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or '''Lyme borreliosis''' is an
Infectious Tick-borne Disease caused by
Borrelia Burgdorferi , a
Gram-negative Spirochete Bacterium . The causative agent
Borrelia Burgdorferi , was first identified by
Willy Burgdorfer , a tick-borne disease expert at
Rocky Mountain Labs ,
Montana .
Lyme disease is named after a cluster of cases that occurred in and around
Old Lyme and
Lyme ,
Connecticut in
1975 . Before 1975, elements of ''Borrelia'' infection were also known as Tickborne meningopolyneuritis,
Garin-Bujadoux Syndrome ,
Bannwarth Syndrome or sheep tick fever. It is transmitted to
Humans , as well as
Dogs ,
Horses and other domesticated animals, by the bite of infected ticks.
The disease was first documented as a
Skin Rash in
Europe in
1883 . Over the years, researchers there identified additional features of the disease, including an unidentified pathogen, its response to
Penicillin , the role of the ''Ixodes'' tick (wood tick) as its vector, and other symptoms including those affecting the
Central Nervous System .
Researchers in the US had been aware of tick infections since the early 1900s. For example, an infection called
Tick Relapsing Fever was reported in
1905 , and the wood tick, which carries an agent that causes
Rocky Mountain Spotted Fever , was identified soon after. However, the full
Syndrome now known as Lyme disease, was not identified until a cluster of cases thought to be juvenile
Rheumatoid Arthritis occurred in three towns in southeastern Connecticut, in the
United States . Two of these towns, Lyme and
Old Lyme , gave the disease its popular name.
In
1982 a novel
Spirochete was isolated and cultured from the midgut of ''Ixodes'' ticks, and subsequently from patients with Lyme disease. The infecting agent was first identified by
Jorge Benach , and soon after isolated by
Willy Burgdorfer , a scientist at the
National Institutes Of Health , who specialized in the study of spirochete microorganisms. The spirochete was named ''
Borrelia Burgdorferi '' in his honor. Burgdorfer was the partner in the successful effort to culture the spirochete, along with
Alan Barbour .
''Borrelia burgdorferi'' has been isolated in skin specimens of white-footed mice in museum specimens as far back as the
1870s in
Massachusetts .
Lyme disease is caused by
Spirochetal Bacteria from the
Genus ''Borrelia'', which has well over three hundred known genomic
Strains . The ''Borrelia''
Species known to cause Lyme disease are collectively known as ''Borrelia burgdorferi'' sensu lato, and have been found to have greater
Strain Diversity than previously estimated.
1 Until recently it was thought that only three genospecies caused Lyme disease: ''B. burgdorferi'' sensu stricto (predominant in
North America , but also in
Europe ), ''B. afzelii'', and ''B. garinii'' (both predominant in
Eurasia ). However, newly discovered genospecies have also been found to cause disease in humans: ''B. lusitaniae''
2 in
Europe (especially
Portugal ),
North Africa and
Asia , ''B. bissettii''
34 in the
U.S. and
Europe , and ''B. spielmanii''
56 in
Europe . Additional ''B. burgdorferi'' sensu lato genospecies suspected of causing illness, but not confirmed by culture, include ''B. valaisiana'' (
Eurasia , especially
England ,
Switzerland and the
Netherlands ); ''B. japonica'', ''B. tanukii'' and ''B. turdae'' (
Japan ); ''B. sinica'' (
China ); and ''B. andersonii'' (
U.S. ). Some of these species are carried by ticks not currently recognized as carriers of Lyme disease. ''Note: At present, diagnostic tests are based only on B. burgdorferi sensu stricto (the only species used in the U.S.), B. afzelii and B. garinii.''
Apart from this group of closely related genospecies, additional ''Borrelia'' species of interest include ''B. lonestari'', a spirochete recently detected in the ''Amblyomma americanum'' tick (lone star tick) in the U.S.
