Persistence studies USA

[itsybitsyone]

Aberer E; Kersten A; Klade H; Poitschek C; Jurecka W.
1996 Heterogeneity of Borrelia burgdorferi in the skin. American Journal of Dermatopathology, 18(6):571-9
Neuralgias arising 6 months after ECM in spite of antibiotic therapy were evident in a seronegative patient who showed perineural rod-like borrelia structures."


Bayer ME; Zhang L; Bayer MH.
1996 Borrelia burgdorferi DNA in the urine of treated patients with chronic Lyme disease symptoms. A PCR study of 97 cases
Infection, 24 No.5
The urine of 74.2% of patients previously treated with antibiotics for Lyme disease was found to be positive for B. burgdorferi DNA using PCR testing. All patients (n=97) had prior documented EM rash and had received a minimum of 3 weeks to 2 months oral or intravenous antibiotics. In 4 patients, PCR results were temporarily negative after treatment, but became positive again 4-6 weeks later. All patients suffered .continuing, often gradually worsening
Lyme disease-like symptoms. ...it seems to be characteristic for most of the patients in our study that, after antibiotic-free periods of a few months, they had again become increasingly ill with neurological and arthritic symptoms, so that treatment had been resumed.


Valesova H; Mailer J; Havlik J; Hulinska D; Hercogova J.
1996 Long-term results in patients with Lyme arthritis following treatment with ceftriaxone.
Infection, 24(1):98-102
Long term clinical results in 26 patients at 36 months were complete response or marked improvement in 19, relapse in six and new manifestations in four of the cases, respectively..



Nanagara R; Duray PH; Schumacher HR Jr.
1996
Ultrastructural demonstration of spirochetal antigens in synovial fluid and synovial membrane in chronic Lyme disease: possible factors contributing to persistence of
organisms.
Human Pathology, Vol 27(10):1025-34
Electron microscopy [both EM and IEM were used] adds further evidence for persistence of spirochetal antigens in the joint in chronic Lyme disease. Locations of spirochetes or spirochetal antigens both intracellulary and extracellulary in deep synovial connective tissue as reported here suggest sites at which spirochaetes may elude host immune response and antibiotic treatment.. If spirochetes are already sequestered in tissue that is inaccessible to antibiotics such as in the fibrinous and collagen tissue or within fibroblasts, high-dose parenteral antibiotics, or combination therapies with long duration may be needed to kill the living spirochetes..


Weber K.
1996 Treatment failure in erythema migrans: a review.
Infection, 24:73-5.
[From the abstract:] .Patients with erythema migrans can fail to respond to antibiotic therapy. Persistent or recurrent erythema migrans, major sequelae such as meningitis and arthritis, survival of Borrelia burgdorferi and significant and persistent increase of antibody titres against B. burgdorferi after antibiotic therapy are strong indications of a treatment failure. Most, if not all, antibiotics used so far have been associated with a treatment failure in patients with erythema migrans..

[itsybitsyone]

Branigan P; Rao J; Rao J; Gerard H; Hudson A; Williams W; Arayssi T;Pando J; Bayer M; Rothfuss S; Schumacher HR .Clayburne G; Sieck M;
1997 PCR evidence for Borrelia burgdorferi DNA in synovium in absence of positive serology.
American College of Rheumatology, Vol 40(9) Suppl, Sept, p.S270
PCR evidence for Borrelia has been identified in synovial biopsies of patients with clinical pictures that had not initially suggested Lyme disease.
All [6 PCR-positive] patients were negative for antibodies to Borrelia and some were PCR positive in synovium despite previous treatment with antibiotics..
.


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
www.ncbi.nlm.nih.gov/pubmed/1044 ... d_RVDocSum

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.


Heritable susceptibility to severe Borrelia burgdorferi-induced arthritis is dominant and is associated with persistence of large numbers of spirochetes in tissues.
Yang L, Weis JH, Eichwald E, Kolbert CP, Persing DH, Weis JJ.
Department of Pathology, University of Utah School of Medicine, Salt Lake City 84132.
Infect Immun. 1994 Feb;62(2):492-500.

