LATE AND CHRONIC LYME DISEASE

From: JWissmille (jwissmille_at_aol.com)
Date: 06/23/04 

Date: 23 Jun 2004 00:41:26 GMT

LATE AND CHRONIC LYME DISEASE
Sam T. Donta, MD*
 
* 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 MD
Boston Medical Center
650 Albany Street-8th floor
Boston MA 02118
(617) 638-6017
(617) 638-6009 (fax)
sam.donta@bmc.org (email)
 
 
 
INTRODUCTION
        
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 underlying infection.
 
PATHOGENESIS
 
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.
 
DIAGNOSIS
 
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 organisms.
            
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 proteins.
            
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 test.
 
TREATMENT
 
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 usually 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 protein binding.
            
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
hydroxychloroquine (see below) (10).
            
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. 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 (eg 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.
 
FUTURE DIRECTIONS
 
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 therapy. 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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