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Oral doxycycline versus intravenous ceftriaxone for European Lyme neuroborreliosis: a multicentre, non-inferiority, double-blind, randomised trial
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Oral doxycycline versus intravenous ceftriaxone for European Lyme neuroborreliosis: a multicentre, non-inferiority, double-blind, randomised trial Unn Ljøstad, Eirik Skogvoll, Randi Eikeland, Rune Midgard, Tone Skarpaas, Åse Berg, Åse Mygland
Summary Lancet Neurol 2008; 7: 690–95 Published Online June 21, 2008 DOI:10.1016/S14744422(08)70119-4 See Reflection and Reaction page 665 Department of Neurology, Sørlandet Hospital HF, Kristiansand, Norway (U Ljøstad MD, Å Mygland PhD); Unit for Applied Clinical Research, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway (E Skogvoll PhD); Department of Neurology, Sørlandet Hospital HF, Arendal, Norway (R Eikeland MD); Department of Neurology, Molde Hospital, Molde, Norway (R Midgard PhD); Microbiology Unit, Division of Laboratory Medicine, Sørlandet Hospital HF, Kristiansand, Norway (T Skarpaas MD); Department of Medicine, the University Hospital of Stavanger, Stavanger, Norway (Å Berg MD); Institute of Clinical Medicine, University of Bergen, Bergen, Norway (Å Mygland); and Hospital of Rehabilitation, Rikshospitalet University Hospital, Kristiansand, Norway (Å Mygland) Correspondence to: Unn Ljøstad, Department of Neurology, Sørlandet Hospital HF, Kristiansand, Serviceboks 416, N-4604 Kristiansand, Norway [email protected]
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Background Use of intravenous penicillin and ceftriaxone to treat Lyme neuroborreliosis is well documented, although oral doxycycline could be a cost-effective alternative. We aimed to compare the efficacy of oral doxycycline with intravenous ceftriaxone for the treatment of Lyme neuroborreliosis. Methods From April, 2004, to October, 2007, we recruited consecutive adult patients from nine hospitals in southern Norway into a non-inferiority trial. Inclusion criteria were neurological symptoms suggestive of Lyme neuroborreliosis without other obvious causes, and presence of any of the following: a CSF white-cell count of more than five per mL; intrathecal production of specific Borrelia burgdorferi antibodies; or acrodermatitis chronicum atrophicans. Patients were randomly allocated to receive 200 mg oral doxycycline or 2 g intravenous ceftriaxone once per day for 14 days, in a double-blind, double-dummy design. A composite clinical score (range 0 to 64, 0=best) was based on standardised interviews and clinical neurological examination. The primary outcome was reduction in clinical score at 4 months after the start of treatment. Analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT00138801. Findings Of 118 patients who underwent randomisation, 102 completed the study (mean clinical score at baseline 8·5 [SD 4·1]). 4 months after the start of treatment, mean score improvement in the doxycycline group (n=54) was 4·5 (95% CI 3·6 to 5·5) points and that in the ceftriaxone group (n=48) was 4·4 (3·4 to 5·4) points (95% CI for difference between groups –0·9 to 1·1; p=0·84). 26 (48%) patients in the doxycycline group and 16 (33%) in the ceftriaxone group had total recovery (95% CI for difference between groups –4% to 34%; p=0·13). Side-effects possibly related to treatment were reported in 21 (37%) and 26 (46%) patients in these groups, respectively (–28% to 9%; p=0·30). Three patients discontinued ceftriaxone treatment owing to adverse events. Interpretation Oral doxycycline is as efficient as intravenous ceftriaxone for the treatment of European adults with Lyme neuroborreliosis. Funding Sørlandet Kompetansefond.
Introduction Lyme borreliosis is a multisystem infectious disease, caused by the tick-borne spirochete Borrelia burgdorferi (Bb) sensu lato. The Bb sensu lato complex consists of several genotypes of which at least three—Bb sensu stricto, B garinii, and B afzelii—are pathogenic in human beings. These species differ with respect to organotropism, clinical phenotype, and geographical distribution, but all three can cause neuroborreliosis. The dominating species in Europe are B garinii and B afzelii, and the most common manifestations of European Lyme neuroborreliosis are painful radiculopathy and cranial neuropathy (especially of the facial nerve) with pleocytosis in the CSF. Other manifestations are myelopathy, encephalopathy, and peripheral neuropathies, but these are rare. Antibiotic treatment is strongly recommended in Lyme neuroborreliosis. Most guidelines suggest 14-day courses of intravenous regimens with penicillin or ceftriaxone, which seem to have similar clinical efficacy.1 Oral antibiotics have several advantages, such as fewer
complications, greater ease of use, and much less expense.2 Doxycycline has shown excellent results in vitro against Bb, good CNS penetration, and good clinical efficacy in some small and unmasked studies.3–10 The aim of this study was to investigate whether oral doxycycline was as efficient as intravenous ceftriaxone for the treatment of European Lyme neuroborreliosis in adults.
Methods Patients Consecutive patients with neurological symptoms suggestive of Lyme neuroborreliosis (new neurological symptoms or findings without other obvious causes, or both) were eligible if one or more of the following additional criteria were met: CSF white-cell count of more than five per mL (healthy erythrocyte count), intrathecal production of Bb antibodies, or verified acrodermatitis chronicum atrophicans. Patients were excluded if they met any of the following criteria: allergy to any of the intervention medications or previous type I reaction to penicillin; treatment with cephalosporin, www.thelancet.com/neurology Vol 7 August 2008
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penicillin, or tetracycline in the past 14 days; age younger than 18 years; or pregnancy or breastfeeding. Patients were recruited from nine hospitals in coastal areas of southern Norway where Lyme neuroborreliosis is endemic. All care providers were familiar with diagnosis and treatment of Lyme neuroborreliosis. Some diagnostic inaccuracy was inevitable at randomisation because of the absence of a diagnostic gold standard in Lyme neuroborreliosis,11,12 low diagnostic sensitivity of intrathecal Bb antibody production in the early phase of the disease,13 and the need to start treatment before antibody results were available. The inclusion criteria were therefore deliberately broad, and patients were subsequently classified as having definite, possible, or no Lyme neuroborreliosis throughout the course of the disease according to strict criteria (panel 1). We tested patients who did not have intrathecal Bb antibody production for tick-borne encephalitis virus by use of serum antibodies, and for varicella zoster virus, herpes simplex virus, and enterovirus by PCR of CSF. All patients gave written informed consent, and the study was approved by the Regional Committee for Medical Research Ethics in southern Norway and the Norwegian Data Inspectorate.
