Lyme disease: controversial issues …

John J Halperin MD

Neuroimmunology

Updated 04.29.2024
Released 05.22.2001
Expires For CME 04.29.2027

Lyme disease: controversial issues

Author: John J Halperin MD

See Contributor Disclosures

Editor: John E Greenlee MD

Lyme disease: controversial issues

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Introduction

Overview

Lyme disease continues to hold a unique position on the battlefront between evidence-based medicine and populist-supported, anecdote-derived care. Studies support the efficacy of standard courses of antimicrobial therapy in patients with active Lyme disease and demonstrate the lack of benefit of prolonged courses in patients with chronic, nonspecific symptoms. National organizations of infectious disease specialists, neurologists, and rheumatologists have analyzed all available evidence and concluded current recommendations are appropriate. A counterculture has promulgated its own “evidence-based guidelines,” relying heavily on data with a high risk of bias. Patients are caught in the middle. Against this backdrop, the author reviews the current understanding of this disease and its treatment, focusing on the key sources of controversy and highlighting studies further supporting the standard diagnostic and therapeutic approach.

Key points

	• Borrelia burgdorferi, the tick-borne spirochete that causes Lyme disease, can infect the central or peripheral nervous system in up to 10% to 15% of patients.
	• Clinical phenomena associated with neuroborreliosis typically include cranial neuropathy (most often the facial nerve), radiculoneuropathy, and lymphocytic meningitis.
	• Diagnosis after the first month of infection relies primarily on demonstration of a B burgdorferi-specific antibody response.
	• Sensitivity of serologic testing after the first 3 to 6 weeks of infection is extremely high.
	• Specificity of serologic testing is extremely high using 2-tier testing, with a screening ELISA followed – ONLY if this first ELISA is positive or borderline – by either a Western blot or second, independent ELISA.
	• No other technique has comparable overall accuracy.
	• The most specific laboratory support for the diagnosis of CNS infection is the demonstration of intrathecal production of anti-borrelia antibodies, particularly in the presence of a CSF pleocytosis or increased CSF protein.
	• Treatment with a 2- to 4-week course of oral doxycycline is curative in most neuroborreliosis patients. Parenteral treatment may be needed either if there is evidence of brain or spinal cord parenchymal involvement or if objectively demonstrable active disease persists after oral treatment.
	• Misconceptions that commonly occurring nonspecific neurocognitive symptoms are evidence of “chronic Lyme disease” or “posttreatment Lyme disease syndrome” have led to the use of prolonged, inappropriate antibiotic treatment. Multiple studies have shown this to be unhelpful and not infrequently dangerous.

Historical note and terminology

The term "Lyme disease" was first coined in the mid-1970s. Over the course of the ensuing decades, a previously unrecognized pathogen has been well characterized, diagnostic tests for its presence have been developed, the clinical spectrum of disease has been described, and therapeutic regimens have been refined. At the same time, small areas of scientific uncertainty have been disproportionately emphasized to justify inappropriate diagnosis and ever more aggressive and biologically implausible treatment regimens.

Part of the controversy derives from the notion that this disease is entirely novel and had never been described before the 1970s -- notwithstanding that this now includes a half century of accrued evidence. In fact, a closely related disorder was recognized in Europe a century ago. The typical expanding erythroderm (termed erythema migrans), and an acute meningoradiculitis syndrome with pain and weakness (that came to be known as Garin-Bujadoux-Bannwarth syndrome) were linked to bites by hard-shelled Ixodes ticks. Then, in the 1970s, several mothers in Old Lyme, Connecticut, recognized a surprisingly high incidence of what was diagnosed as juvenile rheumatoid arthritis among children in a small geographical region. Excellent epidemiological detective work led to the understanding that this was not juvenile rheumatoid arthritis, but a tick-borne infection. Within a few years the causative organism, Borrelia burgdorferi, was identified. At the same time, the strong similarities to the European syndrome of Garin-Bujadoux-Bannwarth were recognized, and parallel research in Scandinavia led to the identification of the closely related Borrelia species responsible for that syndrome.