In human Lyme disease, symptoms with widely varying levels of severity have been observed.
A mouse model of Lyme disease has been developed which allows analysis of mice with mild, moderate, and severe pathologies after inoculation with the spirochete Borrelia burgdorferi. To determine whether the differences in symptoms reflect differences in the number of spirochetes persisting in affected tissues, a sensitive PCR technique was developed to detect B. burgdorferi DNA in virtually any tissue of an infected mouse. This analysis, which detects DNA from as few as three spirochetes, revealed the presence of B. burgdorferi DNA in many tissues from severely arthritic C3H/HeJ mice as early as 1 week postinfection.
The heart, ear, and ankle were particularly heavily infected, although B. burgdorferi DNA was also detected in spleen, liver, brain, kidney, bladder, uterus, and lymph nodes.
In contrast, much lower levels of spirochete DNA were detected in tissues of infected BALB/c mice, which develop less severe arthritis when infected with B. burgdorferi than do C3H/HeJ mice. This difference was evident throughout the 5-week analysis. A competitive PCR method allowed determination of the absolute number of spirochete gene sequences in infected tissues. Ankles and hearts from C3H/HeJ mice were found to harbor 10(7) copies of the B. burgdorferi ospA gene, while these tissues from BALB/c mice contained 5- and 10-fold less B. burgdorferi DNA, respectively.
The genetic regulation of severe pathology was analyzed by infecting the offspring of a cross between C3H/HeJ and BALB/c mice. The F1 mice developed severe arthritis and contained high levels of Borrelia DNA in the heart and ankle, similar to the C3H/HeJ parent.
These findings indicate that susceptibility to severe arthritis is a dominant trait and suggest that it may correlate with high levels of persisting spirochetes.
Models of pathology in Lyme disease should take into consideration the fact that severity of pathology may be directly related to the number of organisms in infected tissues.

[itsybitsyone]

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
www.ncbi.nlm.nih.gov/entrez/quer ... t=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.

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
www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract
Abstract:
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.

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

Chronic septic arthritis caused by Borrelia burgdorferi.
Battafarano DF, Combs JA, Enzenauer RJ, Fitzpatrick JE. Clin Orthop 1993 Dec(297): 238-41
www.ncbi.nlm.nih.gov/entrez/quer ... t=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.

[itsybitsyone]

Seronegative chronic relapsing neuroborreliosis [see comments]
Lawrence C, Lipton RB, Lowy FD, Coyle PK. Eur Neurol 1995; 35(2): 113-7
www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract
AUTHOR AFFILIATION: Department of Medicine, Albert Einstein College
of Medicine, New York, N.Y., USA.
SOURCE: Eur Neurol 1995;35(2):113-7
CITATION IDS: PMID: 7796837 UI: 95317331
COMMENT: Comment in: Eur Neurol 1996;36(6):394-5

We report an unusual patient with evidence of Borrelia burgdorferi infection who experienced repeated neurologic relapses despite aggressive antibiotic therapy. Each course of therapy was associated with a Jarisch-Herxheimer-like reaction. Although the patient never had detectable free antibodies to B. burgdorferi in serum or spinal fluid, the CSF was positive on multiple occasions for complexed anti-B. burgdorferi antibodies, B. burgdorferi nucleic acids and free antigen.