Procedures Patients were randomly allocated to receive 14 days’ treatment with 200 mg oral doxycycline per day or 2 g intravenous ceftriaxone per day. Our hypothesis was that oral doxycycline was not inferior to intravenous ceftriaxone with respect to clinical efficacy in the treatment of European Lyme neuroborreliosis. As an outcome measure, a composite clinical score based on standard neurological interview and clinical examination (range 0 to 64, 0=best; panel 2) was recorded by experienced clinicians at inclusion, and at 13 days and at 4 months after the start of treatment. A lumbar puncture was undertaken, and the CSF cell count was measured at the same timepoints. The primary endpoint was clinical improvement at 4 months after the start of treatment, defined as clinical score at inclusion minus clinical score at 4 months. Secondary endpoints were the number of patients with full recovery (ie, 0 in clinical outcome score) at 4 months after the start of treatment, reduction in CSF cell count at 4 months, and clinical improvement and reduction in CSF cell count at day 13 of treatment. Computerised allocation to intravenous ceftriaxone or oral doxycycline was done in advance at the clinical trials office in blocks of four patients, stratified according to early disease (duration of symptoms <6 months) and late disease (duration of symptoms >6 months). Lists were distributed to the pharmacies included in the study, and patients were allocated according to these lists following a telephone call to the trial management office. The investigators who generated the randomisation sequence did not take any further part in the study, and no clinicians were aware of the assignment sequence at any time. www.thelancet.com/neurology Vol 7 August 2008
Panel 1: Case definitions Definite neuroborreliosis (all three criteria fulfilled) 1 Neurological symptoms suggestive of Lyme neuroborreliosis without other obvious reasons 2 CSF pleocytosis (>5 leucocytes per mL) 3 Intrathecal Bb antibody production Possible neuroborreliosis (criterion 1 and one of 2–5 fulfilled) 1 Neurological symptoms suggestive of Lyme neuroborreliosis without other obvious reasons 2 CSF pleocytosis (>5 leucocytes per mL) 3 Intrathecal Bb antibody production 4 Bb antibodies in serum 5 Erythema migrans during past 4 months
Panel 2: Clinical score Subjective complaints (maximum score=12) Malaise Fatigue Pain Memory problems Concentration difficulties Paraesthesia Objective findings (maximum score=52) Facial palsy* Reduced hearing* Vision loss* Reduced sensibility in face* Paresis of eye muscles* Other cranial neuropathies Tremor Ataxia Nuchal rigidity Confusion Other CNS findings Truncus radiculopathy* Arm radiculopathy* Leg radiculopathy* Arm paresis* Leg paresis* Clinical outcome score is the sum of subjective and objective findings. Each item is scored 0=none, 1=mild, 2=severe (maximum total score=64). *Left and right sides scored separately.
Patients, nurses administering the interventions, and doctors assessing the clinical scores were all unaware of group assignment. Blinding was achieved via doubledummy design—ie, all patients received 14 days of intravenous infusion (ceftriaxone or placebo) and oral treatment (doxycycline or placebo). Because the ceftriaxone fluid was yellow, bags used for intravenous treatment were wrapped at the pharmacy by people not participating in the treatment or follow-up of patients, 691
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and lines were wrapped by the nurses before the medication was administered. Although no systematic assessment was done, the blinding was deemed successful for the doctors because they did not take part in practical administration of the drugs, and successful for the patients because wrapping was complete and none of them reported identification of their treatment. Nurses were instructed not to inform others if they unintentionally saw the yellow colour of ceftriaxone. The allocation scheme was not revealed until all patients were examined at 4 months after the start of treatment, apart from for one patient whose intravenous ceftriaxone treatment was extended by 1 week because of an increased CSF cell count at day 13 of treatment. We examined CSF samples for Bb intrathecal antibody production with the IDEIA Lyme neuroborreliosis kit (DakoCytomation, Cambridgeshire, UK), using purified native flagella from the B afzelii DK1 strain as antigens. In this assay, corrections for impairment of the blood– brain barrier are unnecessary,14 and intrathecal production of antibodies is detected when, according to the manufacturer’s recommendation, the antibody index of ODCSF/ODserum multiplied by (ODCSF−ODserum) is 0·3 or more (where OD is optical density).
136 patients assessed for eligibility
18 not included 9 did not meet inclusion criteria 8 refused to participate 1 forgot enrolment
Statistical analysis Blinded analysis of results from the first 16 patients suggested a mean clinical score reduction of 6 (SD 3). The participating clinicians agreed that detection of a mean group difference larger than 1·5 units in favour of ceftriaxone would be desirable, corresponding to a standardised difference (SD/mean) of 1·5/3=0·5. With a one-sided test and significance level of 0·05, 50 patients in each group would be needed to reject a null hypothesis of inferiority with 80% power.15 To compensate for dropouts and potentially non-assessable patients, we aimed to enrol 120 patients. For comparison of unpaired categorical data, we used Pearson’s χ² test. For continuous outcome variables, we used a linear model with treatment group and clinical presentation as factors, and baseline clinical score as a covariate. The non-parametric Mann-Whitney U test was used when the outcome variable was clearly not normal. For the main outcome, we report p values for the traditional tests of superiority in which p>0·05 indicates no difference, and for the reverse test in which
Oral doxycycline (n=54) Mean age (years)
54 (13)
Sex (female)
26 (48%)
17 (35%)
Coexisting diseases
22 (41%)
14 (29%)
Tick bite
30 (56%)
26 (54%)
Erythema migrans
17 (31%)
5 (10%)
Definite
37 (69%)
34 (71%)
Possible
17 (31%)
14 (29%)
Symptom duration >6 months Mean duration of symptoms (weeks) Mean CSF cell count (n)
59 assigned to intravenous ceftriaxone
59 assigned to oral doxycycline
692
4 (8%)
10 (19)
8 (13)
194 (237)
178 (187)
Mean CSF protein (g/L)
1·2 (0·7)
1·3 (0·8)
Mean clinical score
8·2 (4·1)
8·9 (4·1)
Mean subjective score
4·3 (2·3)
5·1 (2·3)
Bannwarth’s syndrome*
18 (33%)
12 (25%)
Facial palsy
12 (22%)
9 (19%)
Other cranial neuropathies
2 (4%)
3 (6%)
13 (24%)
18 (38%)
Ataxia
2 (4%)
0 (0%)
Myelopathy
1 (2%)
0 (0%)
Cognitive deficiency
0 (0%)
1 (2%)
Arm paresis
1 (2%)
1 (2%)
Radiculopathy
55 received 14 days of intravenous ceftriaxone
Figure 1: Trial profile
6 (11%)
Main objective findings
1 did not receive allocated treatment owing to late delivery from pharmacy 3 discontinued owing to adverse events
48 analysed
52 (13)
Neuroborreliosis diagnosis
118 randomised
1 lost to follow-up (refused) 6 excluded owing to new diagnosis
Intravenous ceftriaxone (n=48)
59 received 14 days of oral doxycycline
2 lost to follow-up (both refused) 3 excluded owing to new diagnosis
54 analysed
ACA and paraesthesias
1 (2%)
0 (0%)
Only subjective complaints
4 (7%)
4 (8%)
Data are mean (SD) or number of patients (%), unless otherwise stated. ACA=acrodermatitis chronicum atrophicans. *Includes lymphocytic CSF pleocytosis, cranial neuropathy, and radiculopathy.
Table 1: Baseline demographic, clinical, and laboratory characteristics of patients
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Oral doxycycline (n=54) Mean reduction in clinical score at 4 months (points) Mean reduction in clinical score at 13 days (points) Patients with clinical score 0, 4 months after start of treatment
4·5 (3·6 to 5·5)
Intravenous ceftriaxone (n=48) 4·4 (3·4 to 5·4)
3·0 (2·0 to 4·0)
3·6 (2·6 to 4·7)
26 (48%)
16 (33%)
95% CI*
p*
(–0·9 to 1·1)
0·84
(–1·7 to 0·4)
0·21
(–4% to 34%) 0·13
Data are mean reductions (95% CI) or n (%) unless otherwise stated. Times are from the start of treatment. *95% CI and p values for the effect of doxycycline compared with ceftriaxone (ie, in favour of doxycycline).
Table 2: Clinical outcome according to intervention
significance (p<0·05) confirms non-inferiority.16 All analyses was done with the statistical software SPSS, version 15.0. Analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT00138801.
