 Sep;27,11:1091-3. Epub 2007 Apr 4.
Seronegative Lyme arthritis. Holl-Wieden A, Suerbaum S, Girschick
HJ. Children's hospital, Section of Pediatric Rheumatology,
Immunology and Infectious diseases, University of Wuerzburg,
Josef-Schneider-Str. 2, 97090 Wuerzburg, Germany.
Year Page Study Title
15
2007 71 Pol Merkur Lekarski. 2007 Sep;23,135:174-8. Concentration of
soluble forms of selectins in serum and in cerebrospinal fluid in
group of patients with neuroborreliosis--a preliminary study
Moniuszko AM, Pancewicz SA, Ko ndrusik M, Zajkowska J,
Grygorczuk S, Swierzbi·ska R. Akademia Medyczna w Bia·ymstoku,
Klinika Chorób Zaka·nych i Neuroinfekcji.
2008 72 Volume 358:428-431 January 24, 2008 Number An Appraisal of
"Chronic Lyme Disease" To the Editor: Feder et al., Oct. 4 issue,
2008 75 Persistence of Borrelia burgdorferi Following Antibiotic
Treatment in Mice Antimicrobial Agents and Chemotherapy,
published online ahead of print on 3 March 2008 Emir Hodzic,
Sunlian Feng, Kevin Holden, Kimberly J. Freet, and Stephen W.
Barthold
2008 75 Antimicrobial Agents and Chemotherapy, May 2008, p. 1728-1736,
Vol. 52, No. 50066-4804 Persistence of Borrelia burgdorferi
following Antibiotic Treatment in Mice Emir Hodzic, Sunlian Feng,
Kevin Holden, Kimberly J. Freet, and Stephen W. Barthold*
2008 76 Pol Arch Med Wewn. 2008 May;118 5:314-7. : Neuroborreliosis with
extrapyramidal symptoms: a case report. Biesiada G, Czapiel J,
Sobczyk-Krupiarz I, Garlicki A, Mach T. Department of Infectious
Diseases, Division of Gastroenterology, Hepatology, and Infectious
Diseases, Jagiellonian University School of Medicine, Kraków,
Poland.
gbiesiada@op.pl
2008 76 J Neuroinflammation. 2008 Sep 25;5:40. Persisting atypical and
cystic forms of Borrelia burgdorferi and local inflammation in
Lyme neuroborreliosis. Miklossy J, Kasas S, Zurn AD, McCall S, Yu
S, McGeer PL.
2008 77 Microb Pathog. 2008 Sep 20. Borrelia burgdorferi expression of the
bba64, bba65, bba66, and bba73 genes in tissues during persistent
infection in mice. Gilmore RD Jr, Howison RR, Schmit VL, Carroll
JA.
2008 78 Med Hypotheses. 2008;70,5:967-74. Epub 2007 Nov 5. The
association between tick-borne infections, Lyme borreliosis and
autism spectrum disorders. Bransfield RC, Wulfman JS, Harvey
WT, Usman AI.
Year Page Study Title
16
2008 79 Journal of Veterinary Diagnostic Investigation Vol. 20 Issue 3,
321-324 Copyright © 2008 by the American Association of
Veterinary Laboratory Diagnosticians: Validation of an in-clinic
enzyme-linked immunosorbent assay kit for diagnosis of Borrelia
burgdorferi infection in horses. Amy L. Johnson1, Thomas J. Divers
and Yung-Fu Chang
2009 80 J Antimicrob Chemother. 2009 Jun;63 6:1163-72. Epub 2009 Apr 17.
Assessment of methylthioadenosine/S-adenosylhomocysteine
nucleosidases of Borrelia burgdorferi as targets for novel
antimicrobials using a novel high-throughput method. Cornell KA,
Primus S, Martinez JA, Parveen N.
2009 81 Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18656-61. Epub 2009
Oct 20. Destruction of spirochete Borrelia burgdorferi round-body
propagules (RBs) by the antibiotic tigecycline. Brorson Ø, Brorson
SH, Scythes J, MacAllister J, Wier A, Margulis L.
