Repeated Antibiotic treatment in Chronic Lyme Disease

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Repeated Antibiotic Treatment in Chronic Lyme Disease

A. Fallon, MD, Felice Tager, PhD, Keilp, PhD, Nicola Weiss, PhD,

R. Liebowitz, MD, New York State Psychiatric Institute and Columbia

University Department of Psychiatry, New York, New York; Lesley Fein, MD,

Private Practice, West Caldwell, New Jersey; Liegner, MD, Private

Practice, West Caldwell, New Jersey.

[Journal of Spirochetal and Tick-Borne Diseases 6(4):94-102, 1999. © 1999

Lyme Disease Foundation, Inc.]

Abstract

Patients with chronic Lyme disease who experience persistent cognitive

deficits despite having received the recommended antibiotic treatment pose a

therapeutic dilemma. This pilot study was designed to assess whether

additional antibiotic therapy is beneficial.

Enrolled in the study were 23 patients with complaints of persistent memory

problems who had previously received 4-16 weeks of intravenous antibiotic

therapy. Patients were tested at baseline and 4 months later. During this

interval, the private physician determined treatment (intravenous,

intramuscular, oral, or none). Assessments included standardized measures of

cognition, depression, anxiety, and functional status.

Between times 1 and 2, 5 patients were given no antibiotics and 18 were

given additional antibiotics: 7 intravenously, 4 intramuscularly, and 7

orally. At time 1, there were no statistically significant group differences

in cognition, depression, or anxiety between those who later received

antibiotics and those who didn't. At time 1, the 23 patients were also

functionally disabled. At time 2, compared with patients who received no

antibiotics, patients given antibiotics scored better on overall and

individual measures of cognition. Patients given intravenous antibiotics

showed the greatest functional improvement (pain, physical functioning,

energy) and the most cognitive improvement, even when controlling for

baseline differences in cognition between the treatment groups. Patients who

did not have a reactive Western blot currently or historically were just as

likely to improve cognitively as patients with reactive Western blot

results.

This uncontrolled study suggests that repeated antibiotic treatment can be

beneficial, even among patients who have been previously treated and even

among patients who are currently Western blot negative, with the intravenous

route of treatment being the most effective. A double-blind

placebo-controlled study is needed to confirm these results.

Introduction

Lyme disease, caused by infection with the spirochete Borrelia burgdorferi,

can result in a chronic illness that persists despite standard courses of

antibiotic therapy. Characterized by persistent fatigue, arthralgias,

myalgias, peripheral neurologic disorders, and/or central neurologic

problems including mild to severe encephalopathy,[1-3] chronic Lyme disease

(CLD) may result in significant functional disability.[4,5]

Two main etiologies have been invoked to explain the persistent symptoms:

persistent infection and a postinfectious immunoinflammatory disorder.

The persistent infection hypothesis is based on several lines of evidence.

Uncontrolled clinical case reports indicate that some patients benefit from

longer and repeated courses of antibiotic therapy.[6-9] Microbiological

studies have shown that, even after antibiotic therapy, persistence of the

organism may be demonstrated by either culture or polymerase chain reaction

analysis in animals and humans.[10-17] Further, microbiologists speculate

that persistence may be promoted by the ability of B burgdorferi to lodge

intracellularly in human endothelial cells, astrocytes, fibroblasts, and

macrophages[18-23] and to modify its shape into potentially

antibiotically-protected cyst-like forms.[24,25] According to the persistent

infection theory, failure of antibiotic therapy result from an intracellular

location of the organism, the selection of resistant strains, or

sequestration of the organism in " protected " sites, such as the central

nervous system.