25
Before treatment Day 13 Month 4
20
Role of the funding source 15 Clinical score
The sponsor of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
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Results From April, 2004, to October, 2007, we recruited 118 patients (figure 1). One patient did not receive allocated medication because of late delivery from the pharmacy, two discontinued medication because of adverse events and were also lost to follow-up, and three changed their mind and refused to be followed up. Furthermore, ten patients were excluded because of new diagnoses: tick-borne encephalitis virus (n=4), myasthenia gravis (n=1), chronic inflammatory demyelinating polyneuropathy (n=1), coronary disease (n=1), cervical radiculopathy (n=1; also discontinued medication because of an adverse event), multiple sclerosis (n=1), and spontaneous intracranial hypotension (n=1). Therefore, 102 patients were included in the final analysis; table 1 shows their baseline characteristics. Lumbar puncture was done in all 102 patients at inclusion, in 100 at day 13 of treatment, and in 88 at 4 months after the start of treatment. After adjustment for clinical presentation and baseline scores, mean improvement in the clinical outcome scale after 4 months (mean 19 [SD 2·4] weeks) was 4·5 (95% CI 3·6 to 5·5) points for oral doxycycline and 4·4 (3·4 to 5·4) points for intravenous ceftriaxone. Treatment groups were thus similar (p=0·84 for superiority or p=0·006 with respect to the null hypothesis of inferiority), and the upper limit of the one-sided 95% CI for difference between groups (−∞ to 0·75) was well within the prespecified limit of 1·5 score units. Analyses of all 109 patients who completed the 4-month follow-up showed a similar mean improvement between the doxycycline and ceftriaxone groups (4·5 [3·6 to 5·4] vs 4·3 [3·3 to 5·3] points, 95% CI for difference –0·8 to 1·2 points; p=0·69). The groups were also similar with respect to secondary clinical endpoints www.thelancet.com/neurology Vol 7 August 2008
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0 Oral doxycycline
Intravenous ceftriaxone
Figure 2: Clinical scores at various stages of treatment Boxes indicate IQR, horizontal bars within boxes indicate medians, horizontal lines outside boxes indicate maximum and minimum values that are not outliers, and white circles indicate outliers (values between 1·5 and 3 box-lengths from the 75th percentile or 25th percentile).
(table 2) and reduction in CSF cell count at 13 days (p=0·89) and at 4 months (p=0·56) after the start of treatment. Figures 2 and 3 show clinical scores and CSF cell counts at different stages. At 4 months after the start of treatment, patients with early Lyme neuroborreliosis (n=92) improved more than did those with late disease (n=10; 6·7 [95% CI 6·1 to 7·2] vs 2·3 [0·7 to 3·9] score points; p<0·0001), but no difference was seen with respect to treatment regimens (p=0·70). The ten patients with late Lyme neuroborreliosis presented with the following: radiculopathy (n=2); Bannwarth’s syndrome (n=1); cranial nerve palsy (n=2); cognitive difficulties (n=1); paresis and unsteadiness (n=1); acrodermatitis chronicum atrophicans and paraesthesias (n=1); and pain, malaise, and paraesthesias (n=2). Patients with definite and possible Lyme neuroborreliosis improved equally well (4·6 [3·5 to 5·6] vs 4·4 [3·3 to 5·4] points; p=0·78). Clinical improvement at 4 months after the start of treatment did not differ between the oral doxycycline and intravenous ceftriaxone regimens when definite and possible Lyme 693
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Before treatment Day 13 Month 4
1200
1000
Clinical score
800
600
400
Discussion
200
0 Oral doxycycline
Intravenous ceftriaxone
Figure 3: CSF cell count at various stages of treatment Boxes indicate IQR, horizontal bars within boxes indicate medians, horizontal lines outside boxes indicate maximum and minimum values that are not outliers, white circles indicate outliers (values between 1·5 and 3 box-lengths from the 75th percentile or 25th percentile), and asterisks indicate extreme values (values more than 3 box-lengths from the 75th percentile or 25th percentile).
neuroborreliosis were considered separately (definite, 4·6 [3·0 to 6·2] vs 4·9 [3·3 to 6·5] points, p=0·66; possible, 3·8 [2·3 to 5·2] vs 2·7 [0·9 to 4·4], p=0·29). We registered no real treatment failures. Treatment allocation was revealed and treatment extended for 1 week in one patient allocated to intravenous ceftriaxone because the CSF cell count had increased at day 13; however, this patient had showed clinical improvement. Two patients had a higher outcome score at 4 months after start of treatment (both in the doxycycline group), one probably because of fibromyalgia and the other because of newly diagnosed metastasising prostate cancer. Five patients (three given intravenous ceftriaxone, two given oral doxycycline) had an unchanged outcome score at 4 months after the start of treatment. All five had achieved healthy CSF cell counts and had mainly subjective complaints, which were not regarded as treatment failures. 60 (59%) patients reported residual symptoms at 4 months (28 [52%] given oral doxycycline, 32 [67%] given intravenous ceftriaxone; p=0·13), of whom 29 had only subjective complaints. Remaining objective findings were all mild: facial palsy or other cranial neuropathy (n=11), radiculopathy (n=10), cranial neuropathy and radiculopathy (n=6), paresis (n=2), possible encephalopathy (n=1), and unsteadiness (n=1). Data regarding adverse events were available for 113 patients. 21 (37%) of 57 patients in the oral doxycycline group and 26 (46%) of 56 in the intravenous ceftriaxone group reported side-effects (95% CI for the difference between groups –28% to 9%; p=0·30). Serious adverse events, probably related to the intervention drugs, were reported in three patients treated with intravenous 694
ceftriaxone (cholecystitis [n=1], stomatitis and proctitis [n=1], and allergy [n=1]) and led to discontinuation of medication. One patient treated with oral doxycycline contracted duodenal ulcer, which was probably due to a combination of acetylsalicylic acid and non-steroidal antiinflammatory drugs, and did not cause discontinuation of antibiotic treatment. The other side-effects were generally mild: diarrhoea (n=17), nausea (n=13), diarrhoea and nausea (n=2), constipation (n=9), or rash (n=3). We registered no cases of photosensitivity, but all patients were recommended to be cautious when sunbathing.
This randomised trial shows that oral doxycycline has a similar efficacy to intravenous ceftriaxone for 14-day treatment of European Lyme neuroborreliosis. Clinical improvement at 4 months after the start of treatment was similar in the two intervention groups. We saw no differences in the reduction of CSF cell count or speed of clinical improvement, and no true treatment failures. Side-effects occurred with similar frequency, but the only adverse events that led to discontinuation of treatment occurred with intravenous ceftriaxone. However, the study was neither designed nor powered to investigate side-effects. More than half the patients in both groups reported mild residual symptoms at 4 months after the start of treatment. Slow recovery was in accordance with previous studies showing remaining symptoms in 25–59% of patients 2–5 years after treatment for Lyme neuroborreliosis.17–19 Although residual symptoms have been speculated to be due to survived bacteria, and antibiotic treatment beyond 14 days could be beneficial, available evidence argues against these notions. An open randomised study20 showed similar efficacy of 2 weeks versus 4 weeks of intravenous ceftriaxone for late Lyme borreliosis (30% neuroborreliosis) defined as symptom duration of more than 3 months, and a recent randomised placebo-controlled study21 of disseminated Lyme disease (60% neuroborreliosis) showed no additional benefit of extended oral amoxicillin treatment after 3 weeks of intravenous ceftriaxone. Furthermore, an additional 4–12 weeks of antibiotic courses in post-Lyme-disease syndrome is not efficient.22–24 Recovery was less pronounced in patients with pretreatment symptom duration of more than 6 months, but clinical response did not differ between the interventions in this subgroup. Whether late Lyme neuroborreliosis (symptom duration >6 months) or parenchymal CNS Lyme neuroborreliosis requires different treatment is unclear. Our study was not powered to analyse this hypothesis, but our unselected cohort of patients included all stages and clinical manifestations of Lyme neuroborreliosis, and no patients needed to be retreated. In Europe, Lyme neuroborreliosis is mainly caused by B garinii or B afzelii, whereas in the USA, Lyme www.thelancet.com/neurology Vol 7 August 2008
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neuroborreliosis is caused by B burgdorferi sensu stricto. The different strains could differ with respect to clinical presentations, laboratory findings, and antibiotic susceptibility.25–27 To what extent this diversity should affect the choice of antibiotics remains unclear, and the clinical efficacy of oral doxycycline in US Lyme neuroborreliosis should be further examined. The clinical score used in this study is as similar as possible to assessment made in everyday clinical practice. It accounts for both subjective and objective complaints, has a fine-graded scale, and can therefore reasonably be assumed to have both external and internal validity.28 Some interobserver disagreement is expected in a multicentre trial, but the randomised design of our study keeps this problem to a minimum. In conclusion, this randomised trial shows that oral doxycycline is an efficient treatment for European Lyme neuroborreliosis in adults.