7 ''B. lonestari'' is suspected of causing
STARI (Southern Tick-Associated Rash Illness), an illness which follows a lone star tick bite and clinically resembles Lyme disease, but whose sufferers consistently test negative for Lyme. There is currently no diagnostic test available for STARI, and no official treatment protocol, though antibiotics are generally prescribed. The ''B. miyamotoi'' spirochete, related to the
Relapsing Fever group of spirochetes, is suspected of causing illness in
Japan . Spirochetes similar to ''B. miyamotoi'' have recently been found in both ''I. ricinus'' ticks in
Sweden and ''I. scapularis'' ticks in the
U.S. 89
One of the most striking features of ''B. burgdorferi'' as compared with other
Eubacteria is its unusual
Genome , which is far more complex than that of its spirochetal cousin ''
Treponema Pallidum '', the agent of
Syphilis .
10 The genome of ''B. burgdorferi'' includes a linear
Chromosome approximately one
Megabase in size, with 21
Plasmids (12 linear and 9 circular) - by far the largest number of plasmids found in any known bacterium.
11 Genetic exchange, including plasmid transfers, contributes to the
Pathogenicity of the organism.
12 Long-term culture of ''B. burgdorferi'' results in a loss of some plasmids and changes in expressed protein profiles. Associated with the loss of plasmids is a loss in the ability of the organism to infect laboratory animals, suggesting that the plasmids encode key genes involved in
Virulence .
''B. burgdorferi'' is a highly specialized, motile, two-membrane, spiral-shaped
Spirochete ranging from about 9-32
Microns in length. It is often described as
Gram-negative and has an outer membrane with
LPS , though it stains only weakly in the
Gram Stain . ''B. burgdorferi'' is a
Microaerophilic organism, requiring little oxygen to survive. It lives primarily as an
Extracellular pathogen, although it can also hide
Intracellularly (see
Mechanisms Of Persistence section).
Like other spirochetes such as ''
T. Pallidum '' (the agent of
Syphilis ), ''B. burgdorferi'' has an axial filament composed of
Flagella which run lengthwise between its cell wall and outer membrane. This structure allows the spirochete to move efficiently in corkscrew fashion through
Viscous media, such as
Connective Tissue . As a result, ''B. burgdorferi'' can disseminate throughout the body within days to weeks of infection, penetrating deeply into tissue where the immune system and antibiotics may not be able to eradicate the infection.
''B. burgdorferi'' is very slow growing, with a doubling time of 12-24 hours (in contrast to pathogens such as
Streptococcus and
Staphylococcus , which have a doubling time of 20-30 minutes). Since most
Antibiotics kill bacteria only when they are dividing, this longer doubling time necessitates the use of relatively longer treatment courses for Lyme disease. Antibiotics are most effective during the
Growth Phase , which for ''B. burgdorferi'' occurs in four-week cycles. Some clinicians have observed that chronic Lyme patients commonly experience a worsening of symptoms every four weeks; these periodic flare-ups are thought to correspond to the growth phase of ''B. burgdorferi''.
13
While ''B. burgdorferi'' is susceptible to a number of
Antibiotics In Vitro , there are contradictory reports as to the efficacy of antibiotics
In Vivo . ''B. burgdorferi'' may persist in humans and animals for months or years despite a robust immune response and standard antibiotic treatment, particularly when treatment is delayed and dissemination widespread. Numerous studies have demonstrated persistence of infection despite antibiotic therapy.
141516171819202122
Various survival strategies of ''B. burgdorferi'' have been posited to explain this phenomenon,
23 including the following:
- ''Physical sequestration of B. burgdorferi in sites that are inaccessible to the immune system and antibiotics'', such as the Brain 24 and Central Nervous System . New evidence suggests that ''B. burgdorferi'' may use the host's Fibrinolytic system to penetrate the Blood-brain Barrier .25
- '' Intracellular invasion.'' ''B. burgdorferi'' has been shown to invade a variety of cells, including Endothelium ,26 Fibroblasts ,27 Lymphocytes ,28 Macrophages ,29 Keratinocytes ,30 and Synovium .3132 By 'hiding' inside these cells, ''B. burgdorferi'' is able to evade the immune system and is protected to varying degrees against antibiotics,33 34 allowing the infection to persist in a chronic state.
