Chronic Lyme Disease: The Controversies and the Science

Paul M Lantos

Expert Rev Anti Infect Ther. 2011;9(7):787-797.

Does Chronic Lyme Disease Exist?

Most patients who are diagnosed with chronic Lyme disease have prolonged somatic and/or neurocognitive symptoms, such as fatigue, arthralgias or memory impairment, but usually lack the objective findings classically associated with Lyme disease. The term 'chronic Lyme disease' implicitly suggests that these symptoms are caused by infection with B. burgdorferi, and it is often argued that infection with this organism may become persistent despite antimicrobial therapy. These assumptions, however, have not translated to any accepted clinical, pathologic or microbiologic definition of the term. One clinical practice guideline devoted to the management of chronic Lyme disease included a provisional definition so broad that Lyme disease could not be differentiated from the myriad other medical conditions (Box 2).^[30] Without a definition, the term lacks meaning and it becomes fruitless to debate about whether or not 'chronic Lyme disease' exists as such.

Unable to precisely say what chronic Lyme disease is, we must next examine the features of patients referred for Lyme disease to discern whether there emerges a subset who have verifiable Lyme disease, and who appear to have chronic, treatment-refractory infection. In seven studies conducted in endemic areas, comprising a total of 1902 patients referred for suspected Lyme disease, only 7–31% had active Lyme disease and 5–20% had previous Lyme disease.^[31–37] Among the remainder, 50–88% had no evidence of ever having had Lyme disease (Figure 1). Most of these patients had either an alternative medical diagnosis or a functional somatic syndrome such as chronic fatigue syndrome or fibromyalgia. A substantial number were diagnosed with Lyme disease based on an inability to make an alternative diagnosis – referred to in one paper as 'diagnosis of Lyme disease by exclusion'.^[36] Primary psychiatric diagnoses, psychiatric comorbidity and psychological traits such as catastrophization and negative affect are also common.^[32,34] Many had symptoms of long duration and had received multiple courses of antibiotics directed at Lyme disease. Similar observations were made in Vancouver, British Columbia, where Lyme disease is very rare; of 65 patients referred for Lyme disease, 61 had either an alternative medical diagnosis or a functional somatic syndrome, and nine had a primary psychiatric diagnosis.^[38]

(Enlarge Image)

Figure 1.

Categorization of persons referred for Lyme disease in endemic areas. Alternative diagnoses are categorized differently in the cited references, but include definite alternative medical diagnoses, chronic functional syndromes (e.g., fibromyalgia), symptomatic persons with no adequate explanation and asymptomatic persons referred because of abnormal test results.
Data taken from [31–37].

These studies underscore the degree of concern about Lyme disease in clinical practice, but even in the most highly endemic areas, less than a third of referred patients prove to have the disease in the end. The remainder appears to divide into at least three broad categories: those with alternative medical diagnoses, those with functional somatic syndromes, and a minority who have persistent symptoms that follow treatment for Lyme disease. This is true, notwithstanding the results of diagnostic testing: while a negative test may help exclude Lyme disease in patients with a low pretest probability, a positive test does not necessarily confirm the diagnosis in this scenario.^[39] The positive predictive value of Lyme serodiagnostics is poor in patients with only nonspecific symptoms. Patients may coincidentally have positive Lyme serology for a variety of reasons, including asymptomatic seroconversion, generation of cross-reactive antibodies in other infectious or inflammatory diseases, or a previous treated episode of Lyme disease, and the prevalence of asymptomatic seropositivity may match or exceed the cumulative incidence of confirmed disease.^{[31,35,36,39–46]}

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Box 1. Nomenclature of *Borrelia burgdorferi*sensu lato genospecies.
Borrelia burgdorferisensu lato refers to a complex of 18 related genospecies. Of these, B. burgdorferisensu stricto, B. gariniiand B. afzeliiare responsible for Lyme disease in Europe. B. burgdorferisensu stricto is the sole agent of Lyme disease in North America. Other genospecies within the complex may have medical importance, but this is currently investigational. As the clinical, microbiologic and taxonomic distinctions within this group are beyond the scope of this article, the designation B. burgdorferiis used here for brevity in place of B. burgdorferisensu lato [125].

Box 2. Operational definition of chronic Lyme disease published by the International Lyme and Associated Diseases Society.
For the purpose of the ILADS guidelines, 'chronic Lyme disease' is inclusive of persistent symptomatologies including fatigue, cognitive dysfunction, headaches, sleep disturbance and other neurologic features, such as demyelinating disease, peripheral neuropathy and sometimes motor neurone disease, neuropsychiatric presentations, cardiac presentations including electrical conduction delays and dilated cardiomyopathy and musculoskeletal problems. ILADS: International Lyme and Associated Diseases Society.
Taken from [30].