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Contributors UL was responsible for conception and design of the study and for data acquisition, analyses, and interpretation. RE, RM, ÅB, and TS participated in the acquisition of data. ES contributed to conception and design of the study and data analysis and interpretation. ÅM contributed to conception and design of the study and data acquisition, analysis, and interpretation. All authors revised and approved the final version of the manuscript.
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Conflicts of interest We have no conflict of interest. Acknowledgments The trial was solely funded by Sørlandet Kompetansefond. We thank the research department of Sørlandet Hospital Kristiansand for supporting our work; Jan Schepel, Tibor Nagy, and Odd Sættem for recruiting patients for the study; and Torstein Gundersen and Svein Gunnar Gundersen for advice regarding the trial protocol. References 1 Halperin JJ, Shapiro ED, Logigian E, et al. Practice parameter: treatment of nervous system Lyme disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2007; 69: 91–102. 2 Cunha BA. Intravenous-to-oral antibiotic switch therapy. A costeffective approach. Postgrad Med 1997; 101: 111–22. 3 Hunfeld KP, Brade V. Antimicrobial susceptibility of Borrelia burgdorferi sensu lato: what we know, what we don’t know, and what we need to know. Wien Klin Wochenschr 2006; 118: 659–68. 4 Karlsson M, Hammers S, Nilsson-Ehle I, Malmborg AS, Wretlind B. Concentrations of doxycycline and penicillin G in sera and cerebrospinal fluid of patients treated for neuroborreliosis. Antimicrob Agents Chemother 1996; 40: 1104–07. 5 Ogrinc K, Logar M, Lotric-Furlan S, Cerar D, Ruzic-Sabljic E, Strle F. Doxycycline versus ceftriaxone for the treatment of patients with chronic Lyme borreliosis. Wien Klin Wochenschr 2006; 118: 696–701. 6 Kohlhepp W, Oschmann P, Mertens HG. Treatment of Lyme borreliosis. Randomized comparison of doxycycline and penicillin G. J Neurol 1989; 236: 464–69. 7 Karlsson M, Hammers-Berggren S, Lindquist L, Stiernstedt G, Svenungsson B. Comparison of intravenous penicillin G and oral doxycycline for treatment of Lyme neuroborreliosis. Neurology 1994; 44: 1203–07.
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10
11
12
13
14
16 17
18 19
20
21
22
23
24
25
26
27 28
Karkkonen K, Stiernstedt SH, Karlsson M. Follow-up of patients treated with oral doxycycline for Lyme neuroborreliosis. Scand J Infect Dis 2001; 33: 259–62. Dotevall L, Hagberg L. Successful oral doxycycline treatment of Lyme disease-associated facial palsy and meningitis. Clin Infect Dis 1999; 28: 569–74. Borg R, Dotevall L, Hagberg L, et al. Intravenous ceftriaxone compared with oral doxycycline for the treatment of Lyme neuroborreliosis. Scand J Infect Dis 2005; 37: 449–54. Halperin JJ, Logigian EL, Finkel MF, Pearl RA. Practice parameters for the diagnosis of patients with nervous system Lyme borreliosis (Lyme disease). Quality Standards Subcommittee of the American Academy of Neurology. Neurology 1996; 46: 619–27. Stanek G, O’Connell S, Cimmino M, et al. European Union Concerted Action on Risk Assessment in Lyme Borreliosis: clinical case definitions for Lyme borreliosis. Wien Klin Wochenschr 1996; 108: 741–47. Ljostad U, Skarpaas T, Mygland A. Clinical usefulness of intrathecal antibody testing in acute Lyme neuroborreliosis. Eur J Neurol 2007; 14: 873–76. Hansen K, Lebech AM. Lyme neuroborreliosis: a new sensitive diagnostic assay for intrathecal synthesis of Borrelia burgdorferi— specific immunoglobulin G, A, and M. Ann Neurol 1991; 30: 197–205. Machin D, Campbell M, Fayers P, Pinol A. Sample size tables for clinical studies. Oxford: Blackwell Science, 1997. Blackwelder WC. “Proving the null hypothesis” in clinical trials. Control Clin Trials 1982; 3: 345–53. Berglund J, Stjernberg L, Ornstein K, Tykesson-Joelsson K, Walter H. 5-y follow-up study of patients with neuroborreliosis. Scand J Infect Dis 2002; 34: 421–25. Ljostad U, Mygland A, Skarpaas T. [Neuroborreliosis in Vest-Agder]. Tidsskr Nor Laegeforen 2003; 123: 610–13. Vrethem M, Hellblom L, Widlund M, et al. Chronic symptoms are common in patients with neuroborreliosis—a questionnaire followup study. Acta Neurol Scand 2002; 106: 205–08. Dattwyler RJ, Wormser GP, Rush TJ, et al. A comparison of two treatment regimens of ceftriaxone in late Lyme disease. Wien Klin Wochenschr 2005; 117: 393–97. Oksi J, Nikoskelainen J, Hiekkanen H, et al. Duration of antibiotic treatment in disseminated Lyme borreliosis: a double-blind, randomized, placebo-controlled, multicenter clinical study. Eur J Clin Microbiol Infect Dis 2007; 26: 571–81. Klempner MS, Hu LT, Evans J, et al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med 2001; 345: 85–92. Krupp LB, Hyman LG, Grimson R, et al. Study and treatment of post Lyme disease (STOP-LD): a randomized double masked clinical trial. Neurology 2003; 60: 1923–30. Fallon BA, Keilp JG, Corbera KM, et al. A randomized, placebocontrolled trial of repeated IV antibiotic therapy for Lyme encephalopathy. Neurology 2008; 70: 992–1003. Strle F, Ruzic-Sabljic E, Cimperman J, Lotric-Furlan S, Maraspin V. Comparison of findings for patients with Borrelia garinii and Borrelia afzelii isolated from cerebrospinal fluid. Clin Infect Dis 2006; 43: 704–10. Sicklinger M, Wienecke R, Neubert U. In vitro susceptibility testing of four antibiotics against Borrelia burgdorferi: a comparison of results for the three genospecies Borrelia afzelii, Borrelia garinii, and Borrelia burgdorferi sensu stricto. J Clin Microbiol 2003; 41: 1791–93. Steere AC. Lyme disease. N Engl J Med 2001; 345: 115–25. Bland JM, Altman DG. Statistics notes: validating scales and indexes. BMJ 2002; 324: 606–07.