With the characterization of the causative organisms, serologic tests were rapidly developed to identify individuals exposed to them. Unfortunately for the field, microbiological culture and other direct diagnostic testing (nucleic acid detection, antigen detection) have been far more technically challenging than in most other bacterial infections. This, coupled with the inherent technical limitations of serologic testing, has led to an interesting pair of phenomena. Growing from the disease's populist roots, some physicians and patients have adopted an ever more expansive interpretation of the range of disorders thought to be linked to it, feeling that patients may have the diagnosis based purely on a clinical gestalt despite the complete absence of objectively verifiable evidence. Others contend that only phenomena linked to this disease by decades of medical tradition can legitimately be considered part of "Lyme borreliosis”. As always, the truth lies somewhere in between, but discovering where exactly that is remains the dilemma (11).

The debate revolves around three areas that, although conceptually separate, form important and mutually reinforcing sources of confusion: (1) diagnostic testing, (2) clinical phenomenology, and (3) treatment response (27).

Scientific basis

	• Although borrelia can be identified in skin biopsies in the majority of patients with erythema migrans, culture and nucleic acid–based testing are very insensitive in patients with disseminated disease and are not recommended in suspected Lyme neuroborreliosis.
	• Serodiagnosis relies on 2-tier testing: initial testing with an ELISA or similar quantitative technique, with positive or borderline results confirmed with either a Western blot or second orthogonal ELISA.
	• Western blots are not readily interpretable in seronegative individuals. Western blot interpretation is based on statistical analysis of large numbers of tests and not on the uniqueness of any particular bands. Criteria differ with European Borrelia strains because of greater strain variability than in the United States.
	• The most specific diagnostic tool for CNS Lyme neuroborreliosis is measurement of intrathecal synthesis of anti-borrelia antibody, for which serum and CSF specific antibody concentrations (ELISA) are measured, normalized for overall immunoglobulin production in each compartment, then expressed as a ratio of CSF:serum antibody, or antibody index.
	• Measurement of CSF borrelia specific antibody concentration in isolation is not useful. Western blots of CSF are not clinically useful.
	• A CSF pleocytosis is generally present in patients with active CNS infection.
	• The clinical hallmark of this infection is the occurrence of one or more elements of a clinical triad: mononuclear cell meningitis, cranial neuritis (primarily facial nerve palsy), or painful radiculoneuritis (painful radicular symptoms with attendant sensory, motor, and reflex changes in the distribution of one or a few nerve roots), typically occurring in the early disseminated phase of infection.
	• Patients with the acute radiculopathy may have a myelopathy at the same segmental level.
	• Patients may develop other forms of mononeuropathy multiplex, including plexopathies, in which CSF need not be abnormal.
	• The entity referred to as Lyme encephalopathy may occur during active systemic infection but is rarely indicative of CNS infection or inflammation.
	• Post treatment Lyme disease symptoms are not indicative of CNS infection. It is not clear if these occur more frequently after Lyme disease treatment than in the general population.
	• Standard recommended oral antibiotic regimens (2 to 4 weeks) are highly effective, with parenteral regimens used primarily in those with parenchymal CNS disease or those with objectively demonstrable treatment failure with oral regimens. Longer courses are associated with increased complications without improved outcomes.
	• Serologic testing does not provide a marker of disease activity, and treating until the serology becomes negative is inconsistent with standard medical practice.
	• As in other bacterial infections, some symptoms persist after adequate antimicrobial therapy. Continued treatment until all symptoms resolve is inconsistent with standard medical practice.

Diagnostic testing. Culture of B burgdorferi from clinical material is technically difficult. The organism requires special medium that is not generally available in clinical laboratories. It is slow growing, so cultures must be maintained for weeks before they can be considered negative. The number of microorganisms present in readily obtainable tissue or fluid samples is small (except for cutaneous lesions, but these are clinically virtually pathognomonic, rendering culture unnecessary), limiting sensitivity because any given sample may or may not contain spirochetes.

Other technologies that might be expected to improve sensitivity have been disappointing (66). Results with nucleic acid detection-based techniques depend on the primer selected, are prone to false positives and negatives (if not carefully performed) and vary substantially among laboratories (53). Like culture, diagnostic sensitivity is particularly low in CSF, presumably because very few bacteria are present (69). Work with “pre-enrichment”—inoculating CSF directly into culture medium at the time of lumbar puncture, then incubating for 2 to 6 weeks before testing—has not materially improved diagnostic sensitivity (47). Antigen detection techniques (particularly the Lyme urine antigen test) have been popular in some circles, but reproducibility has been highly problematic (46). Assays of cell-mediated immunity, such as the EliSpot, are similarly popular but problematic (46). Detection of immune complexes containing Borrelia antigens has been reported by a few laboratories, but the findings have not been widely reproduced. As a result, testing for the presence of antibody to B burgdorferi, primarily by enzyme linked immunosorbent assay (ELISA), remains the diagnostic method of choice.