- ''Altered Morphological Forms , i.e. Spheroplasts (cysts, granules).''
- ---The existence of ''B. burgdorferi'' spheroplasts, which lack a Cell Wall , has been well documented In Vitro ,35363738394041 In Vivo ,4243 and in an Ex Vivo model.44 The fact that energy is required for the spiral bacterium to convert to the cystic form suggests that these altered forms have a survival function, and are not merely end stage degeneration products. The spheroplasts are indeed Virulent and Infectious , able to survive under adverse environmental conditions, and have been shown to revert back to the spiral form in vitro, once conditions are more favorable.45464748
- ---A number of other factors make ''B. burgdorferi'' Spheroplasts a key factor in the relapsing, chronic nature of Lyme disease. Compared to the spiral form, spheroplasts have dramatically reduced surface area for immune surveillance. They also express different surface proteins - another reason for Seronegative disease (i.e. False-negative antibody tests), as current tests only look for antibodies to surface proteins of the ''spiral'' form. In addition, ''B. burgdorferi'' spheroplasts are generally ''not'' susceptible to the Antibiotics traditionally used for Lyme disease. They have instead shown sensitivity in vitro to Antiparasitic drugs such as Metronidazole ,49 Tinidazole ,50 and Hydroxychloroquine ,51 to which the spiral form of ''B. burgdorferi'' is not sensitive.
- '' Antigenic variation''. Like the ''Borrelia'' that cause Relapsing Fever , ''B. burgdorferi'' has the ability to vary its surface proteins in response to Immune attack.52 This ability is related to the genomic complexity of ''B. burgdorferi'', and is another way ''B. burgdorferi'' evades the immune system to establish a chronic infection.
- '' Immune System suppression.'' Complement inhibition, induction of anti-inflammatory Cytokines such as IL-10 , and the formation of Immune Complexes have all been documented in ''B. burgdorferi'' infection. Furthermore, the existence of immune complexes provides another explanation for Seronegative disease (i.e. False-negative antibody tests of Blood and Cerebrospinal Fluid ), as studies have shown that substantial numbers of seronegative Lyme patients have antibodies bound up in these complexes.535455
In Europe, ''Ixodes ricinus'', known commonly as the sheep tick, castor bean tick, or European castor bean tick is the transmitter. On the east coast of North America, ''Ixodes scapularis'' ( Black-legged Tick or Deer Tick ) has been identified as the key to the disease's spread. On the west coast, the tick responsible for spread of the disease is ''Ixodes pacificus'' (Western black-legged tick).
The number of reported cases of the disease have been increasing, as are endemic regions in the United States. Lyme disease is reported in nearly every state in the U.S., but there are concentrated areas in the northeast, mid-Atlantic states, Wisconsin , Minnesota , and northern California . Lyme disease is endemic to Europe and Asia .
The longer the duration of tick attachment, the greater the risk of disease transmission, but at minimum the tick must be attached for at least 12 hours for the spirochete to be transferred.
There are many urban legends about the proper and effective method to remove a tick. One legend states that something hot (cigarette; burnt match) should be applied to the back of the tick, which causes the tick to remove it's head from the victim. It further states that ticks "screw" their heads into their victims; therefore, one must "unscrew" the head. These legends are incorrect and dangerous. Proper removal of a tick: use a pair of tweezers, grab the head of the tick, and pull it out. If the head is not completely removed, local infection of the person/animal bitten may result, and a doctor should be consulted (or a veterinarian if the tick was removed from a pet).
In the fall, large acorn forests attract deer and mice infected with ''B. burgdorferi''. During the following spring, the ticks lay their eggs. The mouse population then "booms." Tick eggs hatch into larvae, which feed on the mice, thus infecting the larvae. The infected larvae molt into "nymphs" (this is the ticks' "juvenile form"). Infected nymphs feed on humans from spring through summer, thus transmitting the bacteria to people. ''Note: on the west coast, Lyme disease is spread by the western black-legged tick (Ixodes pacificus), which has a different life cycle.''