Repeated Isolation of Borrelia burgdorferi from the Cerebrospinal Fluid of Two Patients Treated for Lyme Neuroborreliosis.
Cimperman J, Strle F, Maraspin V, Lotric S, Ruzic Sabljic E, Picken RN. 1996 VII Int Conf Lb abs #D657 University of California, Berkeley, p 181.
The clinical diagnosis of neuroborreliosis (NB) remains challenging and the efficacy of antibiotic therapy in its treatment is uncertain. We present the case histories of two patients with NB who had unusual clinical presentations and failed to respond to conventional antibiotic therapy.
Patient #1 was a 20 year old woman who presented with lymphocytic meningitis. No antibodies against Borrelia burgdorferi (BB) were detectable in her serum and cerebrospinal fluid (CSF). Subsequently, 1.5 months later, BB was cultured from the CSF and the patient was treated with ceftriaxone (2g/day for 14 days). The patient was asymptomatic for 3.5 months; thereafter, she developed a right lumboischialgia. Analgesic therapy was unsuccessful. The CSF showed increased proteins (0.98 g/L), but again no antibodies against BB were detectable in serum and CSF. However, BB was once again cultured from the CSF. The patient was treated again with ceftriaxone and subsequently recovered. Currently, the patient is lost for follow-up.
Patient #2 was a 51 year old female who developed erythema migrans (EM) following a tick bite. At that time she received no antibiotic treatment. Two months later she developed multiple neurologic symptoms including headache, vertigo, nausea, left nervus trigeminus paresthesia, memory/ concentration disorders and depression, as well as myalgia, arthralgia, and ocular symptoms. Low titres of IgM antibodies against Bb were detected in the serum; serologic tests for neurotropic viruses and syphilis were negative. Routine CSF tests were normal; no anti-Bb antibodies were detectable. VEP were abnormal, while CT, MRI of the brain and EEG were all normal. Bb was cultured from the CSF 9 months after the initial presentation with EM. The patient was treated with ceftriaxone (2g/day) for 14 days. Two months after treatment, Bb was again isolated from the CSF. Four months after the initial therapy, the symptoms persisted and, in addition, monoarthritis developed. Antibiotic therapy was repeated and included ceftriaxone (2g/day) for 21 days. The patient improved approximately one month after completion of the latter therapy.
The above results demonstrate that: (1) negative serology does not exclude diagnosis of NB, (2) Bb can persist in the CSF following antibiotic treatment, (3) standard ceftriaxone therapy (2g/day for 14 days) may not be sufficient for the treatment of NB
.


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. Infect Immun. 1991 Feb;59(2):671-8
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, indicating 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.

[itsybitsyone]

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
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.



Priem S; Burmester GR; Kamradt T; Wolbart K; Rittig MG; Krause A.
1998
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.
Annals of the Rheumatic Diseases, 57(2):118-21
[Persistence:] .Paired SF [synovial fluid] and SM [synovial membrane] specimens and urine samples from four patients with ongoing or recurring Lyme
arthritis despite previous antibiotic therapy were investigated. RESULTS: In all four cases, PCR with either primer set was negative in SF and urine, but was
positive with at least one primer pair in the SM specimens..
[Diagnosis:] .CONCLUSIONS: These data suggest that in patients with treatment resistant Lyme arthritis negative PCR results in SF after antibiotic therapy
do not rule out the intraarticular persistence of B burgdorferi DNA. Therefore, in these patients both SF and SM should be analysed for borrelial DNA by
PCR as positive results in SM are strongly suggestive of ongoing infection..

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.

[itsybitsyone]

Preac-Mursic V; Pfister HW; Spiegel H; Burk R; Wilske B;
Reinhardt S; Bohmer R.
1993 First isolation of Borrelia burgdorferi from an iris biopsy.
Journal of Clinical Neuroophthalmology,
Sep;13(3):155-61; discussion 162
.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..


Reik L Jr. 1993 Stroke due to Lyme disease. Neurology, 43(12):2705-7
[From the abstract:] "A 56-year-old Connecticut woman suffered multiple strokes 18 months after antibiotic treatment for early Lyme disease with facial palsy.
Pleocytosis, intrathecal synthesis of anti-Borrelia burgdorferi antibody, and the response to antibiotic treatment substantiated the diagnosis of neuroborreliosis


Dinerman H; Steere AC.
1992 Lyme disease associated with fibromyalgia.
Annals of Internal Medicine, 117:281-5
15 patients with Lyme disease and symptoms of fibromyalgia were followed in a long-term study. .None of the patients had had fibromyalgia before the onset
of Lyme disease.. All patients received antibiotic therapy, in most cases 2 g/d intravenous ceftriaxone for 2 to 4 weeks.
[Persistence:] .Case Report: [After 2 weeks ceftriaxone] The knee swelling gradually resolved over the next 3 months, but he [the patient] began to have
symptoms of fibromyalgia including marked fatigue and more diffuse pain and stiffness in the wrists, elbows, shoulders, and knees. Because his symptoms
persisted, he was given a second 2-week course of ceftriaxone 1 year later. Although his symptoms improved somewhat with treatment, his fatigue and joint
pain worsened again within several months, and he also experienced intermittent headache, memory difficulties, and irritability... Because of the slight spinal
fluid pleocytosis and because he had already received two courses of ceftriaxone, he was treated with imipenim, 250 mg, every 8 hours for 30 days. His
symptoms again improved for several months, but then worsened. During the subsequent year, in addition to his previous symptoms, he developed radicular
pain along the chest wall, numbness and sensitivity on the right side of the face, and numbness in the left hand and foot..
[Diagnosis:] .None of the patients had an elevated erythrocyte sedimentation rate..
[Seronegativity:] .The small percentage of patients who are seronegative by enzyme-linked immunosorbent assay (ELISA) later in the illness usually have
positive Western blots or cellular immune responses to borrelial antigens (9,10)..





