By Sam Donta,M.D.
Following the introduction of Borrelia burgdorferi into the skin
by an infected tick, the organisms begin to spread both locally
and systemically. Several days typically elapse before the
appearance of the first sign of infection, i.e., erythema
chronicum migrans (ECM), or other less typical rashes (29).
The rash occurs in fewer than 50% of patients with Lyme Disease
(8,10), but the true incidence of Lyme Disease in the absence
of a rash is unknown.
The occurence of multiple rashes is indicative of systemic spread
of the organisms. Multiple rashes usually do not occur until 2-4 weeks following the initial tick bite. This is the same time
period during which the organisms are being disseminated to their
target tissues and cells. The incidence of multiple rashes was
initially reported to occur in as many as 50% of cases, but has
been much less common in the last two decades, probably because
of frequent use of antibiotics.
Approximately 4-6 weeks following the tick bite, the first
systemic symptoms (other than multiple rashes) occur in some
patients, usually in the form of “flu” (15). These symptoms
include sore throat, severe headaches and neck aches, and severe
fatigue. Rhinitis, sinusitis, and cough are not usually present,
distinguishing this “flu” from other influenza-like illnesses.
While the Lyme-flu symptoms can spontaneously resolve, patients can experience recurrent “flu”.
Soon after the onset of Lyme-flu, fatigue, arthralgias and/or
myalgias may begin. The arthralgias appear to primarily involve
the large joints (i.e., knees, elbows, hips, shoulders), although
smaller joints (e.g., wrists, hands, fingers, toes) may be
involved(29). Some patients may have actual arthritis, often oligoarticular, more frequently in men than in women. Earlier estimates were that 50-75% of patients who developed late Lyme Disease had arthritis, but more recent analyses suggest that the incidence of actual arthritis in patients with late or chronic disease is closer to 25% (33).
Neck stiffness is common. The pains are described as severe, jumping from joint to joint, and may be present for only short periods of time. Pain in the teeth or in the temporal-mandibular joints is not uncommon. Rib and
chest pains occur frequently, leading some patients to seek care
in emergency rooms and urgent care centers for evaluation of
possible cardiac disease. Frequently as well are paresthesias such
as burning, numbness and tingling, and itching. Some patients
experience crawling sensations, vibrations, or electric shock-like
sensations. Rarely is there any actual palsy of the affected areas, making this much more of a neurosensory, rather than a motor, disease.
In addition to paresthesias, purely neurological symptoms and signs include headaches, an aseptic meningitis, facial nerve (Bell’s)
palsy, and encephalitis or encephalopathy that may be manifested by cognitive dysfunction, especially short-term memory loss, and
psychiatric symptoms such as panic, anxiety, or depression (14).
The aseptic meningitis and Bell’s palsy tend to occur within the
first few months following the tick bite, but may also occur as
part of reactivation disease (9).
Other symptoms may include fevers (usually low grade, but may be high), sweats (which may be severe), visual dysfunction (described
primarily as blurriness, but can include optic neuritis or uveitis),
tinnitus, sensitivity to sounds, or hearing loss. Shortness of
breath, palpitations and/or tachycardia, abdominal pains, diarrhea or irritable bowel, testicular or pelvic pain, urinary frequency
or urgency, dysequilibrium, and tremors are also common symptoms.
Some of the dysautonomia symptoms can be disabling.
Rarer symptoms may relate to panniculitis and hepatitis. Rarely as well are
congenital and intrautero infection; when this occurs, it appears
to be similar to toxoplasmosis and rubella, i.e., a primary infection
during the first trimester. The occurrence of optic neuritis or
uveitis raises other possibilities such as multiple sclerosis, but
can be part of Lyme Disease.
The course of the disease can best be described as persistent, but
with periods of worsening symptoms, often cyclical every few weeks
or monthly. Especially disconcerting are persistent symptoms such
as headaches and fatigue that can be exhausting. Some patients are more symptomatic than are others, which may reflect genetically- determined differences in responsiveness or extent of infection.
