The Open Neurology Journal




ISSN: 1874-205X ― Volume 13, 2019

Issues in the Diagnosis and Treatment of Lyme Disease



Sam T Donta*
Department of Medicine (Infectious Diseases), Falmouth Hospital, USA

Abstract

Since the identification of the causative organism more than 30 years ago, there remain questions about the di-agnosis and treatment of Lyme Disease. In this article, what is known about the disease will be reviewed, and approaches to the successful diagnosis and treatment of Lyme disease described.

In considering the diagnosis of Lyme disease, a major problem is the inability of documenting the existence and location of the bacteria. After the initial transfer of the bacteria from the Ixodes tick into the person, the spirochetes spread locally, but after an initial bacteremic phase, the organisms can no longer be reliably found in body fluids. The bacteria are proba-bly present in subcutaneous sites and intracellular loci. Currently, the use of circulating antibodies directed against spe-cific antigens of the Lyme borrelia are the standard means to diagnose the disease, but specific antibodies are not an ade-quate means to assess the presence or absence of the organism. What is needed is a more Lyme-specific antigen as a more definitive adjunct to the clinical diagnosis.

As for the treatment of Lyme disease, the earliest phase is generally easily treated. But it is the more chronic form of the disease that is plagued with lack of information, frequently leading to erroneous recommendations about the type and du-ration of treatments. Hence, often cited recommendations about the duration of treatment, eg four weeks is adequate treatment, have no factual basis to support that recommendation, often leading to the conclusion that there is another, per-haps psychosomatic reason, for the continuing symptoms. B. burgdorferi is sensitive to various antibiotics, including pe-nicillins, tetracyclines, and macrolides, but there are a number of mitigating factors that affect the clinical efficacy of these antibiotics, and these factors are addressed. The successful treatment of Lyme disease appears to be dependent on the use of specific antibiotics over a sufficient period of time. Further treatment trials would be helpful in finding the best regimens and duration periods.

At present, the diagnosis of Lyme disease is based primarily on the clinical picture. The pathophysiology of the disease remains to be determined, and the basis for the chronic illness in need of additional research. Whether there is continuing infection, auto-immunity to residual or persisting antigens, and whether a toxin or other bacterial-associated product(s) are responsible for the symptoms and signs remains to be delineated.

Keywords: Lyme disease, chronic, brain SPECT.


Article Information


Identifiers and Pagination:

Year: 2012
Volume: 6
First Page: 140
Last Page: 145
Publisher Id: TONEUJ-6-140
DOI: 10.2174/1874205X01206010140

Article History:

Received Date: 28/4/2012
Revision Received Date: 22/6/2012
Acceptance Date: 2/7/2012
Electronic publication date: 30/11/2012
Collection year: 2012

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© Sam T Donta; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.


* Address correspondence to this author at the Department of Medicine Infectious Disease, PO Box 944, Falmouth MA 02541, USA; Tel: 508-540-1306; Fax: 508-540-0133; E-mail: sdonta@comcast.net




INTRODUCTION

The causative agent of Lyme disease is the spirochete, Borrelia burgdorferi, the species named after the discoverer of the organism, Willy Burgdorfer [1 Burgdorfer W, Barbour AG, Hayes SF, et al. Lyme disease-a tick-borne spirochetosis? Science 1982; 216: 1317-9.]. After the initial transfer of the bacteria from the Ixodes tick to the affected individual, the spirochetes spread locally at the site of the bite, but after an initial bacteremic phase that may last for up to 90 days, but usually for a few weeks [2 Nowakowski J, McKenna D, Nadelman RB, et al. Blood cultures for patients with extracutaneous manifestations of Lyme disease in the United States Clin Infect Dis 2009; 49: 1733-5.], the organisms can no longer be reliably cultured or otherwise detected in blood, urine, spinal fluid or other body fluids.

