Microscopy, Culture or PCR-verified cases
of persistent [seronegative] Lyme borreliosis
(
list far from complete - please send note on corrections / additions to kroun@ulmar.dk )
Cultivation of Borrelia
burgdorferi from joint fluid three months after treatment of facial palsy due
to Lyme borreliosis [letter]
Schmidli J, Hunziker T,
Moesli P, Schaad UB. J Infect Dis 1988 Oct; 158(4): 905-6
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=89010012&dopt=Abstract
15.5y girl. Tickbite Oct. 1986. No EM. No 'flu'.
Jan. 1987 left facial palsy. Positive Bb serology.
Amoxicillin-clavulanate 625mg x4, 12d - discontinued due to
rash. Betamethasone 1mgx2, 2 weeks. Lumbar puncture, normal CSF.
Oral doxycycline 100mgx2, 14d, facial palsy resolved. Two months later
arthritis in the right knee. Cloudy joint fluid 60ml, positive
culture for Bb. Ceftriaxone 4g/d, 3g - 2g/d, 11d.
Spirochetes in the spleen
of a patient with chronic Lyme disease.
Cimmino MA, Azzolini A,
Tobia F, Pesce CM. Am J Clin Pathol 1989 Jan; 91(1): 95-7
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2910019&dopt=Abstract
A 54-year-old man had intermittent evening fever,
arthralgia, transient erythematous macular eruption on the skin, and
splenomegaly of two year's duration. Immunofluorescence tests for
Borrelia burgdorferi serum antibodies gave 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.
Latent Lyme
neuroborreliosis: presence of Borrelia burgdorferi in the cerebrospinal fluid
without concurrent inflammatory signs.
Pfister HW, Preac Mursic
V, Wilske B, Einhaupl KM, Weinberger K. Neurology 1989 Aug; 39(8): 1118-20
http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=89344421
17y old Male, 20 tickbites Aug-Dec while jogging in forest
.. Dec 87 bilat. tinnitus developed during two weeks was the ONLY
symptom
IgG seropositive for anti-Bb (1:64) with normal IgM titers (indicates
'late'), indicated lumbar puncture. Bb could be cultured
from CSF, without any concurrent signs of inflammation or intrathecal
antibodyformation. CSF: 1 WBC/µl and 21 mg/dl protein.
Excerpts:
Neither oligoclonal IgG bands ...... nor intrathecal production of specific
antibodies against B. burgdorferi could be demonstrated .... The CSF/serum
ratio for antibodies against B. burgdorferi (RBb) was 0,28% .... Three
months later .... Repeated lumbar puncture revealed 2 white cells/µl and 23
mg/dl protein without demonstration of oligoclonal IgG bands or intrathecal
production of antibodies against B burgdorferi.
The only symptom - tinnitus - didn't respond to usual antibiotic
treatment(?), so authors conclude this symptom was unrelated to Bb.
Would this young man - months or years later - have
developed symptoms of neuroborreliosis ?
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. Infection 1989 Nov-Dec;
17(6): 355-9
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=90129322&dopt=Abstract
1. 5y boy. July 1985 EM. Aug 1985 Lymphocytic meningitis. Seropositive
for IgG and IgM, no antibodies in CSF. Penicillin V orally
100000 u/kg/d, 14d. Spinal-fluid showed fewer cells. September 1985 facial
palsy, again pleocytosis in CSF. Doxyc. orally 2mg/kg, 10d. Gradually CFS
normalized. April 1986 relapse, Bb was isolated from CSF
after 4 weeks in BSK-medium. Penicillin 200000 u/kg, 22d. August
1986 relapse/reinfection with EM and painful meningoradiculitis, Bb
antibodies now negative in CFS and serum. Culture not done!
2. 49y man. EM, typical signs of LMR-Bannwarth S developed 7
weeks later. Pleocytosis and elevated protein in CSF. Both Borrelia
IgM and IgG positive in serum. Penicillin i.v. 20 MU/d, 10d. Four
days after therapy normal examination and no complaints, CSF declining
parameters, positive Borrelia-index. Three months later CSF normal,
Borrelia-index now negative, but Bb was cultured from CSF!
3. 26y woman. Headache, radicular pain. Normal neurological
exam. Multiple horseflie bites. CSF pleocytosis and elevated
protein. Negative Borrelia-ELISA in CSF and serum. Ceftriaxone
i.v. 2g/d , 10d. Improved. 7.5 month later recurrent episodes of radicular
pain, headache, arthralgia, fever. Normal neurological exam. Negative
serology. Normal CSF. Bb cultured from CFS after 6 weeks in MKP-medium. Cefotaxime
3 x 2g/d i.v., 14d.
4. 44y man. EM june 88, no other complaints. Seropositive. Bb
isolated from skin biopsy from border of EM.
Phenoxymethylpenicillin 1 MU x3/d, 12d. Three months later
normalized serology, but Bb was again isolated from skin biopsy adjacent to the
scar of the first biopsy. No other manifestations of Borreliosis.
Ceftriaxone 2g, 21d. Later skin-culture negative.
5. 40y man. EM, fatigue, headache. Penicillin G 10 MUx1,
10d, starting 5 weeks after the tick bite. Serum Borrelia IgG and
IgM negative. Two months after treatment headache and fatique, low
Borrelia-titre positive. At bite area, but no sign of EM, was culture positive
for Bb, 2.2 mo. after treatment.
6. 60y woman. Oct. 87 EM 32x20 cm of duration 6 months.
Methylprednisolone 4 mg daily for asthma for years. Sep. 87 she had doxycycline
200 mg daily, 10d, by family physician for cold. Palpitations, dizziness, but
had had angina pectoris for years. IgM and IgG against Bb negative.
Bb isolated from edge of EM oct 20, 87. Pt. refused to
take more antibiotic.
Randomized comparison of
ceftriaxone and cefotaxime in Lyme neuroborreliosis.
Pfister HW, Preac Mursic
V, Wilske B, Schielke E, Sorgel F, Einhaupl KM. J Infect Dis 1991 Feb; 163(2):
311-8
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1988514&dopt=Abstract
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 27 patients examined were clinically asymptomatic [i.e 10/27 =
37% were symptomatic]. 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.
[Isolation of Borrelia
burgdorferi in the cerebrospinal fluid of 3 children with neurological
involvement]
Peter O, Bretz AG,
Zenhausern R, Roten H, Roulet E. Schweiz Med Wochenschr 1993 Jan 13; 123(1-2):
14-9
Isolation of Borrelia burgdorferi from the CSF is relatively
rare. The present report describes the first three isolations in Switzerland.
Clinically, our first observation confirmed the frequent association of B. burgdorferi
with peripheral facial paresis in children. The other two cases illustrate the
variety of symptoms in neuro-borreliosis.
1. In the first case the culture was positive
after 6 weeks. The results of serologic tests (indirect
immunofluorescence and ELISA) for detection of antibodies against B.
burgdorferi were negative or non-significant in this child's serum.
On the other hand, specific antibodies (IgG) were detected in the
serum by western blot.
2. Culture of the second CSF already showed Borrelia growth
after 10 days. Immunofluorescence revealed high antibody titers (1/256) against
B. burgdorferi in this patient's serum. IgG showed a weakly positive reaction
in western blot. The reliability of this result was confirmed by isolation of
Borrelia.
In neither of the two CSF could intrathecal synthesis
of specific antibodies be demonstrated.
3. In the third case, however, immunofluorescence showed IgG
antibody titers of 1/128 in the CSF and 1/512 in serum. Intrathecal synthesis
of specific antibodies was demonstrated with an index of 13.4 (norm < 2).
Western blot confirmed the specificity of the reactions observed with the serum
and CSF IgG. Culture of CSF produced significant growth of Borrelia within 7
days. Protein profile and reactions with poly- and monoclonal antibodies
confirmed that the three strains belonged to B. burgdorferi.(ABSTRACT TRUNCATED
AT 250 WORDS)
Fatal encephalitis caused
by concomitant infection with tick-borne encephalitis virus and Borrelia
burgdorferi.
Oksi J, Viljanen MK, Kalimo
H, Peltonen R, Marttia R, Salomaa P, Nikoskelainen J, Budka H, Halonen P. Clin
Infect Dis 1993 Mar; 16(3): 392-6
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8452951&dopt=Abstract
We describe a 38-year-old farmer from the southwestern
archipelago of Finland where both tick-borne encephalitis (TBE) virus and
Borrelia burgdorferi are endemic. He presented with fever and headache,
developed severe meningoencephalitis in 3 days, and, after 1 month, died
without regaining consciousness. High titers of IgG and IgM antibodies
to TBE virus were present in both serum and CSF. Serology for Borrelia was
negative. Autopsy revealed necrotizing encephalitis and myelitis
with involvement of the dorsal root ganglion. With use of polymerase
chain reaction tests, segments of two separate genes of B. burgdorferi were
amplified from the patient's CSF. This case demonstrates that the
possibility of dual infection should be considered for patients residing in
geographic areas where Ixodes ticks may carry both the TBE virus and B.
burgdorferi. We believe that the most severe damage in this case was caused by
TBE virus rather than by B. burgdorferi. Nevertheless, the coinfection might
have contributed to the fatal outcome that has not been previously observed in
Finnish patients with TBE.
[Pt. was initially treated with penicillin plus gentamicin,
next day changed to cefotaxime, later erythromycin was added ... plus
dexamethasone. All discontinued when TBE virus infection was confirmed. Later
highly febrile from pneumonia (40oC), imipenem, rifampicin
and vancomycin and amphotericin B. Imipenem-sensitive E.coli was
isolated from the trachea. Later Clostridum difficile was isolated from a stool
sample obtained while the patient had diarhea. .... Died.]
"With use of ELISA, significantly raised antibodies to
sonicated whole B. burgdorferi and to purified endoflagellar antigen were not detected
in either serum or CSF (table 1). A CSF specimen for
polymerase chain reaction (PCR) was taken." ....."With use
of the PCR method, a B. burgdorferi-specific segment of a gene coding for 41-kD
endoflagellin [7] and a Borrelia-specific segment of 16S rDNA [8] were
amplified from the CSF (table 1)."
