These two placebo-controlled randomized trials [11] used the same study design and outcome measures with the distinguishing feature that one trial enrolled seropositive patients while the other trial enrolled seronegative patients. The total sample size was 129 patients. The treatment period was 90 days: 30 days of IV ceftriaxone (2 gms/day) followed by 60 days of oral doxycycline (100 bid) or 30 days of IV placebo followed by 60 days of oral placebo. After treatment, the patients were followed for 90 days. The primary outcome measures at 6 months were categorical variables based on change from baseline on the physical and mental health-related quality of life composite indices of the Short form general health survey (SF-36)(trichotomized to “worsening”, “no change” or “improvement”) [12]. Secondary outcome measures assessed change in neurocognition and in psychiatric symptoms. For the seropositive patients entrance criteria did not require documentation of classic symptoms of Lyme disease, but did require documentation of having received recommended treatment for Lyme disease. For the seronegative patients, entrance criteria required documentation of an erythema migrans rash. Additionally, patients had to report functional impairment related to musculoskeletal or cognitive symptoms that had begun within 6 months of the infection and that had been present for at least 6 months (but less than 12 years). Patients were excluded if they had received more than 60 days of prior IV antibiotics, had known hypersensitivity to study medications, had active synovitis or positive PCR for Bb in the CSF or blood.

At six months, no placebo-drug differences were noted for change on the primary outcome measure of the SF-36 using a preset cutoff for improvement; this was true for the seropositive patients, the seronegative patients, and both groups combined. In addition, no placebo-drug differences were noted for change on the secondary outcome measures of cognition and depression. In these studies, the treatment was reported as ineffective and it was not clinically recommended.

Limitations of this study include:

1. not requiring docu-mentation of objective manifestations of Lyme disease for enrollment of all study patients;
2. not requiring that patients meet a specific severity level for impairment on the primary measure of interest at the start of the study;
3. inadequately sensitive data analytic methodology:
   1. not including in the analytic method an adjustment for baseline levels of impair-ment (even though in the seronegative sample there was a significant baseline difference on the SF-36),
   2. no assess-ment for the potential moderating effect of baseline level of impairment on treatment outcome, and
   3. using a statisti-cally inefficient test for comparison between the groups (e.g., categorizing a variable that is measured continuously); and
4. a low dose of oral doxycycline that would not be adequate for CNS penetration. By not requiring documentation of the signs of Lyme disease, it cannot be certain that all patients in the study had had objective manifestations of Lyme disease previously. The exclusion of patients with post-treatment active synovitis would be consistent with the IDSA’s definition of PTLDS [1] as this would be an objective finding on clinical exam, however patients with other objective findings (e.g., cognitive impairment on testing or elevated protein in the CSF) weren’t excluded. Although patients who enrolled in this study were required to report that their symptoms led to functional impairment and the patients as a group did report substantial physical impairment, this study differed from the subsequent studies by not requiring a predetermined severity level for enrollment on the primary outcome measure of interest. While the mean impairment on the physical composite measures of the SF-36 was moderately severe for the group as a whole, the distribution may have included some patients who had such low levels of impairment that a treatment effect would have been hard to demonstrate even with a potent treatment. The sample of patients in this study, unlike the two subsequent studies [7,10], was therefore a heterogeneous collection of patients with respect to severity and baseline level of impairment. Not adjusting for baseline levels in the main analyses may have decreased the power of the test, since baseline levels of impairment typically are related to post treatment scores and change scores. Power was further decreased by categorizing the change scores and premature study discontinuation which lowered the final sample size. Because the analytic method did not include an assessment of the potential interaction effect of baseline severity and treatment group on outcome, true treatment effects distinguishing the drug and placebo groups (e.g., larger drug effects among more impaired subjects) may have been missed. Two patients given active treatment had a serious adverse event – pulmonary embolus in one and fever, anemia, and GI bleeding in the other. Particular strengths of these two studies were the relatively large sample size and the requirement that the seronegative patients have a history of physician documented erythema migrans.