The course of Lyme disease was initially described as being in stages, ie I, II, III, but this was later revised as occurring in three phases, ie Early Lyme disease, Early Disseminated Lyme disease, and Late Lyme disease [3 Steere AC. Lyme Disease N Engl J Med 2001; 345: 115-25.]. This latter description is somewhat more accurate, but there is often no separation between early and late or persistent/ chronic Lyme disease, ie patients may progress from early to persisting symptoms without having obvious disseminated erythema migrans lesions that are characteristic of Early Disseminated Lyme disease. There are many patients as well who have early disease, but then no further symptoms for a number of weeks or months.

WHAT TO DO ABOUT TICK BITES

One of the issues is what to do if a patient has only a tick bite without a rash or other symptoms. In this case, presuming the tick is imbedded, some advice has been that nothing need be done unless the tick has been imbedded for more than 48 hours [4 Piesman J, Mather TN, Sinsky RJ, et al. Duration of tick attachment and Borrelia burgdorferi transmission J Clin Microbiol 1987; 25: 557-8.]. This recommendation relies on the results of animal experiments, but it remains uncertain whether this applies to the natural setting in humans. In the absence of a more definitive way to determine whether the individual has been infected, a practical approach would be to have the tick analyzed to be sure it is an Ixodes tick and it is positive by PCR-DNA or IFA for the borrelial spirochete. These tests are available, and results obtained in a few days. If the test is negative, there is no need for any treatment; if positive, the recommendation would be to treat with amoxicillin, cefuroxime, or doxycycline, the duration of treatment unknown, but 1-2 weeks a reasonable period of time in the absence of any symptoms.

In the absence of testing the tick, the choice is either to wait until any rash or other symptoms appear, or empirically treat with a “double-dose” of doxycycline, ie 200mg [5 Nadelman RB, Nowakowski J, Fish D, et al. Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite N Engl J Med 2001; 345: 79-84.]. Although this treatment might prevent the establishment of infection in most people who have been bit, there are failures to this approach, and patients who are given this treatment should be cautioned to observe for any symptoms over the subsequent few months.

MANAGING THE PATIENT WITH ERYTHEMA MIGRANS RASH

If a typical erythema migrans rash appears, the diagnosis is confirmed, and a course of treatment with doxycycline, amoxicillin, or cefuroxime has been shown to be efficacious [6 Nadelman RB, Luger SW, Frank E, et al. Comparison of cefuroxime axetil and doxycycline in the treatment of early Lyme disease Ann Intern Med 1992; 117: 273-80.]. The duration of treatment is usually 2-4 weeks, but it would seem logical and prudent to continue treatment if there are associated symptoms, albeit non-specific in nature, until those symptoms resolve, usually another few weeks, especially as there is no diagnostic tool to determine whether the infection is still present or has been eradicated. If there are subsequent or relapsing symptoms, treatment should be promptly reinstituted, usually with doxycycline, but may require other treatments to resolve the symptoms.

MANAGING PATIENTS WITHOUT TYPICAL ERYTHEMA MIGRANS RASH

Patients with early Lyme disease may not have a typical erythema migrans rash, making the diagnosis more difficult. Indeed, half or more patients who have a rash do not have a typical “bulls-eye” rash [7 Steere AC, Sikand VK, Meurice F, et al. Vaccination against Lyme disease with recombinant Borrelia burgdorferi outer-surface lipoprotein A with adjuvant Lyme Disease Vaccine Study Group N Engl J Med 1998; 339: 209-15.]. In this case, the clinician needs to include the diagnosis of Lyme disease if there are other symptoms, albeit non-specific, if the patient has an otherwise unexplained persisting illness. Serologic testing for Lyme disease is often helpful, but if the screening ELISA type tests are negative, a Western Blot should be performed, looking especially for IgM reactivity [8 Donta ST. Chronic and Late Lyme Disease Med Clin North Am 2002; 86: 341-9.]. Treatment of such patients would be empirical, consisting of similar regimens as with patients with typical early Lyme disease.