First isolation of Borrelia
burgdorferi from an iris biopsy.
Preac Mursic V, Pfister
HW, Spiegel H, Burk R, Wilske B, Reinhardt S, Bohmer R. J Clin
Neuroophthalmol 1993 Sep; 13(3): 155-61; discussion 162
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8106639&dopt=Abstract
The persistence of Borrelia burgdorferi
in six patients is described. Borrelia burgdorferi has been cultivated
from iris biopsy, skin biopsy, and cerebrospinal fluid also after antibiotic
therapy for Lyme borreliosis. Lyme Serology: IgG antibodies to B. burgdorferi
were positive, IgM negative in four patients; in two patients both IgM and
IgG were negative. Antibiotic therapy may abrogate the
antibody response to the infection as shown by our results. Patients
may have subclinical or clinical disease without diagnostic antibody titers.
Persistence of B. burgdorferi cannot be excluded when the serum is negative for
antibodies against it.
Demonstrates
6 cases with persistent culture positive Bb, isolated from 1) iris, 2) skin and
3-6) 4 x CSF,
1) pos. iris culture despite previous tx doxy 200mg/dg
4 weeks. x 2, seropositive;
2) EM +culture, tx doxy 200mg/dg 10 days. Seronegative.
1 yr iritis, not responsive to steroid, but to ceftriaxon.
3) Weak seropos. CSF normal, neg. index, but culturepos.
CSF
4) Weak seropos. CSF normal, neg. index, but culturepos.
CSF
5) tickbite, penicillin orally x 2 for 12 days. 4
month later CSF elev. prot. 6/3 cells, seronegative +
CSF-seronegative, but CSF culturepos. for Bb.
6) Weak seropositive in serum, CSF negative, Bb was cultured from CSF.
Persistence of Borrelia
burgdorferi in ligamentous tissue from a patient with chronic Lyme borreliosis.
Haupl T, Hahn G, Rittig M, Krause A, Schoerner C, Schonherr U, Kalden JR,
Burmester GR. Arthritis Rheum 1993 Nov; 36(11): 1621-6
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=94059203&dopt=Abstract
Excerpts:
CASE REPORT
The patient, a 48-year old woman, presented with progressive disturbance of the
central vision in her right eye. Ophthalmoscopy demonstrated multifocal
choroiditis, with 1 focus involving the macula lutea. The patient reported
that 2 months previously, a tick had bitten her left lower leg, near the
ankle, and she had experienced occipital headaches and a macular skin lesion.
Serologic tests performed at our university revealed a positive IgG antibody
titer against B burgdorferi. Other infectious diseases, particularly
toxoplasmosis, were excluded by laboratory evaluations. The patient was treated
with 200 mg/day of doxycycline (orally) for 6 weeks (Figure
1). The visual disturbance was ameliorated, the inflammatory foci of the
choroid diminished, and scar tissue formed.
Four weeks after the end of antibiotic therapy, the patient began to
experience brief episodes of an asymmetric arthritis, primarily involving the
metacarpophalangeal (MCP) and proximal interphalangeal joints. Routine
electrocardiography (EKG) revealed negative P waves, with an ectopic atrial
pacemaker that had not been present on an EKG performed at gall bladder surgery
1 year previously. On ophthalmoscopic examination of the eye fundus, there
was no evidence of a recurrence of the choroiditis.
Tests for antinuclear antibodies, immune complexes (by Clq binding assay and
polyethylene glycol precipitation), rheumatoid factor (RF), immunoglobulins,
serum complement levels, and C-reactive protein levels all gave normal or
negative results. HLA phenotyping revealed HLA-A24/26:B7/27;Bw4/6;Cw2/7;DRl5(DR2
split);DQ1. Despite the presence of the HLA-B27 antigen, there was no evidence
of any typical manifestation of a seronegative spondylarthropathy.
Therapy was started with 2 gm of ceftriaxone, intravenously, for 14
days (Figure 1). Within the next 4 weeks, the ectopic atrial rhythm
converted to a normal sinus rhythm, and the arthritis disappeared. After 2
months free of clinical symptoms, the visual disturbances recurred. Ophthalmoscopy
showed reactivation of the initial foci of choroiditis. Analysis of CSF
demonstrated normal levels of albumin and IgG, no disturbance of the blood-CSF
barrier, negative findings on immunofluorescence (IF) analysis for B
burgdorferi-specific antibodies, and a normal cell count; thus, there was no
evidence of an inflammatory process involving the central nervous system.
Antibiotic therapy with a combination of 300 mg of roxithromycin, 1,600 mg
of sulfamethoxazole, and 320 mg of trimethoprim per day, which has been
described as effective in several cases of advanced Lyme borreliosis (6,7), was
initiated. However, tenosynovitis and mild arthralgia of the patient's hands
occurred. Despite concurrent antibiotic therapy, "trigger thumb"
developed within 2 weeks, accompanied by pronounced pain of the MCP joint, and surgical
splitting of the flexor retinaculum was performed (Figure 1).
After exsanguination of the patient's right arm, surgery was performed in a
bloodless field. The macroscopic appearance was typical of "trigger
finger." A specimen of the altered ligament was obtained, with particular
attention to avoiding surface contamination of the tissue sample. The specimen
was rinsed several times in saline and medium, and was placed in culture with
modified BSK medium. The patient's postoperative course was without
complications, and normal functioning of the operated thumb was achieved. Six
weeks after the course of antibiotics, the choroid foci were scarring. Unfortunately,
the patient had an irreversible, 70% reduction of vision in the right eye. Approximately
3 weeks later, the arthralgia also disappeared. Currently, after approximately
2 ˝ years of followup, there has been no evidence of reactivation of the Lyme
borreliosis.
METHODS AND
RESULTS
Immunofluorescence assay and findings. The IF assay was performed as described
earlier, using the German isolate of B burgdorferi, PKo 2-85 (3,8). Serum
samples were preabsorbed with Treponema phagedenis lyophilysate (Behringwerke,
Marburg, Germany). For the detection of specific IgM antibodies, a second
absorption step with RE absorbent (Behringwerke) was performed. Using this
technique, titers in control sera were <1:16. In parallel, the serum samples
were analyzed using a commercial B burgdorferi enzyme-linked immunosorbent
assay (ELISA) kit (Viramed, Munich, Germany), with a protein preparation of B31
Borrelia,, as antigen. A positive, a negative, and a borderline control
specimen served as internal standards. The ratio between the optical density of
the serum samples versus that of the borderline specimen was used to quantitate
the results. Ratios >1.0 were considered positive; those <1.0 were
negative.
IF analysis revealed positive titers of IgG, but not IgM, antibody directed
against B burgdorferi only during the early stage of infection when the patient
presented with the first episode of choroiditis. Analysis by ELISA revealed
comparable results, with specific IgG ratios of 1.15 at the onset of disease
and 0.85 in the later stage. The IgG titer rapidly decreased within a few weeks
after the first antibiotic therapy, and remained negative in both the IF and
ELISA evaluations, despite progression of the disease.
Immunoblot analysis and findings. For immunoblot analysis, we used a method
previously described (9), in which lysed specimens of whole B burgdorferi
strain PKo 2-85 and LW2, the isolate from the patient (see below) (protein
concentration 100 µg/ml), were separated by sodium dodecyl
sulfate-polyacrylamide gel electrophoresis (5 µg of protein per lane) in a 10%
gel. Proteins were transferred to nitrocellulose and incubated with the sera at
a dilution of 1:100, which we had previously found yielded optimum results. Bound
immunoglobulins were visualized by application of peroxidase-conjugated
reagents. Polyclonal antisera from patients with Lyme disease and monoclonal
antibodies against outer surface protein A (OspA) and flagellin (the latter
kindly provided by M. D. Kramer, Institute of Immunology and Serology,
University of Heidelberg, Germany) were used to compare the isolated spirochete
LW2 and the B burgdorferi strain PKo 2-85 by immunoblot.
All serum samples from the patient were tested against protein preparations of
both the LW2 and the PKo 2-85 strain, on immunoblots. There were no significant
differences in reactivity to the isolates. Upon repeated analysis of several
consecutive serum samples, only nonspecific faint bands (75 kd, 41 kd, and 15
kd) were revealed, demonstrating a pattern different from that found in typical
patients with stage III disease (10).
Preparation of mononuclear cells and results of lymphocyte proliferation assay.
Peripheral blood mononuclear cell (PBMC) separation and antigen stimulation
were performed as described previously (8.9) Freshly isolated cells (105/well)
were stimulated in triplicate with either 105 or 106 PKo 2-85 B burgdorferi per
well, 10 µg/ml of recombinant OspA, 10 µg/ml recombinant flagellin (41-kd
protein) from B burgdorferi (both expressed and purified as described elsewhere
[9]), or 7 µg/well of T phagedenis lyophilysate. Previous studies had shown
these to be optimal concentrations (8,9). Control wells received either medium
alone or tetanus toxoid (10 µg/ml; Behringwerke). Samples from normal blood
donors were run in each assay to exclude any nonspecific response. It has been
clearly documented by appropriate separation experiments (9) that reactivity to
Borrelia antigens under these conditions is T cell derived.
Stimulation of the patient's PBMC with the 2 strains of B burgdorferi as well
as with OspA resulted in significantly elevated 3H-thymidine uptake at all times
tested (compared with normal PBMC) (Figure 1). Tetanus toxoid induced high
levels of 3H-thymidine uptake, between 143,000 and 181,000 Dcounts per minute
(stimulation values in the presence of antigen minus those in the absence of
antigen). In the earlier disease stages and prior to ceftriaxone therapy,
proliferation to Borrelia antigens corresponded well to the clinical course,
despite negative findings on IF and ELISA testing, reaching peak values at peak
disease activity, as manifested by intermittent arthritis and cardiac
involvement (Figure 1). After the ceftriaxone therapy and a 2-month
symptom-free period, PBMC proliferation decreased, but during a period of minor
inflammatory reactivation of the disease, was still elevated. The patient's
symptoms at that time were choroiditis, mild arthralgia, and the development of
"trigger finger." B burgdorferi was isolated from ligament samples.