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Oral doxycycline versus intravenous ceftriaxone for European Lyme neuroborreliosis: a multicentre, non-inferiority, double-blind, randomised trial Unn Ljøstad, Eirik Skogvoll, Randi Eikeland, Rune Midgard, Tone Skarpaas, Åse Berg, Åse Mygland
Summary Lancet Neurol 2008; 7: 690–95 Published Online June 21, 2008 DOI:10.1016/S14744422(08)70119-4 See Reflection and Reaction page 665 Department of Neurology, Sørlandet Hospital HF, Kristiansand, Norway (U Ljøstad MD, Å Mygland PhD); Unit for Applied Clinical Research, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway (E Skogvoll PhD); Department of Neurology, Sørlandet Hospital HF, Arendal, Norway (R Eikeland MD); Department of Neurology, Molde Hospital, Molde, Norway (R Midgard PhD); Microbiology Unit, Division of Laboratory Medicine, Sørlandet Hospital HF, Kristiansand, Norway (T Skarpaas MD); Department of Medicine, the University Hospital of Stavanger, Stavanger, Norway (Å Berg MD); Institute of Clinical Medicine, University of Bergen, Bergen, Norway (Å Mygland); and Hospital of Rehabilitation, Rikshospitalet University Hospital, Kristiansand, Norway (Å Mygland) Correspondence to: Unn Ljøstad, Department of Neurology, Sørlandet Hospital HF, Kristiansand, Serviceboks 416, N-4604 Kristiansand, Norway [email protected]
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Background Use of intravenous penicillin and ceftriaxone to treat Lyme neuroborreliosis is well documented, although oral doxycycline could be a cost-effective alternative. We aimed to compare the efficacy of oral doxycycline with intravenous ceftriaxone for the treatment of Lyme neuroborreliosis. Methods From April, 2004, to October, 2007, we recruited consecutive adult patients from nine hospitals in southern Norway into a non-inferiority trial. Inclusion criteria were neurological symptoms suggestive of Lyme neuroborreliosis without other obvious causes, and presence of any of the following: a CSF white-cell count of more than five per mL; intrathecal production of specific Borrelia burgdorferi antibodies; or acrodermatitis chronicum atrophicans. Patients were randomly allocated to receive 200 mg oral doxycycline or 2 g intravenous ceftriaxone once per day for 14 days, in a double-blind, double-dummy design. A composite clinical score (range 0 to 64, 0=best) was based on standardised interviews and clinical neurological examination. The primary outcome was reduction in clinical score at 4 months after the start of treatment. Analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT00138801. Findings Of 118 patients who underwent randomisation, 102 completed the study (mean clinical score at baseline 8·5 [SD 4·1]). 4 months after the start of treatment, mean score improvement in the doxycycline group (n=54) was 4·5 (95% CI 3·6 to 5·5) points and that in the ceftriaxone group (n=48) was 4·4 (3·4 to 5·4) points (95% CI for difference between groups –0·9 to 1·1; p=0·84). 26 (48%) patients in the doxycycline group and 16 (33%) in the ceftriaxone group had total recovery (95% CI for difference between groups –4% to 34%; p=0·13). Side-effects possibly related to treatment were reported in 21 (37%) and 26 (46%) patients in these groups, respectively (–28% to 9%; p=0·30). Three patients discontinued ceftriaxone treatment owing to adverse events. Interpretation Oral doxycycline is as efficient as intravenous ceftriaxone for the treatment of European adults with Lyme neuroborreliosis. Funding Sørlandet Kompetansefond.
Introduction Lyme borreliosis is a multisystem infectious disease, caused by the tick-borne spirochete Borrelia burgdorferi (Bb) sensu lato. The Bb sensu lato complex consists of several genotypes of which at least three—Bb sensu stricto, B garinii, and B afzelii—are pathogenic in human beings. These species differ with respect to organotropism, clinical phenotype, and geographical distribution, but all three can cause neuroborreliosis. The dominating species in Europe are B garinii and B afzelii, and the most common manifestations of European Lyme neuroborreliosis are painful radiculopathy and cranial neuropathy (especially of the facial nerve) with pleocytosis in the CSF. Other manifestations are myelopathy, encephalopathy, and peripheral neuropathies, but these are rare. Antibiotic treatment is strongly recommended in Lyme neuroborreliosis. Most guidelines suggest 14-day courses of intravenous regimens with penicillin or ceftriaxone, which seem to have similar clinical efficacy.1 Oral antibiotics have several advantages, such as fewer
complications, greater ease of use, and much less expense.2 Doxycycline has shown excellent results in vitro against Bb, good CNS penetration, and good clinical efficacy in some small and unmasked studies.3–10 The aim of this study was to investigate whether oral doxycycline was as efficient as intravenous ceftriaxone for the treatment of European Lyme neuroborreliosis in adults.
Methods Patients Consecutive patients with neurological symptoms suggestive of Lyme neuroborreliosis (new neurological symptoms or findings without other obvious causes, or both) were eligible if one or more of the following additional criteria were met: CSF white-cell count of more than five per mL (healthy erythrocyte count), intrathecal production of Bb antibodies, or verified acrodermatitis chronicum atrophicans. Patients were excluded if they met any of the following criteria: allergy to any of the intervention medications or previous type I reaction to penicillin; treatment with cephalosporin, www.thelancet.com/neurology Vol 7 August 2008
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penicillin, or tetracycline in the past 14 days; age younger than 18 years; or pregnancy or breastfeeding. Patients were recruited from nine hospitals in coastal areas of southern Norway where Lyme neuroborreliosis is endemic. All care providers were familiar with diagnosis and treatment of Lyme neuroborreliosis. Some diagnostic inaccuracy was inevitable at randomisation because of the absence of a diagnostic gold standard in Lyme neuroborreliosis,11,12 low diagnostic sensitivity of intrathecal Bb antibody production in the early phase of the disease,13 and the need to start treatment before antibody results were available. The inclusion criteria were therefore deliberately broad, and patients were subsequently classified as having definite, possible, or no Lyme neuroborreliosis throughout the course of the disease according to strict criteria (panel 1). We tested patients who did not have intrathecal Bb antibody production for tick-borne encephalitis virus by use of serum antibodies, and for varicella zoster virus, herpes simplex virus, and enterovirus by PCR of CSF. All patients gave written informed consent, and the study was approved by the Regional Committee for Medical Research Ethics in southern Norway and the Norwegian Data Inspectorate.