MANAGING PATIENTS WITH NO TICK BITE OR RASH WHO PRESENT WITH LATE LYME DISEASE

Patients with early Lyme disease, and some who were not aware of any tick bite or rash, may present several weeks or even a few months later with one of several clinical pictures that can be classified as late Lyme disease. These include aseptic meningitis, Bell’s palsy, heart block, and arthritis. In this case, ELISA tests are usually positive, but if negative, a Western Blot should be performed [8 Donta ST. Chronic and Late Lyme Disease Med Clin North Am 2002; 86: 341-9.]. Treatment of such patients may require more prolonged treatment, or antimicrobial agents other than doxycyline, amoxicillin, cefuroxime, or intravenous ceftriaxone.

DIAGNOSIS OF LYME DISEASE IN PATIENTS WITH PERSISTING OR RELAPSING SYMPTOMS

There are patients who are not aware of any tick bite or any rash, who present with an illness consisting of a combination of symptoms, but without objective signs, that include persisting fatigue, arthralgias or myalgias, paresthesias, and neurocognitive dysfunction that could be due to Lyme disease (Table 1). Such patients frequently undergo various numerous evaluations, including rheumatology, neurology, and infectious disease consultations, without any definitive diagnosis, and are often classified as having chronic fatigue syndrome, fibromyalgia, or depression. They are also often told they do not have Lyme disease. The facts, however, are that there are no currently available tests to determine whether the spirochetes are actually present or not present in an individual, and whether the bacteria are active or inactive. Hence, often cited recommendations about the duration of treatment, eg four weeks is curative or adequate treatment, have no factual basis to support that recommendation, disregarding the clinical picture, and leading to the conclusion that there is another, perhaps psychosomatic reason, for the continuing symptoms. As there is overlap in symptomatology between patients who are diagnosed as having chronic fatigue syndrome, fibromyalgia, and those who have persisting symptoms with Lyme disease [8 Donta ST. Chronic and Late Lyme Disease Med Clin North Am 2002; 86: 341-9., 9 Clauw DJ, Chrousos GP. Chronic pain and fatigue syndromes:overlapping clinical and neuroendocrine features and potential pathogenic mechanisms Neuroimmunomodulation 1997; 4(3 ): 134-53.], there is great difficulty clinically in knowing who amongst those with chronic fatigue and fibromyalgia might have persisting Lyme disease.

Table 1

Symptoms of Chronic Lyme Disease




Table 2

Western Blot vs ELISA in Chronic Lyme Disease




Table 3

Localization of Brain SPECT Scan Perfusion Defi-cits in Patients with Chronic Lyme Disease*




Table 4

Recommended Reatment Regimens for Chronic Lyme Disease




In patients with relapsing or persisting symptoms, screening tests such as ELISA are usually negative, but Western Blots often show antibody reactions to highly specific proteins, eg 23kd, 31kd, 34kd, 39kd, 93k, especially by IgM, that support the clinical diagnosis [8 Donta ST. Chronic and Late Lyme Disease Med Clin North Am 2002; 86: 341-9.,10 Donta ST. Tetracycline therapy of chronic Lyme Disease Clin Infect Dis 1997; 25: S52-6.,11 Donta ST. Macrolide Therapy of Chronic Lyme Disease Med Sci Monit 2003; 9: 136-42.] (Table 2). The Western Blot criteria that were initially adopted for surveillance purposes, then subsequently used clinically, were based on patients with Late Lyme Disease, who have objective signs, such as swelling in usually a single joint such as the knee, that appeared subsequent to a documented tick bite and/or typical erythema migrans rash and whose screening ELISA test is strongly positive [12Centers for Disease Control. Recommendations for test performance and interpretation from the Second National Conference on Serologic Diagnosis of Lyme Disease MMWR 1995; 44: 590-1.,13 Dressler F, Whalen JA, Reinhardt BN, Steere AC. Western blotting in the serodiagnosis of Lyme disease J Infect Dis 1993; 167: 392-400.]; however, these criteria did not include patients with chronic persisting symptoms, and subsequent studies have demonstrated that two-thirds or more of these patients have negative screening tests, but positive Western Blot reactions, especially by IgM. Even in those patients with more obvious late Lyme disease, the criteria of needing 5 of ten reactions on IgG Western Blot to make a diagnosis is not supported by the published data, wherein a reaction to even one specific protein of B. burgdorferi has a 90% positive correlation with the clinical diagnosis.