This randomized double-masked placebo-controlled trial of post-Lyme syndrome [7] enrolled 55 patients with persistent severe fatigue at least 6 or more months after antibiotic therapy. Patients had to provide physician documentation of previously having met objective criteria for Lyme disease (EM or CDC-defined late manifestation of Lyme disease confirmed by ELISA and Western blot serology) and of having been previously treated with at least 3 weeks of antibiotics six months or more before study entry. Patients were excluded who had concurrent disorders not related to Lyme disease that could cause fatigue. For study entry, patients had to have at least moderate fatigue as assessed by the score on the Fatigue Severity Scale-11 (FSS-11) that occurred in conjunction with onset of Lyme disease. Patients were not excluded if they had observable neurologic findings or other objective deficits on routine general or neurologic examination. Patients received 28 days of IV ceftriaxone or placebo following by 5 months of no treatment. The primary outcome time point was 6 months. Although there were two primary clinical measures (fatigue and cognitive response time) and one biological measure (an experimental measure of CSF infection - Osp A), at the time of enrollment impairment was required only on the fatigue measure. Meaningful improvement on the FSS-11 was assessed categorically with responder status determined by a decrease of 0.7 points or more. Meaningful improvement on the response time measure required a change of 25% or more. The results demonstrated that significantly more patients assigned to ceftriaxone showed improvement in disabling fatigue compared to the placebo group (RR 3.5, p<0.001). No drug-placebo difference was noted in cognitive response time or in Osp A. Four patients (3 on placebo) had adverse events that required hospitalization. The authors, while concluding that ceftriaxone did result in improvement in severe fatigue, concluded that the risks associated with treatment and the lack of benefit in other outcome measures mitigated against recommending repeated antibiotic therapy.

Among the 4 post-treatment Lyme syndrome studies, the STOP-LD study is the one that most clearly demonstrated efficacy for drug over placebo on a primary outcome measure. Perhaps because of this, the study results have been carefully scrutinized and critiqued [1,5]. In the comments below, we review each of these critiques to evaluate their merit in either supporting or dismissing the favorable efficacy result of the study.

Critique #1 :“Only 1 of 3 Primary Outcome Measures Showed a Treatment Effect”

The 3 outcome measures were:

• Fatigue Severity Scale;
• cognitive test of mental processing speed; and c) clearance of Borrelial Osp A antigen.

a. Fatigue.

Improvement was noted on the only primary outcome measure on which patients were enrolled. The Fatigue Severity Scale (FSS-11) was employed as the primary enrollment measure and as the primary outcome measure for fatigue, as this is a measure that had been psychometrically validated by the authors. On this fatigue measure, the percentage of responders to drug was high (64%) compared to placebo (18.5%) (p<0.001). In other words, based on this measure, the drug treatment was effective. To appropriately assess efficacy of a treatment, patients in a controlled trial must have meaningful impairment on the measure of interest at the start of the study. Given that all patients were required to have prominent fatigue at the start of the STOP-LD study, it is reasonable for fatigue to have been a primary outcome measure to assess efficacy. On the other outcome measures however (cognitive processing speed or Osp A antigen), patients were not enrolled based on presence of impairment or abnormality; (e.g., only 9 of the 55 patients were positive for Osp A antigen at baseline). This study therefore was not able to adequately test efficacy on these latter measures.

The therapeutic effect of additional IV ceftriaxone therapy on the fatigue measure was demonstrated even more robustly within the subgroup of study participants who at the time of enrollment were serologically IgG Western blot positive. In this more homogenous subgroup, the responder rate for the drug treated group was 6 times higher than in the placebo treated group (80% vs 13%, p<0.01). See Fig. (1).

Fig. (1). Percentage of Responders on Fatigue Severity Scale in 2 placebo controlled trials of post-treatment Lyme disease.

A critique of the fatigue study result has been that while there was a responder rate difference on the primary fatigue severity scale measure, there was no significant improvement in fatigue as assessed by a secondary visual analog scale (VAS) of fatigue intensity. The VAS, however, was a secondary measure whose validity was not clearly established, and may have simply been a less sensitive scale. Never the less The authors of this study themselves note that the VAS results were consistent with the FSS-11 results: “The change in the fatigue VAS showed a similar pattern to the FSS-11, with a trend toward more improvement in the ceftriaxone vs the placebo group at 6 months (p=.0.01). In addition, at 6 months, the mean (SD) VAS scores were lower in the ceftriaxone than in the placebo group (4.8 (2.5) vs 6.5 (2.1); p=0.01)”.

b. Cognitive slowing.

The authors of this study defined a 25% improvement in cognitive response time as a clinically meaningful response. Although the authors note that the enrolled Lyme patients had worse response time scores than historical normative controls, they do not clarify how many patients in this study actually were impaired on this measure. In the discussion, they emphasize that the observed cognitive deficits were “relatively mild, which may have contributed to the lack of a treatment effect on cognition”. This important point highlights a key issue: if patients aren’t sufficiently impaired, a treatment effect is unlikely to be seen even with a very potent treatment. Given the small sample size of this study and the lack of major impairment on this outcome measure at the time of enrollment, statistical power is limited to demonstrate a treatment effect on this measure. This study most likely was not adequately powered to assess the efficacy of drug vs. placebo on cognitive slowing.

c. Clearance of Osp A antigen.