The postinfectious immunoinflammatory hypothesis also is supported by

several lines of evidence. At least for Lyme arthritis, it has been

suggested that patients who carry the HLA-DR4 or DR2 allele are more

vulnerable to developing antibiotic-resistant chronic Lyme arthritis.[26]

For neurologic Lyme disease, only one study reported an association with

these alleles,[27] whereas other European studies were not able to find such

an association.[28,29] Molecular mimicry may also account for a portion of

persistent Lyme disease, but the evidence for this has been indirect, based

on the observation that antibodies from patients with Lyme disease have been

found to cross-react with ganglosides, myelin, and a 64-kd protein seen in

normal human axons.[30-34] Flagellin protein may generate cross-reactive

antibodies to myelin basic protein (eg, elevation has been seen among

patients with neuroborreliosis). Finally, persistent neurologic Lyme disease

may not be caused by autoimmunity but, instead, caused by the damage done by

persistent activation of inflammatory cytokines by remnants of pieces of the

spirochete. Elevated levels of interleukin-6, tumor necrosis factor-alpha,

and nitric oxide are known to be produced by neural cells exposed to B

burgdorferi.[35,36] These cytokines can induce many of the symptoms of

fatigue and malaise associated with CLD.

Uncertainty regarding the etiology of CLD has led to considerable

polarization within the medical community regarding etiology and concern

over the serious consequences associated with either undertreating or

overtreating patients. In view of the complexity of borreliae and the

intricacy of the host-pathogen interactions, it is likely that individual

patients may suffer from persistent infection, residual damage, an ongoing

autoimmune reaction, or any combination of these.

Given the etiological uncertainty regarding CLD and the importance of

measuring response to treatment in an objective way, in 1993 we designed an

uncontrolled pilot study to determine whether patients with persistent

memory complaints after the diagnosis and treatment of Lyme disease, who

have been previously adequately treated, show quantitative cognitive

improvement with repeated antibiotic treatment over a four-month interval.

Methods

Patients

Institutional Review Board approval was obtained for this study from the New

York State Psychiatric Institute. Prior to formal assessments, patients were

interviewed by the primary investigator to confirm study eligibility and to

obtain signed informed consent.

Adults age 18-65 with previously diagnosed and treated Lyme disease who

complained of persistent cognitive symptoms were recruited from the offices

of community physicians who practice in Lyme endemic areas. The diagnosis of

Lyme disease was based on the following criteria: a) exposure to a Lyme

endemic area; a history of a physician-diagnosed erythema migrans rash

and/or a positive serological test for Lyme disease (ELISA, Western blot);

and c) a history of clinical symptoms typical of Lyme disease affecting the

cardiac, neurologic, and/or articular systems. To be eligible for our study,

all patients had to have been previously treated with at least 4 and no more

than 16 weeks of intravenous antibiotics prior to study enrollment. Because

this study was designed prior to the establishment of the two-tiered

serologic testing method now recommended by the Center for Disease Control

and Prevention (CDC),[37] our criteria used the prior CDC standard of either

a reactive ELISA or a reactive Western blot. Although some patients had

cerebral spinal fluid studies done previously and/or magnetic resonance

imaging scans, these studies were not requirements for study entry.

Assessments

Patients were evaluated at baseline and four months later on a battery of

standardized tests. These tests evaluated disability (MOS Short-form 36

Functional Status Questionnaire), anxiety (Zung Anxiety Scale), depression

(Beck Depression Inventory), and cognition (Wechsler Adult Intelligence

Scale, the Wechsler Memory Scale, and the Controlled Oral Word Association

Test). Between the two assessment points, patients returned to their private

physician.

Neuropsychological change was assessed in two ways. First, the group's mean

change between Time 1 and Time 2 on each of the neuropsychological tests was

assessed. Second, a composite z-score was created for each individual by

adding the number of standard deviations away from published age norms on

the following 16 tests: each of the 11 subtests of the WAIS, the 4 tests of

the Wechsler Memory Scale (Verbal Memory, Visual Memory,

Attention/Concentration, Delayed Memory), and the Controlled Oral Word

Association Test.