Procedures Patients were randomly allocated to receive 14 days’ treatment with 200 mg oral doxycycline per day or 2 g intravenous ceftriaxone per day. Our hypothesis was that oral doxycycline was not inferior to intravenous ceftriaxone with respect to clinical efficacy in the treatment of European Lyme neuroborreliosis. As an outcome measure, a composite clinical score based on standard neurological interview and clinical examination (range 0 to 64, 0=best; panel 2) was recorded by experienced clinicians at inclusion, and at 13 days and at 4 months after the start of treatment. A lumbar puncture was undertaken, and the CSF cell count was measured at the same timepoints. The primary endpoint was clinical improvement at 4 months after the start of treatment, defined as clinical score at inclusion minus clinical score at 4 months. Secondary endpoints were the number of patients with full recovery (ie, 0 in clinical outcome score) at 4 months after the start of treatment, reduction in CSF cell count at 4 months, and clinical improvement and reduction in CSF cell count at day 13 of treatment. Computerised allocation to intravenous ceftriaxone or oral doxycycline was done in advance at the clinical trials office in blocks of four patients, stratified according to early disease (duration of symptoms <6 months) and late disease (duration of symptoms >6 months). Lists were distributed to the pharmacies included in the study, and patients were allocated according to these lists following a telephone call to the trial management office. The investigators who generated the randomisation sequence did not take any further part in the study, and no clinicians were aware of the assignment sequence at any time. www.thelancet.com/neurology Vol 7 August 2008
Panel 1: Case definitions Definite neuroborreliosis (all three criteria fulfilled) 1 Neurological symptoms suggestive of Lyme neuroborreliosis without other obvious reasons 2 CSF pleocytosis (>5 leucocytes per mL) 3 Intrathecal Bb antibody production Possible neuroborreliosis (criterion 1 and one of 2–5 fulfilled) 1 Neurological symptoms suggestive of Lyme neuroborreliosis without other obvious reasons 2 CSF pleocytosis (>5 leucocytes per mL) 3 Intrathecal Bb antibody production 4 Bb antibodies in serum 5 Erythema migrans during past 4 months
Panel 2: Clinical score Subjective complaints (maximum score=12) Malaise Fatigue Pain Memory problems Concentration difficulties Paraesthesia Objective findings (maximum score=52) Facial palsy* Reduced hearing* Vision loss* Reduced sensibility in face* Paresis of eye muscles* Other cranial neuropathies Tremor Ataxia Nuchal rigidity Confusion Other CNS findings Truncus radiculopathy* Arm radiculopathy* Leg radiculopathy* Arm paresis* Leg paresis* Clinical outcome score is the sum of subjective and objective findings. Each item is scored 0=none, 1=mild, 2=severe (maximum total score=64). *Left and right sides scored separately.
Patients, nurses administering the interventions, and doctors assessing the clinical scores were all unaware of group assignment. Blinding was achieved via doubledummy design—ie, all patients received 14 days of intravenous infusion (ceftriaxone or placebo) and oral treatment (doxycycline or placebo). Because the ceftriaxone fluid was yellow, bags used for intravenous treatment were wrapped at the pharmacy by people not participating in the treatment or follow-up of patients, 691
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and lines were wrapped by the nurses before the medication was administered. Although no systematic assessment was done, the blinding was deemed successful for the doctors because they did not take part in practical administration of the drugs, and successful for the patients because wrapping was complete and none of them reported identification of their treatment. Nurses were instructed not to inform others if they unintentionally saw the yellow colour of ceftriaxone. The allocation scheme was not revealed until all patients were examined at 4 months after the start of treatment, apart from for one patient whose intravenous ceftriaxone treatment was extended by 1 week because of an increased CSF cell count at day 13 of treatment. We examined CSF samples for Bb intrathecal antibody production with the IDEIA Lyme neuroborreliosis kit (DakoCytomation, Cambridgeshire, UK), using purified native flagella from the B afzelii DK1 strain as antigens. In this assay, corrections for impairment of the blood– brain barrier are unnecessary,14 and intrathecal production of antibodies is detected when, according to the manufacturer’s recommendation, the antibody index of ODCSF/ODserum multiplied by (ODCSF−ODserum) is 0·3 or more (where OD is optical density).
136 patients assessed for eligibility
18 not included 9 did not meet inclusion criteria 8 refused to participate 1 forgot enrolment
Statistical analysis Blinded analysis of results from the first 16 patients suggested a mean clinical score reduction of 6 (SD 3). The participating clinicians agreed that detection of a mean group difference larger than 1·5 units in favour of ceftriaxone would be desirable, corresponding to a standardised difference (SD/mean) of 1·5/3=0·5. With a one-sided test and significance level of 0·05, 50 patients in each group would be needed to reject a null hypothesis of inferiority with 80% power.15 To compensate for dropouts and potentially non-assessable patients, we aimed to enrol 120 patients. For comparison of unpaired categorical data, we used Pearson’s χ² test. For continuous outcome variables, we used a linear model with treatment group and clinical presentation as factors, and baseline clinical score as a covariate. The non-parametric Mann-Whitney U test was used when the outcome variable was clearly not normal. For the main outcome, we report p values for the traditional tests of superiority in which p>0·05 indicates no difference, and for the reverse test in which
Oral doxycycline (n=54) Mean age (years)
54 (13)
Sex (female)
26 (48%)
17 (35%)
Coexisting diseases
22 (41%)
14 (29%)
Tick bite
30 (56%)
26 (54%)
Erythema migrans
17 (31%)
5 (10%)
Definite
37 (69%)
34 (71%)
Possible
17 (31%)
14 (29%)
Symptom duration >6 months Mean duration of symptoms (weeks) Mean CSF cell count (n)
59 assigned to intravenous ceftriaxone
59 assigned to oral doxycycline
692
4 (8%)
10 (19)
8 (13)
194 (237)
178 (187)
Mean CSF protein (g/L)
1·2 (0·7)
1·3 (0·8)
Mean clinical score
8·2 (4·1)
8·9 (4·1)
Mean subjective score
4·3 (2·3)
5·1 (2·3)
Bannwarth’s syndrome*
18 (33%)
12 (25%)
Facial palsy
12 (22%)
9 (19%)
Other cranial neuropathies
2 (4%)
3 (6%)
13 (24%)
18 (38%)
Ataxia
2 (4%)
0 (0%)
Myelopathy
1 (2%)
0 (0%)
Cognitive deficiency
0 (0%)
1 (2%)
Arm paresis
1 (2%)
1 (2%)
Radiculopathy
55 received 14 days of intravenous ceftriaxone
Figure 1: Trial profile
6 (11%)
Main objective findings
1 did not receive allocated treatment owing to late delivery from pharmacy 3 discontinued owing to adverse events
48 analysed
52 (13)
Neuroborreliosis diagnosis
118 randomised
1 lost to follow-up (refused) 6 excluded owing to new diagnosis
Intravenous ceftriaxone (n=48)
59 received 14 days of oral doxycycline
2 lost to follow-up (both refused) 3 excluded owing to new diagnosis
54 analysed
ACA and paraesthesias
1 (2%)
0 (0%)
Only subjective complaints
4 (7%)
4 (8%)
Data are mean (SD) or number of patients (%), unless otherwise stated. ACA=acrodermatitis chronicum atrophicans. *Includes lymphocytic CSF pleocytosis, cranial neuropathy, and radiculopathy.
Table 1: Baseline demographic, clinical, and laboratory characteristics of patients
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Oral doxycycline (n=54) Mean reduction in clinical score at 4 months (points) Mean reduction in clinical score at 13 days (points) Patients with clinical score 0, 4 months after start of treatment
4·5 (3·6 to 5·5)
Intravenous ceftriaxone (n=48) 4·4 (3·4 to 5·4)
3·0 (2·0 to 4·0)
3·6 (2·6 to 4·7)
26 (48%)
16 (33%)
95% CI*
p*
(–0·9 to 1·1)
0·84
(–1·7 to 0·4)
0·21
(–4% to 34%) 0·13
Data are mean reductions (95% CI) or n (%) unless otherwise stated. Times are from the start of treatment. *95% CI and p values for the effect of doxycycline compared with ceftriaxone (ie, in favour of doxycycline).
Table 2: Clinical outcome according to intervention
significance (p<0·05) confirms non-inferiority.16 All analyses was done with the statistical software SPSS, version 15.0. Analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT00138801.