There are problems with this as an outcome measure. First, this is an experimental test of uncertain sensitivity and specificity. Second, presence of the Osp A antigen was detected in only 9 of 55 patients; a primary efficacy assessment of change in response to treatment cannot be based on a sample size of 9. The study was under-powered to detect any realistic change in clearance of OspA antigen. As noted by the authors, “The primary biologic outcome measure, CSF OspA antigen, was present in only 16% of patients at baseline and was not a useful marker of outcome”. The study results therefore using this primary outcome measure should not be included in the final determination of whether IV ceftriaxone is effective as a treatment for PTLDS.

Summary.

This study was adequately powered to test only one of the 3 primary outcome measures: the only clinical measure on which patients were enrolled (ie, fatigue) and on which they were definitively impaired. For the disabling fatigue commonly seen among patients with PTLDS, sustained efficacy using IV ceftriaxone was demonstrated.

This placebo-controlled randomized trial enrolled 37 patients with post-treatment Lyme encephalopathy. Patients were assigned to treatment with 10 weeks of IV ceftriaxone or placebo in a 2:1 randomization followed by no treatment for 14 weeks. The primary end-points were week 12 for efficacy and week 24 for longer-term durability. As this was a study of Lyme encephalopathy, the primary measure of interest assessed cognition, with a specific focus on memory. Patients had to have both subjective cognitive complaint and objectively confirmed deficits in memory; patients with other known causes of cognitive impairment were excluded. The criteria for the diagnosis of Lyme disease required: a) documentation of physician-diagnosed erythema migrans or a later manifestation of Lyme disease meeting CDC surveillance criteria with a positive or equivocal ELISA confirmed by positive Western blot serology; and b) a positive IgG Western blot at the time of study entry. All patients also had to have had at least 3 weeks of prior IV ceftriaxone or IV cefotaxime treatment for Lyme disease. Because repeated neurocognitive testing can result in improvement merely because of the practice effect, healthy controls were included to control for this effect. There were therefore 3 groups (patients on drug, patients on placebo, and healthy controls). Over the course of the 24 weeks of this study, there was a significant group difference (p= 0.04) in cognitive change across time among the 3 groups; this difference was attributed to the initial improvement in overall cognition at week 12 in the drug group followed by the loss of that improvement by week 24. On the drug vs healthy control comparison at week 12, the improvement in cognition for the drug-treated group was greater than the improvement (presumably from the practice effect) noted in the healthy control group (p< 0.01). On the specific drug vs placebo comparison at week 12, the preferential improvement for drug in overall cognition fell at the margin of significance (p= 0.053); because this fell at the margin of significance and because the sample size was small, this result must be viewed with caution, and requires replication for confirmation of a treatment effect, as there is a slightly increased risk that this result occurred by chance. In this study, a statistically significant domain by treatment interaction effect was not seen; this indicates that the improvement in cognition was broadly distributed across the six cognitive domains and not specific to the primary domain of memory on which the study was powered. On the planned analysis of the secondary measures of pain, fatigue, and physical functioning, an interaction effect was noted with baseline severity such that the benefit of drug over placebo increased as baseline severity increased; the improvement observed at week 12 was sustained to week 24 for pain and physical functioning. Several patients had potentially serious side effects (e.g., 2 had thrombus formation at the PICC line, 1 had a staphylococcal infection, and 1 had biliary pain and stones that required cholecystectomy). On balance, given the marginal cognitive benefit at week 12, the lack of sustained cognitive benefit to week 24, and the risks, the concluding clinical recommendation from this study was that repeated IV antibiotic therapy followed by no treatment for 14 weeks was not recommended for sustained improvement in cognition.

It has been suggested that the initial improvement in cognition during the time of active drug treatment from baseline to week 12 may have been a “regression to the mean” effect. Fig. (2) demonstrates the change in cognition over time for the 3 groups in the Lyme encephalopathy study, indicating a comparable slope of improvement in cognitive performance over 24 weeks for the placebo and healthy control groups vs. a steeper slope of improvement for the drug group from baseline to week 12 followed by a decline to week 24. Regression to the mean is unlikely to account for the preferential improvement in the drug group between baseline and week 12 primarily because after drug was discontinued there was a regression away from the mean on the cognitive scores. While regression toward the mean is a well-established phenomenon, regression away from the mean is not. The improvement during the first 12 weeks (on antibiotics for 10 of these weeks) followed by worsening in the second 12 weeks (off antibiotics) would be more consistent with an active drug treatment effect that was not sustained. Also worth noting is that the differences at baseline in the drug and placebo groups on cognition were not statistically significant.