Serum was collected from 19 of the 23 patients for Lyme serology testing,

which was sent to BBI Clinical Laboratories for analysis. Serum from 16

patients was also sent to the University Hospital of Stony Brook for B

burgdorferi-specific immune complex assays.[38,39]

Treatment

Because this was a pilot clinical study, treatment over the four-month

interval was not controlled. Patients were treated according to the clinical

judgment of their physicians. Most patients were treated with antibiotics

[oral, intramuscular (IM), or intravenous (IV)] whereas smaller numbers of

others received no antibiotics. For exploratory analyses, patients were

divided into 4 subgroups based on the treatment chosen by their private

physician: none, oral, IM, IV.

Because the treatment was chosen by numerous different private internists,

the treatments varied greatly both in the actual choice of antibiotic, the

duration of treatment during the interval, and whether or not different

routes of antibiotics were used simultaneously or sequentially (eg, oral and

IM, oral and IV). The only constant was that patients on IM antibiotics were

all given penicillin G (benzathine penicillin G) for the first time. The

majority of patients on oral antibiotics alone during the assessment

interval were maintained on the antibiotics that they had been on prior to

study entry. To be included in the oral, IM, or IV antibiotic groups,

patients had to have received at least 10 days of treatment during the

interim.

Statistics

Statistical tests included paired sample t-tests, analyses of variance

(ANOVA), Tukey's HSD, Pearson Correlation, and analyses of covariance

(ANCOVA) to control for baseline differences. Significance was defined as a

two-tailed P-value of less than or equal to .05.

Results

Description of Sample

There were 23 patients enrolled. Mean age was 42.7 years (SD 13.25), ranging

from 20-65 years with a gender distribution of 30% male and 70% female. The

mean length of time since diagnosis was 21.33 months (SD 22.2), ranging from

2 to 168 months. The symptom history of these 23 patients since the onset of

Lyme disease included the following: memory loss (100%), arthralgias (96%),

word-finding problems (91%), headaches (91%), excessive fatigue (87%), sleep

disturbance (87%), irritability and mood lability (87%), arthritis (52%),

recalled tick bite (39%), erythema migrans (total: 39% of which 26% were

physician-diagnosed at the time and 13% were considered retrospectively by

physicians to have been erythema migrans based on description), and Bell's

palsy (13%). Of the 23 patients, 22 had had a reactive ELISA or Western blot

for Lyme disease. The one historically seronegative patient had a clinical

history of a physician diagnosed erythema migrans, arthritis, and Bell's

palsy; this patient's serum was reactive on IgM Western blot from BBI

Clinical Laboratories.

Study laboratory results on 19 patients were as follows. ELISA: IgG -- 1/19

reactive, 11/19 equivocal; IgM -- 0/19 reactive, 2/19 equivocal. Western

blot: IgG -- 0/19 reactive, 5/19 equivocal; IgM -- 4/19 reactive, 7/19

equivocal. In 5 of 19 patients either a reactive ELISA or Western blot was

found.

Assays for B burgdorferi-specific immune complexes were conducted on 16

patients. IgG B burgdorferi-immune complexes -- 8/16 reactive. IgM B

burgdorferi-immune complexes -- 3/16 reactive. Neither IgG nor IgM B

burgdorferi-immune complexes was found in 9 of 16 patients.

The mean duration of prior antibiotic treatment is shown in Table 1. An

ANOVA failed to find a difference between the subgroups on the extent of

prior oral antibiotics and prior IV antibiotics.

Time 1 (Baseline) Scores

Cognition

At baseline, the 23 patients as a group had average verbal, performance, and

full scale IQ. However, these patients, as a group, had significant

impairments in verbal memory, general memory, and delayed memory on the

Wechsler Memory Scale when compared with the WAIS Verbal IQ and Full Scale

IQ. When the 23 patients were subdivided into the 4 treatment groups and the

baseline results on specific cognitive tests were compared using an ANOVA,

no significant differences were found. Similarly, when comparison was made

using a Tukey HSD analysis of multiple comparisons, no significant

differences were found on the cognitive tests. In addition, at baseline,

there were no statistically significant differences between the 4 treatment

subgroups on the mean composite z score (oral 1.167.7; IV -3.6622.6, IM

4.265.3; none -4.967.2).