25
Before treatment Day 13 Month 4
20
Role of the funding source 15 Clinical score
The sponsor of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
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Results From April, 2004, to October, 2007, we recruited 118 patients (figure 1). One patient did not receive allocated medication because of late delivery from the pharmacy, two discontinued medication because of adverse events and were also lost to follow-up, and three changed their mind and refused to be followed up. Furthermore, ten patients were excluded because of new diagnoses: tick-borne encephalitis virus (n=4), myasthenia gravis (n=1), chronic inflammatory demyelinating polyneuropathy (n=1), coronary disease (n=1), cervical radiculopathy (n=1; also discontinued medication because of an adverse event), multiple sclerosis (n=1), and spontaneous intracranial hypotension (n=1). Therefore, 102 patients were included in the final analysis; table 1 shows their baseline characteristics. Lumbar puncture was done in all 102 patients at inclusion, in 100 at day 13 of treatment, and in 88 at 4 months after the start of treatment. After adjustment for clinical presentation and baseline scores, mean improvement in the clinical outcome scale after 4 months (mean 19 [SD 2·4] weeks) was 4·5 (95% CI 3·6 to 5·5) points for oral doxycycline and 4·4 (3·4 to 5·4) points for intravenous ceftriaxone. Treatment groups were thus similar (p=0·84 for superiority or p=0·006 with respect to the null hypothesis of inferiority), and the upper limit of the one-sided 95% CI for difference between groups (−∞ to 0·75) was well within the prespecified limit of 1·5 score units. Analyses of all 109 patients who completed the 4-month follow-up showed a similar mean improvement between the doxycycline and ceftriaxone groups (4·5 [3·6 to 5·4] vs 4·3 [3·3 to 5·3] points, 95% CI for difference –0·8 to 1·2 points; p=0·69). The groups were also similar with respect to secondary clinical endpoints www.thelancet.com/neurology Vol 7 August 2008
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0 Oral doxycycline
Intravenous ceftriaxone
Figure 2: Clinical scores at various stages of treatment Boxes indicate IQR, horizontal bars within boxes indicate medians, horizontal lines outside boxes indicate maximum and minimum values that are not outliers, and white circles indicate outliers (values between 1·5 and 3 box-lengths from the 75th percentile or 25th percentile).
(table 2) and reduction in CSF cell count at 13 days (p=0·89) and at 4 months (p=0·56) after the start of treatment. Figures 2 and 3 show clinical scores and CSF cell counts at different stages. At 4 months after the start of treatment, patients with early Lyme neuroborreliosis (n=92) improved more than did those with late disease (n=10; 6·7 [95% CI 6·1 to 7·2] vs 2·3 [0·7 to 3·9] score points; p<0·0001), but no difference was seen with respect to treatment regimens (p=0·70). The ten patients with late Lyme neuroborreliosis presented with the following: radiculopathy (n=2); Bannwarth’s syndrome (n=1); cranial nerve palsy (n=2); cognitive difficulties (n=1); paresis and unsteadiness (n=1); acrodermatitis chronicum atrophicans and paraesthesias (n=1); and pain, malaise, and paraesthesias (n=2). Patients with definite and possible Lyme neuroborreliosis improved equally well (4·6 [3·5 to 5·6] vs 4·4 [3·3 to 5·4] points; p=0·78). Clinical improvement at 4 months after the start of treatment did not differ between the oral doxycycline and intravenous ceftriaxone regimens when definite and possible Lyme 693
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Before treatment Day 13 Month 4
1200
1000
Clinical score
800
600
400
Discussion
200
0 Oral doxycycline
Intravenous ceftriaxone
Figure 3: CSF cell count at various stages of treatment Boxes indicate IQR, horizontal bars within boxes indicate medians, horizontal lines outside boxes indicate maximum and minimum values that are not outliers, white circles indicate outliers (values between 1·5 and 3 box-lengths from the 75th percentile or 25th percentile), and asterisks indicate extreme values (values more than 3 box-lengths from the 75th percentile or 25th percentile).
neuroborreliosis were considered separately (definite, 4·6 [3·0 to 6·2] vs 4·9 [3·3 to 6·5] points, p=0·66; possible, 3·8 [2·3 to 5·2] vs 2·7 [0·9 to 4·4], p=0·29). We registered no real treatment failures. Treatment allocation was revealed and treatment extended for 1 week in one patient allocated to intravenous ceftriaxone because the CSF cell count had increased at day 13; however, this patient had showed clinical improvement. Two patients had a higher outcome score at 4 months after start of treatment (both in the doxycycline group), one probably because of fibromyalgia and the other because of newly diagnosed metastasising prostate cancer. Five patients (three given intravenous ceftriaxone, two given oral doxycycline) had an unchanged outcome score at 4 months after the start of treatment. All five had achieved healthy CSF cell counts and had mainly subjective complaints, which were not regarded as treatment failures. 60 (59%) patients reported residual symptoms at 4 months (28 [52%] given oral doxycycline, 32 [67%] given intravenous ceftriaxone; p=0·13), of whom 29 had only subjective complaints. Remaining objective findings were all mild: facial palsy or other cranial neuropathy (n=11), radiculopathy (n=10), cranial neuropathy and radiculopathy (n=6), paresis (n=2), possible encephalopathy (n=1), and unsteadiness (n=1). Data regarding adverse events were available for 113 patients. 21 (37%) of 57 patients in the oral doxycycline group and 26 (46%) of 56 in the intravenous ceftriaxone group reported side-effects (95% CI for the difference between groups –28% to 9%; p=0·30). Serious adverse events, probably related to the intervention drugs, were reported in three patients treated with intravenous 694
ceftriaxone (cholecystitis [n=1], stomatitis and proctitis [n=1], and allergy [n=1]) and led to discontinuation of medication. One patient treated with oral doxycycline contracted duodenal ulcer, which was probably due to a combination of acetylsalicylic acid and non-steroidal antiinflammatory drugs, and did not cause discontinuation of antibiotic treatment. The other side-effects were generally mild: diarrhoea (n=17), nausea (n=13), diarrhoea and nausea (n=2), constipation (n=9), or rash (n=3). We registered no cases of photosensitivity, but all patients were recommended to be cautious when sunbathing.
This randomised trial shows that oral doxycycline has a similar efficacy to intravenous ceftriaxone for 14-day treatment of European Lyme neuroborreliosis. Clinical improvement at 4 months after the start of treatment was similar in the two intervention groups. We saw no differences in the reduction of CSF cell count or speed of clinical improvement, and no true treatment failures. Side-effects occurred with similar frequency, but the only adverse events that led to discontinuation of treatment occurred with intravenous ceftriaxone. However, the study was neither designed nor powered to investigate side-effects. More than half the patients in both groups reported mild residual symptoms at 4 months after the start of treatment. Slow recovery was in accordance with previous studies showing remaining symptoms in 25–59% of patients 2–5 years after treatment for Lyme neuroborreliosis.17–19 Although residual symptoms have been speculated to be due to survived bacteria, and antibiotic treatment beyond 14 days could be beneficial, available evidence argues against these notions. An open randomised study20 showed similar efficacy of 2 weeks versus 4 weeks of intravenous ceftriaxone for late Lyme borreliosis (30% neuroborreliosis) defined as symptom duration of more than 3 months, and a recent randomised placebo-controlled study21 of disseminated Lyme disease (60% neuroborreliosis) showed no additional benefit of extended oral amoxicillin treatment after 3 weeks of intravenous ceftriaxone. Furthermore, an additional 4–12 weeks of antibiotic courses in post-Lyme-disease syndrome is not efficient.22–24 Recovery was less pronounced in patients with pretreatment symptom duration of more than 6 months, but clinical response did not differ between the interventions in this subgroup. Whether late Lyme neuroborreliosis (symptom duration >6 months) or parenchymal CNS Lyme neuroborreliosis requires different treatment is unclear. Our study was not powered to analyse this hypothesis, but our unselected cohort of patients included all stages and clinical manifestations of Lyme neuroborreliosis, and no patients needed to be retreated. In Europe, Lyme neuroborreliosis is mainly caused by B garinii or B afzelii, whereas in the USA, Lyme www.thelancet.com/neurology Vol 7 August 2008
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neuroborreliosis is caused by B burgdorferi sensu stricto. The different strains could differ with respect to clinical presentations, laboratory findings, and antibiotic susceptibility.25–27 To what extent this diversity should affect the choice of antibiotics remains unclear, and the clinical efficacy of oral doxycycline in US Lyme neuroborreliosis should be further examined. The clinical score used in this study is as similar as possible to assessment made in everyday clinical practice. It accounts for both subjective and objective complaints, has a fine-graded scale, and can therefore reasonably be assumed to have both external and internal validity.28 Some interobserver disagreement is expected in a multicentre trial, but the randomised design of our study keeps this problem to a minimum. In conclusion, this randomised trial shows that oral doxycycline is an efficient treatment for European Lyme neuroborreliosis in adults.