The disease does not appear to be progressive or destructive, as
with cancer, nor is it fatal, but can be very debilitating.
The incidence of asymptomatic infection has not been adequately
delineated. There appear to be substantial numbers of patients
who remain asymptomatic, but reactivate their disease a number of
months or years later, following trauma, pregnancy, a medical
illness for which an antibiotic is prescribed, or other stresses,
including psychological stresses (9). The Lyme OspA vaccine has
appeared to reactivate Lyme Disease in a number of individuals who
knew, but some who did not know, they had prior Lyme Disease (11).
The mechanisms responsible for the reactivation of the disease
have not been defined, but may include both molecular mimicry and
The pathogenesis of Lyme Disease remains to be defined. From the
available studies, it would appear that the organisms are trophic
for either the endothelial cells of the blood vessels that serve
the nervous system or for the glial or neural cells themselves
(4,24,26,31). Accumulating evidence supports the hypothesis of
a persistent infection as the cause of the persisting or relapsing
symptoms (26,31). Whether molecular mimicry is involved in the
pathogenesis of some of the symptoms remains more speculative (18).
Although arthritis can occur in Lyme Disease, the organisms can
only rarely be found in synovial tissue. And as many of the
arthralgias that occur in the disease do not respond well to
antiinflammatory agents, the disease is more of an infectious
neuropathy than an actual invasion of synovial or bursal tissues.
The diagnosis rests heavily on the clinical symptomatology.
When there are clinical signs, e.g., rash, aseptic meningitis,
optic neuritis, arthritis, an appropriate differential
diagnosis must be pursued. On a clinical basis, “chronic
fatigue syndrome” or “fibromyalgia” cannot be readily
distinguished from chronic Lyme Disease. Indeed, accumulating
experience suggests that Lyme Disease may be a frequent cause
of fibromyalgia or chronic fatigue (8,12).
Other microbes have been proposed as causative agents of multisymptom disorders that are being termed chronic fatigue and fibromyalgia, especially
more recently recognized mycoplasma species such as M.fermentans
and M.genitalium, but definitive proof of cause and effect has
not yet been established (6, 23).
There has been an attempt to separate “late” Lyme Disease
from “chronic” Lyme Disease, the former being manifested by
objective signs of arthritis or neurological disease (32).
Some have denied the existence of chronic disease, inferring
that these patients suffer from psychiatric disorders; some
have used the term “chronic” to mean post-treatment disease
(“post-Lyme”), assuming that the infection has been treated,
and the remaining symptoms are in the same realm as those
patients who have “fibromyalgia” or “chronic fatigue” (27, 30).
These assertions are speculative and remain unproven. That
chronic Lyme Disease actually exists, and is likely the most
common form of the disease, is supported by epidemiologic
studies demonstrating that 30-50-% of treated and untreated
patients go on to develop a multisymptom disorder typical of,
and indistinguishable from, fibromyalgia and chronic fatigue
(1, 28). As with other multisymptom disorders, chronic Lyme
Disease is a clinical syndrome consisting of fatigue,
arthralgias and myalgias,and other nervous system dysfunction(7).
Furthermore, the results of treatment studies appear to support
the hypothesis that persistent infection is responsible for the
chronic symptoms. It is likely that Lyme Disease will serve as
a useful model for other chronic multisymptom disorders. Whether
the pathogenesis of “late” Lyme Disease differs from that of
the chronic form of the disease remains to be established.
Routine laboratory tests are usually normal in Lyme Disease.