Two-tier testing was introduced to address problems with specificity that are inherent in serologic diagnosis. When (and only when) an initial quantitative assay (ELISA or IFA) demonstrates elevated serum immunoreactivity to the causative organism, a second test is performed to determine specificity. For 25 years, the second test has been a Western blot, which provides a qualitative overview of the specific proteins to which the patient's antibodies bind. Results are interpreted based on the statistical analysis of findings in large numbers of patients and controls, identifying combinations of bands with collectively high positive and negative predictive values, an approach that greatly increased specificity of serodiagnosis in North American patients. The substantially greater strain variability among European Borrelia species requires somewhat different criteria, relying on a smaller number of bands (13). In both U.S. and European guidelines, the emphasis is on IgG antibodies after the first few weeks of infection, at which point IgM is largely irrelevant and should be ignored. Measurement of antibodies to the VlsE antigen appears to be better at diagnosing infections with both U.S. and European strains, including potentially being more sensitive early in the disease than even IgM detection (13). Studies have validated testing using two orthogonal recombinant antigen-based ELISAs (such as a C6 ELISA followed by one to VlsE) (06), allowing the use of two standardized, automated tests instead of an ELISA followed by a qualitative Western blot.

Finally, specific diagnosis of central nervous system infection (CNS Lyme neuroborreliosis) has been particularly controversial. Because the sensitivity of culture for B burgdorferi in the cerebrospinal fluid of patients with Lyme meningitis has generally been on the order of 10%, this method has not been helpful. Nucleic acid detection results have varied widely, but clinical sensitivity of this also seems poor (69). Therefore, analogous to the diagnosis of systemic infection, the most useful diagnostic tool has been to measure the intrathecal production of anti-B burgdorferi antibodies to demonstrate that there is proportionately more specific antibody in the CSF than in serum, which is reflected in an antibody index. Here, too, estimates of sensitivity vary substantially. The published European guidelines for the diagnosis of neuroborreliosis require the presence of both a CSF pleocytosis and intrathecal antibody production to diagnose definite neuroborreliosis (55; 13). Some work suggests false negatives occur primarily in very early disease just as in peripheral blood serologic testing. Other negatives that have been interpreted as “false” occur in patients whose neuroborreliosis is limited to the peripheral nervous system, in whom abnormal CSF is not necessarily expected. Interestingly, although CSF IgM responses might be expected to be highly diagnostic (because IgM does not cross the blood brain barrier), this has not proved to be the case (71). Notably, a common strategy in the U.S. has been to consider lumbar puncture only in patients with a clinically consistent picture and a positive or borderline serology. European studies have emphasized the importance of always performing lumbar punctures in patients suspected of having Lyme neuroborreliosis based on the occurrence of a small number of seronegative patients with intrathecal antibody production, thereby making the U.S. strategy potentially problematic. A 2023 study in which 28 of 127 patients with Lyme neuroborreliosis had intrathecal antibody production but negative peripheral blood serologies may help clarify the situation (85). All 28 had a positive or borderline serum ELISA but were considered seronegative because of a negative confirmatory test. (Two others did not have a second-tier test performed and, therefore, were presumed negative.) Given that the artificial intelligence used to assess CSF compares first-tier ELISAs in CSF and serum, this “seronegativity” is not entirely surprising. At least four mechanisms might explain this observation:

(1) Both serum and CSF results could be false positives, suggesting the presence of an immune stimulus within the CNS that cross-reacts with B burgdorferi, which would be intriguing in and of itself.

(2) In seronegative, AI-positive individuals, testing could have occurred early in infection—before the breadth of the serum IgG response was sufficient to give a positive second-tier response.

(3) If somewhat later in infection, the autonomous CSF response could have either matured earlier, or been more robust, than that in serum.

(4) Given the much lower background antibody concentration in CSF, the signal-to-noise ratio in CSF may have led to an evident specific response in CSF that is obscured in serum. Although the actual mechanism remains to be elucidated—and whether this concern will be less problematic with modified 2-tier testing—it seems reasonable that in individuals with a clinical picture plausibly related to Lyme neuroborreliosis and a positive or borderline serum first-tier test, CSF examination should be considered.