2010 81 Persistence of borrelial DNA in the joints of Borrelia
burgdorferi-infected mice after ceftriaxone treatment HETA
YRJÄNÄInen 1 , JUKKA HYTÖNen 1 , PAULIINA HARTIALA 1 ,
JARMO OKSI 2 and MATTI K. VILJANEN Departments of
1Medical Microbiology and Immunology and 2 Medicine, University
of Turku, Turku, Finland
Evidential support for the case of Chronic Infection:
17
1: Ann Intern Med. 1986 Jun;104,6:798-800. Borrelia burgdorferi in joint fluid in chronic
Lyme arthritis. Snydman DR, Schenkein DP, Berardi VP, Lastavica CC, Pariser KM.
Although indirect evidence suggests that chronic Lyme arthritis is caused by persistent
infection with Borrelia burgdorferi, direct visualization has been lacking. We report the
demonstration of B. burgdorferi from synovial fluid aspirated from the right knee of a
31-year-old man with Lyme arthritis for more than 1 year. After 6 days, culture medium
inoculated with synovial fluid showed one motile and several nonmotile spirochetes. Direct
immunofluorescence staining showed reactivity with anti-B. burgdorferi serum. Spirochetes were
not seen in subcultured material. The patient's arthritis improved with high-dose intravenous
penicillin. Identification of B. burgdorferi from the joint fluid of a patient with long-standing
arthritis supports the concept that the arthritis is due to persistent infection.
2: J Am Acad Dermatol. 1986 Sep;15,3:459-63.Treating erythema chronicum migrans of Lyme
disease. Berger BW.
The efficacy of antibiotic treatment of 117 patients with erythema chronicum migrans of Lyme
disease was evaluated in terms of the necessity for retreatment and the prevention of the late
manifestations of Lyme disease.Fifty-six patients with a minor form of the illness did not
require retreatment and did not develop late manifestations following antibiotic treatment.
Three pregnant patients were included in this group.Fourteen of sixty-one patients with a major
form of the illness required retreatment, and five developed posttreatment late
manifestations of Lyme disease consisting of Bell's palsy and persistent joint pain. Although
the preferred antibiotic for treating erythema chronicum migrans of Lyme disease has not been
conclusively established, tetracycline and penicillin proved effective. The use of probenecid plus
penicillin may be of benefit to patients with the major form of the illness.
3: 1: Arthritis Rheum. 1987 Apr;30,4:448-50.Failure of tetracycline therapy in early Lyme
disease. Dattwyler RJ, Halperin JJ.
We describe the clinical courses of 5 patients with Lyme disease who developed significant late
complications, despite receiving tetracycline early in the course of their illness. All 5 patients
had been treated for erythema chronicum migra ns with a course of tetracycline that met or
exceeded current recommendations. The late manifestations of Lyme disease included arthritis,
cranial nerve palsy, peripheral neuropathy, chronic fatigue, and changes in mental function. Our
findings suggest that the use of tetracycline at a dosage of 250 mg, 4 times a day for 10 days, as a
treatment for early Lyme disease should be reconsidered. To determine optimal therapy for early
Lyme disease, a study that compares an increased dosage of tetracycline with alternative
18
treatments is indicated.
4: Arthritis Rheum. 1987 Jun;30,6:705-8. Lyme meningoencephalitis: report of a severe,
penicillin-re sistant case. Diringer MN, Halperin JJ, Dattwyler RJ.
Although Lyme disease frequently attacks the central nervous system, this involvement is rarely
severe, and high-dose intravenous penicillin usually is adequate treatment. The patient we
describe developed severe Lyme meningoencephalitis despite receiving a full course of
penicillin, and his condition continued to deteriorate after reinstitution of this treatment.
Intravenous chloramphenicol was used successfully and resulted in a substantial improvement.
5: Pediatr Infect Dis J. 1988 Apr;7,4:286-9. Borrelia burgdorferi in a newborn despite oral
penicillin for Lyme borreliosis during pregnancy. Weber K, Bratzke HJ, Neubert U, Wilske B,
Duray PH.
Department of Medicolegal Medicine, Dermatology and Microbiology, University of Munich,
Federal Republic of Germany. "We now demonstrate B. burgdorferi in the brain and liver of a
newborn whose mother had been treated with oral penicillin for LB [Lyme borreliosis] during
the first trimester of pregnancy. ..The death of the newborn was probably due to a respiratory
failure as a consequence of perinatal brain damage.?