Lyme disease can be transmitted from an infected mother to fetus through the Placenta during pregnancy, possibly resulting in stillbirth.5657 The risk of transmission is minimized if the mother receives prompt antibiotic treatment, though physicians disagree as to the duration of treatment required.
There is also some anecdotal, largely unconfirmed evidence of Sexual Transmission .
Lyme disease has many signs and symptoms, but skin signs, Arthritis and/or various Neurological symptoms are often present. Like Syphilis , the symptoms frequently seem to resolve, yet the disease progresses. Conventional therapy is with antibiotics. People who suspect they have been exposed to Lyme disease should consult a doctor with knowledge of the disease immediately.
- Erythema Migrans rash (EM) - Contrary to popular belief, the characteristic "bull's-eye" rash with central clearing is ''not'' the most common form. Rashes that are homogeneously red are seen more frequently.5859 Multiple painless EM rashes may occur, indicating disseminated infection.
The Incubation Period from infection to the onset of symptoms is usually 1–2 weeks, but can be much shorter (a couple of days), or even as long as one month.
The late symptoms of Lyme disease can appear months from infection. Fatality can occur when the spirochete enters brain fluids and causes meningitis, or due to conductivity defects in the heart.
Lyme disease is sometimes misdiagnosed as Multiple Sclerosis , rheumatoid arthritis, Fibromyalgia , Chronic Fatigue Syndrome (CFS), or other (mainly Autoimmune and neurological) diseases, which leaves the infection untreated and allows it to further penetrate the organism. Many of these conditions may also be misdiagnosed as Lyme disease, e.g. due to false-positive Lyme serology. However it should be noted that Chronic Fatigue Syndrome (CFS) is by definition a Diagnosis Of Exclusion , meaning it would be inaccurate to say that a patient does not have Lyme ''because'' he or she has CFS. The substantial overlap in symptomology between Lyme and CFS makes this a crucial point.60
The most reliable method of diagnosing Lyme disease is a clinical exam by an experienced practitioner, taking into account symptoms, history, and possible exposure to ticks in an Endemic area. Clinicians who diagnose strictly based on the U.S. Centers For Disease Control (CDC) Case Definition For Lyme are in error, as the CDC explicitly states that this definition is intended for Surveillance purposes only, and is "not intended to be used in clinical diagnosis."6162
The EM Rash , which does not occur in all cases, is considered sufficient to make a diagnosis of Lyme disease and prompt treatment without further testing. In fact because of the undisputed high rate of false negatives during the early stage of the disease (before a sufficient antibody response has been established), it is recommended that tests ''not'' be performed when a patient has an EM Rash .6364
The Serological laboratory tests available are the Western Blot and ELISA . In the two-tiered protocol recommended by the CDC according to their Case Definition , the ELISA is performed first, and if it is positive or equivocal, a Western Blot is then performed to support the diagnosis. The reliability of testing in diagnosis remains controversial (see The Lyme Controversy--Testing ).
False-positive results for the Western blot IgM are described with varicella-zoster virus,6566
Epstein-Barr virus,6768 cytomegalovirus. and herpes simplex type virus 2.69 However studies show the Western blot IgM has a Specificity of 94-96% for patients with symptoms suggestive of Lyme disease.7071
False-negative test results have been widely reported in both early and late disease.72737475
Polymerase Chain Reaction (PCR) tests for Lyme disease may also be available to the patient. A PCR test attempts to detect the genetic material ( DNA ) of the Lyme disease spirochete, whereas the Western blot and ELISA tests look for antibodies to the organism. PCR tests are rarely susceptible to False-positive results but can often show False-negative results.
Lyme disease is a mimic, and as one can see from the list of Symptoms , can imitate other diseases very easily. The Lyme Spirochete can cross the Blood-brain Barrier and affect the CNS and the Brain , which is very hard to treat without antibiotics that cross the barrier as well.
For early cases, prompt treatment is usually curative. The severity and treatment of Lyme disease can be complicated due to late diagnosis, failure of antibiotic treatment, simultaneous infection with other tick-borne diseases including Ehrlichiosis , Babesiosis , and Bartonella , and immune suppression in the patient (sometimes resulting from inappropriate treatment with steroids).