Box 3. Proposed definition of post-Lyme disease syndromes.
Inclusion criteria An adult or child with a documented episode of early or late Lyme disease fulfilling the case definition of the CDC. If based on erythema migrans, the diagnosis must be made and documented by an experienced healthcare practitioner. After treatment of the episode of Lyme disease with a generally accepted treatment regimen, there is resolution or stabilization of the objective manifestation(s) of Lyme disease. Onset of any of the following subjective symptoms within 6 months of the diagnosis of Lyme disease and persistence of continuous or relapsing symptoms for at least a 6-month period after completion of antibiotic therapy: Fatigue Widespread musculoskeletal pain Complaints of cognitive difficulties Subjective symptoms are of such severity that, when present, they result in substantial reduction in previous levels of occupational, educational, social or personal activities. Exclusion criteria An active, untreated, well-documented coinfection, such as babesiosis. The presence of objective abnormalities on physical examination or on neuropsychologic testing that may explain the patient's complaints. For example, a patient with antibiotic refractory Lyme arthritis would be excluded. A patient with late neuroborreliosis associated with encephalopathy, who has recurrent or refractory objective cognitive dysfunction, would be excluded. A diagnosis of fibromyalgia or chronic fatigue syndrome before the onset of Lyme disease. A prolonged history of undiagnosed or unexplained somatic complaints, such as musculoskeletal pains or fatigue, before the onset of Lyme disease. A diagnosis of an underlying disease or condition that might explain the patient's symptoms (e.g., morbid obesity, with a BMI [calculated as weight in kilograms divided by the square of height in meters] ≥45; sleep apnea and narcolepsy; side effects of medications; autoimmune diseases; uncontrolled cardiopulmonary or endocrine disorders; malignant conditions within 2 years, except for uncomplicated skin cancer; known current liver disease; any past or current diagnosis of a major depressive disorder with psychotic or melancholic features; bipolar affective disorders; schizophrenia of any subtype; delusional disorders of any subtype; dementias of any subtype; anorexia nervosa or bulimia nervosa; and active drug abuse or alcoholism at present or within 2 years). Laboratory or imaging abnormalities that might suggest an undiagnosed process distinct from post-Lyme disease syndrome, such as a highly elevated erythrocyte sedimentation rate (150 mm/h); abnormal thyroid function; a hematologic abnormality; abnormal levels of serum albumin, total protein, globulin, calcium, phosphorus, glucose, urea nitrogen, electrolytes or creatinine; significant abnormalities on urine analysis; elevated liver enzyme levels; or a test result suggestive of the presence of a collagen vascular disease. Although testing by either culture or PCR for evidence of Borrelia burgdorferiinfection is not required, should such testing be done by reliable methods, a positive result would be an exclusion.
Taken from [26].

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Key Issues

Chronic Lyme disease lacks an accepted clinical definition, and in practice the term has been applied to a wide variety of patients. The majority of patients referred for chronic Lyme disease have no objective evidence of the infection, and most often have an alternative medical diagnosis or a 'functional' syndrome such as fibromyalgia or chronic fatigue syndrome.
Fatigue, pain and cognitive impairment are the primary complaints among patients who are diagnosed with chronic Lyme disease. However, these symptoms are very common in the general population, and the evidence does not show that they occur any more commonly in patients with a history of Lyme disease.
A small minority of patients treated for Lyme disease will go on to have prolonged pain, fatigue or cognitive impairment in the absence of objective signs of treatment failure. Still fewer have severe or disabling symptoms.
There is no controlled evidence that viable Borrelia burgdorferipersists in patients with prolonged, subjective symptoms following confirmed Lyme disease.
The duration of initial antibiotic therapy for Lyme disease does not influence the likelihood of prolonged somatic or cognitive symptoms. On the other hand, the duration and severity of symptoms prior to treatment do predict the likelihood of prolonged symptoms during convalescence.
To date, four prospective, double-blinded, placebo-controlled trials have investigated the utility of prolonged antibiotics in patients with subjective 'post-Lyme disease syndromes'. With only one exception (fatigue) in one trial, no primary outcome measure favored treatment over placebo.
Potentially severe adverse events due to antibiotic therapy and intravascular access devices are common in patients being treated for post-Lyme disease syndromes. These events directly correlate with duration of treatment. Thus, because of a lack of benefit and strong evidence of harm, lengthy courses of antibiotics are not justified in patients with post-Lyme disease syndromes.

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