Apparent intrathecal antibody production can persist for years after the infection has been successfully treated, and the CSF pleocytosis may be slow to resolve. Consequently, much effort has focused on identifying alternative markers more closely linked to active infection, with a particular focus on the CSF concentration of CXCL13, a B cell attracting cytokine. CXCL13 appears to increase very early in this infection and decreases rapidly with successful treatment (65; 60). Its major limitation is its specificity: it is elevated in many CNS inflammatory states. Although its concentration appears to be greater in spirochetal CNS infections, substantial overlap has made it difficult to define a useful diagnostic cutoff value (59; 15). Work measuring plasma neurofilament light chain concentration suggests that, as in other CNS insults, levels may be elevated in acute Lyme neuroborreliosis, similarly normalizing rapidly with successful treatment (54). Notably, no relationship was observed between this plasma marker and persistent post-treatment symptoms.

Clinical phenomena. There has been particular confusion and controversy surrounding the clinical phenomenology of nervous system Lyme disease. Some clinicians (primarily non-neurologists) and many patients seem to forget that there are three prerequisites for the diagnosis of nervous system Lyme disease: (1) the existence of nervous system disease, (2) the presence of Lyme disease, and (3) a causal relation between the two.

Most agree that Lyme disease causes lymphocytic meningitis, radiculoneuritis (painful nerve inflammation, typically with objectively demonstrable dermatomal sensory, motor, and reflex changes), and cranial neuropathies, particularly the facial nerve. In European patients, the most common manifestation in adults is painful radiculitis; in children it is cranial neuropathies, almost always facial palsy (76; 70). Less agreement exists on the characteristics of other types of neuropathy and other CNS changes, particularly encephalomyelitis and encephalopathy (56).

It has long been stated that neuroborreliosis is more common with the more prevalent European strains, particularly B garinii, and arthritis with the predominant U.S. strain, B burgdorferi, sensu stricto, even though most epidemiologic studies suggest about 10% to 15% of patents develop nervous system involvement in both populations. Presumably, as there has been increased early recognition and treatment of this infection, both numbers may have evolved. A population-based study from Ontario found that of the 19% presenting with early disseminated infection, 94% had neurologic symptoms, 63% had erythema migrans, and 10% had cardiac (37). Of the 42% diagnosed with late disseminated infection, all had rheumatologic symptoms. However, of these, 93% had arthralgias, and just 7% had frank arthritis; 55% had neurologic symptoms, and 9% had cardiac involvement. Combining early and late disseminated presentations, 2.9% had frank arthritis and 41% had neurologic (broadly defined) presentations. A similarly large systematic study from Germany found that Lyme arthritis occurred in 2.8% and neuroborreliosis in 3.8% (narrowly defined) (08).

A variety of forms of peripheral nervous system involvement has been described. A mononeuritis multiplex often occurs both in the affected limb and more diffusely in patients with acrodermatitis chronica atrophicans (34), a chronic cutaneous manifestation of Borrelia infection seen in Europe but rarely, if ever, in North America. North American patients also develop a mononeuropathy multiplex, with neurophysiologic and neuropathologic characteristics similar to those seen in European patients (31). Clinical presentation can be as a plexopathy, a severe patchy or diffuse polyneuropathy (similar clinically to that first described by Garin and Bujadoux), or a mild confluent mononeuropathy multiplex, presenting clinically as a subacute stocking-glove neuropathy. Interestingly, the identical peripheral nervous system changes have been consistently demonstrated in rhesus macaque monkeys experimentally infected with B burgdorferi (19).

Central nervous system parenchymal involvement, though rare, similarly can take a variety of forms. Best described is the focal spinal cord inflammation sometimes occurring at the same level as nerve root inflammation in the syndrome of Garin-Bujadoux-Bannwarth (39). Rarely, patients may develop primarily white matter inflammation, a leukoencephalitis, with spasticity and other "white matter" signs, abnormal brain MRIs, and inflammatory changes in CSF (41). The spirochete may have a specific tropism for oligodendroglia, leading to predominant involvement of the white matter (64). Patients with this prolonged CNS infection often have oligoclonal bands and increased total IgG synthesis in the CSF, raising the possibility of misdiagnosis as multiple sclerosis. However, in these patients, because the chronic immune stimulation causing these abnormalities is directed against a specific organism, virtually all should have demonstrable intrathecal production of Borrelia-specific antibody. Treatment should arrest disease progression in most of these patients. If the infection is eradicated, clinical improvement may occur over time as with any self-limited encephalitis.