6: Ann N Y Acad Sci. 1988;539:346-51. Treatment of erythema chronicum migrans of Lyme
disease. Berger BW. Department of Dermatology, New York University School of Medicine, New
York 10016.
Between June 1981 and July 1987 the efficacy of antibiotic treatment of 215 patients with
erythema chronicum migrans of Lyme disease was evaluated in terms of the necessity for
retreatment and the prevention of the late manifestations of Lyme disease. The principal
antibiotics utilized to treat 161 patients through 1986 were varying doses of tetracycline, or
penicillin alone or in combination with probenecid. Two of 8 0 patients with a minor form of the
illness and 17 of 81 patients with a major form of the illness required retreatment. There were
four patients who did not respond to retreatment with their original medication. A 15- to 30-day
course of amoxicillin, 500 mg q.i.d., and probenecid, 500 mg q.i.d., or doxycycline, 100 mg t.i.d.,
and on three occasions ceftriaxone, 2-4 g/day i.v., were used to treat 54 patients in 1987.
Although it is too early to judge the efficacy of treatment in these patients, increases in the
incidence of Herxheimer reactions and drug eruptions were observed. Strict compliance with
treatment protocols and the possibility of reactions to medications should be thoroughly
discussed with patients.
19
7: 1: Arthritis Rheum. 1988 Apr;31,4:487-95. Spirochetal antigens and lymphoid cell surface
markers in Lyme synovitis. Comparison with rheumatoid synovium and tonsillar lymphoid
tissue. Steere AC, Duray PH, Butcher EC.
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
Using monoclonal antibodies to spirochetal antigenes and lymphoid cell surface markers, we
examined the synovial lesions of 12 patients with Lyme disease, and compared them with
rheumatoid synovium and tonsillar lymphoid tissue. The synovial lesions of Lyme disease
patients and rheumatoid arthritis patients were similar and often consisted of the elements found
in normal organized lymphoid tissue. In both diseases, T cells, predominantly of the
helper/inducer s ubset, were distributed diffusely in subsynovial lining areas, often with nodular
aggregates of tightly intermixed T and B cells. IgD-bearing B cells were scattered within the
aggregates, and a few follicular dendritic cells and activated germinal center B cells were
sometimes present. Outside the aggregates, many plasma cells, high endothelial venules, scattered
macrophages, and a few dendritic macrophages were found. HLA-DR and DQ expression was
intense throughout the lesions. In 6 of the 12 patients with Lyme arthritis, but in none of those
with rheumatoid arthritis, a few spirochetes and globular antigen deposits were seen in and
around blood vessels in areas of lymphocytic infiltration. Thus, in Lyme arthritis, a small
number of spirochetes are probably the antigenic stimulus for chronic synovial inflammation.
8: AMA. 1988 May 13;259,18:2737-9 Fatal adult respiratory distress syndrome in a patient with
Lyme disease. Kirsch M, Ruben FL, Steere AC, Duray PH, Norden CW, Winkelstein A.
Department of Medicine, Montefiore Hospital, University of Pittsburgh School of Medicine, PA
15213.
A dry cough, fever, generalized maculopapular rash, and myositis developed in a 67-year-old
woman; she also had markedly abnormal liver function test results. Serologic tests proved that
she had an infection of recent onset with Borrelia burgdorferi, the agent that causes Lyme
disease. During a two-month course of illness, her condition remained refractory to
treatment with antibiotics, salicylates, and steroids. Ultimately, fatal adult respiratory distress
syndrome developed; this was believed to be secondary to Lyme disease.
9: J Infect Dis. 1988 Oct;158,4:905-6. Cultivation of Borrelia burgdorferi from joint fluid three
months after treatment of facial palsy due to Lyme borreliosis. Schmidli J, Hunziker T, Moesli
P, Schaad UB.