There are additional issues relating to the criteria for a positive IgM test on Lyme Western blot. The recommended criteria for diagnosis of early Lyme disease are that there be 2 of 3 positive reactions to one of three borrelial proteins, ie 23kd, 39kd, or 41kd proteins. But if there are similar reactions in patients with later manifestations or persisting symptoms, the recommended interpretation is that these are false positive results. This interpretation lacks any logical or scientific foundation, and has added to confusion about the value of serologic data. Observations in numerous patients over the past 25 years suggest that these positive IgM reactions in patients with chronic symptoms are meaningful as a surrogate for disease activity [8 Donta ST. Chronic and Late Lyme Disease Med Clin North Am 2002; 86: 341-9.,10 Donta ST. Tetracycline therapy of chronic Lyme Disease Clin Infect Dis 1997; 25: S52-6.,11 Donta ST. Macrolide Therapy of Chronic Lyme Disease Med Sci Monit 2003; 9: 136-42.].

Brain SPECT scans can often be helpful in supporting the clinical diagnosis of chronic active Lyme disease. Perfusion deficits occur in 75% of patients with neurocognitive dysfunction [14 Donta ST, Noto RB, Vento JA. SPECT Brain Imaging in Chronic Lyme Disease Clin Nuclear Med 2012; 37(9 ): 219-2.]. The deficits occur primarily in the temporal, parietal, and frontal lobes (Table 3), and these deficits resolve with successful treatment. In contrast, MRI of the brain may in 15% of patients show T2 signal hyperintense lesions indistinguishable from those seen with multiple sclerosis. Hence, SPECT scans and MRI studies of the brain in patients with relapsing, persisting symptoms can be useful adjuncts to the clinical diagnosis.

What has not been particularly helpful is analysis of CSF fluid in patients with persisting symptoms. There is a continuing recommendation that patients who have neurologic symptoms such as short-term memory loss or mood changes will have positive antibody or PCR-DNA results in spinal fluid, but only rarely have spinal fluid examinations yielded positive results.

There are other adjunctive tests that may be helpful in the diagnosis and management of patients with persisting symptoms. CD57 levels have been proposed as a means of monitoring the severity of the illness, but its specificity for Lyme disease has not been demonstrated [15 Stricker RB, Winger EE. Decreased CD57 lymphocyte subset in patients with chronic Lyme disease Immunol Lett 2001; 76: 43-8.], and there are patients who are symptomatic with normal CD57 levels and those who are not with subnormal CD57 levels. Similarly, the role of other immunologic responses, specifically cell-mediated associated responses, in the diagnosis and management of patients with Lyme disease remains to be proven. It seems reasonable to assume that the cell-mediated arm of the immune system is involved in chronic and intracellular based infections, and there are some observations that cell-mediated responses to specific Lyme antigens are increased in patients with Lyme disease, but more studies are needed, especially longitudinal studies, to evaluate the utility of these tests in such patients.