Most controversial has been the entity referred to as Lyme encephalopathy (31). This disorder was originally described in individuals with unequivocal and long-standing active systemic Lyme disease, such as Lyme arthritis or other late manifestations. Described before there was widespread lay and medical recognition of Lyme disease, and consequently, at a time when a significant number of patients were untreated for an extended period of time, this consisted of difficulty with cognitive functioning clearly demonstrable both on mini-mental status testing and on formal neuropsychologic testing. In most patients, brain MRI scans and CSF exams failed to suggest CNS infection. It is likely that this disorder represents the same type of cognitive difficulty seen in patients with most other systemic (non-neurologic) inflammatory illnesses, perhaps mediated by circulating cytokines produced outside the CNS in response to infection, which then enter the CNS where they have neuroactive effects (14). Because the nervous system is neither infected nor damaged in these individuals, neurologic recovery following treatment is typically excellent (57).

A small proportion of these individuals have indeed had evidence of CNS infection, with abnormal brain MRIs and CSF. Like other patients with Lyme encephalitis, this disorder does respond to antimicrobial therapy (51). Because the parenchymal damage tends to be rather limited, recovery is generally excellent.

Emphasis on these encephalopathic symptoms in active Lyme disease led to the notion that this state could occur either as the sole manifestation of Lyme disease, absent other evidence of inflammation, or after otherwise successful treatment of the infection–the latter becoming known as “post-treatment Lyme disease symptoms/syndrome” (PTLDS). PTLDS is thought to consist of persistent difficulties with cognition, memory, and fatigue despite appropriate treatment for Lyme disease (12). Although one study suggested a slight excess in this symptom complex among patients who had previously been treated for Lyme borreliosis (3.9% higher than in population controls) (74), most studies describe the prevalence of 10% to 20% in individuals 1 year after treatment as no different than among contemporaneously-followed healthy controls (68; 67; 10; 72; 84; 80; 01). Several non-Lyme disease-specific factors have been identified as predictors of persistent symptoms: presence of multiple comorbidities (78). Patients’ initial negative expectation of a treatment response and assumption that treatment was not with active drug (75) and the presence initially of either paresthesia, elevated stress score, or a combination thereof elevated Beck Depression Inventory score plus number of pain sites (81). Importantly, multiple studies have found that few if any patients with persistent symptoms have had prior neuroborreliosis (12; 24; 02). Even more importantly, multiple studies have found that only a minority of patients seen in referral centers for these symptoms have any objective evidence of prior Lyme borreliosis. In fact, many have had other diagnoses for which appropriate treatment was delayed by this misdiagnosis (24; 42). Notably, additional antimicrobial therapy clearly does not provide meaningful benefit to these patients and carries significant risk (45; 20; 04; 22; 05; 16).

Given the 2% prevalence of these nonspecific symptoms in the general population, post-treatment Lyme disease symptoms/syndrome may well represent the chance co-occurrence of unrelated disorders, with symptoms attributed to Lyme disease because of anchoring bias (52; 31). Alternatively, this may reflect a post-infectious syndrome analogous to that described following COVID-19 (38). Finally, although some work has suggested possible persistence of small numbers of B burgdorferi in experimentally infected monkeys (18), there is no evidence that this elicits any type of host response, causes any symptoms, requires treatment, or in any way contributes to continued disease.

Treatment. Numerous studies have demonstrated that both oral and parenteral antimicrobial regimens are highly effective in treating patients with clear-cut Lyme disease (46). Several analyses have found that most commonly used antimicrobial regimens are equally efficacious (72; 83; 03). The usual approach is to treat all but the most serious infections with oral regimens first, followed by parenteral regimens in the small number of individuals in whom this is not curative. Oral regimens have been shown to be effective in European patients with Lyme meningitis and cranial neuritis (44). Published European neuroborreliosis treatment guidelines explicitly recommend oral treatment for Lyme meningitis or peripheral nervous system involvement, with parenteral treatment solely for individuals with parenchymal CNS involvement (55; 36; 63). Corresponding studies have not been performed in patients infected in the United States. However, given that the antimicrobial sensitivities of U.S. and European B burgdorferi strains are comparable, similar treatment recommendations are reasonable in U.S. patients. Moreover, one European study has demonstrated that oral doxycycline can effectively treat many patients with parenchymal CNS infection (07). Controlled, randomized trials show no clear benefit of extending parenteral treatment beyond 2 weeks (58); however, many centers dealing with large numbers of patients have seen enough relapses after 2 weeks of treatment that it has become customary to treat for 3 to 4 weeks.