Agger W; Case KL; Bryant GL; Callister SM.
1991 Lyme disease: clinical features, classification, and epidemiology in the upper midwest.
Medicine (Baltimore) Mar;70(2):83-90
.Despite longer and more frequent parenteral therapy, late Lyme disease frequently required retreatment, owing to poor clinical response (p less than .05)..



MacDonald AB; Berger BW; Schwan TG.
1990
Clinical implications of delayed growth of the Lyme borreliosis spirochete, Borrelia burgdorferi.
Acta Trop, Dec;48(2):89-94
.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 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..


Logigian EL; Kaplan RF; Steere AC.
1990 Chronic neurologic manifestations of Lyme disease. New England Journal of Medicine,
Nov 22; 323(21):1438-44
[From the abstract:] .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..
[From the article:] .Discussion.....These chronic neurologic abnormalities began months to years after the onset of infection, sometimes after long periods of
latency, as in neurosyphilis....The typical response of our patients to antibiotic therapy supports the role of spirochetal infection in the pathogenesis of each
of the syndromes described here......The likely reason for relapse is failure to eradicate the spirochete.......This is reminiscent of far advanced
neurosyphilis....... This last article is one of many studies that show continuing symptoms are most likely due to persistence of the spirochete..

Schoen RT.
1989 Treatment of Lyme disease. Connecticut Medicine, Vol 53(6):335-337
[Treatment/Relapse:] .As in other spirochetal infections, antibiotic therapy is most effective early in the illness. ... TREATMENT PROBLEMS...Late Disease:
Not all patients with neurologic manifestations or with arthritis respond to oral or intravenous antibiotic therapy (19), and in many of these individuals,
retreatment may be necessary. Retreatment is also appropriate in individuals who relapse, for example, with recurrent arthritis. ...Late in the illness, cases
refractory to antibiotic therapy may be encountered..

[itsybitsyone]

Steere AC; Duray PH; Butcher EC.
1988
Spirochetal antigens and lymphoid cell surface markers in Lyme synovium and tonsillar lymphoid tissue.
Arthritis & Rheumatism, 31:487-495
[Persistence:] .Synovial tissue was obtained from 12 patients with Lyme disease who underwent arthroscopic synovectomy between 1984 and 1986. ...All
patients had received antibiotic therapy and nonsteroidal antiinflammatory drugs (NSAIDs) prior to arthroscopic synovectomy. (p.488) ....Using monoclonal
antibodies to the 31- or 41-kd polypeptides of B burgdorferi, a few spirochetes and globular antigen deposits were seen in and around normal or injured
blood vessels in areas of lymphocytic infiltration, in 6 of the 12 patients (Figure 4).. (p.492)
.Similarly [as in tertiary syphilis or tuberculoid leprosy], the antigenic stimulus in Lyme arthritis would appear to be a small number of live spirochetes,
demonstrated here by monoclonal antibodies, which may persist in the synovial lesion for years..



Dattwyler RJ; Volkman DJ; Luft BJ; Halperin JJ; Thomas J; Golightly MG.
1988 Seronegative Lyme disease. Dissociation of specific T- and B-lymphocyte responses to Borrelia burgdorferi.
New England Journal of Medicine, 319(22):1441-6
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.