PATHOGENESIS AND PATHOPHYSIOLOGY OF LYME DISEASE

Once the spirochetes enter the subcutaneous tissue, they likely localize in neuronal tissues [16 Cadavid D, O’Neill T, Schaefer H, Pachner AR. Localization of Borrelia burgdorferi in the nervous system and other organs in a nonhuman primate model of Lyme disease Lab Investig 2000; 80: 1043-54.,17 Embers ME, Barthold SW, Borda JT, et al. Persistence of Borrelia burgdorferi in Rhesus Macaques following Antibiotic Treatment of Disseminated Infection PLoS One 2012; 7(1 ): e29914.], probably sensory ganglia, commensurate with the various clinical manifestations, but perhaps as well in other sites and cells such as endothelial or glial cells [8 Donta ST. Chronic and Late Lyme Disease Med Clin North Am 2002; 86: 341-9.]. They may persist in subcutaneous sites, but their long-term survival is likely in intracellular loci. The location in subcutaneous tissues, especially near the surface, is consistent with the ability of larvae of the Ixodes ticks to become infected when they take a blood meal from a deer or white-footed mouse, as well as in experiments of xenodiagnosis [18 Barthold SW, Hodzic E, Imai DM, et al. Ineffectiveness of tigecycline against persistent Borrelia burgdorferi Antimicrob Agents Chemother 2010; 54: 643-51.]. Whether the spirochetes are randomly located in subcutaneous space or whether they are present in endothelial cells of capillaries or in the ends of dendritic cell processes has yet to be determined. As for an intracellular locus, an acidic endosome such as the lysosome or a late endosome is the likely location, support for which hypothesis are the observations that macrolide antibiotics, which are highly effective in vitro and which can be transported to all endosomes, are ineffective clinically, but are effective if the acidic endosome can be alkalinized, as with agents such as hydroxychloroquine and amantadine [11 Donta ST. Macrolide Therapy of Chronic Lyme Disease Med Sci Monit 2003; 9: 136-42.,19 Maurin M, Benoliel AM, Bongrand P, Raoult D. Phagolysosomal alkalinization and the bactericidal effect of antibiotics: the Coxiella burnetii paradigm J Infect Dis 1992; 166: 1097-2.]. Further supporting this hypothesis is that acidifying agents such as ascorbic acid (vitamin C), appear to counteract the effect of the lysosomotropic agents.

How the spirochetes cause symptoms remains to be determined. It would seem unlikely that their physical presence alone would cause any symptoms. It’s more likely that they either produce a noxious substance or substances, ie toxin, that perturbs the nerve cell or other cells that may be involved, causing symptoms such as pain, paresthesias, cognitive impairment, or that there is some host response to the spirochete or a product thereof. The possibility that there may auto-immune reactions has been raised, but there is not compelling evidence that this is the major pathophysiologic mechanism involved in the disease. Nor is there any evidence that persisting symptoms might be due to post-infectious sequelae such as damage to certain cells. That has been discovered a toxin that affects neuronal and other neural-related cells in tissue culture, and it remains to be determined whether this is a responsible mechanism for the symptomatology [20 Donta ST, Martin SE, Meeting IDSA, Denver CO, Cartwright MJ. A Novel toxin (Bbtox1) of Borrelia burgdorferi Abstracts of Annual 1998.].

ANTIBIOTIC TREATMENT OF PATIENTS WITH LATE OR CHRONIC LYME DISEASE

Patients who have previously been diagnosed as having Lyme disease who have relapsing symptoms are often given the diagnosis of post-treatment Lyme disease, the implication being that they no longer have the infection, but this assumption is not based on any specific diagnostic criteria. The assumption is primarily based on the lack of improvement in a treatment trial that used a regimen consisting of one month of intravenous ceftriaxone followed by two months of oral doxycyline [21 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.]. That regimen did indeed seem to be ineffective, but the reasons for the lack of efficacy were not adequately addressed, especially the lack of consideration that there may be other regimens that might be effective. B. burgdorferi is sensitive in vitro to various antibiotics, including the penicillins, tetracyclines, and macrolides, but there are a number of mitigating factors that affect the clinical efficacy of these antibiotics. Not all antibiotics are equally effective in treating various infections, so it should not be surprising that there might be other successful regimens. Indeed, based on pharmacologic considerations, there appear to be highly effective regimens consisting of either tetracycline itself, or the combination of a macrolide anitibiotic (eg erythromycin, clarithromycin, azithromycin) with a lysosomotropic agent such as hydroxychloroquine [10 Donta ST. Tetracycline therapy of chronic Lyme Disease Clin Infect Dis 1997; 25: S52-6.,11 Donta ST. Macrolide Therapy of Chronic Lyme Disease Med Sci Monit 2003; 9: 136-42.].