Patients with chronic Lyme disease have been shown to experience a level of physical Disability equivalent to that seen in Congestive Heart Failure .76
The disease is rarely fatal in and of itself, although deaths have been reported.7778798081
The best prevention involves avoiding areas in which ticks are found and can reduce the probability of contracting Lyme disease. Other good prevention practices include wearing clothing that covers the entire body when in a wooded area; using mosquito/tick repellent; after exposure to wooded areas, check parts of the body (including hair) for ticks.
A Vaccine against a North American strain of the spirochetal bacteria was available between 1998 and 2002 . When taking it off the market, the manufacturer cited poor sales, though some people believe that the actual reason was that the vaccine was not safe or effective at all. Safety/Efficacy concerns re: Lyme vaccine: LYMErix Controversy
The advice of the UK's Hospital For Tropical Diseases is that significant exposure (an attached mite for more than twelve hours) should be managed, as in America & Germany, with Doxycycline 100mg twice a day for three days.Antibiotic Prophylaxis After Tick Bite
For Prevention Of Lyme Disease An Annotated Bibliography
Patients should be advised to report any Erythema Migrains over the subsequent two to six weeks. If there should be suspicion of disease, then a course of Doxycycline should be immediately given for ten days; without awaiting serology tests which only yield positive results after an interval of one to two months.
Traditional treatment of ''acute'' Lyme disease usually consists of a minimum two-week to one-month course of antibiotics. Oral antibiotics do not reliably cure the disease except in the very early phase, before the bacteria have a chance to disseminate throughout the body and cross the Blood-brain Barrier .
''Chronic'' or ''late'' diagnosed Lyme is often treated with IV antibiotics, frequently ceftriaxone, for a minimum of four weeks. As it is thought to inhibit the once a month breeding cycle of borrelia burgdorferi, a longer course is recommended.
With little research conducted specifically on ''chronic'' Lyme disease, treatment remains controversial. Currently there are two sets of peer-reviewed published guidelines; one advocates extended courses of antibiotics for chronic Lyme patients, while the other recommends no treatment (see The Lyme Controversy--Two Standards Of Care ). Double-blind , Placebo-controlled trials of long-term antibiotics for chronic Lyme have produced mixed results (see The Lyme Controversy--Long-term Antibiotic Therapy ).
Many alternative (or supplemental) therapies have been suggested. Clinical trials of large doses of IV sodium ascorbate (vitamin C) have been shown to kill cancer cells and possibly parasites in the body. Largely due to this, there are many chronic lyme disease sufferers turning to natural therapies, such as those outlined at Lyme Photos .
It should be noted that the most important factor in treating lyme disease is finding a doctor that is familiar with the disease and all of the possible treatments. Some experts, such as Dr. Joseph J. Burrascano recommend both (sometimes long-term) IV treatment and a cocktail of various vitamins.
Though there is no doubt that Lyme disease exists, there is considerable controversy as to the prevalence of the disease, the proper procedure for diagnosis and treatment, and the likelihood of a chronic, antibiotic-resistant Lyme infection.
On one side are those who believe that Lyme disease is relatively rare, easily diagnosed with available blood tests, and easily treated with two to four weeks of antibiotics. On the other side are those who believe that Lyme disease is under-diagnosed, that available blood tests are unreliable, and that extended antibiotic treatment is often necessary.82838485 The majority of public health agencies such as the U.S. Centers For Disease Control maintain the former position, and recommend adherence to the IDSA Guidelines . While this narrower position is sometimes described as the "mainstream" view of Lyme disease, physician surveys suggest otherwise. Studies show that physicians practicing in Endemic areas in the U.S. are evenly split in their views, with the majority recognizing Seronegative Lyme disease, and roughly half prescribing extended courses of antibiotics for chronic Lyme disease.8687
Confusion about the significance of the U.S. Centers For Disease Control Case Definition for Lyme disease lies at the heart of the controversy over diagnosis. The CDC has explicitly stated that the following definition is meant to be used for Surveillance purposes, ''not'' diagnostic purposes.