Schmidli J; Hunziker T; Moesli P; et al.
1988 Cultivation of Borrelia burgdorferi from joint fluid three months after treatment of facial palsy due to Lyme borreliosis.
Journal of Infectious Diseases, 158:905-906
.Despite clinical resolution of paralysis, subsequent arthritic complication occurred. To our knowledge, this is the first report of the successful isolation of
B. burgdorferi from synovial fluid and the subsequent propagation through serial passage. This positive culture strongly suggests that the spirochetes were
not eradicated by the initial antimicrobial regimens [12 days amoxicillin-clavulanate followed by two weeks of doxycycline, 200 mg/d]. ...Other possible
explanations of treatment failure, such as insufficient patient compliance or reinfection by B. burgdorferi, were excluded by close medical and parental
supervision.. The patient was subsequently treated with 14 days intravenous ceftriaxone. Her arthritic symptoms resolved, and she remained symptom-free
during an 11-month follow-up period.



Dattwyler RJ; Halperin JJ.
1987 Failure of tetracycline therapy in early Lyme disease. Arthritis & Rheumatism, 30:448-450
"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 migrans with a course of tetracycline that met or exceeded current recommendations.



Berger BW.
1986 Treating erythema chronicum migrans of Lyme disease. Journal of Am Acad Dermatology, Sep;15(3):459-63
.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..



Steere AC; Malawista SE; Hardin JA; Ruddy S; Askenase PW; Andiman WA
1977 Erythema chronicum migrans and Lyme arthritis. The enlarging clinical spectrum. Annals of Internal Medicine, 86:685-698
"We remain skeptical that antibiotic therapy helps... Eight of our patients received penicillin, erythromycin, or cephalexin before entering the study because of the
skin lesion. In one of them, the lesion persisted for 2 months despite therapy, longer than in any of the other study patients, and seven of the eight patients still
. developed joint, neurologic, or cardiac abnormalities..
“Particularly puzzling has been the observation that organisms are extremely
difficult to find in infected tissue, using either microbiologic or morphologic
techniques. However, in many instances continued infection appears to be
essential for symptoms to persist, no matter how small the number of
organisms, as antimicrobial therapy is generally followed by clinical
improvement.”

[itsybitsyone]