Isolation and characterization of B burgdorferi strain LW2. Tissue samples from
the flexor retinaculum of the patient's right thumb were taken during surgery
for the "trigger finger." Samples were cultured at 370C under
microaerophilic conditions, in modified BSK medium. Cultures were evaluated
weekly for spirochetes in the supernatant, as detected by darkfield microscopy.
After 3 weeks, viable spirochetes were seen. This particular spirochete,
designated LW2, was used as antigen for immunoblot. B burgdorferi-specific
immune sera and monoclonal antibodies against OspA and flagellin stained
protein bands in a pattern comparable to that of the PKo 2-85 bacterial antigen
(data not shown). An aliquot of this supernatant was examined for B
burgdorferi-specific gene sequences by polymerase chain reaction (PCR)
amplification and Southern blot.
PCR and Southern blot techniques. Cultured spirochetes from the patient's
tissue specimen were investigated by standard PCR procedures (11). We used
primers which amplified a 276-basepair segment (kb-ladder; Gibco BRL Life
Technologies. Munich, Germany) of the 41-kd flagellin protein of B burgdorferi
(primer 5'-TTCAGGGTCTCAAGCGTCTTGGACT-3'; reverse primer
5'-GCATTTTCAATTTTAGCAAGTGATG-3') (12,13). The amplification protocol consisted
of 40 cycles: 1-minute denaturation at 940C, 30-second annealing at 500C, and
-minute extension at 670C.
An amplification product, which could be hybridized by Southern blot technique
with the 32P-g-ATP-labeled probe
5'-CTCTGGTGAGGGAGCTCAAACTGCTCAGGCTGCACCGGTTCAAGAGGGT-3' (13) using Hybond-N
nylon-blotting membranes (Amersham, Amersham, UK), was obtained. The amplimer,
which was characterized by Picken (13), is derived from the central,
nonhomologous region of the flagellin gene. It has been shown to be both
specific for B burgdorferi and discriminatory for 3 groups of this spirochete,
based on the nucleic acid sequence. Water, synovial tissue from a patient with
rheumatoid arthritis, and B burgdorferi strain PKo 2-85 were used as negative
and positive controls for the studies.
Electron microscopy techniques and results. Transmission electron microscopy
was performed on the ligament tissues. The specimen was removed from the
culture medium and prepared and analyzed as described previously (14). Semithin
sections were cut from the plastic block for the light microscopic evaluation. Thin
sections were cut from selected areas and placed onto copper grids
(Polysciences, St. Goar, Germany). After counterstaining with 10% uranyl
acetate, followed by 2.8% lead citrate (both from Merck, Darmstadt, Germany),
sections were studied using Siemens EM 101 (Munich, Germany) and Zeiss EM 902
(Wetzlar, Germany) electron microscopes.
The ligament tissue was found to be heavily infiltrated by spirochetes. Some of
the organisms lay between unaltered collagen fibers (Figure 2A); others were
closely attached to the cell surface of the fibroblasts (Figure 2B). There were
numerous fibroblasts deeply invaginated by the spirochetes, thereby creating
membrane-bound cavities. These cavities appeared as vacuoles in transverse
tissue sections.
DISCUSSION
The patient whose case is presented herein had relapsing Lyme borreliosis, with
choroiditis, arthritis, carditis, and tendinitis. The humoral immune response
correlated with neither the cellular reactivity in vitro nor the clinical
activity of the disease manifestations. Repeated antibiotic treatment was
necessary to stop the progression of disease, but obviously did not completely
eliminate B burgdorferi from all sites of infection. This was confirmed by the
culture of viable B burgdorferi from a ligament sample obtained surgically. This
organism characterized by molecular biology studies by our group, was
subsequently evaluated in a genomic comparison study of other isolates. In that
study, Wallich et al identified the genogroup AAA (flagellin type at, heat
shock protein [HSP] 60 type A, and HSP 70 type A), and OspA genotype I (15). Electron
microscopy of the ligament revealed spirochetes situated between collagen
fibers or associated with fibroblasts, deeply invaginating these cells. This is
the first time that B burgdorferi was isolated from human ligamentous material.
These data indicate that vital B burgdorferi persisted (a) despite several
courses of antibiotic therapy, (b) even when clinical symptoms subsided, and
(c) even when no humoral immune response was detectable by ELISA or by IF. Therefore.
the hypothesis may he raised that an inadequate immune response as well as an
evasion into immunologically privileged sites may be the mechanisms of
microbial persistence in patients with chronic Lyme borreliosis.
The specific humoral and cellular immune responses to B burgdorferi, which were
elevated during early disease manifestations, apparently were not sufficient to
eliminate the pathogen. In the later stage, these specific immune responses
became discordant, with negative humoral and positive cellular immunity, as has
been described in another cohort with chronic disease (16) [Dattwyler RJ et al.
Seronegative Lyme disease: dissociation of specific T- and B-lymphocyte
response to Borrelia burgdorferi, NEJM 1988; 319:1441-46].
Interestingly, the cellular immune responses were also directed against the
surface protein OspA during each recurrence of clinical symptoms, even though
anti-OspA antibodies were not detectable by immunoblot. Interpretation of this
dissociation of the humoral and cellular immune responses is difficult and
requires further investigation. Initial experiments with T cell clones in
patients with chronic Lyme disease (17) [Yssel H et al. Borrelia burgdorferi
activates a T helper type 1-like T cell subset in Lyme arthritis. J Exp Med 1991
Sep 1; 174(3): 593-601] suggest that selective activation of a T cell subset
may occur, producing a restricted pattern of cytokines which are incompetent to
activate B cells.
Even in the presence of an ineffective immune response, antibiotic therapy should
have eradicated the spirochetes and stopped the disease progression in our
patient. However, several of the treatment regimens recommended in the
then-current literature, including combination therapies which have been
described as effective in several refractory cases of advanced-stage disease
(6,7), did not eliminate the pathogen. Of interest, our patient showed the DR15
(split of DR2) HLA type (possibly even homozygous), which has been shown to be
associated with a poor response to antibiotic therapy in chronic B burgdorferi
infection (4) [Steere Ac et al, Association of chronic Lyme arthritis with
HLA-DR4 and HLA-DR2 alleles, NEJM 1990; 323:219-23]. Possible explanations for
the persistence of Borrelia are that spirochetes either develop resistance to
the antibiotics (though not experimentally documented so far) or escape into
sites at which drug levels are ineffective. The detection of spirochetes
between collagen fibers of bradytrophic dense connective tissue supports the
second hypothesis. Moreover, the motility of spirochetes has been shown to be
enhanced in fluids as viscous as the extracellular matrix (18) [Kimsey RB et al
Motility of Lyme disease spirochetes in fluids as viscous as the extracellular
matrix. JID 1990; 162: 1205-8]. The hypothesis of evasion supports the use of
more aggressive therapy as described in recent reports (19), in which 3-4 weeks
of intravenous antibiotics was suggested as first-line treatment when systemic
manifestations develop, such as the choroiditis in our patient.
Although our electron microscopic studies were of a subcultured ligament
specimen, and therefore in vitro effects cannot be excluded, it is of great
interest that spirochetes penetrated into the extracellular matrix without
causing apparent destruction. Spirochetes had also deeply invaginated into
fibroblasts, thereby suggesting transcellular passage. Penetration of cell
monolayers by B burgdorferi has been demonstrated (20) [Comstock LE et al:
Penetration of endothelial cell monolayers by Borrelia burgdorferi. Infect
Immun 1989; 57:1626-28]. In conclusion, an inappropriate immune response as
well as the evasion of B burgdorferi into specific sites that are only slightly
accessible to antibiotics and immunologic attack, may be mechanisms that lead
to chronic infection with B burgdorferi.
Addition:
Intracellular location protect Bb from antibiotics that do not cross
cell-membranes ex. penicillin, cephalosporin [Georgilis K et al. Fibroblasts
protect the Lyme disease spirochete, Borrelia burgdorferi, from ceftriaxone in
vitro. J Infect Dis 1992 Aug; 166(2): 440-4]
Electron microscopy and the polymerase chain reaction of spirochetes
from the blood of patients with Lyme disease.
Hulinska D, Krausova M, Janovska D, Rohacova H, Hancil J, Mailer H. Cent
Eur J Public Health 1993 Dec; 1(2): 81-5
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=94272413&dopt=Abstract
95 patients,
only 3/30 attempts were culture positive, but by Immune electron microscopy IEM
9 of 30 blood samples demonstrated borreliae.
The decisive diagnostic method was:
1. serology
and clinical symptoms in 65 and
2. in
30 patients by visualization of spirochetes by IEM in heparinised blood (9)
3. CSF
(13) or
4. skin
from EM (8).
8/30 IEM
positive had EM, 21 could be classified as early Lyme borreliosis with
neurological symptoms, 6 as late stage Lyme borreliosis (encephalomyelitis).
14 had antibodies only in blood, 6 both in blood and CSF, the remaining 10
non-reactive by 2 different tests.
The one
blood culture positive patient had prior history of EM followed by
meningoradiculitis and positive IgM and IgG in serum the second [with positive
culture] had facial palsy with complaints of headache, weakness and pain in the
arms that lasted 8 days, while the serology being negative. The other (third)
with positive culture had a long history of Lyme borreliosis with arthralgias
and complaints fulfilling the criteria for neuroborreliosis. He had an erythema
and often removed ticks from his dog. During his illness he had all symptoms of
Lyme borreliosis and also positive serology. He was in good condition after
having taken antibiotics for 3 months before the blood culture was done.
One patient with positive IEM and subsequent (positive) culture went through
all phases of Lyme borreliosis and two years of persisting complaints! … after
repeated treatment [drug? dose? duration?]
Our culture of spirochetes from the patient with meningoradiculitis followed
after skin Erythema migrans confirmed the presence of B. garinii, identified by
PCR, which caused the neurological disorder - even in the presence of
antibodies and antibiotic treatment. One patient remained symptomatic for a period
for two years after repeated treatment, but B. burgdorferi was cultured when
the patient was relatively well.