Anxiety/Depression

On the Beck Depression Inventory, the 23 Lyme patients had a mean score of

16.0610.02 (range 2-43) indicating a mild level of depression for the group.

On the Zung Anxiety Index, the mean score was 53.569.18, indicating a

moderate level of anxiety for the group (range 41-74). There were no

treatment subgroup differences on these two measures on a group ANOVA. No

significant correlation was noted between the anxiety/depression scores and

the degree of cognitive impairment at baseline. Anxiety and depression,

however, were positively correlated (r = .647, P = .001).

Functional status

The scores on the subtests of the MOS-SF 36 Disability measure revealed

marked disability among these patients with CLD: energy/fatigue 23.6617.9,

pain 35.8624.7; emotional well-being 51.1623.5, general health 39.4624.2;

physical functioning 49.1621.5; role (physical) 13.6625.3, role (emotional)

39.4644.4; social functioning 40.3631.1. There was no significant group

difference among the 4 treatment subgroups on emotional well being, general

health, physical functioning, role (emotional), role (physical), or social

functioning. However, the groups were significantly different on

energy/fatigue, with the least energy being reported by the patients who

were subsequently given a course of IV antibiotic treatment (IV 9.265.6; IM

31.6629 2, oral 22.9611.6; none 37.0618.6, F = 3.2, P = .048).

Treatment

During the four-month interval between assessments, 5 of the patients were

given no treatment, 7 were given oral antibiotics only, 7 were given IV

antibiotics (with or without oral antibiotics), and 4 were given IM

antibiotics (with or without oral antibiotics). For the patients on one or

more oral treatments only, these antibiotics included doxycycline,

minocycline, amoxacillin, penicillin, azithromycin, clarithromycin,

cefuroxime, and cefixime. The IM antibiotic used was benzathine penicillin

G. Intravenous antibiotics included imipenem, cefotaxime, ceftriaxone, and

vancomycin. Table 2 specifies the percentage of time between Time 1 and Time

2 the patients in each group were given antibiotics. No significant

difference was noted between the groups of antibiotically-treated patients

on the number of weeks treated between Time 1 and Time 2.

Time 2 Scores

Cognitive Change

A) Overall cognitive change. For the 18 antibiotically treated patients, the

composite z score between Time 1 and Time 2 improved 6.1 standard deviations

(t = 2.8, P = .012) compared with an improvement of only 2.8 standard

deviations among the 5 patients who received no treatment (ANCOVA Any Abx v

None, F = 4.9, P = .039).

Overall cognitive change by type of treatment. When the 23 patients were

sorted into subgroups based on treatment received during the interim and

their Time 2 scores were compared (controlling for baseline z-score

differences), patients retreated with IV antibiotics did the best: the

composite z-score improved 11.8 SD (median 8.9) for the 7 IV patients, 2.4

SD (median 2.5) for the 6 IM patients, 2.3 SD (median 2.0) for the 7 po

patients (ANCOVA IV v PO, F = 6.9, P =.023), and 2.8 SD (median 2.0) for the

5 no antibiotic patients (ANCOVA IV v None, F = 10.58, P = .010).

C) Overall cognitive change and duration of treatment. There was no

significant correlation between duration of time on antibiotics and

composite z-score improvement. However, when the sample was divided into

three groups based on the percentage of time on antibiotics between Time 1

and Time 2 (No Abx; Abx 50% of the time or less; Abx >50% of the time), the

composite z-score improvement was 2.8 SD, 4.9 SD, and 6.5 SD respectively,

suggesting that longer term treatment may be beneficial.

D) Neuropsychological subtest improvement. Comparing Time 1 and Time 2 using

a paired samples t-test for the 18 antibiotically treated patients, marked

improvement was noted in a variety of subtests including full scale IQ,

performance IQ, verbal memory, general memory, attention/concentration, and

delayed memory(Figure; Table 3). To examine whether memory within

individuals improved over the four-month period, the difference between

general memory and verbal IQ was calculated for each patient. The 18

patients given antibiotics significantly improved (narrowing the distance

between general memory and verbal IQ by 4.6 scaled points) over the

four-month interval whereas the 5 patients given no antibiotics worsened

(broadening the distance between the two scores by 7.6 scaled points)

(ANCOVA F = 5.22, P = .033).