Attacks typically are intermittent and last from 3 days to 12 months. The knees are affected most
20
often, but migratory arthritis is common and other large and small joints may be involved. Only
very few Borrelia strains have been cultured from joint specimens worldwide However, a high
percentage of patients with Lyme arthritis, 85%, have evidence of B burgdorferi DNA,
detected by PCR, in the synovial fluid The local persistence of B burgdorferi in the joint over a
long period of time might be related to the exacerbations of symptoms after chondrocyte cell
transplantation. B burgdorferi is difficult to detect in synovial fluid, and cultures are positive only
rarely
10: 1: N Engl J Med. 1988 Dec 1;319,22:1441-6. Comment in: N Engl J Med. 1989 May
11;320,19:1279-80.Seronegative Lyme disease. Dissociation of specific T- and B-lymphocyte
responses to Borrelia burgdorferi. Dattwyler RJ, Volkman DJ, Luft BJ, Halperin JJ, Thomas J,
Golightly MG.
Department of Medicine, State University of New York, School of Medicine, Stony Brook
11794-8161.
The diagnosis of Lyme disease often depends on the measurement of serum antibodies to Borrelia
burgdorferi, the spirochete that causes this disorder.Although prompt treatment with
antibiotics may abrogate the antibody response to the infection, symptoms persist in some
patients. We studied 17 patients who had presented with acute Lyme disease and received
prompt treatment with oral antibiotics, but in whom chronic Lyme disease subsequently
developed. Although these patients had clinically active disease, none had diagnostic levels of
antibodies to B. burgdorferi on either a standard enzyme-linked immunosorbent assay or
immunofluorescence assay. On Western blot analysis, the level of immunoglobulin reactivity
against B. burgdorferi in serum from these patients was no greater than that in serum from
normal controls. The patients had a vigorous T-cell proliferative response to whole B.
burgdorferi, with a mean, +/- SEM, stimulation index of 17.8 +/- 3.3, similar to that, 15.8 +/- 3.2,
in 18 patients with chronic Lyme disease who had detectable antibodies. The T-cell response of
both groups was greater than that of a control group of healthy subjects, 3.1 +/- 0.5; P less than
0.001.We conclude that the presence of chronic Lyme disease cannot be excluded by the
absence of antibodies against B. burgdorferi and that a specific T-cell blastogenic response to
B. burgdorferi is evidence of infection in seronegative patients with clinical indications of
chronic Lyme disease.
11: 1: Am J Clin Pathol. 1989 Jan;91,1:95 7. Spirochetes in the spleen of a patient with chronic
Lyme disease. Cimmino MA, Azzolini A, Tobia F, Pesce CM Istituto Scientifico di Medicina
Interna, Università di Genova, Italy.
A 54-year-old man had intermittent evening fever, arthralgia, transient erythematous macular
21
eruption on the skin, and splenomegaly of two year's duration. Immunofluorescence tests for
Borrelia burgdorferi serum antibodies had positive results, but G-penicillin treatment was
ineffective. Splenectomy with lymph node biopsy was performed to rule out lymphoproliferative
disorders. Borrelia-like spirochetes were identified histologically in the spleen; this finding
was consistent with persistence of B. burgdorferi organisms in inner organs in chronic Lyme
disease.
12: 1: Conn Med. 1989 Jun;53,6:335-7. Treatment of Lyme disease. Schoen RT.
Lyme disease, a tick-transmitted spirochetal infection, can be divided into three stages that can
overlap or occur alone. The goals of antibiotic therapy in stage one are to shorten the duration of
early disease and to prevent the development of later stages20of the illness. This can usually be
accomplished with oral antibiotic therapy. Later stages of the illness are frequently more
difficult to treat, requiring prolonged oral or intravenous antibiotic therapy.
13: Infection. 1989 Jul-Aug;17,4:216-7. High-dose intravenous penicillin G does not prevent
further progression in early neurological manifestation of Lyme borreliosis. Kohler J,
Schneider H, Vogt A.
Neurologische Universitätsklinik und Poliklinik, Freiburg.
We report two cases of Lyme borreliosis, LB, with erythema migrans, EM, and simultaneous
meningopolyneuritis with radicular pain and lymphocytic pleocytosis in the cerebrospinal fluid,
CSF. EM and pain disappeared completely under high-dose penicillin G therapy within few a
days. Pathological findings in CSF improved. Nevertheless, during and after therapy,
neurological signs of LB developed: cranial nerve palsies as well as paresis of extremity
muscles with radicular distribution.