Living with Lyme [see comments]
Vartiovaara I. Lancet 1995 Apr 1; 345(8953): 842-4
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=95206022&dopt=Abstract
The patient
- a physician, psychiatrist, who at the time was editor of the Finnish Medical
Journal, tells his own story - a must read for all physicians, since he
describes not only the technical details of his disease, but also about how
difficult the situation is, when a physician becomes a patient.
He contracted Lyme disease when attending a meeting in Vancouver, where he got
bitten by a tick in bed at night and three weeks later he was sick.
A history of antibiotic-responsive Lyme borreliosis, but relapsing when
treatment was discontinued. Seronegative.
PCR positive for borrelia in CFS+blood after three antibiotic treatments.
Subacute multiple-site osteomyelitis caused by Borrelia
burgdorferi.
Oksi J, Mertsola J,
Reunanen M, Marjamaki M, Viljanen MK. Clin Infect
Dis 1994 Nov; 19(5): 891-6
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7893875&dopt=Abstract
In a
pediatric case of severe multiple-site osteomyelitis caused by Borrelia burgdorferi,
the presence of spirochetes in a bone lesion was documented both by culture and
by the polymerase chain reaction (PCR). Positive PCR results were also obtained
with culture fluid yielding spirochetal growth and with acute-phase serum. Although
the disease evidently was a late manifestation of Lyme borreliosis, antibodies
to B. burgdorferi were low in titer and were restricted to the IgM class. The
distribution of osteomyelitic lesions in multiple bones and the positive PCR
results obtained with serum argue for hematogenous spread of the spirochetes. Before
the specific diagnosis was established, the patient received several potent
antimicrobial drugs, without a favorable outcome. In contrast, therapy with
ceftriaxone led to a rapid cure that persisted thereafter. We conclude that
infection due to B. burgdorferi must be considered a possible cause of subacute
pediatric osteomyelitis.
Antibodies against whole sonicated Borrelia burgdorferi spirochetes,
41-kilodalton flagellin, and P39 protein in patients with PCR- or
culture-proven late Lyme borreliosis.
Oksi J, Uksila J, Marjamaki M, Nikoskelainen J, Viljanen MK. J Clin
Microbiol 1995 Sep; 33(9): 2260-4
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=96025135&dopt=Abstract
41 patients;
only PCR or Culture proven LATE Lyme Borreliosis; 19 had only weekly positive
or borderline antibody levels and 7 were seronegative.
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. Infection
1996 Jan-Feb; 24(1): 9-16
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=97005145&dopt=Abstract
[published
erratum appears in Infection 1996 Mar-Apr;24(2):169] = "On page 12,
because of technical reasons it was unfortunately not mentioned that
information regarding Case I was provided by Dr. D. Hassler."]
In vitro
investigation. Amoxicillin, doxycycline, cefotaxime, ceftriaxone, azithromycin
and penicillin G. Killing effekt investigated during a 72h exposure in
MPK-medium and human serum with negative Lyme borreliosis serological tests.. Twenty
clinical isolates were used ...
Exerpts:
.. the results show that the kill kinetics of the borreliae differs from
antibiotic to antibiotic. The killing rate of a given antibiotic for borreliae
is less dependent on the concentration of the antibiotic than on the reaction
time. Furthermore, the data show that the killing effect of isolates of B. garinii
differs from that in B. afzelii species. Very interesting and
unexpected is the different effect of antibiotics on isolates within one
species. Also the different reaction of one strain to tested antibiotics is
surprising.....
In summary, the result of killing kinetics suggest that:
1. The
strains of B. afzelii and B. garinii spp. react differently against antibiotics
used in the treatment of Lyme disease.
2. The
different reactions of strains to antibiotics also exists within one species.
3. There
exist different effects of one antibiotic against strains tested as well as
different reactions of the strain to antibiotics tested.
4. The
killing rate of a given antibiotic is dependent on reaction time of
antibiotics.
5. B.
garinii strains seem to be more sensitive to antibiotic tested than B. afzelii
strains.
6. The
antibiotics take a long time to become effective.
7. The
different killing kinetics of B. burgdorferi sensu lato strains can be of
importance in a treatment regimen.
Furthermore,
the persistense of B. burgdorferi s.l. and clinical recurrences in patients
despite seemingly adequate antibiotic treatment is described. The patients had
clinical disease with or without diagnostic antibody titre to B. burgdorferi. Includes
five case stories showing culture confirmed relapses after 12-14 days treatment
courses.
Case 1: 51y
man plexus neuritis. Positive serology for Borreliae IgG, WB. Cefotaxime 3x2g a
day 12 days. Antibodies to Borreliae disapperead in months.
Five years later a new attack with headache and pseudoradicular pain located in
the region of the right arm plexus. Negative Bb and Western Blot. Half
a year later progressive cardiac pain and dyspnoe on exertion. Angiography and
echocardiography revealed 3rd degre mitral insufficiency. The patient had a
history of 7 years of cardiomyopathy. Mitral valve replacement was carried out.
Borreliae was cultured after prolonged incubation (9 weeks) from the
excised mitral valve. Bb antibodies negative (ELISA, WB, IFT).
Case 2: 13y
old boy with right gonarthritis. Positive IgG and IgM serology for Borrelia. Treated
with ceftriaxone 2g/day for 14 days. Joint swelling diminished, but later
recurred. Six
months later synovectomy grew Borrelia afzelii from synovia as well as from the
effusion.
Case 3: painfull knees, treated with corticosteroid.
Lyme-IFGT-IgG borderline. Treated with ceftriaxone 2g/day for 14 days.
Recurrent arthritis. About half a year later IgG in serum and and synovial
fluid was positive. B. afzelii was isolated from the effusion.
Case 4: 35y man. One year history of headache, intensive
back pain, skin eruption (lymphocytoma benignum) and arthralgia. Serum
Borrelia-titer negative. Borreliae were isolated from skin biopsy (B. garinii).
Cefriaxone 2g/day 14 days. The back pain diminished, other
symptoms persisted. Doxycycline dose? 10 days. Persistent arthralgias. Antibody
titers against Bb s.l. negative, but Borreliae was isolated from a subsequent
biopsy. Oral penicillin dose? for 14 days. The antibiotic
treatment resulted in reduction of arthralgias [comment: but not symptom
free, not cured?]
Case 5: 28y woman. Arthralgia multiple joints.
Corticosteroids and doxycycline dose? duration?. After a 2-year history of pain
and an increase in inflammation in the knee and hands synovectomy was
performed. Borrelia IgM and IgG was negative, but nevertheless B.
afzelii was isolated from hand synovia and the patient was treated
with ceftriaxone.
Inflammatory brain changes
in Lyme borreliosis. A report on three patients and review of literature.
Oksi J, Kalimo H,
Marttila RJ, Marjamaki M, Sonninen P, Nikoskelainen J, Viljanen MK. Brain
1996 Dec; 119 ( Pt 6): 2143-54
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9010017&dopt=Abstract
Case 1:
The patient was a 51-year old woman with a history of progressive lymphoedema
of the left lower limb since 1954. She had suffered from erysipelas in the left
lower leg and erythema nodosum in both legs, and had also had recurrent fever
episodes several times a year. Lung fibrosis, heart insufficiency and chest
pain atypical of coronary heart disease developed at the age of 30-35 years.
She had received long-term corticosteroids and several courses of antimicrobial
drugs.
In 1985, the patient had a 3 week period of fever and facial
redness suggestive of lupoid erythema. Despite corticosteriod treatment, a
spiking fever persisted. At hospital, no infection focus was found.
Antimalarial drugs, combined with methylprednisolone were given for two years,
but episodes of mild fever reappeared. Antinuclear antibodies and antibodies
against extractable antigens were repeatedly negative. Anti-DNA-antibodies were
found slightly positive.
After september 1988, she was hospitalized several times for prolonged
vomiting, fatigue, fever, dizziness and progressive walking difficulties with
ataxia and short gait. In addition, impairment of memory, taste, and hearing
occurred. In february 1988, the erythrocyte sedimentation rate (ESR) was 125
mm/h serum C-reactive protein 83mg/ml (normal <10 mg/ml), and leucocytes 9.2
x 109 with 96% granulocytes. Sinus X-ray showed sinuitis, and the
brain CT showed an empty sella. Despite treatment with methylprednisolone and
i.v. erythromycin, the ESR and C-reactive protein remained elevated. At CSF
examinations (February 1989 and January 1991), leucocyte counts and protein
concentrations were normal, as was the IgG/albumin ratio, but one or two
subfractions were observed with protein electrophoresis. In January 1991, MRI
of the brain showed enlarged ventricles, cortical atrophy, and marked
degenerative changes in the periventricular areas (Fig. 1A). Total serum
immunoglobulins were normal, but immune electrophoresis showed an M-komponent
(IgG lambda). Circulating immune complexes also occurred. Rheumatoid factor,
antinuclear antibodies, anticardiolipin, TPHA (treponema pallidum
haemagglutinations test), anti-phospholipid antibodies, and antibodies
against B. burgdorferi were negative in serum. Leucocytes were 3.5 x 109
/l with an excess of band forms. In August 1991, CSF examination showed no
inflammatory cells, a slightly elevated protein concentration of 762 mg/l, and
no antibodies against B. burgdorferi. Culture of CSF in BSK-II medium
showed very slow growth of spirochetes during 3 months. Using monoclonal
antibodies, immunoflourescence and PCR, the spirochete was identified as B.
burgdorferi s.l.
In December 1991, antimicrobial treatment with ceftriaxone (2g i.v. daily) was
instituuted. The patient improved slightly, and therapy was continued after 3
weeks with oral amoxicillin (500 mg every 8 h) and oral probenecid (500 mg
every 8 h).
After 1 week on amoxicillin the patient developed urticaria. Oral doxycycline
(100 mg every 12 h) was substituted and continued until July 1992. During this
treatment, the walking difficulties and fever episodes recurred. All cultures
for fungi and common bacteria were negative. In January 1992, brain MRI showed
slight progression of the periventricular lesions from the image obtained 1
year earlier. In March and July 1992, subdural haemorrhages of unknown origin
were evacuated.
