Treatment of Lyme Disease
The treatment of early Lyme Disease has been examined in numerous well-documented studies. Largely because the diagnosis is easy to confirm when the erythema migrans rash is present, the academic research community has focused its efforts on the treatment of early or acute Lyme Disease. (Erythema migrans is the red, expanding rash that develops after the tick bite.) Studies demonstrate that 3-4 weeks of oral antibiotics (doxycycline, cefuroxime, amoxycillin) results in remission and apparent cure in most cases.
Once the tick-borne spirochete, Bb (Borrelia burgdorferi) has disseminated in the blood stream to other areas (such as the Central Nervous System or the joints), optimal dosing and duration of treatment is more uncertain. Physician organizations have produced guidelines to assist the clinician in making treatment decisions (IDSA, AAN, ILADS). These guidelines, while helpful for early Lyme disease or the more classic manifestations of Lyme disease, are in conflict over the treatment approach for patients with chronic Lyme disease. The reader is advised to review the different guidelines. To assist the reader in making his/her own determination about how to treat patients with chronic Lyme disease, in the paragraphs that follow we will summarize the findings from the 4 controlled studies of post-treatment or chronic Lyme disease that have been conducted in the United States over the last decade.
Klempner et al (2001) recruited patients with persistent symptoms and impairment despite treatment for well-documented Lyme disease. For the first 3 months, all patients were randomly assigned to receive either: a) one month of cefriaxone (2 grams/d) followed by 2 months of oral doxycycline (100 tid); or b) one month of IV placebo followed by 2 months of oral placebo. Between months 4-6, all patients were antibiotic-free. In this study, prior to randomization, patients were divided into two groups – those who remained IgG Western blot positive at the time of entry into the study (seropositive group) and those who were no longer seropositive (seronegative group). Although the study design was identical for both groups of patients, this research project has been referred to as 2 studies because the groups were separated prior to randomization. The primary outcome measure was improvement on one of the two primary indices of the Short-form 36 – physical composite scale and mental composite scale. The primary end-point was 6 months, although assessments were also made at 3 months. The authors of this study found no difference in categorical improvement on the self-report functional disability scale between those patients who were randomized to the antibiotic arm or to the placebo arm. The authors also noted that the treatment itself could cause significant risk – as one patient experienced a pulmonary embolus. The conclusion was that this regimen of treatment was ineffective and potentially harmful for patients with persistent symptoms.
Krupp et al (2003) recruited patients with persistent fatigue after treatment for well-documented Lyme disease. For the first month, patients received either IV ceftriaxone (2 gms/day) or IV placebo. For months 2-6, patients were on no antibiotics. The primary outcome measure was the fatigue severity scale, as patients were recruited into the study based on fatigue severity. Additional outcome measures included a cognitive measure of processing speed and an experimental measure of OSP A antigen in the CSF. The primary outcome time-point was month 6. The authors of this study found that a significantly greater proportion of patients randomized to ceftriaxone had categorical improvement in fatigue compared to patients randomized to placebo (69% vs 23%, p<.01). The authors also found that the proportion of responders was greater for patients who were IgG Western blot positive at the time of study entry compared to those who were IgG negative (80% vs 13%, p<.01). Some patients in this study did have adverse effects related to either the PICC line or the study medication, including 3 cases of IV sepsis and one of anaphylaxis. Although 3x as many patients given IV ceftriaxone for one month showed a meaningful improvement in fatigue compared to those patients given IV placebo, the authors of this study recommended against a course of IV antibiotics for patients with persistent fatigue after prior treatment for Lyme disease. While the rationale for this conclusion was not entirely clear, considerations included the lack of improvement in cognition and the risk of adverse effects. The authors of this study did question whether the sample size was sufficiently large to detect a treatment effect for improvement in mental processing speed as the impairment was on average only mild in this group.
Fallon et al (2008) conducted a study of persistent Lyme encephalopathy to examine whether a repeated course of IV antibiotic therapy would be beneficial for those patients with cognitive impairment and a prior history of having been treated with IV antibiotics for well-documented Lyme disease. In this study, all patients had to meet criteria for memory impairment and have a persistently positive IgG Western blot. Unlike earlier studies that relied on self-report measures to assess primary outcome, the primary outcome method in this study was the objective measurement of cognition through the use of neuropsychological tests; because patients were recruited for memory impairment, the primary domain of interest was memory. Patients also completed self-report questionnaires, such as the SF-36 which was used in the Klempner et al study and the Fatigue Severity Scale which was used in the Krupp et al study. The primary end-point for efficacy was 3 months. Durability of response was assessed at 6 months. Patients were randomly assigned to either IV ceftriaxone or IV placebo for 10 weeks. Because cognition was of primary interest in this study and because it is a well-known phenomenon that people do better when the same tests are repeated several months later, this study included the assessment of a sample of
healthy volunteers. This study therefore had 3 groups – patients given IV ceftriaxone, patients given IV placebo, and healthy volunteers who were given the same assessments at the same intervals. The primary finding from this study was that there was a significant difference in the pattern of cognitive change across the 24 weeks of this study for the 3 groups and that this difference was due to the overall cognitive improvement in the drug-treated group apparent at 3 months. On the primary domain of interest (memory), however, there was no significant difference at either week 12 or week 24 across groups. While patients on placebo and healthy volunteers showed a gradual improvement in cognition over time, the patients given IV ceftriaxone showed a greater improvement at the primary endpoint of 3 months but then lost their gains during the antibiotic-free interval to 6 months. (Please refer to the figure.)