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Contributors UL was responsible for conception and design of the study and for data acquisition, analyses, and interpretation. RE, RM, ÅB, and TS participated in the acquisition of data. ES contributed to conception and design of the study and data analysis and interpretation. ÅM contributed to conception and design of the study and data acquisition, analysis, and interpretation. All authors revised and approved the final version of the manuscript.
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Conflicts of interest We have no conflict of interest. Acknowledgments The trial was solely funded by Sørlandet Kompetansefond. We thank the research department of Sørlandet Hospital Kristiansand for supporting our work; Jan Schepel, Tibor Nagy, and Odd Sættem for recruiting patients for the study; and Torstein Gundersen and Svein Gunnar Gundersen for advice regarding the trial protocol. References 1 Halperin JJ, Shapiro ED, Logigian E, et al. Practice parameter: treatment of nervous system Lyme disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2007; 69: 91–102. 2 Cunha BA. Intravenous-to-oral antibiotic switch therapy. A costeffective approach. Postgrad Med 1997; 101: 111–22. 3 Hunfeld KP, Brade V. Antimicrobial susceptibility of Borrelia burgdorferi sensu lato: what we know, what we don’t know, and what we need to know. Wien Klin Wochenschr 2006; 118: 659–68. 4 Karlsson M, Hammers S, Nilsson-Ehle I, Malmborg AS, Wretlind B. Concentrations of doxycycline and penicillin G in sera and cerebrospinal fluid of patients treated for neuroborreliosis. Antimicrob Agents Chemother 1996; 40: 1104–07. 5 Ogrinc K, Logar M, Lotric-Furlan S, Cerar D, Ruzic-Sabljic E, Strle F. Doxycycline versus ceftriaxone for the treatment of patients with chronic Lyme borreliosis. Wien Klin Wochenschr 2006; 118: 696–701. 6 Kohlhepp W, Oschmann P, Mertens HG. Treatment of Lyme borreliosis. Randomized comparison of doxycycline and penicillin G. J Neurol 1989; 236: 464–69. 7 Karlsson M, Hammers-Berggren S, Lindquist L, Stiernstedt G, Svenungsson B. Comparison of intravenous penicillin G and oral doxycycline for treatment of Lyme neuroborreliosis. Neurology 1994; 44: 1203–07.
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10
11
12
13
14
16 17
18 19
20
21
22
23
24
25
26
27 28
Karkkonen K, Stiernstedt SH, Karlsson M. Follow-up of patients treated with oral doxycycline for Lyme neuroborreliosis. Scand J Infect Dis 2001; 33: 259–62. Dotevall L, Hagberg L. Successful oral doxycycline treatment of Lyme disease-associated facial palsy and meningitis. Clin Infect Dis 1999; 28: 569–74. Borg R, Dotevall L, Hagberg L, et al. Intravenous ceftriaxone compared with oral doxycycline for the treatment of Lyme neuroborreliosis. Scand J Infect Dis 2005; 37: 449–54. Halperin JJ, Logigian EL, Finkel MF, Pearl RA. Practice parameters for the diagnosis of patients with nervous system Lyme borreliosis (Lyme disease). Quality Standards Subcommittee of the American Academy of Neurology. Neurology 1996; 46: 619–27. Stanek G, O’Connell S, Cimmino M, et al. European Union Concerted Action on Risk Assessment in Lyme Borreliosis: clinical case definitions for Lyme borreliosis. Wien Klin Wochenschr 1996; 108: 741–47. Ljostad U, Skarpaas T, Mygland A. Clinical usefulness of intrathecal antibody testing in acute Lyme neuroborreliosis. Eur J Neurol 2007; 14: 873–76. Hansen K, Lebech AM. Lyme neuroborreliosis: a new sensitive diagnostic assay for intrathecal synthesis of Borrelia burgdorferi— specific immunoglobulin G, A, and M. Ann Neurol 1991; 30: 197–205. Machin D, Campbell M, Fayers P, Pinol A. Sample size tables for clinical studies. Oxford: Blackwell Science, 1997. Blackwelder WC. “Proving the null hypothesis” in clinical trials. Control Clin Trials 1982; 3: 345–53. Berglund J, Stjernberg L, Ornstein K, Tykesson-Joelsson K, Walter H. 5-y follow-up study of patients with neuroborreliosis. Scand J Infect Dis 2002; 34: 421–25. Ljostad U, Mygland A, Skarpaas T. [Neuroborreliosis in Vest-Agder]. Tidsskr Nor Laegeforen 2003; 123: 610–13. Vrethem M, Hellblom L, Widlund M, et al. Chronic symptoms are common in patients with neuroborreliosis—a questionnaire followup study. Acta Neurol Scand 2002; 106: 205–08. Dattwyler RJ, Wormser GP, Rush TJ, et al. A comparison of two treatment regimens of ceftriaxone in late Lyme disease. Wien Klin Wochenschr 2005; 117: 393–97. Oksi J, Nikoskelainen J, Hiekkanen H, et al. Duration of antibiotic treatment in disseminated Lyme borreliosis: a double-blind, randomized, placebo-controlled, multicenter clinical study. Eur J Clin Microbiol Infect Dis 2007; 26: 571–81. Klempner MS, Hu LT, Evans J, et al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med 2001; 345: 85–92. Krupp LB, Hyman LG, Grimson R, et al. Study and treatment of post Lyme disease (STOP-LD): a randomized double masked clinical trial. Neurology 2003; 60: 1923–30. Fallon BA, Keilp JG, Corbera KM, et al. A randomized, placebocontrolled trial of repeated IV antibiotic therapy for Lyme encephalopathy. Neurology 2008; 70: 992–1003. Strle F, Ruzic-Sabljic E, Cimperman J, Lotric-Furlan S, Maraspin V. Comparison of findings for patients with Borrelia garinii and Borrelia afzelii isolated from cerebrospinal fluid. Clin Infect Dis 2006; 43: 704–10. Sicklinger M, Wienecke R, Neubert U. In vitro susceptibility testing of four antibiotics against Borrelia burgdorferi: a comparison of results for the three genospecies Borrelia afzelii, Borrelia garinii, and Borrelia burgdorferi sensu stricto. J Clin Microbiol 2003; 41: 1791–93. Steere AC. Lyme disease. N Engl J Med 2001; 345: 115–25. Bland JM, Altman DG. Statistics notes: validating scales and indexes. BMJ 2002; 324: 606–07.
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