The ESR is most often normal, distinguishing it from some of
the inflammatory disorders such as rheumatoid arthritis or
lupus. Culture of the borrelia is possible early in the
disease, usually from biopsies of the erythema migrans rash;
however, most laboratories are not capable of culturing the
The only currently available useful laboratory tests are the
immunologically-based ELISA and Western blot assays. The
recommendation was made in 1994 to have a two-tiered testing
system in which the Western Blot would only be done on ELISA- positive samples (5). The recommendation was based primarily on
the results obtained from patients with arthritis (13), did not
take into account the chronic form of the disease, and was made
despite the lack of consistent reproducibility of results between
various laboratories (2, 16).
The ELISA has been shown to be an unreliable test in many patients with Lyme Disease, both in early infection and later disease (8, 10). Part of the reason for the lack of sensitivity of the ELISA is the use of whole organisms, resulting in a high amount of background absorbance.
After correction for the high background, only a small percentage of
positives can be detected. Because Western blots separate the
proteins of the borrelia, specific reactions can be visualized,
and more accurate interpretations of the results made. Over 75%
of patients with chronic Lyme Disease are negative by ELISA,
while positive by Western blot (8, 10). Patients with
oligoarticular arthritis may be more likely to have robust IgG
responses and positive ELISA tests and IgG Western Blots (13).
By Western blot analyses, the first immunologic reactions in
Lyme Disease are to the 41kd flagellar protein, and the 23kd
OspC protein. Typically, at the time of the ECM rash, there will
be an IgM reaction against the 23kd and 41kd proteins, and no IgG
reactions. Within the next few weeks, the IgM reactions persist,
sometimes accompanied by less specific reactions against 60kd and
66kd proteins, and IgG reactions are now visible against the 23kd
and 41kd proteins. Thus, in the presence of an appropriate
clinical picture, the immunoreactivity against the 23kd and 41kd
proteins appear to be diagnostic of Lyme Disease.
Whereas the 41kd protein is not unique to B. burgdorferi, the 23kd
protein appears to be unique. Also apparently unique proteins of
B.burgdorferi are the 31kd (Osp A) and 34kd (Osp B) outer membrane proteins, and the 35kd, 37kd, 39kd, and 83/93kd proteins. Reactions
to the 31kd proteins are not usually seen until after a year or more following the onset of disease. Not all patients with symptoms for
more than one year, however, display reactions to the outer membrane
Most symptomatic patients have specific reactions on IgM
Western blots (8,10). With resolution of the symptoms, the IgM
reactions disappear or attenuate. IgG reactivity may continue
to be present with resolution of symptoms, but it typically also
disappears or attenuates with successful therapy. There are some
patients (20%) who have symptoms, but whose Western blots are
negative (8,10). If the borrelial organisms remain intracellular,
with no extracellular reemergence once established, this could
explain the absence of additional or persistent immune responses.
PCR (Polymerase Chain Reaction) is a highly sensitive means to
detect microbial DNA or RNA, and it was hoped that this technique
would find an important role in the diagnosis of Lyme Disease.
Thus far, however, despite the specificity of this method,
borrelial DNA or RNA has not been reliably detected in the blood,
urine, or spinal fluid of patients with early or later forms of
Lyme Disease, findings again supportive of an intracellular
reservoir for the borrelia.
It should be possible to develop a better, highly specific ELISA
for Lyme Disease, using recombinant 41kd, 23kd, 31kd and/or 34kd
(and perhaps other B.burgdorferi-specific) proteins. Currently,
however, the Western blot assay is the most reliable immunologic
In vitro, B. burgdorferi is sensitive to several antibiotics
(20,25). This assumption is complicated, however, because of
the long incubation times needed to determine minimum
inhibitory concentrations (MIC), as the borrelia have doubling
times of 20-24 hrs. With these limitations, the results of a
few studies show minimum bactericidal concentrations (MBC) to
penicillin of 8ug/ml, ampicillin: 2ug/ml, tetracycline: 1-2ug/ml,
doxycycline: 2ug/ml, ceftriaxone: 0.5ug/ml, cefotaxime: 0.5ug/ml,
cefuroxime: 1-2ug/ml, cefixime: 8ug/ml,erythromycin: 0.5ug/ml,
clarithromycin: 0.5ug/ml, azithromycin: 0.5ug/ml,
and ciprofloxacin: 4ug/ml.