On August 7, 1992,
plasma and bone marrow specimens were positive for B. burgdorferi PCR. Treatment with ceftriaxone (2g i.v.
daily) was reinstituted, the patient reacting with high fever. Empirical
antifungal therapy with amphotericin B was also started. These treatments were
continued until the patient died on September 12, 1992.
At autopsy, the pathological changes were slighter than expected. The
spleen was slightly enlarged. Chronic liver stasis and mild pulmonary oedema
were detected. No signs of fungal infection were seen. Neuropathological
examination showed a chronic left-sided subdural haematoma. Its structure was
compatible with the haemorrhages ocurring 6 and 12 months before death. An
increased number of plasma cells were present within the organizing connective
tissue of the haematoma. In subcortical and periventricular white matter,
diffuse demyelination with mild perivascular inflammation was seen (Fig. 1B and
C). In one of the six analysed brain tissue specimens, B. burgdorferi DNA
was detected by the PCR.
Case 2:
This 40-year old man had previously been healthy, apart from reactivation of a
genital herpes infection some weeks before. He recalled no tick bites or
erythema migrans. On December 26, 1992, he had a generalized seizure and was
admitted to the hospital. Another seizure ocurred on the day of admission.
Brain CT was normal. On admission, CSF examination showed an unremarkable
increase of protein level (688 mg/l) with no inflammatory cells. The PCR assays
for herpes simlex virus (HSV) and antibodies against viruses were negative in
the CSF. Serum IgM antibodies against B. burgdorferi were found at a low
level and IgG antibodies against Chlamydia pneumoniae were moderately
elevated. Serum C-reactive protein was 50 mg/l, lactic dehydrogenase 927 U7l
(normal value <20 U/l), but the changes were transient. Other labororatory tests
were normal including serum hepatitis B surface antigen, antibodies against HIV
and herpes virus. The EEG showed an irrative focus in the left hemisphere.
On December 30, MRI of the brain showed three small frontal lesions at the
bottom of the left frontal lobe near the meninges. The imaging of these lesions
was enhanced using contrast medium (Fig. 3A). In the right pleural cavity, a
chest X-ray examination showed fluid, which disappeared in 2 weeks. The CT
showed a central cystic lesion n the left kidney, but no abnormal findings were
obtained in the mediastinum, lungs, or pleural cavities. On December 31, a CSF
examination showed 4 x 106 /l lymphocytes, but protein (373 mg/l),
and angiotensin convertase enzyme and lysozyme concentrations were normal. The
CSF antibodies against herpesviruses, B. burgdorferi, and Treponema pallidum
were negative as was antigen for HSV and PCR for B. burgdorferi. The PCR for
HSV was positive with this specimen. Culture for viruses and mycobacteria
remained negative.
On January 8, 1993,
a frontally located lesion was resected for suspected malignancy. Histopathological
studies showed
lymphocytes in the walls of leptomeningeeal and small penetrating arteries as
well as in the perivascular space of the latter (Fig. 2B). The adjacent cortex
was slightly oedematous with very mild astrocytic gliosis. A PCR analysis of
three separate brain specimens detected DNA of B. burgdorferi. The IgM
(but not IgG) antibodies against B. burgdorferi were positive only in the first
pretreatment sample serum samples, but negative thereafter. The circulating
immune complexes and complement activation products were positive. The IgG
antibodies against C. pneumoniae were elevated at a constant level, but IgM
antibodies remained negative, indicating that the IgG antibodies were of
earlier origin. A neuropsychological investigation showed memory impairment
affecting verbal function anf slightly impaired fluency of verbal expression.
Anticonvulsive therapy with carbamazepine was started. Table two shows changes
in the antimicrobial treatment schedule and the development of the brain
lesions appearing on MRI. During the antibiotic treatment, MRI of the brain
showed new lesions, one enhancing lesion (2 cm in diameter), suggestive of
focal vasculitis, located medially from the post-operative area, and later,
enhancing lesions at the bottom of the right frontal lobe and a frontal lobe
sulcus (Fig. 3A and B). However, the initial lesion at the bottom of the lest
frontal lobe behind the orbita was now markedly smaller than at previous
examination. Later images showed that the first lesion was constantly reducing
in size, and five months after onset of antibiotic therapy all the new foci of
the putative vasculitic process had also disappeared. The antibiotic therapy
was discontinued on July 5, 1993.
The patient was asymptomatic at the end of therapy. Whole body bone scanning
was carried out in June 1993 because of a history of pain in the thoracic spine
some months earlier. Slightly increased uptake of isotope in the thoracic spine
was seen, but the finding was considered unspecific. The EEG after sleep
deprivation was normal in July 1993.
Five months after the end of antibiotic therapy, brain MRI showed a new
focus located adjacent to the third ventricle (Fig. 3 A and B). Oral
antibiotic treatment was started (the patient was asymptomatic: see table 2).
The next MRI showed that the treatment had probably had beneficial effect on
the former lesions, but again, a new focus in frontal sulcus and a relatively
large pathological area in periventricular white matter were detected (Fig.
3B). On May 17, 1994, DNA of B. burgdorferi was detected by PCR in the
patients plasma specimen (Table 2). Intravenous antibiotic therapy was
reinstituted and continued for 100 days. Thereafter, on MRI studies of the
brain, all lesions and perivascular enhancement have disapperared, and no new
lesions have developed to date (Table 2). The antiepileptic therapy has been
discontinued, and no new seizures have occurred.
Case 3:
In the summer of 1993, this previously healthy 11-year-old girl had visited an
area in Southern Finland where Lyme borreliosis is endemic. In September 1993,
occasional episodes of hyperactivity followed by headache were observed by her
family. On October 1, she developed paresis of the right lower limb. On October
7, she was admitted to a local hospital and 1 week later to the Oulu University
Central Hospital. Standing on the right leg alone was difficult, and walking
was slightly impaired. On October 13, CT of the brain showed a periventricular
low density enhancing lesion. 10x6 mm2 in diameter, and located in
the left parietal lobe white matter. The lesion was suggestive of a neoplasm.
On the next day, using MRI, the dimensions of the enhancing lesion were found
to be 40x20x8 mm3 and the surrounding oedematous area was 20-30 mm
thick (fig. 4A). The EMG was normal. Abdominal ultrasonography showed mild
splenomegaly. On October 22, a craniotomy was carried out. In the area of the
enhancing lesion, shown by MRI, elastic and stretchy tissue with abnormal white
colour was detected. On histological examination, focal necrotic areas were
found, surrounded by foamy macrophages, reactive astrocytes and oedema. (Fig
4B). An increased number of small vessels with thickened walls and prominent
endothelial cells were also seen. Lymphocytes occurred in the walls of some
vessels.
Haemoglobin, ESR and serum C-reactive protein values were normal. Serum total
immunoglobulins were normal, except for a slightly increased value of IgM at 1.94
g/l (normal value 0.35-1.63 g/l). Serum rheumatoid factor, antinuclear
antibodies extractable nuclear antigens, anti-DNA and anti-phospholipid
antibodies were negative, and so were antibodies against several viruses. On
November 4, lumbar puncture was carried out. The CSF specimen gave a negative
virus culture as HSV PCR, but B. burgdorferi PCR was positive with two
separate CSF specimens (detected at two separate runs).
December 21, 1993, antibiotic therapy with ceftriaxone (2 g i.v. daily) was
started for 4 weeks followed by therapy with oral amoxicillin (500 mg every 8
h) combined with oral probenecid (500 mg every 8 h). On February 1, the
antibiotic therapy was stopped because of bloody diarrhoea. Culture and toxn
detection for Clostridium difficile were negative. The diarrhoe was cured with
oral metronidazole.
On Februray 1, 1994, MRI of the brain showed reduction of abnormal tissue
around the operative area. At this time, no enhancement was seen in the walls
of the cavity. At a follow-up of 1 year, recovery was observed witho only a
slight abnormality in walking. No new symptoms developed.
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. Ann Rheum Dis 1998 Feb;57(2):118-21
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9613343&dopt=Abstract
Case 1: 50y M, acute arthritis left knee. High Lyme IgG.
Doxycycline 200mg/d and diclofenac, and intraarticular dexamethasone. Arthritis
persisted.
B. burgdorferi DNA in SF, Ceftriaxone 2g/d, 2 weeks. Arthritis improved
significantly but recurred after about six weeks. Treated with ceftriaxone
again. Although SF PCR became negative, gonarthritis persisted. A popliteal
cyst developed and a bursitis of the left elbow occurred. An arthroscopic
synovectomy of the left knee and a bursectomy were performed. Ceftriaxone 2g
for 28d, doxycyclin2 200 mg for 30 d.
Case 2: 51y F, 2 month history of bilateral gonarthritis,
remembered tickbite and EM-like lesion at the right thigh years ago. IgG
positive ELISA & Western Blot and B. burgdorferi PCR in SF positive.
Doxycycline 200mg/d for 35d without effect. Ceftriaxone 2g/d for 3 weeks w only
moderate success. Two mo after treatement gonarthritis persisted. An
arthrocentesis and synovial biopsy was performed.
Case 3: 28y F, subtotal arthroscopic synovectomy of the
right knee had been performed elsewhere because of a gonarthritis with
pronounced synovial proliferation… persisted for 9 months. … positive Lyme
serology both IgM & IgG. Ceftriaxone 2g 14 d. treatment discontinued at day
11 because of an allergic rash. Gonarthritis persisted. PCR positive in SF
doxycycline 200mg/d for 30d. In addition corticosteroid intraarticularly.
However only a temporary improvement of the arthritis was seen … Arthroscopy …
SF and SM samples.
Case 4: 43y F, bilateral gonarthritis 7 mo, ELISA &
Western Blot high IgG, PCR for B. burgdorferi in SF and urine positive.
Ceftriaxone 2g 14d without improvement. A few weeks later the patient was seen
in another hospital with an acute polyarthritis involving both wrists and
several metacarpophalangeal joints and a deterioration of the right
gonarthritis. Doxycycline 200mg/d 30d and prednisolone 10-20 mg/d. Again there
was no sufficient response … A closed needle arthrocentesis with synovial
biopsy of the right knee was performed.