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



Lyme Disease and the clinical Spectrum of Antibiotics responsive Chronic Meningoencephalomyelitides
Liegner KB, Duray P, Agricola M, Rosenkilde C, Yannuzzi LA, Ziska M, Tilton RC, Hulinska D, Hubbard J, Fallon BA.
J Spiro Tick Diseases 1997; 4:61-73
Intensive study of four patients with chronic meningoencephalomyelitis believed due to Lyme disease revealed seronegativity and/or variable seroreactivity and chronic persistent infection as common threads. Evaluation of these complex cases required determined study over time using all known methods (i.e., culture isolation, histologic, immunohistochemical, electron micrographic, direct antigen detection as well as standard serologic methods) on tissues as well as serial study of blood, cerebrospinal fluid (CSF) and urine.
Prolonged intravenous antibiotic therapy conferred clinical benefit in each case and withholding of treatment resulted in clinical deterioration.
These 4 cases demonstrate:
1. Long term seronegativity for borrelia despite longterm symptomatology consistent with borreliosis
2. Repeatedly antibiotic responsive while relapses occurred when treatment was paused or decreased
3. Difficulty in discriminating chronic active Lyme borreliosis from MS (case 4) and lupus (case 1).
4. Severe worsening whenever steroid treatment is used in chronic active Lyme borreliosis.
5. Severe debilitating illness from borreliosis and death following vascular hemorrhage
Case #1
A 39-year-old woman with a two-year history of progressing spastic quadraparesis, cranial nerve palsies, and persistent unexplained CSF pleocytosis was evaluated beginning in 1989. She had been diagnosed with idiopathic thrombocytopenic purpura (ITP) in 1975 and underwent splenectomy in 1976. She had lived in northern Westchester county, New York and northern California but gave no history of tick attachments or of erythema migrans. No diagnosis was established after a year of observation and testing, and serologic studies for Lyme disease in serum and CSF were repeatedly negative. CSF examination in 1990 showed lymphocytic pleocytosis, elevated IgG, and absence of oligoclonal bands or myelin basic protein. Anticardiolipin and antinuclear antibodies were present and Raji cell assay and C1Q immune complexes were elevated. HIV and HTLV-1 antibodies were negative.
An empiric trial of intravenous antibiotic treatment with cefotaxime (CFOTX) for 21 days in April 1990 resulted in no clinical improvement and no change in CSF pleocytosis. Thereafter she was treated with 4 months of minocycline with no clinical benefit. The patient remained wheelchair-bound.
B. burgdorferi grew from CSF in December 1991 at which time the patient first became seropositive despite at least 4 years of clinical illness. She was treated with CFOTX (4 g IV Q 8 hrs once weekly) with complete resolution of pleocytosis after 13 weeks and constitutional symptoms improved. Despite continuation of once weekly IV therapy for 10 months, there was gradual neurologic deterioration. Intravenous antibiotics were discontinued December 1992.
Methylprednisolone sodium succinate was given intravenously, 1 g daily for 5 days, followed by prednisone over a six-week period for the possibility of systemic lupus erythematosus. Pleural effusions developed within one week of starting steroids along with severe encephalopathy and debilitation. She could not remember conversations held minutes earlier and was unable to hold a cup, roll over in bed, or transfer from bed to wheelchair. Computed axial tomography of the chest revealed pleuropericardial effusions (Fig 1). A pleuropericardial window was created for diagnostic and therapeutic purposes. Fibrinous pericarditis was present with infiltration of plasma cells and macrophages and spirochete-compatible structures were seen with modified Steiner silver and phycoerythrin stains, as well as a touch preparation (Figs 2-5). Intravenous CFOTX 6 g daily was administered for the next 3fi months with dramatic improvement of her encephalopathy. The pleuropericardial effusions improved (Fig 6). The patient was able to walk 500 feet with a rolling walker and was able to go home. A further 3 months of daily CFOTX was administered but the patient's health insurer refused authorization for any subsequent intravenous antibiotic therapy. The patient became increasingly encephalopathic over the next 6 months. Daily intravenous CFOTX was reinstituted in June 1994 and mental status improved as confirmed by serial neuropsychological testing before and after 4 months of treatment. Several specimens of plasma and urine between February and July of 1995 were found to be PCR positive for B. burdorferi-specific DNA. From July 1995 through April 1996 the patient was treated with intramuscular benzathine penicillin. On this treatment she felt poorly, encephalopathy worsened, and she lost the ability to ambulate. Plasma PCR for B. burdorferi-specific DNA was again positive February 1996. CSF analysis March 1996 showed 14 lymphocytes/mm3, elevated protein (57 mg %) and slight elevation of IgG. Oligoclonal bands were present in both CSF and serum. Myelin basic protein was absent. CSF Lyme PCR and OspA antigen were negative as were Lyme-specific immune complexes in serum and CSF. Authorization for additional intravenous antibiotic therapy was refused by the insurer. Encephalopathy and debilitation worsened (Table I).
Case #2
In the fall of 1985 a 61-year-old outdoorsman residing in the Catskill region of New York State developed a large round rash on one thigh. A physician was consulted but no treatment was given. The following winter unrelenting headache, low grade fever, paresthesias and truncal instability developed. Lumbar puncture demonstrated lymphocytic pleocytosis. Lyme ELISA was negative. Dysphasia and a progressive stroke syndrome developed. A diagnosis of "vasculitis" was given and the patient was treated with steroids and cyclophosphamide for a number of months with progressive deterioration to a level of functioning slightly above a persistent vegetative state. Lyme ELISA was positive in 1988. Treatment with intramuscular ceftriaxone (CFTRX) for 14 days resulted in slight improvement. In 1992, computed axial tomography of the brain showed massive hydrocephalus (Fig 7). Electroencephalogram revealed status epilepticus and phenobarbital was prescribed. Lyme serology was negative in one laboratory, yet positive in another. Western blot was nondiagnostic, showing only a 41 kiloDalton band. CSF examination revealed the presence of oligoclonal bands without myelin basic protein and very elevated CSF IgG. Serum showed elevated C1Q immune complexes. OspA antigen capture assay in CSF was strongly positive. The patient was given daily intravenous CFTRX for one month, then weekly CFOTX (4 g IV Q 8 hr x 3 doses) for one year, with modest improvement in his neurologic status. The patient succumbed to his disease July 1993. Autopsy revealed severe hydrocephalus (Figs 8,9) and florid meningoencephalomyelitis and ependymitis (Figs 10-13). The CSF was positive for OspA antigen and Lyme-specific immune complexes. Spirochetes were not visualized on histopathologic and immunohistochemical study by light microscopy but borrelia-compatible structures were visualized in formalin-fixed tissues studied by electron microscopy (Figs 14-16) and brain tissue and dura mater were PCR positive for detection of B. burgdorferi-specific oligonucleotides (Figs 17A,B)[7] (Table II).
About case 3 & 4 from discussion (for full story see above link):
Case 3 had a clear clinical history indicating Lyme disease. Despite intensive study laboratory corroboration for the diagnosis could not be obtained for some 13 years. A prior six-week course of intravenous CFTRX did not prevent the development of meningoencephalomyelitis. An eight-month course of intravenous CFOTX was required to resolve disturbed CSF parameters. Lyme-specific immune complexes were demonstrable in the final three of five cerebrospinal fluid examinations and key Lyme disease-compatible bands finally developed on Western blot in serum thereafter. She has been seronegative by ELISA throughout, calling into serious question the validity of using this assay alone as a screening test.
Case 4 demonstrates how closely neuroborreliosis can mimic multiple sclerosis. Given now that seronegativity occurs in Lyme disease, distinguishing the two disorders may be a daunting task. The patient showed resolution of markers thought to be pathognomonic for multiple sclerosis in CSF along with clinical improvement following intensive intravenous antibiotic treatment. Relapse of abnormal CSF findings and of neurologic signs occurred with suspension of intensive treatment. Resolution again followed a second course of intravenous therapy. This case suggests that neuroborreliosis may be misdiagnosed as multiple sclerosis.