At the time of the first rash, any one of several antibiotics
appear to be effective, if given for 2 weeks, according to several
published studies. However, a number of patients so treated
developed subsequent symptoms of arthralgias, fatigue, and
paresthesias, with positive Western blots, who were then
successfully treated with longer courses of antibiotics (8, 10).
The recommendation at this time, therefore, is that tetracycline,
doxycycline, or amoxicillin be used for 1 month if ECM is the
only symptom of Lyme Disease.
Once any other symptoms appear, the treatment of Lyme Disease
for only 2-4 weeks is associated with frequent failures and
relapses (8, 10). Our initial experience suggested that a 3 month course of tetracycline was associated with a higher success rate(8).
In patients with symptoms present for more than six months, the
treatment course may need to be more prolonged, or a retreatment
course of varying length may be needed. In patients with symptoms
for more than a year, 12-18 months may be needed for complete resolution of symptoms. The rationale for a longer treatment course is based on extensive observations (8,10), plus the analogy to the longer treatment courses required for tuberculosis, leprosy, Q fever, and certain fungal diseases.
With Lyme Disease, the slow growth rate and metabolic activity of the borrelia would seem to correlate with the need for longer treatment periods.
Once treatment is initiated for patients beyond the earliest
signs of infection, their symptoms frequently increase during
the first several days, or even for the first several weeks of
therapy. For patients with preexisting symptoms of more than a
few months, relief of any of their symptoms may not occur until
after 4-6 weeks of therapy (8, 10). Typically, there are short
periods of relief, followed by relapsing or migrating symptoms;
with continued therapy there are longer symptom-free periods.
Some arthralgias may require 3 months or more to resolve, and
fatigue may be the last symptom to disappear.
The preference for tetracycline evolved because of the large
number of failures that were noted in patients who had been
on ampicillin and doxycycline. Patients generally had some
response to doxycycline, but it was uaually not complete, nor
long-lasting. Tetracycline may be more effective than
doxycycline simply because of the greater dose, i.e., 100mg
of doxycycline twice daily is not equivalent to 500mg of
tetracycline three times daily; also, doxycycline is highly
protein-bound, compared to tetracycline, which could limit the
availability of free drug to diffuse into tissues and cells.
Some physicians use doxycycline at doses of 300-400mg daily to
try to achieve a successful result. A strict comparison
between doxycycline and tetracycline has not yet been
made. Minocycline has also been used by some physicians, with
varying success, but faces the same issues of dosage and
Of the beta lactams used for the treatment of Lyme Disease, the
most efficacious appears to be ceftriaxone. In limited comparitive trials, cefotaxime appears to be equally efficacious, and high-dose
IV penicillin may also be effective.
In early Lyme Disease, oral amoxicillin is as effective as doxycycline. In later disease, many failures are noted, despite the use of up to 3 grams of amoxicillin daily, with probenicid. Cefixime would also not appear to be
effective therapy. Cefuroxime axetil has been evaluated only in
the treatment of early Lyme Disease, and appears comparable to
doxycycline. Limited reports of its use in later Lyme Disease have
not shown it to be efficacious.
The role of the newer macrolides in the treatment of Lyme
Disease needs further assessment. Erythromycin has been regarded
as ineffective, despite its good in vitro sensitivities.