14: 1: Dtsch Med Wochenschr. 1989 Oct 20;114,42:1602-6. Neuro-borreliosis or intervertebral
disk prolapse? [Article in German] Dieterle L, Kubina FG, Staudacher T, Büdingen HJ.
Abteilung für Neurologie und klinische Neurophysiologie, St.-Elisabethen-Krankenhaus
Ravensburg.
Between September 1986 and November 1988, 17 patients were hospitalized and treated for
neuro-borreliosis. Ten of them had been admitted with suspected lumbar or cervical root or
compression syndrome. Only four patients recalled a tick bite, only three an erythema migrans.
Uni- or bilateral facial paresis was a prominent feature in six patients. Three of 14 patients had no
IgG antibodies against Borrelia, either in serum or cerebrospinal fluid at the initial examination,
22
two had positive titres in serum only. Despite antibiotic treatment, usually 10 mega U
penicillin three times daily, six patients had a recurrence by April, 1989, treated with
penicillin again or with twice daily 100 mg doxycycline or 2 g ceftriaxon. In four of them a
residual painful polyneuropathy remains.
15: 1: Infection. 1989 Nov-Dec;17,6:355-9.Survival of Borrelia burgdorferi in antibiotically
treated patients with Lyme borreliosis. Preac-Mursic V, Weber K, Pfister HW, Wilske B, Gross
B, Baumann A, Prokop J. Neurologische Klinik Grosshadern, München, FR Germany.
The persistence of Borrelia burgdorferi in patients treated with antibiotics is described. The
diagnosis of Lyme disease is based on clinical symptoms, epidemiology and specific IgG and IgM
antibody titers to B. burgdorferi in serum. Antibiotic therapy may abrogate the antibody response
to the infection as shown in our patients. B. burgdorferi may persist as shown by positive culture
in MKP-medium; patients may have subclinical or clinical disease without diagnostic antibody
titers to B. burgdorferi.We conclude that early stage of the disease as well as chronic Lyme
disease with persistence of B. burgdorferi after antibiotic therapy cannot be excluded when
the serum is negative for antibodies against B. burgdorferi.
[Persistence:] However, some patients later developed symptoms of the disease despite
antibiotic treatment, 9-11. Because of these observations it has become questionable if a
definite eradication of B. burgdorferi with antibiotics is possible, p.357. ..The central nervous
system invasion by spirochetes and a persistence of Treponema pallidum after penicillin G
therapy is common in neurosyphilis, 22,23, p.358.[Treatment:] In view of the hitherto failure of
treatment, low CSF concentration of penicillin G, survival of B. burgdorferi in patients treated
with antibiotics, the moderate penicillin G susceptibility o f the organism and unpredictable
progression of the disease, it seems appropriate to treat patients with substantially larger
doses of antibiotics and/or longer than is provided in present treatment regimens.
p.358.[Seronegativity:] As shown, negative antibody-titers do not provide evidence for successful
therapy; antibody-titers may become negative despite persistence.
16: Acta Trop. 1990 Dec;48, 2:89-94.Clinical implications of delayed growth of the Lyme
borreliosis spirochete, Borrelia burgdorferi. MacDonald AB, Berger BW, Schwan TG.
Department of Pathology, Southampton Hospital, New York 11968.
Lyme borreliosis, a spirochetal infection caused by Borrelia burgdorferi, may become clinically
active after a period of latency in the host.Active cases of Lyme disease may show clinical relapse
following antibiotic therapy. The latency and relapse phenomena suggest that the Lyme disease
spirochete is capable of survival in the host for prolonged periods of time. We studied 63 patients
with erythema migrans, the pathognomonic cutaneous lesion of Lyme borreliosis, and examined
23
in vitro cultures of biopsies from the active edge of the erythematous patch. Sixteen biopsies
yielded spirochetes after prolonged incubations of up to 10.5 months, suggesting that Borrelia
burgdorferi may be very slow to divide in certain situations. Some patients with Lyme
borreliosis may require more than the currently recommended two to three week course of
antibiotic therapy to eradicate strains of the spirochete which grow slowly.