Patients were evaluated 8 to 10 weeks after antibiotic
therapy. All still seropositive and had active arthritis. Urine samples were
collected and within one week SF and SM specimens were obtained ... In
none of the urine or SF samples could B. burgdorferi DNA be detected, in
contrast SM samples was positive.
Patients 1,2,4: cefotaxime 2g x3 3 weeks, followed by six weeks oral
doxycycline or minocycline 200mg/d. Pt. 3: imipenem 1.0g x3 for 2 weeks,
doxycycline 200mg six weeks. In all four patients arthritis completely subsided
within 4-6 mo and did not recur at a median observation period of 18 mo.
No mentioning of any extraarticular symptoms.
[Pars plana vitrectomy in
Borrelia burgdorferi endophthalmitis][German]
Meier P, Blatz R, Gau M,
Spencker FB, Wiedemann P. Klin Monatsbl Augenheilkd 1998 Dec;213(6):351-4
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10048013&dopt=Abstract
BACKGROUND: Ocular manifestations of Lyme borreliose present
with unusual forms of conjunctivitis, keratitis, optic nerve disease, uveitis,
vitritis and rarely endophthalmitis.
CASE REPORT: A 57-year-old man working as logger in Saxony-Anhalt suffering
from an endophthalmitis on his left eye was referred to us. The vision of his
left eye was intact light perception and hand motions. The slit-lamp
examination revealed severe inflammation of the anterior chamber with hypopyon,
posterior synechiae, and opacity of the posterior lens capsule. Funduscopy
showed no red reflex, no retinal details. In the local hospital serum analysis
was performed and showed in Western-Blot IgM- and IgG-antibodies against
Borrelia burgdorferi. Despite of intravenous application of ceftriaxon for 14
days panuveitis persisted, and endophthalmitis developed when antibiotic
therapy was finished.
RESULTS: During pars plana vitrectomy a sharply delineated cystic lesion
containing yellowish fluid was revealed, and creamy yellow fluid was aspirated.
Microscopically in hematoxylin-eosin stained slides of the aspirate
structures consistent with Borrelia burgdorferi were found.
Postoperatively vision increased to 1/15. Despite of a second intravenous
ceftriaxon treatment for 14 days we observed a retinal vasculitis in the follow
up of 6 months.
CONCLUSIONS: Despite intravenous ceftriaxon-therapy borrelia burgdorferi must
have survived in the vitreous body. Further investigations are required with
respect to the use of other antibiotics or immunosuppressives.
Borrelia burgdorferi
detected by culture and PCR in clinical relapse of disseminated Lyme
borreliosis.
Oksi J, Marjamaki M,
Nikoskelainen J, Viljanen MK. Ann Med 1999 Jun;31(3):225-32
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=99369287&dopt=Abstract
http://www.annmed.org/duo/annmed.check_login?fname=1999_31_3_225-32.html
A total of 165 patients with disseminated
Lyme borreliosis (diagnosed in 1990-94, all seropositive except one
culture-positive patient) were followed after antibiotic treatment. 32/165 = 19,4%
had clinical relapse after more than 3 months antibiotic treatment for
borreliosis.
In 13/32 (40,6%) could the relapse be verified by either positive PCR
(12) and/or positive culture (3) for B. burgdorferi.
2/104 (1,9%) of the asymptomatic had positive PCR. These were not treated and
didn't have sign of relapse since, according to personal communication (120900)
with Oksi.
At time of proven relapse 6/13 (46%) were seronegative! (12/13 were
seropositive at initial diagnosis, i.e. 5 pts. developed seronegativity despite
proven persistency !!)
5/13 (38%) had circulating immunecomplexes, of these 3 were seronegative.
1 patient (10) was seronegative throughout the whole course
of illness despite both positive culture and PCR in CSF and positive biopsy and
plasma PCR at relapse
! This patient had been treated with ceftriaxone IV 2g for 3 weeks,
followed by 24 weeks of doxycycline 100 g bid and amoxicillin 1 week - a total
of 28 weeks (6-7 months).
1 patient (8) had been treated for as long as 47 weeks (11 months) including 7
weeks of intravenous ceftriaxone - primary diagnosis was confirmed by positive
biopsy and the relapse 44 weeks after treatment confirmed by a positive plasma
PCR.
1 patient (2) had relapse 130 weeks after 1. treatment, that had lasted
16 weeks. Pt. was seropositive initially (both IgM and IgG), but seronegative
at relapse, relapse confirmed by positive PCR, no history of reinfection in the
meantime.
Persistence of Borrelia
garinii and Borrelia afzelii in patients with Lyme arthritis.
Hulinska D, Votypka J,
Valesova M. Int J Med Microbiol Virol Parasitol Infect Dis 1999
Jul;289(3):301-18
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10467661&dopt=Abstract
We repeatedly detected DNA of Borrelia garinii or B. afzelii
and Borrelia-like structures in the blood, joint fluid or in the synovium of 10
patients with Lyme arthritis by means of the polymerase chain reaction and
immunoelectron microscopy at 2-4-month intervals in the course of two years.
All samples were analyzed using primers which amplified the 16S rRNA gene
sequence of Borrelia burgdorferi sensu lato and nucleotide sequences for the
OspA gene. No cross hybridization occurred with DNA from human cells and with
DNA from other bacteria. Capture and labelling with monoclonal antibodies
of aggregated antigens, membranes and flagellae were evident in the blood of 7
patients, in 4 synovial membranes and 2 synovial fluids. Borreliae were found
in blood capillaries, in collagen and in clusters surrounding inflammatory
cells in the synovium of patients with recurrent infections who carried IgM and
IgG antibodies to OspA and to 83 kDa core protein.
After significant improvement for several weeks after treatment,
arthritis recurred in six patients. Synoviocyte hyperplasia,
inflammatory infiltration and concentric adventitial fibroplasia were seen in
the synovium of the patients with persisting borreliae. Only two patients were
infected with B. afzelii, the others with B. garinii.
Lyme arthritis in a
12-year-old patient after a latency period of 5 years.
Albert S, Schulze J,
Riegel H, Brade V. Infection 1999;27(4-5):286-8
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10885847&dopt=Abstract
Lyme arthritis (LA) may be confused with other rheumatic
diseases, particularly in the absence of a history of erythema migrans (EM). We
report the case of a 12-year-old patient who developed a large effusion of the
right knee joint. The titer for antinuclear antibodies was 1:80 and the test
for rheumatoid factor was negative. Investigations for antibody
response to Borrelia burgdorferi demonstrated remarkable elevation of IgG
antibody and no specific IgM response.These results were confirmed by
immunoblotting reactivity with the bands p83/100, p58, p43, p41, p39, OspA,
p30, OspC, p21, and p17. We subsequently learned that the
child had suffered a tick bite followed by an EM 5 years earlier and had been treated
with trimethoprim/sulfamethoxazole at that time. The patient now was given
intravenous ceftriaxone, 2 g daily for 14 days. In the absence of clinical
improvement 3 weeks later a knee joint aspiration was performed which resulted
in a positive polymerase chain reaction (PCR) test for B. burgdorferi DNA
(OspA) in the synovial fluid.The patient fully recovered 2 months
later without further treatment. The case indicates that the latency period
between EM and onset of LA may last up to 5 years. In addition to serologic
test methods, analysis of synovial fluid using PCR may be decisive for making
the final diagnosis of LA.
[Persistence of Borrelia
burgdorferi sensu lato in patients with Lyme borreliosis][Czech]
Honegr K, Hulinska D,
Dostal V, Gebousky P, Hankova E, Horacek J, Vyslouzil L, Havlasova J. Epidemiol
Mikrobiol Imunol 2001 Feb;50(1):10-16
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11233667&dopt=Abstract
In 18 patients with Lyme borreliosis the
authors proved the persistence of Borrelia burgdorferi sensu lato by
detection of the causal agent by immune electron microscopy or of its DNA by
PCR in plasma or cerebrospinal fluid after an interval of 4-68 months. Clinical
manifestations common in Lyme borreliosis were present in only half the
patients, in the remainder non-specific symptoms were found. In nine
subjects with confirmed Borrelia burgdorferi sensu lato in the cerebrospinal
fluid the cytological and biochemical finding was normal. Examination
of antibodies by the ELISA method was negative in 7 of 18 patients during the
first examination and in 12 of 18 during the second examination. In all negative
examinations the specific antibodies were assessed by the Western blot or ELISA
method after liberation from the immunocomplexes. In the authors'
opinion it is advisable to examine repeatedly plasma and other biological
material from potentially affected organs by PCR and subjects with persisting
or relapsing complaints after the acute form of Lyme borreliosis as well as to
examine cerebrospinal fluid in case on non-specific symptoms and concurrent
pathic EEG or MR findings.
Fatal adult respiratory
distress syndrome in a patient with Lyme disease.
Kirsch M, Ruben FL,
Steere AC, Duray PH, Norden CW, Winkelstein A. JAMA1988 May 13; 259(18): 2737-9
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=88188323&dopt=Abstract
Case
A 67-year-old woman
who lived on a farm near Pittsburgh first noted lethargy, weakness,
lower-extremity stiffness, and myalgias on May 16, 1986, one week after a
weekend trip to the Maryland shore. Soon thereafter, a dry cough, swelling of
her hands, fever, anorexia, and a rash on her extremities and trunk developed.
Although she had no known history of a tick bite, a presumptive diagnosis of
Rocky Mountain spotted fever was made, and a two-week course of tetracycline
hydrochloride, 250 mg orally four times a day, was prescribed.
Because of persistent symptoms, she was referred to Montefiore Hospital in
Pittsburgh. Examination showed a maculopapular eruption on her trunk and hands.
Although antibody titers for Rocky Mountain spotted fever were negative, both
the IgM and IgG antibody titers in response to the Lyme disease spirochete Borrelia
burgdorferi were markedly elevated (Table), as determined by enzyme-linked
immunosorbent assay.2 She completed her tetracycline course without
improvement in her condition.
She was admitted to the hospital on June 17, 1986. Her temperature was 16.7oC.