Figure. Change in cognitive scores for 18 antibiotically treated chronic

Lyme disease patients.

E) Cognitive change associated with treatment received. When an ANCOVA was

used to compare the Time 2 scores of the patients based on the treatment

received during the interim, the IV group generally performed better than

patients in the other groups. Significantly greater improvement was noted

for the IV group compared with the oral group on the subtests of

attention/concentration (F = 13.2, P = .005), general memory (F = 5.9, P =

..038) and visual memory (F = 8. 1, P = .019). Marked improvement was also

seen among the IV patients on verbal fluency and verbal memory. When the IV

group was compared to the oral group, greater improvement was noted for the

IV group on the subtests of attention/concentration (F = 4.2, P = .064),

general memory (F = 5.3, P = .042), and visual memory (F = 27.1, P <.001).

F) Cognitive change associated with current laboratory seropositivity. No

significant difference in mean improvement in cognition (composite z-score)

was noted comparing antibiotically treated patients who did and who did not

have currently reactive B burgdorferi-specific antibody levels using the

criteria of either BBI Clinical Laboratories (ELISA or Westem blot) or Dr.

Coyle's Immune Complex assay. When we separated patients into two groups

based on whether or not they met the two-tiered testing requirement of a

reactive or equivocal ELISA and a reactive Western blot historically, no

significant differences in mean improvement in cognition were noted.

Anxiety/Depression

A) Overall change in depression/anxiety. Mild improvement on the Zung

Anxiety scale and Beck Depression Inventory was noted among all 23 patients

between Time 1 and Time 2. Significant improvement on the " Emotional

Well-being " and " Role-Emotional " subtests of the MOS-SF 36 Rand functional

status measure was noted among the 23 patients as a whole.

Overall psychiatric change by type of treatment. When the change in

scores on anxiety and depression for the antibiotically treated patients

between Time 1 and Time 2 were examined, a significant improvement was noted

on the anxiety scale using a paired sample t-test. (Table 3). However, when

an ANCOVA was used comparing Time 2 scores (controlling for Time 1 scores),

no significant differences in anxiety or depression scores were noted based

on presence or absence of antibiotic therapy or on route of treatment.

Neither were significant changes noted between the individual subgroups on

the scales of emotional well being and role functioning attributed to

emotional health.

C) Correlation between psychiatric improvement and cognitive change. The

percentage improvement in anxiety (10.7619.4) was not correlated with

improvement in cognitive z-score (5.3668.22) among all 23 patients (r =

..415, P = .044). Nor was there a significant correlation between percentage

change in depression and improvement in cognition. Improvement in anxiety

was, however, significantly correlated with improvement in depression (r =

..459, P = .032).

Functional Status Improvement

A) Overall change in functional status. On the MOS-36SF for the

antibiotically treated patients comparing Time 2 and Time 1, significant

improvement was noted in the domains of energy/fatigue (t = 2.4, P = .030),

pain (t = 3.6, P = .003), physical functioning (t = 2.4, P = .028), role

physical (t = 2. 1, P = .048), and social functioning (t = 3.2, P = .005).

However, no significant differences were noted when an ANCOVA was used to

compare the Time 2 scores of the patients who received no antibiotics and

the patients who received any antibiotic, indicating that both groups showed

functional improvement.

Overall functional change by type of treatment. A significant difference

was not found using an ANCOVA when the functional status improvement of each

of the 4 groups were examined together. However, when the patients who

received IV antibiotics were compared with the other 3 groups (IM, oral, and

no treatment) as a whole, there was greater improvement, even when baseline

differences are controlled for, among the IV-treated patients in the areas

of pain (F = 3.0, P = .099), energy/fatigue (F = 6.2, P = .020), general

health (F = 3.9, P =.063), physical functioning (F = 6.8, P = .017), role

physical (F = 4.5, P = .047), social functioning (F = 5.0, P = .037), and

emotional well-being (F = 5.4, P = .031).