17: Infect Immun. 1991 Feb;59,2:671-8. Intracellular localization of Borrelia burgdorferi within
human endothelial cells. Ma Y, Sturrock A, Weis JJ.
Department of Pathology, University of Utah School of Medicine, Salt Lake City 84132.
The later stages of infection by the Lyme disease pathogen, Borrelia burgdorferi, are
characterized by the persistence of the organism in individuals possessing a strong
anti-Borrelia immune response. This suggests that the organism is sequestered in a tissue
protected from the immune system of the host or there is a reservoir of the organism residing
within the cells of the host. In this report, the ability of B. burgdorferi to gain entrance into
human umbilical vein endothelial cells was explored as a model for invasion. Incubation of B.
burgdorferi with human umbilical vein endothelial cells at ratios ranging from 200:1 to 5,000:1
resulted in the intracellular localization of 10 to 25% of B. burgdorferi in 24 h. The intracellular
location of the spirochetes was demonstrated by the incorporation of radiolabeled B. burgdorferi
into a trypsin-resistant compartment and was confirmed by double-immunofluorescence staining
which differentiated intracellular from extracellular organisms. Actin-containing microfilaments
were required for the intracellular localization, indica ting that the host cell participates in the
internalization process. Activation of endothelial cells by agents known to increase the expression
of several adhesion molecules had no effect on the interaction of B. burgdorferi with the
endothelial monolayer. This indicates that the endothelial receptor for B. burgdorferi is
constitutively expressed and that internalization is not dependent upon adhesion molecules
whose expression is induced by inflammatory mediators. The demonstration of B. burgdorferi
within endothelial cells suggest that intracellular localization may be a potential mechanism by
which the organism escapes from the immune response of the host and may contribute to
persistence of the organism during the later stages of Lyme disease.
18: 1991: Journal of Infectious Diseases, Feb;163,2:311-8 Randomized comparison of
ceftriaxone and cefotaxime in Lyme neuroborreliosis. Pfister HW, Preac-Mursic V, Wilske B,
Schielke E, SÃrgel F, Einhäupl KM.
Neurological Department, Klinikum Grosshadern, University of Munich, Federal Republic of
Germany.
24
In this prospective, randomized, open trial, 33 patients with Lyme neuroborreliosis were
assigned to a 10-day treatment with either ceftriaxone, 2 g intravenously, iv, every 24 h, n = 17,
or cefotaxime, 2 g iv every 8 h, n = 16. Of the 33 patients, 30 were eligible for analysis of
therapeutic efficacy. Neurologic symptoms improved or even subsided in 14 patients of the
cefotaxime group and in 12 patients of the ceftriaxone group during the treatment period. At
follow-up examinations after a mean of 8.1 months, 17 of 2 7 patients examined were clinically
asymptomatic. In one patient Borrelia burgdorferi was isolated from the cerebrospinal fluid, CSF,
7.5 months after ceftriaxone therapy. CSF antibiotic concentrations were above the MIC 90 level
for B. burgdorferi in nearly all patients examined. Patients with Lyme neuroborreliosis may
benefit from a 10-day treatment with ceftriaxone or cefotaxime.However, as 10 patients were
symptomatic at follow-up and borreliae persisted in the CSF of one patient, a prolongation of
therapy may be necessary.
19: Medicine, Baltimore. 1991 Mar;70,2:83-90. Lyme disease: clinical features, classification,
and epidemiology in the upper midwest. Agger W, Case KL, Bryant GL, Callister SM.
Section of Infectious Disease, La Crosse Lutheran Hospital, Wisconsin.
Lyme disease can be classified using the terminology of syphilis. In this series of 95 cases from
the upper midwest, early cases, defined as an illness of less than 2 months, were more likely to
have lived in or recently visited a highly endemic area. Unlike late cases, early cases presented
entirely in the nonwinter months, p less than .001. Early disease was further subdivided into
primary and secondary disease. Ninety percent of primary and 43% of secondary cases had
erythema migrans, while no late cases had active erythema migrans, p less than .001. Clinical
manifestations of nonspecific inflammation, except for arthralgia, were more common in early
than late disease, p less than .01. In secondary cases, monoarticular arthritis was slightly more
common than polyarticular arthritis, with the reverse occurring in late disease, p less than .05.