There continue to be various recommendations regarding antibiotic treatment of patients with relapsing or persisting symptoms. While there have not been agreed upon uniform regimens, there has been agreement amongst practitioners involved in treating such patients that more prolonged treatment is needed for more successful outcomes. With the exception of the study that involved a month of intravenous ceftriaxone followed by two months of oral doxycycline, and subsequent studies of either one month or ten weeks of intravenous ceftriaxone [22 Fallon BA, Keilp JG, Corbera KM, et al. A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy Neurology 2008; 70: 992-1003.], there have been no randomized, placebo-controlled trials of longer duration, using other antibiotic regimens. It should not be surprising that longer regimens would be required to treat a chronic infection, especially if the causative organism is not rapidly replicating and is in a protective niche such as an intracellular locus. Such is the case with a number of other infections, including tuberculosis, Q fever, various parasitic and fungal infections, and viral infections such as hepatitis B, hepatitis C, and HIV. In the case of hepatitis B and C, initial recommendations were for 6 weeks of treatment, but with further studies, the recommendation for the duration of treatment was then extended to 12 weeks, then to 24 weeks, and perhaps longer to resolve the infection.

In assessing whether treatment of patients with Lyme disease who have chronic symptoms are responding to the treatment, the lack of objective manifestations and more definitive means to determine whether the infection is being resolved, makes it more difficult to prove that the infection is being successfully treated. Nonetheless, it is the patient’s assessment of whether there is any improvement, just as in treatment of any other medical condition, that is the determinant of progress and success. There are also potential confounding factors, such as whether a given antibiotic is exerting a specific or non-specific effect. In the case of beta-lactam antibiotics such as penicillin and cephalosporins, especially ceftriaxone, recent evidence shows that these antibiotics can affect glutamate transport in the nervous system [23 Rothstein JD, Patel S, Regan MR, et al. Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression Nature 2005; 433: 73-.], and that their clinical effects on patients’ symptoms might not be anti-bacterial in nature, but symptomatic. Patients and physicians have often concluded, perhaps erroneously, that additional treatments with these antibiotics are needed, and in our experience, treatment with this class of antibiotics, including several months of intravenous ceftriaxone, is not curative in patients with chronic symptoms.

Doxycycline is effective treatment for early Lyme disease, but does not appear to be curative in relapsing, persisting Lyme disease. This likely is because of two factors, ie dose, and protein-binding. Most of absorbed doxycycline remains highly protein-bound in the circulation, meaning that the amount of free drug to diffuse into cells is limited. This may be the explanation as to why the original parent compound tetracycline appears to be more effective [10 Donta ST. Tetracycline therapy of chronic Lyme Disease Clin Infect Dis 1997; 25: S52-6.]. The dose of tetracycline used in our published observations that was found to be effective was 1500mg/day; in contrast, doxycycline dosage is 200mg/day, and tetracycline is not highly protein-bound, allowing more free tetracycline to diffuse into cells. In treating patients with tetracycline, a minimum of three months is needed to demonstrate progress, and in patients who have been ill for more than one or two years, 18 months of treatment may be needed to resolve the illness. Whether increasing the dose of doxycycline to 300-400mg/day would be more effective remains uncertain.