;CDC Case Definition for Lyme disease:
# Erythema Migrans rash (at least 5 cm in diameter)
#:
# Positive blood tests (ELISA followed by Western blot) ''AND'' one or more of the following manifestations:
A number of well-documented symptoms of chronic Lyme disease including Encephalopathy 909192
(manifested by Memory Loss , mood changes and Sleep Disturbance ) are not part of the CDC case definition. Therefore clinicians using the CDC criteria for diagnostic purposes may miss some patients who have the disease.93
Additionally, reliance on the CDC case definition for clinical purposes would result in the Misdiagnosis of those with False-negative test results, a widely reported phenomenon (see Diagnosis ).
The debate over testing remains a heated one, with concern over both False-positive s and False-negative s (see Diagnosis ). Tests currently rely on indirect methods of detection (i.e. the body's Immune System response), because it is very difficult to culture the Lyme bacteria directly from patients.
Specific issues with regard to the testing controversy include the following:
- '' Sensitivity of the CDC's testing protocol.'' Critics argue that the CDC's 2-tiered testing protocol ( ELISA test, followed by confirmatory Western Blot test if positive) misses many patients with the disease, leading to False Negative s. A study from the College of American Pathologists concluded that "these tests will not be useful as screening tests until their Sensitivity is improved."94
- ''Inadequate lab standardization.'' Standardization of testing has been found to be inadequate, with a high degree of interlaboratory variability.9596
- ''No Gold Standard for evaluation of tests.'' Without a diagnostic gold standard to identify those with late-stage or chronic Lyme, Circular Reasoning becomes a problem in studies that evaluate the Sensitivity of Serologic tests for this population. Selection Bias is unavoidable if subjects are selected by CDC criteria, since late-stage patients must have tested positive previously in order to qualify for a study. In one of few studies that included late-stage patients with neurological symptoms (a study cited by the CDC to defend the validity of the tests), the authors acknowledge this risk of Selection Bias .97
- ''Positive test criteria is based on early Lyme.'' The CDC's criteria for a positive Western Blot were developed based upon on a study of patients with ''early'' Lyme disease.98 The Serologic response of patients with late-stage disease was not analyzed and incorporated, despite that fact that such cases require a positive Western blot for diagnosis by CDC standards.
- ''Specific markers for late-stage Lyme left out.'' Several highly specific Antibody bands for Lyme (31-kDa and 34-kDa, corresponding to outer surface proteins A and B) were not included in the CDC criteria for a positive Western Blot because they only appear late in the disease.99 As a result, the vast majority of laboratories do not report these bands, even if they are positive. This is one reason some clinicians use laboratories that specialize in Tick-borne Disease , as they usually report all antibody bands.
- ''Tests based on only one strain.'' Current tests at most laboratories are based on only one Strain of ''Borrelia burgdorferi'' (the B31 strain is used in the U.S.) despite the fact that there are over three hundred Strains worldwide and over one hundred in North America.100 Several studies have found that this practice can lead to False-negative s.101102 - another reason some clinicians use Tick-borne Disease specialty labs, which use multiple strains of ''Borrelia burgdorferi'' in the preparation of test kits.
- ''Testing positive after treatment.'' Because the tests measure Antibodies to ''Borrelia burgdorferi'' and not the organism itself, it is theoretically possible to test positive even after the organism has been eradicated. All agree that no treatment is required in asymptomatic patients regardless of test results; however, controversy arises when a patient continues to have symptoms after a course of treatment. In this scenario, those who hold a conservative view believe the infection must have been eradicated by the treatment, and the positive test no longer indicates active infection but rather a persisting antibody response, regardless of the clinical picture. Those who take a broader view of Lyme believe the evidence and clinical picture most likely point to a Persisting Infection requiring further antibiotic treatment.
- ''Concern about False-positive s.'' Many physicians with a conservative view of Lyme believe it is over-diagnosed and over-treated. One of the most widely cited studies concluded that 57% of patients diagnosed with Lyme in an endemic area did not actually have the disease.103 Critics have responded with the following arguments:104105
- --- 45% of those considered "misdiagnosed" in the study received positive results from another laboratory, and negative results from the authors' laboratory. However there was no independent evaluation, and no reason to assume that the authors' laboratory was superior.