On the secondary measures of fatigue, pain, and physical functioning, patients who were more impaired at baseline also showed a greater improvement at week 12 if they had been given IV ceftriaxone and this improvement continued to week 24 on the pain and physical functioning measures. Of concern in this study was that approximately one in five patients enrolled had adverse effects that resulted in either hospitalization or withdrawal of study medication; these included allergic reactions, biliary pain from ceftriaxone-stones, thrombi forming on the PICC line, systemic infection with staph. When the study sample was analyzed in a post-hoc fashion using the same criteria for enrollment and outcome as in the Krupp et al study, the results were nearly identical – patients given IV ceftriaxone showed greater benefit than those given IV placebo. (See Figure).
This Lyme Encephalopathy study had the limitations inherent in a study of small sample size (n=37) and a highly conservative definition of Lyme disease (thus limiting generalizability). Because this study was designed to assess cognition generally and memory specifically, because memory did not show specific improvement, because the cognitive improvement was not sustained, and because there were adverse effects that were potentially dangerous, the authors concluded that 10 weeks of IV ceftriaxone followed by no treatment for 14 weeks was not recommended for sustained cognitive improvement. While the study did suggest that repeated IV antibiotic therapy may result in sustained improvement in other symptoms among the more impaired subgroups (pain, fatigue, physical functioning), these self-report measures were not the primary outcome measures chosen apriori for this study and would require additional study in order to draw definitive conclusions.
What can we conclude about the net impact of these 4 randomized controlled studies conducted among patients with persistent symptoms after treatment? The two Klempner studies were negative while the Krupp study was positive on the primary measure of fatigue upon which the patients were enrolled. The Fallon study showed a moderate improvement in cognition favoring the ceftriaxone group but this improvement was not sustained except on some of the secondary measures. The simplest conclusions would be: a) some studies show clinical improvement in response to repeated antibiotic therapy while others do not; b) IV antibiotics in particular are associated with serious risks; and c) other treatment approaches need to be investigated that are safer and lead to larger and sustained improvement.
Other Treatment approaches for the neuropsychiatric symptoms.
Patients with chronic neuropsychiatric Lyme Disease may benefit from adjunctive therapies that provide symptom relief. For example, patients with an increased sensitivity to noise may benefit from gabapentin (Neurontin) or carbamazepine (Tegretol) treatment. The latter medicine may also be helpful to reduce skin hypersensitivity or headaches. Patients with marked distractibility and inattention may benefit from medicines used to treat Attention Deficit Disorder, such as bupropion (Wellbutrin) or methylphenidate (Ritalin). Patients with prominent fatigue may benefit from treatment with the latter medications as well. Modafinil (Provigil) is often also used to enhance energy among patients with persistent fatigue.
Neurologists are beginning to examine whether the neuropathies experienced by patients with Lyme disease may benefit from treatment with intravenous immune globulin (IVIg) which is considered a safe and effective treatment for autoimmune neuropathies. Mild infusion-related reactions occur often but these can often be controlled by slowing the infusion rate or by symptomatic medications. Serious adverse effects, although rare, may include thromboembolic events (esp among patients with pre-existing vascular disease), renal failure (among patients with renal insufficiency), anaphylaxis (esp among patients with IgA deficiency), or septic meningitis (especially among patients with migraine). Patients with these risk factors should carefully discuss the risks and benefits of IVIg treatment with his/her physician. At this point, given the lack of systematic or controlled studies, IVIg for Lyme neuropathies is an experimental treatment.
Consultation with a psychiatrist can be very helpful both to address the psychological impact of a chronic illness as well as to address the psychiatric symptoms that may have been triggered. Psychiatric medications such as sertraline (Zoloft), fluoxetine (Prozac), paroxetine (Paxil), fluvoxamine (Luvox), and citalopram (Celexa) may be helpful for patients with depressed mood or irritability. Medicines, such as the anti-convulsants (gabapentin, valproate, carbamazepine), are also very good mood-stabilizers and may serve to help patients with marked mood shifts, neuropathic pain, and/or sensory hyperacuities. Other medicines, such as amitriptyline (Elavil), trazadone (Desyryl), quetiapine (Seroquel), or nefazadone (Serzone), may be very helpful for sleep and (if treated with amitriptyline) for reducing pain.
Consultation with a neuropsychologist with expertise in cognitive remediation can also be helpful. Cognitive remediation refers to the retraining of the brain to accomplish tasks that were previously done automatically. Cognitive strengths are used to compensate for current weaknesses. Such approaches have been developed for patients with persistent cognitive deficits after head injury, for example. Similar strategies may be helpful for patients with persistent Lyme Disease. The best places to find experienced remediation therapists would be Centers for Brain Injury Rehabilitation.
Ongoing attention to the problem of "deconditioning" needs to be addressed. Because patients with chronic Lyme Disease often experience dramatic fatigue (much akin to patients with Chronic Fatigue Syndrome), they spend much time in bed and so their muscles lose tone over time. This can lead to an ever worsening syndrome in which patients get tired after exercise and so avoid it. Further deconditioning results such that even less exercise the next time leads to considerable post-exertional fatigue. To counter this cycle, a very gradual but progressive exercise regimen needs to become a daily part of the patient's routine for a maximal return to health.
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