Liver function test results were abnormal (lactic dehydrogenase [LDH], 419 U/L;
aspartate aminotransferase [ASAT], 639 U/L; alanine aminotransferase [ALAT],
418 U/L; and alkaline phosphatase, 223 U/L), but results of the remainder of
the admission studies, including a serum VDRL test, chest roentgenogram, and
electrocardiogram, were unremarkable. A skin biopsy specimen revealed
nonspecific inflammatory changes. Because of the lack of response to
tetracycline, she was given a ten-day course of intravenous penicillin G
potassium, 5 million U every six hours. Her fevers resolved, and her
rash, joint complaints, and liver enzyme abnormalities improved (LDH, 338 U/L;
ASAT, 184 U/L; ALAT, 111 U/L; and alkaline phosphatase, 198 U/L). She was
discharged on June 28.
At home, her rash worsened, and periorbital edema developed. Her constitutional
symptoms persisted, and she was readmitted to the hospital five days later.
Examination revealed an oral temperature of 38.1oC, a pulse rate of
112 beats per minute, and respirations of 20/min. In addition to the
maculopapular rash and periorbital edema, there was moderate swelling and
tenderness over the carpal and interphalangeal joints. There was no muscle
tenderness or pedal edema, and the lungs were clear. The white blood cell count
was 6.0 x 109/L (6.0 x 103/mm3); the
erythrocyte sedimentation rate (Wintrobe) was 47 mm/h; and liver and muscle
enzyme concentrations were elevated (LDH, 508 U/L; ASAT, 429 U/L; ALAT, 162
U/L; alkaline phosphatase, 286 U/L; and creatine kinase, 279 U/L). A chest
roentgenogram showed atelectasis at the left base (Fig 1). The level of immune
complexes was shown to be elevated by the C1q binding assay result of 36%
(norms), <13%) and by the Raji cell assay result of 315 mg of aggregated
human gamma globulin equivalents per liter (normal, <50 mg of aggregated
human gamma globulin equivalents per liter). Serum cryoglobulins were absent.
Antinuclear antibody was present in low titer (1:10), and rheumatoid factor was
positive (1:40). The level of the C3 component of complement was mildly
decreased, at 0.85 g/L (35 g/dl) (normal range, 1.15 to 1.85 g/L [115 to 185
mg/dl]). Titers for hepatitis A, hepatitis B, cytomegalovirus, Epstein-Barr
virus, Trichinella, Legionella pneumophila, and febrile
agglutinins were negative. The patient was given a second course of
intravenous penicillin C potassium, 5 million U every six hours, and enteric
coated aspirin 650 mg orally every four hours.
Initially, her rash,
edema, and arthralgias improved, but her marked lethargy and dry cough
persisted. On her tenth day in the hospital, bibasilar rales were noted, and a
chest roentgenogram demonstrated new findings of bibasilar atelectasis with
bilateral peripheral infiltrates. Prednisone therapy, 20 mg orally three times
a day, was begun. While her rash and edema improved, her liver and muscle
enzyme abnormalities worsened. An abdominal computed tomographic scan showed a
nonhomogeneous liver and was otherwise unremarkable.
Four days later, her oral temperature rose to 38.9oC, and her
respirations were 34/mm. Increased rales were present bilaterally. An arterial
blood gas test done while the patient was breathing 35% 02 showed
the following values: Arterial oxygen pressure, 68 mm Hg; arterial carbon
dioxide pressure, 27 mm Hg; and pH, 7.55. The white blood cell count was 12.4 x
109/L (12.4 10 103/mm3), with 0.04 (4%) band
forms. A chest roentgenogram showed diffuse, bilateral, patchy infiltrates (Fig
1). Blood and urine cultures showed no growth. Lyme disease antibody titers were
still markedly elevated (Table). Immunoblotting demonstrated IgG antibodies
against at least 14 polypeptides of B burgdorferi, including the
31-kilodalton outer-membrane component. Nafcillin and tobramycin
therapy was started empirically.
On the following day, during bronchoalveolar lavage, the patient became
tachypnoic and cyanotic and underwent intubation. A chest roentgenogram now
showed bilateral central infiltrates. The patient was given intravenous
trimethoprim with sulfamethoxazole, and nafcillin therapy was discontinued. She
became increasingly more hypoxemic, requiring a positive end-expiratory
pressure of 15 cm H2O and a fraction of inspired oxygen in the range
of 0.8 to 0.9. On her 19th day in the hospital, an open-lung biopsy specimen
revealed severe, acute, diffuse alveolar damage, compatible with the adult
respiratory distress syndrome (ARDS). There was no evidence of tumor,
infection, or vasculitis. She became progressively more hypoxemic and
hypotensive, and she died six days later.
Pathologic Findings
The cause of death
was diffuse alveolar damage of the lungs (ARDS). Additional findings were
cardiomegaly (370 g with borderline right ventricular hypertrophy (0.3 cm),
fatty liver (1600 g), and acute tubular necrosis of the kidneys. Lymph
nodes showed a transformed lymphocytic response, and, when Dieterle silver
stain was used,3 spirochetes compatible with B burgdorferi
infection were demonstrated (Fig 2). Lung tissue was submitted for
virus isolation and was found to be negative for influenza A and B,
parainfluenza, respiratory syncytial virus, adenovirus, and coxoackievirus.
Antibodies to Leptospira canicola and Leptospira
icterohaemorrhoragiae antibodies were present at less than 1:8 by
complement fixation testing and were not detectable by direct agglutination
testing using serum from July 21, 1986, three days before the patient died.
Comment
After the first
description of Lyme disease in 1975, the clinical spectrum was expanded to
include cardiac and neurologic features.4 This disorder is now
recognized to be a multisystemic disease that triggers a complex immune
response to a spirochetal infection.
The patient described herein presented with cough, fever, a diffuse
rash, and myositis, and she also had abnormal liver function test results. Her
hospital course was essentially characterized by progressive respiratory
failure and fatal ARDS. Levels of IgM and IgG antibodies were markedly
increased in response to B burgdorferi, the agent that causes Lyme
disease. This level of titers has been shown to exhibit
cross-reactivity in patients with syphilis or relapsing fever. We excluded
syphilis with a nonreactive VDRL test and relapsing fever with immunoblotting
studies. Antibodies were demonstrated to 14 polypeptides of B burgdorferi,
including the 31-kilodalton polypeptide, a pattern thought to be specific for
Lyme disease.5 In addition, lymph node sections examined after the
patients death demonstrated spirochetes morphologically compatible with B
burgdorferi. We are confident that the serologic and histologic
evidence described supports the diagnosis of Lyme disease.
The clinical features of our patient were, however, highly atypical for
Lyme disease. Her rash was generalized and prominent on her hands.
This distribution has not previously been reported in Lyme disease and
contrasts with erythema chronicum migrans, the unique clinical marker for this
disorder.6 Although mild hepatitis has been described,6
markedly abnormal liver enzyme levels, myositis, and edema of the hands and
face are not characteristic of Lyme disease. Most important was her progressive
and fatal respiratory failure. The only respiratory symptom described in human
Lyme disease is a nonproductive cough, although spirochetes have been
demonstrated in the lungs of experimentally infected hamsters.7
Since it is recognized that ARDS follows a wide variety of predisposing
conditions we believe that Lyme disease triggered this fatal complication.
How can we explain our patients variant clinical syndrome? This case is
atypical in its presentation, course, response to therapy, and outcome. This
patient received a course tetracycline followed by two courses of high-dose
intravenous penicillin, without improvement. Both of these antibiotic
regimens are considered to be established antispirochetal therapy for Lyme
disease. This suggests that the spirochete was particularly virulent, that the
host defenses were impaired, or that the disease state no longer solely
depended on live spirochetes for its expression. We do not believe that our patient
was immunocompromised. The mechanism by which B burgdorferi causes Lyme
disease is still under study. It is unclear whether certain manifestations of
Lyme disease require a live spirochete for continued disease activity or
whether they result from immune-mediated mechanisms.1 Although
spirochetes were identified in lymph nodes, the transformed lymphocytic
response, the presence of circulating immune complexes and the progression of
disease despite antibiotic treatment indicate an immune-mediated disease.
Lyme disease has become
a prevalent and serious infection. In addition to chronic arthritis,8
this disease has been shown to be the cause of fatal myocarditis,9
panophthalmitis leading to blindness,10 fetal death,11
and central nervous system syndromes suggestive of demyelination.12To
these complications we add respiratory failure and ARDS, which are refractory
to known therapy. Although Lyme disease is endemic in the Northeast, the
Midwest, and the Far West of the United States, it has been reported throughout
the country.13
With an incubation period that ranged from three to 12 days6
and no documented tick bite, we are uncertain whether our patient contracted
the disease in Maryland or in western Pennsylvania.
We urge physicians throughout the United States to consider the multisystemic
features of Lyme disease and to recognize its lethal potential.
Treatment of refractory
chronic Lyme arthritis with arthroscopic synovectomy.
Schoen RT, Aversa JM,
Rahn DW, Steere AC. Arthritis Rheum 1991 Aug; 34(8): 1056-60
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1859481&dopt=Abstract
All seropositive …
18/20 patients received oral or i.v. antibiotic treatment most both, but
treatment drug, dose and duration not specified ...
[thus 2/20 (10%) did not receive any antibiotic treatment (?), which
makes the title'refractory' a bit inappropiate].
Synovia from 12/20 [60%] patients have been analyzed in detail and were similar
to 12 rheumatoid synovia used for comparison … moderate-to-marked synovial cell
hyperplasia, vascular proliferation, and mononuclear cell infiltration,
sometimes with pseudolymphoid follicles ..
In 6/12 patients w/ Lyme arthritis, but in none of those w/
rheumatoid arthritis, a few spirochetes and globular antigen
deposits were seen in and around blood vessels in areas of lymphocytic
infiltration [i.e. 6/20 (30%) had proven persistent infection
in the joint. The paper doesn't tell if 2 of these patients were those
that didn't receive antibiotics, but at least 4(-6) obviously had persistent
infection despite previous antibiotic treatment.]
80% had resolution of joint inflammation .. and they have not had recurrences
during a followup period of 3-8 y …
15% of these patients all of whom were more disabled preoperatively, had no
further synovitis, but still had mild functional limitations at long-term
followup.