Discussion

Diagnostic testing. Although ELISAs are widely used in the serodiagnosis of many infections, many of the conventions usually employed in other disorders have, unfortunately, not been used in the diagnosis of Lyme disease. In most other diseases, changes in antibody titer (acute vs. convalescent) are used to indicate a change in the immune response and, hence, to infer an immune challenge (ie, a current or recent infection). In Lyme disease, a single serologic test result is typically used to infer active infection. In most other diseases, the presence of detectable antibody is taken as evidence of present or past exposure; in Lyme disease, it is often used to suggest current, active infection in need of treatment. In most infections, it is readily accepted that it takes time for the immune system to develop a detectable antibody response; the absence of detectable antibody in very early Lyme disease sometimes leads to delayed diagnosis and treatment and, importantly, is often misinterpreted as evidence that serologic testing has broadly poor sensitivity. Finally, although in most other disorders it is widely accepted that no diagnostic technology has 100% sensitivity and specificity, in Lyme disease this has led to popular misconceptions that laboratory testing is completely unreliable and without any positive or negative predictive value. This unfortunate list of misconceptions and misuse of testing has resulted in tremendous uncertainty on the part of physicians and patients on the appropriate diagnostic and therapeutic strategy.

Although the use of confirmatory Western blots substantially improved the specificity of serodiagnosis, it must be recognized that as with any technique that improves specificity, there is some corresponding loss of sensitivity. In the original work that led to the Western blot criteria, the sensitivity of the IgM criteria was only 32% in patients with early disease, whereas that of the IgG criteria was 83% in individuals with disease of longer standing, a value that has now been improved to over 95% but may still be somewhat limiting in early Lyme neuroborreliosis (82; 85). Even so, common sense would still suggest that in a strongly seropositive patient with a clinical disorder likely to be caused by Lyme disease, a negative Western blot would not absolutely exclude the diagnosis (87). Perhaps more troubling has been the widespread use of Western blots without ELISAs. Because the criteria for Western blot interpretation were developed almost exclusively in patients with positive ELISAs, interpretation in an entirely different group (those with total borrelia binding antibody no different than controls) is problematic and must be done extremely cautiously. Hopefully, the alternative strategy of sequentially using two independent ELISAs will at least remove difficulties with Western blot misinterpretation (44).

In the diagnosis of CNS infection, the role of measurement of intrathecal production of specific antibody has been controversial, a controversy made even more problematic by the observation that apparent excess of intrathecal antibody can persist for many years after successful treatment. Most European experts in the field originally considered this measure an absolute requirement to diagnose CNS infection and only rarely make the diagnosis of nervous system Lyme disease in its absence (55). Studies in early North American Lyme neuroborreliosis also suggest that at least 90% of such patients have specific intrathecal antibody production (31). Some studies of patients with more long-standing infection and CNS symptomatology suggest that only 50% of patients will meet this criterion, although most others have a CSF pleocytosis or increased protein (50). Still other practitioners, viewing these differences, consider CSF examinations to be completely worthless and misleading. It seems clear that the demonstration of intrathecal antibody, particularly if accompanied by other CSF abnormalities, is a sufficient basis for a diagnosis of CNS Lyme disease. Whether it is necessary remains to be established.

Clinical phenomena. Although there is little debate about the classic triad of neurologic disorders (which tend to occur early in infection and are unambiguous in their clinical appearance), considerable controversy surrounds the more indolent and typically later-occurring phenomena. Unfortunately, the early descriptions of the milder, late polyneuropathy (30) emphasized the subjective symptoms more than the equally prominent objective abnormalities on exam and on neurophysiologic testing. Subsequently, some non-neurologists have taken to diagnosing Lyme neuropathy in patients with fluctuating paresthesias, but with no objective evidence of a peripheral neuropathy by any criterion; this is a questionable practice at best. More problematic, these purely subjective symptoms are now considered typical of post Lyme disease syndrome (77; 78).