Discussion

This study suggests that repeated courses of antibiotic treatment may result

in objectively quantifiable cognitive improvement over a four-month interval

among a group of patients each of whom had received more than the standard

recommended course of antibiotic therapy previously. Further, the study

suggests that for patients with Lyme encephalopathy the IV route of delivery

may be most effective, not only in producing dramatic cognitive improvement

but also by enhancing energy and decreasing pain, resulting in better

physical, social, and emotional functioning. These results are consistent

with the observations of physicians who note that many patients with

persistent symptoms appear to benefit from repeated courses of antibiotic

therapy, a phenomenon supportive of the persistent infection hypothesis.

Based on comparison with published data using the same functional disability

measure (Short-Form 36) among patients with other chronic diseases, the 23

CLD patients in this study were more functionally disabled than patients

with congestive heart failure, hypertension, type 1 diabetes mellitus, and

major depression.[40,41] The energy/fatigue and freedom from pain scores

among the Lyme patients were 2-3 times worse than the published scores among

patients with the latter diseases. Role limitations because of physical

health were particularly severe for the Lyme patients, with scores 4-8 times

worse than patients with these other diseases. These results underscore the

seriousness of CLD and the profound impact it has on patients' lives.

Although this study did find marked group effects when comparing cognitive

improvement among those who received antibiotics and those who did not, only

in the subgroup analyses comparing patients who received IV antibiotics to

all others did we find significant differences on the functional disability

measures. This suggests that IV antibiotics may be particularly effective

and that neuropsychological tests may be a more sensitive measure of change

over time than self-report disability measures. Studies of patients with

encephalopathy that rely on the MOS-36SF as a major outcome measure may need

much larger sample sizes and longer durations of follow-up to show

differences between treated and untreated samples.

The majority of the patients in this study were not depressed. The group

anxiety level was moderate in intensity. No significant relationship was

found between amount of depression and anxiety at baseline and overall

cognitive impairment. Nor did we find that the more depressed patients at

baseline had the least amount of cognitive dysfunction, as had been found in

an earlier study of patients with CLD.[42] Contrary to the hypothesis that

attributes many of the symptoms of CLD to somatization, anxiety and/or

depression (ie, a psychogenic hypothesis)[43] the majority of patients with

CLD in our study were not suffering from significant levels of

psycho-pathology. Further, patients who were more depressed or anxious were

just as likely to respond to antibiotic therapy with an improvement in

cognition as those who were less depressed or anxious.

Several factors need to be addressed regarding the limitations and strengths

of this study. First, because we employed the same battery of

neuropsychological tests separated by only four months, a repeated testing

(practice) effect that artificially improved the Time 2 scores most likely

occurred. A repeated testing effect, however, could not alone account for

the marked improvement among the antibiotically-treated patients because

comparable improvement was not noted among the 5 patients who received no

treatment but who also were retested. The fact that the pattern of

improvement sorted out differently for the treatments (IV > other or none)

suggests that there was in fact improvement that could be attributed to the

specific route of antibiotic delivery. This improvement might relate to the

better CNS penetration provided by the IV route or to the drama of an

invasive procedure. If the latter were true, one might expect that the

patients who received IM injections would have shown greater improvement

than the patients who received oral or no treatment because the IM group

also was receiving a new and invasive treatment. This was not the case.

Although we doubt that the drama of IV therapy alone could account for the

marked cognitive and functional improvement noted in our small sample, only

a placebo-controlled IV therapy study could prove this for certain.

Second, because of our small sample size, statistically significant

differences between treatment groups at Time 1 and Time 2 would be hard to

detect. The fact that significant differences did emerge from the Time 2

treatment subgroup analysis is surprising. However, definitive conclusions

about the benefit of a specific route of antibiotic therapy cannot be made

because the treatment selection was neither uniform nor randomly assigned.