Indirect fluorescent antibody testing revealed a ratio of IgM to IgG antibodies to be helpful in
distinguishing early from late disease. Antibacterial therapy in early, primary cases caused
Jarisch-Herxheimer reaction 7% of the time. Despite longer and more frequent parenteral
therapy, late Lyme disease frequently required retreatment, owing to poor clinical response, p
less than .05.
19.5: N Engl J Med. 1991 Apr 18;324(16):1137. Chronic neurologic manifestations of Lyme
disease. Logigian EL, Kaplan RF, Steere AC. Department of Neurology, Tufts University School
of Medicine, Boston, MA 02111.
BACKGROUND AND METHODS. Lyme disease, caused by the tick-borne spirochete Borrelia
burgdorferi, is associated with a wide variety of neurologic manifestations. To define further the
25
chronic neurologic abnormalities of Lyme disease, we studied 27 patients, age range, 25 to 72
years, with previous signs of Lyme disease, current evidence of immunity to B. burgdorferi, and
chronic neurologic symptoms with no other identifiable cause. Eight of the patients had been
followed prospectively for 8 to 12 years after the onset of infection. RESULTS. Of the 27 patients,
24, 89 percent, had a mild encephalopathy that began 1 month to 14 years after the onset of the
disease and was characterized by memory loss, mood changes, or sleep disturbance. Of the 24
patients, 14 had memory impairment on neuropsychological tests, and 18 had increased
cerebrospinal fluid protein levels, evidence of intrathecal production of antibody to B.
burgdorferi, or both. Nineteen of the 27 patients,70 percent, had polyneuropathy with radicular
pain or distal paresthesias; all but two of these patients also had encephalopathy. In 16 patients
electrophysiologic testing showed an axonal polyneuropathy. One patient had leukoencephalitis
with asymmetric spastic diplegia, periventricular white-matter lesions, and intrathecal production
of antibody to B. burgdorferi. Among the 27 patients, associated symptoms included fatigue, 74
percent, headache, 48 percent, arthritis, 37 percent, and hearing loss, 15 percent. At the time of
examination, chronic neurologic abnormalities had been present from 3 months to 14 years,
usually with little progression. Six months after a two-week course of intravenous ceftriaxone, 2 g
daily, 17 patients, 63 percent, had improvement; 6, 22 percent, had improvement but then
relapsed; and 4,15 percent, had no change in their condition. CONCLUSIONS. Months to years
after the initial infection with B. burgdorferi, patients with Lyme disease may have chronic
encephalopathy, polyneuropathy, or less commonly, leukoencephalitis. These chronic
neurologic abnormalities usually improve with antibiotic therapy.
20: Arthritis Rheum. 1991 Aug;34,8:1056-60. Treatment of refractory chronic Lyme arthritis
with arthroscopic synovectomy. Schoen RT, Aversa JM, Rahn DW, Steere AC.
Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06510.
Of 20 patients who underwent arthroscopic synovectomy for refractory chronic Lyme
arthritis of the knee, 16, 80%, had resolution of joint inflammation during the first month
after surgery or soon thereafter, and they have remained well during the 3-8-year followup
period. Three of these 16 patients who were more disabled preoperatively, still had mild
functional limitation at long-term followup. The remaining 4 patients, 20%, had persistent or
recurrent synovitis. We conclude that arthroscopic synovectomy is effective in treating chronic
Lyme arthritis in patients in whom the disease does not respond to antibiotic therapy.
21: 1: Clin Exp Rheumatol. 1992 Jul-Aug;10,4:387-90. Molecular detection of persistent Borrelia
burgdorferi in a man with dermatomyositis. Fraser DD, Kong LI, Miller FW.
National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of
26
Health, Bethesda, Maryland.