The use of a macrolide antibiotic such as clarithromycin or erythromycin, when combined with a lysosomotropic agent such as hydroxychloroquine, has been a very tolerable and successful regimen in treating patients with chronic, persisting symptoms [11 Donta ST. Macrolide Therapy of Chronic Lyme Disease Med Sci Monit 2003; 9: 136-42.]. The use of either antibiotic or hydroxychloroquine alone does not result in any obvious improvement, supporting the hypothesis that the Lyme spirochetes reside in an intracellular acidic endosome. A controlled clinical trial would however be needed to prove this hypothesis. Further to that point, tetracycline, which is active in an acid milieu, is not benefited by the addition of hydroxychloroquine to the regimen. As with tetracycline, treatment with this regimen may also require a number of months to resolve most, if not all symptoms. As a practical approach, courses of treatment are alternated between tetracycline and the macrolide/hydroxychloroquine regimen, consisting of 6 months for each course, until symptoms are resolved (Table 4). Patients who have been ill for shorter periods of time can resolve their symptoms in shorter periods of time than those who have had illness for a few years or more. In patients with longer standing illness, it also takes longer to begin to see any progress, often needing 4-6 months; nonetheless, sustained improvement can be seen in most of these patients over a prolonged period of time.

NON-ANTIBIOTIC TREATMENTS

Symptom-based medications can be helpful in providing some relief of the various symptoms. These include gabapentin to help with pain and neuropathy, anti-depressants, and agents such as trazodone to help with sleep issues. Narcotic medications should be avoided, as patients can easily become addicted, and treatment of the underlying illness becomes more difficult to treat.

The use of various supplements has been advocated by some, but evidence of their efficacy not established, and it would seem prudent to minimize the numbers of medications and supplements taken that might not only add difficulty to interpretation of any progress during the treatment period, but perhaps aid the survival of the spirochetes and retard resolution of the illness. In particular, the use of multivitamins and anti-oxidants is to be avoided, as supplemental vitamin C, as previously noted, would counteract the effects of hydroxychloroquine. As for B vitamins, these might theoretically be aiding the spirochete’s survival, as they are unable to synthesize their own B vitamins; and our observations are that patients on supplemental B vitamins do not respond as favorably to antibiotic treatment as do those not taking these supplements. Patients not taking supplemental B vitamins do not appear to have any deficiencies in these vitamins, so they are not being put at risk by the lack of supplemention. Vitamin D, however, is to be encouraged as it is frequently low in patients with persistent Lyme disease, and may be helpful in providing anti-inflammatory benefit. The use of anti-oxidants such as coenzyme Q10 and vitamin E should also be avoided, as these agents may retard the host’s ability to damage the spirochetes. Recent evidence also suggests that anti-oxidants promote antibiotic tolerance and bio-film formation [24 Nguyen D, Joshi-Datar A, Lepine F, et al. Active starvation responses mediate antibiotic tolerance in biofims and nutrient-limited bacteria Science 2011; 334: 982-6., 25 Shatalin K, Shatalina E, Mironov A, et al. H2S: a universal defense against antibiotics in bacteria Science 2011; 334: 986-.].

FUTURE DIRECTIONS

Currently, the use of circulating antibodies directed against specific antigens of the Lyme borrelia are the standard means to diagnose the disease, but specific antibodies do not provide an adequate means of assessing the presence or absence of the organism. What is needed, in the absence of being able to directly culture the organism, is the development of a more direct detection test against Lyme-specific antigens to provide a more definitive diagnosis.

Also needed are more controlled clinical trials to document and establish better treatment regimens. There is sufficient preliminary evidence to suggest that there are effective regimens, and support for clinical trials using these regimens is needed to make additional progress for this disease. And the development of specific vaccines is needed to ultimately prevent the infection.

CONFLICT OF INTEREST

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

ACKNOWLEDGEMENTS

None declared.

