A California Lyme disease organization is advertising the contents of their latest newsletter, which includes topics such as, “how Lyme persists despite treatment,” and “10 reasons Lyme patients don’t get better.” I’d love to read these interesting bits of fantasy, but I don’t have to. As luck would have it, there’s a nice new summary of such issues:
Nervous System Lyme Disease: Diagnosis and Treatment. Halperin JJ. Curr Treat Options Neurol. 2013 May 12.
Here follows a few highlights from his review.
As with much else in medicine, the diagnosis of Lyme disease is ultimately clinical. This does not mean that any clinician can freely create an arbitrary definition. Rather Lyme disease is associated with a range of clinical and laboratory findings, each of which carries varying positive and negative predictive values, all of which must be considered in arriving at the diagnosis.
Early serologic testing was far from perfect, spawning the often-repeated opinion that it is generally unreliable. However with the development of two-tier testing (screening ELISA followed by confirmatory Western blot for positive or borderline screening tests) and subsequent technical improvements, overall accuracy has increased from the mid 80 % range to the high 90 % range—correctly interpreted and used in the appropriate setting. Several limitations are inherent in all serologic testing. Since, in any infection, it takes several weeks for the humoral response to generate detectable specific antibody, serologic results are predictably negative in the first 3–6 weeks of infection. In other infections diagnosed serologically, acute and convalescent sera are routinely tested to address this — something not normally done in Lyme disease perhaps because of incorrect inferences from reaginic testing in syphilis. About 50 % of patients with EM will be seronegative; patients with this characteristic rash should be treated without even obtaining blood tests.
Finally, and again peculiar to Lyme disease, is the notion that the administration of antibiotics — either at the time of serologic testing, or in a subcurative dose after infection but prior to testing — could render serologic testing falsely negative. The first notion is neither biologically plausible nor supported by any empiric evidence. The second was hypothesized in the 1980’s. This has not been supported by subsequent work and was almost certainly an artifact of the technology in use 25 years ago.
In vitro, B. burgdorferi remains highly sensitive to many common oral antibiotics including tetracyclines, penicillins, and various second and third generation cephalosporins. Although sensitive in vitro to macrolides such as erythromycin and azithromycin, these agents are less effective clinically. Among parenteral antibiotics ceftriaxone and cefotaxime have equivalentefficacy, although the once a day dosing of ceftriaxone makes it easier—and more economical—to administer. Meningeal dose penicillin is effective but may be inferior, based on a small number of Class 3 and 4 studies.
Guidelines generally recommend 3–4 weeks of antibiotic therapy, although there is a paucity of evidence indicating that treatment beyond 2 weeks provides additional benefit.
Most of the controversy regarding treatment of Lyme disease stems from the observation that many patients, particularly those with neuroborreliosis, remain symptomatic following completion of recommended treatment. Persisting symptoms fall into one of several categories. Individuals with focal neurologic damage, such as facial nerve palsy, may have a residual deficit that will slowly recover. This is the natural history of virtually any nervous system insult, and should not lead to confusion. More problematic has been the observation that many patients continue to have non-neurologic systemic symptoms at the completion of treatment. Patients with active Lyme disease often experience the same nonspecific symptoms—malaise, fatigue, aches and pains, cognitive slowness, etc.—seen in those with other active infections and inflammatory states ranging from pneumonia to viral meningitis to active ulcerative colitis. These symptoms often persist after recommended treatment, both in Lyme disease and other disorders. Just as pneumonia treatment would not be extended for such symptoms, or for a persistent infiltrate on chest X-ray, these symptoms do not provide a rationale for continuing treatment in Lyme disease. Similarly, since laboratory testing measures infection-specific antibody and not bacteria, persisting test positivity does not require continued treatment.
The patient population that has drawn the most attention consists of individuals in whom these systemic symptoms occur or persist for more than 6 months after appropriate treatment. Such individuals, referred to as having post-Lyme disease syndrome or, by some, chronic Lyme disease, lack any of the usual objective markers of active disease such as clinically evident new inflammatory involvement of joints, nervous system or other organs. Treatment trials lead to two clear conclusions. First, despite the tremendous amount of attention focused on this disorder, it is quite uncommon. Trials have generally had great difficulty recruiting appropriate subjects, despite screening thousands of individuals who believe they meet criteria for the diagnosis. Second, prolonged treatment with up to 10 weeks of parenteral ceftriaxone confers no lasting benefit, and may entail significant risk, inconvenience, and cost.
A number of novel mechanisms has been suggested to explain this purported state, most of which are based on the assumption of persisting infection. The most common suggestion is that B. burgdorferi adopts a form—intracellular, cyst-like or in a biofilm—that hides it from the host immune response and from antimicrobials. The biggest challenge to this hypothesis (other than the absence of credible evidence that it occurs in humans) is logical. First, there are numerous examples of other infections, tuberculosis being the most common, where individuals harbor more immunogenic microorganisms for years with no symptoms whatever.
The second challenge relates to pathophysiology. There are just 2 potential mechanisms by which a micro-organism can affect its host—directly by secreting exotoxins, molecules that migrate away from the site of infection, and then trigger physiologic effects, or indirectly by triggering a host immune response that then becomes misdirected or overly amplified, causing symptoms. B. burgdorferi does not secrete an exotoxin, excluding the first mechanism. Although it is thought that much of the symptomatology of B. burgdorferi relates to the host immune response, if the pathophysiology of this purported chronic infection requires that the organism remains hidden from the immune response, it becomes implausible to argue that an accentuated immune response is responsible for symptoms.
If this patient population is not suffering from persistent infection, what then is responsible for their ongoing, highly troubling symptoms? Perhaps the best answer comes from a series of epidemiologic studies. First, controlled studies do not generally show these symptoms to be more common in patients treated for Lyme disease than in controls; however, patients treated for Lyme disease are more likely to attribute symptoms to the infection that they had, demonstrating the common human tendency to try to identify associations to explain the otherwise unexplained.
It seems plausible that this syndrome reflects nothing more than the coincidental occurrence of this poorly understood clinical syndrome in individuals who happen to have had Lyme disease. This is not to minimize these symptoms or their impact on the lives of patients with them; however, the evidence seems compelling that they are not evidence of ongoing infection and do not benefit from antimicrobial therapy.