A 40-year-old white man with a several year history of various immunologic disorders, including
anti-Jo-1 autoantibody positive dermatomyositis, developed clinical Lyme disease after being
biten by a tick. The patient was treated with oral tetracycline and his initial symptoms
resolved; however, he suffered an exacerbation of his muscle disease which was difficult to
control despite cytotoxic therapy. Antibiotic therapy was reinstituted after Borrelia
burgdorferi was detected in the patient's peripheral blood leukocytes by the polymerase chain
reaction, PCR. All serologic, T-cell stimulation, and western blot analyses, however, were
negative. The patient's disease responded to oral ampicillin, p robenecid therapy and concurrent
cytotoxic therapy. Subsequent leukocyte PCR testing has been negative for the causative agent of
Lyme disease. This case may provide an example of the in vivo immuno-modulatory effects of
spirochetes in human autoimmune disease. In addition, this case emphasizes the potential
clinical utility of PCR technology in evaluating the persistent sero-negative Lyme disease
which may occur in immunocompromised individuals.
22: 1:20 J Infect Dis. 1992 Aug;166,2:440-4.Fibroblasts protect the Lyme disease spirochete,
Borrelia burgdorferi, from ceftriaxone in vitro. Georgilis K, Peacocke M, Klempner MS.
Department of Medicine, New England Medical Center, Boston, Massachusetts.
The Lyme disease spirochete, Borrelia burgdorferi, can be recovered long after initial
infection, even from antibiotic-treated patients, indicating that it resists eradication by host
defense mechanisms and antibiotics. Since B. burgdorferi first infects skin, the possible
protective effect of skin fibroblasts from an antibiotic commonly used to treat Lyme disease,
ceftriaxone, was examined. Human foreskin fibroblasts protected B. burgdorferi from the lethal
action of a 2-day exposure to ceftriaxone at 1 microgram/mL, 10-20 x MBC. In the absence of
fibroblasts, organisms did not survive. Spirochetes were not protected from ceftriaxone by
glutaraldehyde-fixed fibroblasts or fibroblast lysate, suggesting that a living cell was required. The
ability of the organism to survive in the presence of fibroblasts was not related to its
infectivity.Fibroblasts protected B. burgdorferi for at least 14 days of exposure to ceftriaxone.
Mouse keratinocytes, HEp-2 cells, and Vero cells but not Caco-2 cells showed the same protective
effect. Thus, several eukaryotic cell types provide the Lyme disease spirochete with a protective
environment contributing to its long-term survival.
23: J Am Acad Dermatol. 1993 Feb;28,2 Pt 2:312-4. Recurrent erythema migrans despite
extended antibiotic treatment with minocycline in a patient with persisting Borrelia
burgdorferi infection. Liegner KB, Shapiro JR, Ramsay D, Halperin AJ, Hogrefe W, Kong L.
Department of Medicine, Northern Westchester Hospital Center, Mount Kisco, NY.
27
Erythema migrans recurred in a patient 6 months after a course of treatment with
minocycline for Lyme disease. Polymerase chain reaction on heparinized peripheral blood at
that time demonstrated the presence of Borrelia burgdorferi-specific DNA. The patient was
seronegative by Lyme enzyme-linked immunosorbent assay but showed suspicious bands on
Western blot. Findings of a Warthin-Starry stain of a skin biopsy specimen of the eruption
revealed a Borrelia-compatible structure. Reinfection was not believed to have occurred.
Further treatment with minocycline led to resolution of the erythema migrans.
24: 1: J Infect Dis. 1993 May;167,5:1074-81.Invasion of human skin fibroblasts by the Lyme
disease spirochete, Borrelia burgdorferi. Klempner MS, Noring R, Rogers RA.
Division of Geographic Medicine and Infectious Diseases, New England Medical Center, Tufts
University School of Medicine, Boston, Massachusetts 02111.
The ability of Borrelia burgdorferi to attach to and invade human fibroblasts was investigated by
scanning electron and confocal microscopy. By scanning electron microscopy, B. burgdorferi
were tightly adherent to fibroblast monolayers after 24-48 h but were eliminated from the cell
surface by treatment with ceftriaxone, 1 microgram/mL, for 5 days. Despite the absence of
visible spirochetes on the cell surface after antibiotic treatment, viable B. burgdorferi were
isolated from lysates of the fibroblast monolayers. B. burgdorferi were observed in the perinuclear
region within human fibroblasts by laser scanning confocal microscopy.Intracellular spirochetes
specifically labeled with monoclonal anti-flagellin antibody were also identified by fluorescent
laser scanning confocal microscopy. These observations suggest that B. bu
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