REFERENCES

[1] Burgdorfer W, Barbour AG, Hayes SF, et al. Lyme disease-a tick-borne spirochetosis? Science 1982; 216: 1317-9.
[2] Nowakowski J, McKenna D, Nadelman RB, et al. Blood cultures for patients with extracutaneous manifestations of Lyme disease in the United States Clin Infect Dis 2009; 49: 1733-5.
[3] Steere AC. Lyme Disease N Engl J Med 2001; 345: 115-25.
[4] Piesman J, Mather TN, Sinsky RJ, et al. Duration of tick attachment and Borrelia burgdorferi transmission J Clin Microbiol 1987; 25: 557-8.
[5] Nadelman RB, Nowakowski J, Fish D, et al. Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite N Engl J Med 2001; 345: 79-84.
[6] Nadelman RB, Luger SW, Frank E, et al. Comparison of cefuroxime axetil and doxycycline in the treatment of early Lyme disease Ann Intern Med 1992; 117: 273-80.
[7] Steere AC, Sikand VK, Meurice F, et al. Vaccination against Lyme disease with recombinant Borrelia burgdorferi outer-surface lipoprotein A with adjuvant Lyme Disease Vaccine Study Group N Engl J Med 1998; 339: 209-15.
[8] Donta ST. Chronic and Late Lyme Disease Med Clin North Am 2002; 86: 341-9.
[9] Clauw DJ, Chrousos GP. Chronic pain and fatigue syndromes:overlapping clinical and neuroendocrine features and potential pathogenic mechanisms Neuroimmunomodulation 1997; 4(3 ): 134-53.
[10] Donta ST. Tetracycline therapy of chronic Lyme Disease Clin Infect Dis 1997; 25: S52-6.
[11] Donta ST. Macrolide Therapy of Chronic Lyme Disease Med Sci Monit 2003; 9: 136-42.
[12] Centers for Disease Control. Recommendations for test performance and interpretation from the Second National Conference on Serologic Diagnosis of Lyme Disease MMWR 1995; 44: 590-1.
[13] Dressler F, Whalen JA, Reinhardt BN, Steere AC. Western blotting in the serodiagnosis of Lyme disease J Infect Dis 1993; 167: 392-400.
[14] Donta ST, Noto RB, Vento JA. SPECT Brain Imaging in Chronic Lyme Disease Clin Nuclear Med 2012; 37(9 ): 219-2.
[15] Stricker RB, Winger EE. Decreased CD57 lymphocyte subset in patients with chronic Lyme disease Immunol Lett 2001; 76: 43-8.
[16] Cadavid D, O’Neill T, Schaefer H, Pachner AR. Localization of Borrelia burgdorferi in the nervous system and other organs in a nonhuman primate model of Lyme disease Lab Investig 2000; 80: 1043-54.
[17] Embers ME, Barthold SW, Borda JT, et al. Persistence of Borrelia burgdorferi in Rhesus Macaques following Antibiotic Treatment of Disseminated Infection PLoS One 2012; 7(1 ): e29914.
[18] Barthold SW, Hodzic E, Imai DM, et al. Ineffectiveness of tigecycline against persistent Borrelia burgdorferi Antimicrob Agents Chemother 2010; 54: 643-51.
[19] Maurin M, Benoliel AM, Bongrand P, Raoult D. Phagolysosomal alkalinization and the bactericidal effect of antibiotics: the Coxiella burnetii paradigm J Infect Dis 1992; 166: 1097-2.
[20] Donta ST, Martin SE, Meeting IDSA, Denver CO, Cartwright MJ. A Novel toxin (Bbtox1) of Borrelia burgdorferi Abstracts of Annual 1998.
[21] 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.
[22] Fallon BA, Keilp JG, Corbera KM, et al. A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy Neurology 2008; 70: 992-1003.
[23] Rothstein JD, Patel S, Regan MR, et al. Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression Nature 2005; 433: 73-.
[24] Nguyen D, Joshi-Datar A, Lepine F, et al. Active starvation responses mediate antibiotic tolerance in biofims and nutrient-limited bacteria Science 2011; 334: 982-6.
[25] Shatalin K, Shatalina E, Mironov A, et al. H2S: a universal defense against antibiotics in bacteria Science 2011; 334: 986-.

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Daniel Pesut
(Indiana University School of Nursing, USA)

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."


Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


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