Azithromycin has been reported to be less effective in the
treatment of early Lyme Disease than amoxicillin (21). Some
physicians use clarithromycin and azithromycin in higher dosages
and for longer periods of time, but there have been no reports of
greater success with these drugs than with the tetracyclines or
beta-lactams. In our experience, all macrolides are effective
when combined with a lysosomotropic agent, especially
In evaluating the possible factors, it would appear that
antibiotics that can achieve intracellular concentrations and activity are the most efficacious drugs. The results of studies in Klempner’s laboratory using a tissue culture model of borrelia infection demonstrated that ceftriaxone was incapable of eradicating intracellular organisms (17); similar experiments in Raoult’s laboratory using an endothelial cell model
demonstrated that tetracycline and erythromycin were effective,
but beta lactam antibiotics were not (3). These results are in line with our experience that the tetracyclines and macrolides achieve the greatest success.
In contrast to beta lactams, antibiotics of the tetracycline and macrolide classes are capable of good intracellular penetration. Experience with the macrolide antibiotics has been disappointing, however, when compared with
its in vitro activities against the Lyme borreliae, and with the established efficacy of macrolides against other intracellular parasites such as chlamydia, legionella, mycobacterium-avium intracellulare, and toxoplasma. If, though, the Lyme borreliae reside in intracellular vesicles that are acidic, the macrolides’ activity would be sharply decreased at the lower pH.
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This is in contrast to the tetracyclines, which are active at acid pH; even
so, the activity of doxycycline was shown to be further increased by increasing the pH. In a tissue culture model of ehrlichia infection, the use of lysosomotropic agents such as amantidine, NH4Cl, and chloroquine increased the killing of intracellular organisms by doxycycline (22).
Based on those studies, and the hypothesis that late Lyme Disease symptoms are due to persisting intracellular infection, we have been successfully treating patients using the combination of a macrolide and hydroxychloroquine (10).
As regards “CNS” disease, there is no evidence that ceftriaxone
is more successful than either the tetracyclines or the combination of macrolide and hydroxychloroquine; if our presumption that the pathogenesis of the disease involves the localization of the borrelia to the endothelial cells of the blood vessels serving the nervous system or to glial or neural
cells is correct, then one would not need to have a drug that can cross the blood-brain barrier to be effective. Indeed, the tetracyclines can cross the blood-brain barrier to some extent, and were used when initially introduced into clinical medicine for the treatment of meningitis, with some success.
Macrolide antibiotics do not cross the blood-brain barrier, but have been
effective in treating other CNS infections (e.g., toxoplasmosis), and in our experience have been effective in reversing the neuropsychiatric symptoms and signs (eg SPECT scans) of Lyme Disease (10). With regard to the issue of bactericidal vs bacteristatic effects, any such effect in vivo has not been demonstrated.
Finally, there have been no reports showing any change in antibiotic resistance patterns during the course of treatment. Ultimately, the determination of efficacy of therapy depends on the clinical response.
The diagnosis and treatment of Lyme Disease have been
hampered by less than adequate diagnostic tests and inadequate
comparisons of antibiotic regimens. Specific antigen-based
ELISA tests should result in greater specificity, but
sensitivity of any tests based on measurements of the host
immune response might still be of limited value if the borrelia
remain intracellular. Most useful would be the development of
tests that can determine the presence and extent of any residual
borreliosis. In the therapy of Lyme Disease, double-blind,
placebo-controlled and comparitive trials are needed to answer
the questions relating to duration and class of antibiotic
The apparent failure of a regimen of one month of
IV ceftriaxone, followed by two months or oral doxycyline,
to improve the outcomes of patients with chronic Lyme Disease
(19) was not surprising, based on prior observations that neither
regimen used for a limited duration was capable of yielding
patient improvement (8,10,33). Additional trials are needed to
evaluate whether longer durations of treatment, using tetracycline
itself, or the novel combination of macrolide and lysosomotropic
agent, would be proven effective treatments.
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Sam T. Donta, M.D.
Professor of Medicine,
Divisions of Infectious Disease and BioMolecular Medicine Director, Lyme Disease Unit Boston University Medical Center, Boston, Massachusetts
Corresponding author for proof and reprints:
Sam T Donta M.D.
Boston Medical Center
650 Albany Street, 8th floor
Boston MA 02118