Further confounding the conclusions about the relative benefit of one route

of treatment versus another is that many patients received two antibiotics

simultaneously (ie, oral and IV, oral and IM). The results of our study may

suggest to the reader that oral antibiotic therapy is ineffective for

patients with chronic Lyme encephalopathy because the improvement in

cognition among the patients on oral antibiotics alone was no better than

among the patients who received no antibiotic therapy. We feel that this

conclusion is unwarranted because the patients who had been on oral

antibiotics and whose physician did not choose to switch to another route or

add another route of antibiotic delivery tended to continue on that same

oral antibiotic. In other words, whereas the patients given IV or IM

antibiotics were all starting either a new therapy or one that they had not

received for many months, the patients on oral antibiotics alone were merely

being maintained on an ongoing treatment. However, the study does suggest

that there may be a particular benefit to a repeated course of IV antibiotic

therapy once response has leveled off.

Third, is it possible that fatigue accounted for the poor cognitive

performance among the IV-treated patients at baseline and that a resolution

of their systemic fatigue could account for much of the cognitive

improvement? Krupp et al[42] observed that fatigue was highly correlated

with poor cognitive performance in a sample of patients with persistent Lyme

encephalopathy. In our sample, although there were no statistically

significant cognitive differences at baseline that distinguished the

different groups, there was a difference in the level of fatigue among the

different treatment groups: patients selected for IV antibiotics suffered

the greatest fatigue; patients given oral or IM antibiotics had moderate

levels of fatigue; and patients given no antibiotics had the least amount of

fatigue. If fatigue is a marker of greater illness severity, then the IV

group appears to have been sickest. Based on simple regression to the mean,

their energy levels would have been the most likely to improve, perhaps

contributing to the improvement in their cognitive scores. In fact, when

baseline level of fatigue is used as a covariate, no significant difference

is noted between the treatment groups on the overall degree of cognitive

improvement. In other words, improvement in energy and cognition run

together. One possible explanation for these results relates to a decrease

in fatigue and cognitive disturbance because of a decrease in inflammatory

cytokine production that had been triggered by persistent peripheral or

central infection. Although regression to the mean in fatigue level might

have contributed to some of the cognitive improvement, we doubt that

regression to the mean alone could by itself account for the robust

improvement in cognition seen among the patients given antibiotics in

general (6.1 SD) and IV antibiotics in particular (11.8 SD), particularly

when one considers that the patients who received no antibiotics had the

lowest mean cognitive z-score at baseline and their improvement was far more

modest (2.8 SD).

Fourth, because of the time our study was designed, the laboratory criteria

for inclusion made use of the pre-1994 CDC criteria of either a reactive

ELISA or Western blot. The current CDC guidelines recommend two-tiered

testing: an equivocal or a reactive ELISA is to be followed by a Western

blot assay.[37] If we examine our data comparing the historical laboratory

results of patients who would be considered seropositive by this two-tiered

method with patients whose results did not meet this two-tiered standard

(using the more inclusive, varied, and less standardized Western blot

criteria employed by the individual laboratories conducting the tests at

that time), there is no difference in the cognitive change score between the

two antibiotically-treated groups. In other words, the two-tiered method of

laboratory testing did not help to identify patients who were more or less

likely to respond to antibiotic therapy. Further, it should be noted that

only 4 of the 19 serum samples were Westem blot reactive, and each of these

was a reactive IgM not an IgG Western blot. Of these 7 patients who received

a repeated course of IV antibiotics, none had a reactive Western blot. Had

these patients been denied treatment based on not having a currently

positive Western blot result, these patients most likely would not have

improved.

Fifth, because this was a small uncontrolled pilot study that did not have

randomly assigned and blinded treatment assignment, no definitive

conclusions can be drawn from this study. For example, the study results may

have been adversely effected or skewed by the small numbers of patients, by

the lack of a blinded IV placebo treatment, and by the fact that nonrandom

treatment assignment raises the likelihood that extraneous confounding

factors were present but not identified by us.