[LymeEnigma]

(Neurology 2007, doi:10.1212/01.WNL.0000284604.61160.2d)
Received February 12, 2006
Accepted June 26, 2007

A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy

B. A. Fallon MD, J. G. Keilp PhD, K. M. Corbera MD, E. Petkova PhD, C. B. Britton MD, E. Dwyer MD, I. Slavov PhD, J. Cheng MD, PhD, J. Dobkin MD, D. R. Nelson PhD, and H. A Sackeim PhD

From the Department of Psychiatry (B.A.F., J.G.K., K.M.C., E.P., I.S., J.C., H.A.S.), Department of Biostatistics (E.P.), Department of Neurology (C.B.B.), Department of Medicine (E.D., J.D.), and New York State Psychiatric Institute (B.A.F., J.G.K., K.M.C., E.P., I.S., J.C., H.A.S.), Columbia University, New York; and Department of Cell and Molecular Biology, University of Rhode Island, Kingston (D.R.N.).

Background: Optimal treatment remains uncertain for patients with cognitive impairment that persists or returns after standard IV antibiotic therapy for Lyme disease.

Methods: Patients had well-documented Lyme disease, with at least 3 weeks of prior IV antibiotics, current positive IgG Western blot, and objective memory impairment. Healthy individuals served as controls for practice effects. Patients were randomly assigned to 10 weeks of double-masked treatment with IV ceftriaxone or IV placebo and then no antibiotic therapy. The primary outcome was neurocognitive performance at week 12—specifically, memory. Durability of benefit was evaluated at week 24. Group differences were estimated according to longitudinal mixed-effects models.

Results: After screening 3368 patients and 305 volunteers, 37 patients and 20 healthy individuals enrolled. Enrolled patients had mild to moderate cognitive impairment and marked levels of fatigue, pain, and impaired physical functioning. Across six cognitive domains, a significant treatment-by-time interaction favored the antibiotic-treated group at week 12. The improvement was generalized (not specific to domain) and moderate in magnitude, but it was not sustained to week 24. On secondary outcome, patients with more severe fatigue, pain, and impaired physical functioning who received antibiotics were improved at week 12, and this was sustained to week 24 for pain and physical functioning. Adverse events from either the study medication or the PICC line were noted among 6 of 23 (26.1%) patients given IV ceftriaxone and among 1 of 14 (7.1%) patients given IV placebo; these resolved without permanent injury.

Conclusion: IV ceftriaxone therapy results in short-term cognitive improvement for patients with posttreatment Lyme encephalopathy, but relapse in cognition occurs after the antibiotic is discontinued. Treatment strategies that result in sustained cognitive improvement are needed.