Only [!!!] 20% of the patients had persisitent or recurrent synovitis
.. [is synovectomy a certain cure for a persistent systemic borrelia
infection?]
Authors say they did not find symptoms of extraarticular Lyme borreliosis
... but 1 had facial palsy ….
And the postoperative assessment only includes joint examination not a
neurological examination … a (rheumatological) focus problem ??
Attempts to do culture or PCR were not done.
Culture-confirmed Treatment
Failure of Cefotaxime and Minocycline in a Case of Lyme
Meningoencephalomyelitis in the US.
Liegner KB, Rosenkilde CE,
Campbell GL, Guam TJ, Dennis DT. 1992 V Int Conf Lb abs #63
In 1987, a 37-year-old woman living in Westchester County,
NY, developed spastic paraparesis, bilateral Babinski reflexes, and cranial
nerve and bulbar dysfunction characterized by dysphagia, dysphonia, diplopia,
absent gag reflex, and dysfunction of bowel and bladder control. CSF contained
19 WBC/mm (86% lymphs). A test for antibodies to Borrelia burgdorferi
(Bb) in serum was negative. No etiology was established despite an
extensive workup. Symptoms and signs reportedly worsened gradually from 1988 to
present. There was a past history of splenectomy for idiopathic
thrombocytopenic purpura diagnosed in 1975. In 1989, the right frontal region
and right basal ganglia were abnormal on brain MRI. In January 1990 CSF
contained 6 WBC/mm3 (93% lymphs), but no oligoclonal bands or myelin basic
protein. Paired CSF and serum tests for antibodies to Bb and PCR for
Bb-specific oligonucleotides in CSF were negative. An empiric 21-day course of
cefotaxime (3g/l2 hr i.v.) was given in January, 1990 with no clear clinical
benefit. Following treatment, CSF contained 9 WBC/mm3 (93% lymphs). Four
months of minocycline (200 mg/day p.o.) begun in November, 1990 also yielded no
clear clinical benefit. In December, 1990 a T-cell stimulation test with Bb
antigens was strongly positive. In December, 1991 CSF contained 6
WBC/mm3 (89% lymphs) and elevated IgG. Paired serum and CSF samples
were strongly positive for antibodies to Bb, with a CSF-to-serum index of 1.04.
Culture of this CSF specimen in BSK-Il yielded a strain of Bb. Culture--confirmed
treatment failures have been previously reported for three Lyme
neuroborreliosis cases in Europe. The present case apparently is the first of
this type to be reported from the United States.
Persistence of Borrelia
burgdorferi Antigens in Patients receiving Long-Term Antibiotic Therapy.
Drulle J, Eiras E. 1992
V Int Conf Lb abs#70E
25 Patients, previously diagnosed with Lyme Disease and
treated with long-term antibiotic therapy provided samples of urine, spinal
fluid, synovial fluid, breast milk or tears. All but 3 of the patients were symptomatic at the
time of the testing. Samples were tested by employing a polyclonal antibody
tagged with colloidal gold which is specific to an 83 kilodalton vescicular
protein, also known as a "bleb" and thought to be specific to
Borrelia burgdorferi. In 13 patients antigen was detected [13/25 =
52%]. Persistence of antigen may be related to persisting infection or
may represent lengthy clearance of dead spirochetal debris.
Molecular detection of
persistent Borrelia burgdorferi in a man with dermatomyositis.
Fraser DD, Kong LI,
Miller FW. Clin Exp Rheumatol 1992 Jul-Aug; 10(4): 387-90
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1395222&dopt=Abstract
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,
probenecid 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.
Borrelia burgdorferi
myositis: report of eight patients.
Reimers CD, de Koning J,
Neubert U, Preac Mursic V, Koster JG, Muller Felber W, Pongratz DE, Duray PH.
J Neurol 1993 May; 240(5): 278-83
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=93316101&dopt=Abstract
8 patients w histologic proven myositis of which one
was seronegative - one fatal case
5/8 had normal CK and none (2) or slight abnormality in other laboratory
findings (3 had ESR in range 26-38) see table 2
2 had normal EMG
Patients 4 & 6 were culture positive for borrelia in skin, but not
in muscle biopsies
Treated with antibiotics 10-14 days, patient 1 had persistent
fatique, patient 8 died from cardiac arrest caused by B. burgdorferi
myocarditis, myocardial inflammation at autopsy, where spirochetes were
demonstrated.
Chronic septic arthritis
caused by Borrelia burgdorferi.
Battafarano DF, Combs
JA, Enzenauer RJ, Fitzpatrick JE. Clin Orthop 1993 Dec(297): 238-41
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8242938&dopt=Abstract
Chronic arthritis occurs in 10% of Lyme disease patients. A
patient had chronic septic Lyme arthritis of the knee for seven years despite
multiple antibiotic trials and multiple arthroscopic and open
synovectomies. Spirochetes were documented in synovium and
synovial fluid (SF). Polymerase chain reaction (PCR) analysis of the SF was
consistent with Borrelia infection. Persistent infection should be
excluded with silver stains and cultures in any patient with chronic
monoarticular arthritis and a history of Lyme disease.
Detection of Borrelia
burgdorferi DNA by polymerase chain reaction in synovial fluid from patients
with Lyme arthritis [see comments]
Nocton JJ, Dressler F,
Rutledge BJ, Rys PN, Persing DH, Steere AC. N Engl J Med 1994 Jan 27;
330(4): 229-34
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=94097367&dopt=Abstract
BACKGROUND. Borrelia burgdorferi is difficult to detect in
synovial fluid, which limits our understanding of the pathogenesis of Lyme
arthritis, particularly when arthritis persists despite antibiotic therapy.
METHODS. Using the polymerase chain reaction (PCR), we attempted to detect B.
burgdorferi DNA in joint-fluid samples obtained over a 17-year period. The
samples were tested in two separate laboratories with four sets of primers and
probes, three of which target plasmid DNA that encodes outer-surface protein A
(OspA).
RESULTS. B. burgdorferi DNA was detected in 75 of 88 patients with Lyme
arthritis (85 percent) and in none of 64 control patients. Each of the three
OspA primer-probe sets was sensitive, and the results were moderately
concordant in the two laboratories (kappa = 0.54 to 0.73). Of 73 patients with
Lyme arthritis that was untreated or treated with only short courses of oral antibiotics,
70 (96 percent) had positive PCR results. In contrast, of 19 patients who
received either parenteral antibiotics or long courses of oral antibiotics
(> or = 1 month), only 7 (37 percent) had positive tests (P < 0.001).
None of these seven patients had received more than two months of oral
antibiotic treatment or more than three weeks of intravenous antibiotic
treatment. Of 10 patients with chronic arthritis (continuous joint inflammation
for one year or more) despite multiple courses of antibiotics, 7 had
consistently negative tests in samples obtained three months to two years after
treatment.
CONCLUSIONS. PCR testing can detect B. burgdorferi DNA in synovial fluid. This
test may be able to show whether Lyme arthritis that persists after antibiotic
treatment is due to persistence of the spirochete.
[NOTE: Priem et al. demonstrated that borrelia may be found
in synovial membranes in persistent borrelia arthritis, despite that
simultaneaous synovial fluid was negative for borrelia-antigen !!]
Persistence of Borrelia
burgdorferi despite antibiotic treatment.
Patmas MA . J Spiro
Tick Diseases 1994; 1:101
To the Editor:
It has been suggested that Lyme disease may trigger fibromyalgia and that
antibiotic therapy beyond 30 days is almost always unnecessary [1]. Recently,
two cases demonstrating persistence of Borrelia burgdorferi despite lengthy
antibiotic treatment were noted.
Case Number 1:
In October 1991, a 35-year-old Caucasian female, registered nurse, was referred
for evaluation. She had reported a lesion compatible with erythema chronicum
migrans about one year earlier. After a short course of oral
antibiotics, she noted fatigue, myalgia, and arthralgias and was given
2 weeks of intravenous ceftriaxone 1 g daily with resolution
of her symptoms. Over the next several months, however, her symptoms gradually
returned. An ELISA titer was elevated, and she was started on
ceftriaxone 2 g intravenously daily. After 10 days, the patient developed a
vigorous Jarisch-Herxheimer reaction and was referred to the author. The
patient was switched to cefotaxime 3 g intravenously every 12 hours with
improvement in symptoms. After 6 weeks, the intravenous cefotaxime was changed
to oral clarithromycin 500 mg daily for 6 more weeks with complete resolution
of all signs and symptoms. One week later, the patient discovered that she was
1 month pregnant and, after a normal gestation, delivered a healthy male
infant. The placenta was examined at Brigham and Women's Hospital in
Boston, Massachusetts, where several spirochetes were noted in perivascular and
intervillous spaces on modified Dieterle silver stain.
Case Number 2:
A 47-year-old Caucasian
female was well until an untreated tick bite in 1985. She subsequently
developed a progressive arthritis diagnosed as rheumatoid. After failing
treatment with nonsteroidal anti-inflammatories and remittive agents, the author
saw the patient for the first time in l990. Aspiration of fluid from
the right knee was positive by specific antibody ratio for Lyme disease at
the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson
University Hospital Lyme Disease Research Center. The patient was started on ceftriaxone
2 g intravenously daily for 4 weeks. She had a significant objective
response to treatment but quickly relapsed after it was discontinued. A
second 4-week course of ceftriaxone was given with only moderate improvement.
The patient then sought treatment at several university centers, where she
received experimental treatment for rheumatoid arthritis including monoclonal
antibody therapy. There was no improvement in her condition. By July
1992, the patient developed bilateral aseptic necrosis of the hips. A right
total hip replacement was performed and histopathologic examination revealed
several spirochetes on modified Dieterle silver stain of synovial tissue
performed at the Brigham and Women's Hospital. The patient was then
started on continuous oral antibiotic treatment with azithromycin 250
mg daily. Approximately 6 months later, the patient underwent
left total knee replacement and once again spirochete-like structures were
observed in synovial tissue on modified Dieterle silver stain.
These two cases suggest th