- --- The authors failed to consider the phenomenon of seronegative Lyme disease ( False-negative s).106107108109
- --- Rather than consider the possibility of Persistent Infection , the authors considered treatment failure to be evidence of misdiagnosis, i.e. patients could not possibly have Lyme if they were not cured by a standard course of antibiotics. This was also taken as evidence that all patients with Lyme respond to treatment - another example of Circular Reasoning .
- --- The authors excluded patients from a Lyme diagnosis if they had psychiatric symptoms, despite the fact that Lyme can ''cause'' such symptoms.110111
There is little concrete evidence either for ''or'' against the use of antibiotics for chronic Lyme disease, because only three such Double-blind , Placebo-controlled Clinical Trial s have been funded to date by the U.S. National Institutes Of Health , with conflicting results.
One month of intravenous ceftriaxone followed by two months of low-dose oral doxycycline (or , Paresthesia s or Dysesthesias .
- ''No significant benefit found in physical or mental health.'' However critics maintain that the study contains serious methodological flaws ( ILADS Position Paper ) including the following:112113
- ---The dose of doxycycline used in the study (200mg daily) is too low to penetrate the Central Nervous System ; failure was to be expected at this dose.
- ---This was not in actuality a "long-term" trial as described, but rather a ''short-term'' trial of ceftriaxone, because of the sequential use of two antibiotics with different modes of action (and with the second antibiotic inadequately dosed). Since patients had failed similar treatment previously, it was unlikely that this regimen would produce any benefit.
- ---Cognitive status was measured only subjectively using patient surveys (the SF-36), making it impossible to assess changes in Executive Functioning often seen in chronic Lyme patients. Objective neuropsychiatric testing results were not reported.
- ---The authors’ statement that not a single one of 1800 patients screened were PCR positive for Lyme114 is puzzling in light of numerous studies documenting Persisting Infection in patients who remain symptomatic after treatment.115116 Either Selection Bias resulted in a study population that was not representative of chronic Lyme patients (and thus the study is not Generalizable ), or the accuracy of the authors’ PCR methods is in doubt. In either scenario, the authors' conclusion that chronic Lyme patients do not suffer from persistent infection is invalid.
117
Four weeks of intravenous ceftriaxone or Placebo given to chronic Lyme patients with "persistent severe fatigue".
- ''Significant improvement in Fatigue .'' The treatment effect remained even after adjusting for age, pain, history of psychiatric disorder and depressive symptoms.
- No improvement in Cognitive symptoms. However the only symptom criteria for entrance into the study was severe Fatigue . The authors acknowledge that the patients’ cognitive deficits at baseline were mild, which may explain the lack of treatment effect on cognition.
(not yet published).118119 Results presented on October 22, 2004 at the Columbia University/Lyme Disease Association Conference in Rye, NY (Press release) . Ten weeks of intravenous ceftriaxone or Placebo given to chronic Lyme patients with ongoing memory impairment.
- ''Significant improvement in both physical and cognitive symptoms.'' Physical improvement was maintained at 12 weeks followup. Patients relapsed on cognitive measures at followup, suggesting longer regimens may be required.
- Improvements in cognitive functioning correlated with changes in blood flow to the brain as measured by SPECT scans.
While the results of placebo-controlled studies are mixed, several uncontrolled studies suggest that longer durations of antibiotic treatment may be beneficial for chronic Lyme disease.120121122123124
The widely publicized results of the Klempner study have led some to proclaim that long-term antibiotics are unhelpful for patients with chronic Lyme disease, warning patients and clinicians that the evidence does not support their use. Others see this as an abuse of the concept of Evidence-based Medicine . They argue that treatment failure in one questionably designed clinical trial does not justify such warnings in light of other evidence, and that withholding antibiotic treatment is unethical in the face of patient suffering. Since the optimal choice of antibiotic(s) and treatment duration is unknown and may vary by Strain , many believe additional research on chronic Lyme disease is needed before strict treatment recommendations can be issued.