In summary, our pilot study suggests that repeated courses of antibiotic

therapy, in particular when given intravenously, can be effective for

patients with a history of Lyme disease who have persistent cognitive

problems despite robust prior treatment. In addition, our study suggests

that currently " seronegative " patients may be just as likely to respond to

treatment as currently " seropositive " patients. These " suggestive " findings

need to be tested by a placebo-controlled study using a larger sample size,

randomized and uniform treatment assignment, blinded evaluators, and

separate randomization of patients who meet the CDC's current laboratory

criteria for the diagnosis of Lyme disease and those who don't.

Acknowledgment

The authors wish to thank Coyle, MD, for conducting the immune

complex assays. Partial funding support for this study was provided by the

Lyme Disease Association of New Jersey and a NYS Psychiatric Institute

Research Support Grant.

Table 1. Weeks of treatment with oral, intravenous (IV), or intramuscular

(IM) antibiotic prior to study entry (N = 23).

Oral Group IV Group IM Group No Antibiotic All Groups P

Prior oral antibiotics 27.6619.2 12.7612.5 95.8676.0 19.8626.2 33.2644.2 NS

Prior IV antibiotics 11.1613.3 8.763.9 9.364.6 4.461.5 8.667.9 NS

Prior IM antibiotics 0 0 0 0 0 NS

Abbreviation: NS = not significant.

Table 2. Percentage of time on antibiotics between Time 1 and Time 2 for 23

patients with chronic Lyme disease.

Oral Group IV Group IM Group No Antibiotic All Groups

% of time on oral antibiotics 78.0629.6 46.1643.1 0 0 49.7644.0

% of time on IV antibiotics 0 56.0629.7 0 0 17.0630.6

% of time on IM antibiotics 0 0 77.0627.5 0 13.7631.4

% of time on any antibiotics 78.0629.6 67.2626.9 90.8618.5 0 59.9639.9

Note. There were no significant differences among the antibiotically treated

patients in either the percentage of time on any antibiotic or in the

percentage of time on oral antibiotic during the interim.

Abbreviations: IM = intramuscular; IV = intravenous.

Table 3. Baseline and time 2 scores for antibiotically treated patients

(n=18).

Test Time 1 (SD) Time 2 (SD) t-score Df P

Wechsler Adult Intelligence Scale-Revised

Full scale IQ 102.2616.6 109.1611.9 -3.28 17 .004

Verbal IQ 102.7616.2 106.269.1 -1.46 17 NS

Performance IQ 101.7616.2 110.8614.6 -4.60 17 <.001

Information 10.763.1 10.962.2 -.704 17 NS

Digit span 10.663.3 11.362.5 -1.42 17 NS

Vocabulary 11.063.3 11.362.2 -.56 17 NS

Arithmetic 10.663.4 11.262.2 -.871 17 NS

Comprehension 9.562.8 11.161.8 -3.12 17 .006

Similarities 10.362.8 10.661.6 -.615 17 NS

Picture completion 10.263.6 11.462.8 -1.64 17 NS

Picture arrangement 10.963.5 11.762.9 -1.04 17 NS

Block design 10.163.3 10.962.8 -1.6 17 NS

Object assembly 9.962.9 11.262.4 -2.36 17 .031

Digit symbol 10.163.1 11.163.0 -2.47 17 .028

Wechsler Memory Scale-Revised

Verbal memory 92.9619.1 102.3614.9 -3.09 17 .007

Visual memory 104.1619.5 110.4612.7 -1.50 17 NS

General memory 95.1616.7 106.6614.9 -4.57 17 <.001

Attention/concentration 101.3617.9 108.4612.6 -1.96 17 .066

Delayed memory 94.9616.9 109.9615.8 -4.14 17 .001

Verbal fluency (FAS) 42.2617.2 45.4615.9 -1.03 17 NS

Beck Depression Inventory (n=17) 14.567.5 12.168.0 .863 16 NS

Zung Anxiety Scale 52.868.0 46.369.8 2.48 17 .024

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