Similarly, several issues concerning CNS disease remain confusing. Although intrathecal antibody measurement should differentiate patients with active Lyme encephalomyelitis from those with multiple sclerosis, some clinical situations may not be straightforward. In some patients who appear to have typical multiple sclerosis and also have evidence of Lyme disease, an indirect relationship might, in theory, exist. CNS infection with B burgdorferi (either meningitis or parenchymal involvement) can stimulate local production of gamma-interferon (17) and tumor necrosis factor-alpha. Because the former is known to trigger multiple sclerosis attacks, it would not be surprising if in some patients, multiple sclerosis attacks might be triggered by this infection. In patients in whom this constitutes the first episode of multiple sclerosis, it might be concluded that their relapsing remitting illness is attributable to this infection. However, it seems more likely that Lyme disease is merely one of the many potential triggers of an acute exacerbation, and not the "cause" of relapsing remitting multiple sclerosis or of a relapsing inflammatory CNS disorder.

Similarly, some patients with apparent amyotrophic lateral sclerosis have had serologic evidence of B burgdorferi infection (28; 79). In some, this probably is Lyme neuroborreliosis presenting as a combination of a Lyme-related myelopathy and a predominantly motor polyradiculopathy. In others, the reason for the association is unknown, but may be a chance co-occurrence (62). Importantly, a large study of all Danish patients found to have intrathecal antibody production to B burgdorferi SL over 3 decades found no excess incidence of dementia, Alzheimer disease, Parkinson disease, motor neuron disease, epilepsy, or Guillain-Barre syndrome (25).

Perhaps most confusing has been the concept of Lyme encephalopathy. Initially described in patients with objectively demonstrable cognitive difficulties, this construct is now sometimes used in patients with purely subjective disorders or patients with medical (eg, sleep apnea) or psychiatric (eg, depression) disorders that interfere with concentration but who are neurologically normal. Studies spanning decades have shown that these patients rarely have CNS infection or any evidence of neurologic damage of any sort (29; 57; 14). As for psychiatric disorders, the few systematic studies addressing this subject have indicated that psychiatric disease is no more common in patients with Lyme disease than in those with other chronic illnesses (86; 73), nor is any specific psychiatric disorder associated with this infection (26). Although numerous anecdotes describe individuals with psychiatric disease with acute Lyme disease (including some in whom both disorders improved concurrently), there is little to prove that a consistent or causal relationship exists. On the other hand, some, but by no means all, patients who have been diagnosed as having “chronic Lyme disease” without objective evidence of this infection have been shown to have significant psychiatric comorbidities – although these may more often be Axis II than Axis I disorders (33; 48; 43).

As it has become more difficult to support the argument that some of these syndromes are attributable to Lyme disease, the possibility of coinfections has received increasing attention. The same ticks that transmit B burgdorferi can also carry babesia, ehrlichia, anaplasma, and tick-borne encephalitis complex viruses. To date, however, the evidence in support of these as coinfections causing chronic symptoms has remained limited (23), and there is evidence that patients with both Lyme disease and anaplasma may be less ill than those with either infection alone (35). The possibility of co-infections with the agent of cat-scratch fever has been suggested; this too, though, seems improbable (32). Interestingly, in the current ILADS Guideline recommendations, early treatment with amoxicillin or cefuroxime is recommended to prevent the occurrence of late sequelae of Lyme disease, even though these agents have no efficacy against these co-infections (09).

Finally, several groups have attempted to obtain corroboration of this encephalopathy using brain SPECT scanning. Unfortunately, conventional, qualitative SPECT is highly susceptible to numerous artifacts. Although one highly sophisticated quantitative analysis in a group of patients with other compelling evidence of neuroborreliosis demonstrated significant abnormalities (49), most other work in this field is at best difficult to interpret. Interestingly, in contrast to the regional hypometabolism described in these SPECT studies, at least two PET studies in well characterized patients have demonstrated hypermetabolism in involved areas (40; 61) – more fitting to the local inflammatory state known to be present. Unfortunately, the diagnosis of Lyme encephalopathy is now being made in many individuals in whom the basis for the diagnosis of Lyme disease is tenuous, albeit more compelling than the evidence of an encephalopathy.