Fig. (2). Change in Cognition over time for 3 groups in Lyme Encephalopathy Study: patients were given 10 wks of IV ceftriaxone or pla-cebo and healthy volunteers were evaluated to assess the practice effect.

The planned analysis of the secondary outcome measures of pain, fatigue, and physical impairment produced interaction effects at week 12 favoring drug over placebo as a function of baseline severity, with the drug effect increasing with higher baseline impairment. As a model-based illustration of the study results, Fig. (3) illustrates the improvement in pain, fatigue, and physical functioning in the Lyme encephalopathy study as a function of baseline severity. (The middle panel (“Pain”) from Fig. (3) is reprinted here with permission from the journal Neurology [10]). Significant improvement was sustained among these more impaired patients to week 24 for the measures of pain and physical functioning. These results suggest that for a subgroup of patients with more severe impairment in pain or physical functioning, a course of repeated IV antibiotic therapy can result in sustained long-term benefit.

Fig. (3). Model-based Illustrations from Lyme Encephalopathy Study: change over time as a function of baseline severity on measures of Fatigue, Pain, and Physical Functioning.

Limitations of the Lyme encephalopathy study include the small sample size which would limit the ability to detect less robust treatment effects (n=37 for Lyme patients and 18 for healthy controls), the relative treatment refractoriness of the sample (mean amount of prior therapy: IV 2.3 months, oral 7.7 months) which would reduce the likelihood of finding a treatment effect for repeated treatment, and the limited generalizability of the study findings given the extremely rigorous but narrow criteria used to enter patients.

Because this study sample comprised patients with objectively confirmed evidence of cognitive deficits, the distinction between Lyme encephalopathy and post-treatment Lyme disease syndrome was blurred. Although these patients certainly had the typical post-treatment symptoms of pain, fatigue, and physical dysfunction, the presence of objective impairment in memory raises the question of whether these patients would be better defined as having “late Lyme disease” rather than “post-treatment Lyme disease syndrome”.

Based on the evidence cited above, one cannot conclude that repeated antibiotic therapy is ineffective in improving certain symptoms associated with post-treatment Lyme disease syndrome. Nor can it be concluded that repeated antibiotic therapy is robustly effective. One can conclude however that approximately 60% of patients with persistent post-treatment Lyme fatigue may experience meaningful but partial clinical improvement in fatigue with antibiotic retreatment. Guidelines for Lyme disease that address patients with chronic symptoms therefore need to clarify that the controlled trials of additional antibiotic therapy for post-treatment Lyme symptoms have revealed conflicting results, with some studies demonstrating efficacy and others not showing benefit to repeated treatment.

Specifically, the re-analysis of the results of the chronic Lyme trials leads to the following recommendation for the text of treatment guidelines. “IV ceftriaxone therapy is moderately efficacious for patients with chronic (>6 months) subjective fatigue after recommended antibiotic treatment regimens, but the risk associated with IV antibiotic therapy requires careful discussion with the patient of the cost-benefit ratio. Sustained improvement from IV ceftriaxone therapy for other PTLDS symptoms such as physical dysfunction and pain is uncertain, with positive results suggested by one study but not by other studies.”

The conclusions of this analysis of the chronic Lyme trials emphasize the benefits of repeated antibiotic therapy for patients with specific chronic symptoms. This is done as a counterbalance to the majority of published guidelines which overlook and/or dismiss the evidence that demonstrates that additional antibiotic therapy can lead to sustained benefit. We hope that our review will lead to more carefully detailed and balanced summaries in future guidelines. However, we also wish to emphasize that while some patients do improve with repeated antibiotic therapy, other patients with persistent symptoms do not. Further, as the clinical trials also demonstrate, antibiotic therapy particularly when given intravenously can put the patient at serious risk.

Biomarkers are needed that can help clinicians to discriminate in advance which patients are more likely to benefit from repeated antibiotic therapy vs. those for whom such treatment is unlikely to be beneficial. Future studies must also begin to address non-antibiotic strategies to help improve persistent symptoms. Recent serologic and CSF studies of patients with post-treatment Lyme disease syndrome suggest that a persistently activated immune response may play a role in the pathophysiology of chronic symptoms [15, 16] . Clarification of whether these findings are of pathogenic relevance and whether this immune activation is due to persistent antigenic stimulation (as might occur from persistent Borrelia) or from a post-infectious autoimmune process would be quite beneficial to clinicians seeking to identify more effective and appropriately targeted treatments for these patients.

This manuscript represents a modification of a presentation given by Dr. Fallon to a review panel convened in 2009 by the Infectious Diseases Society of America to re-evaluate its Lyme disease treatment guidelines.

The authors confirm that this article content has no conflicts of interest.