Treatment. The observation that some patients who have been diagnosed as having Lyme disease have symptoms after receiving recommended treatment regimens has led to the use of ever more prolonged and varied courses of treatment. Unfortunately, there is little biological rationale for treatment for longer periods or for many of the unconventional regimens being employed (46). Some clinicians have tried to use resolution of the serologic results to gauge treatment response. Because the "purpose" of the antibody response in any infection is, in part, to persist and protect in the event of future exposures, this strategy is illogical. In other patients in whom laboratory support for the diagnosis of Lyme disease is initially tenuous and who suffer from incapacitating subjective symptoms but have no objective evidence of neurologic (or other medical) disease, response to conventional courses of treatment is often disappointing (43). This occurrence can be attributed to one of two possibilities: either the problem was not caused by this infection in the first place, or the treatment was ineffective. Unfortunately, by drawing the second conclusion, many patients are being exposed to ever longer and more toxic regimens, with no clear goal or endpoint in mind, but with considerable potential risk (21).

Resolution

Diagnostic testing. Even though the preponderance of scientific data suggests there should be little remaining controversy, some continue to advocate strongly that important issues remain unresolved. That notwithstanding, several concepts are helpful when evaluating a patient for possible CNS Lyme disease. Because the principal issue is whether or not the CNS is infected, usual common sense principles should apply. CNS infections almost invariably elicit a local inflammatory response, manifest as a reactive CSF pleocytosis, increased CSF protein, or both. To have a CNS infection with completely normal CSF seems implausible. Moreover, as in the vast majority of other chronic CNS infections in which this has been evaluated, there is local stimulation of the immune system with demonstrable intrathecal production of organism-specific antibodies. Hence, although not necessarily addressing whether or not a patient has infection outside the CNS, it is probably fair to say that completely normal CSF makes CNS infection with B burgdorferi highly unlikely.

Similarly, common sense must be applied to serologic diagnosis. This requires recognition that no test has 100% accuracy, and all testing must be interpreted in its clinical context. If applied appropriately, 2-tier testing provides extremely useful information.

As for the clinical spectrum of this disease, as in any disorder, there will be a continuing evolution in our concept of the full spectrum of clinical manifestations, a fact made surprisingly evident with the identification of genetic markers in other disorders originally described syndromically. Although our concepts of the clinical spectrum of nervous system Lyme disease will undoubtedly continue to evolve, the guiding principle should remain that there must be objective evidence both of nervous system disease and of Lyme disease, and of a plausible link between the two.

Treatment. Unfortunately, this issue often leads to the most dogmatic and heated debates. Despite this, the microbiological and clinical data are clear. B burgdorferi is highly susceptible to the commonly recommended regimens, which typically result in cure rates of 90% to 95%, comparable to many other infections. Exposing patients to the risks of extremely prolonged regimens or of other more toxic agents seems ill advised.

Table 1. Treatment Regimens

Early disease (no neurologic or cardiac involvement)
	Medication, first line
		• doxycycline 100 mg, twice daily for 14 to 21 days. Note: Prior recommendations against using doxycycline in children younger than 8 years old have been eased as considerable evidence has accumulated that the risk with several weeks of doxycycline are minimal. • amoxicillin 500 mg, three times daily, 14 to 21 days. • cefuroxime axetil 500 mg, twice daily, 14 to 21 days. Note: more expensive.
	Medication, second line
		• azithromycin 500 mg daily for 7 to 10 days. Note: may be less effective. • clarithromycin 500 mg, twice daily for 14 to 21 days. Note: may be less effective.
Neurologic disease (either parenchymal central nervous system or peripheral, but resistant to above) or severe cardiac involvement
		• ceftriaxone 2 g intravenously daily for 14 to 28 days. • penicillin 3 to 4 x 106 U intravenously every 4 hours. • cefotaxime 2 g intravenously every 8 hours.
(46)

References

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All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

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John J Halperin MD

Dr. Halperin of Overlook Medical Center and Sidney Kimmel Medical College of Thomas Jefferson University has stock ownership in Johnson & Johnson and has received consultant honorariums from Pfizer.
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John E Greenlee MD

Dr. Greenlee of the University of Utah School of Medicine has no relevant financial relationships to disclose.
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Lyme disease: controversial issues

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Lyme disease: controversial issues

Introduction

Overview

Key points

Historical note and terminology

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Discussion

Resolution

Table 1. Treatment Regimens

References

Contributors

Author

Editor

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