Various central nervous system‐penetrant antibiotics are bactericidal in vitro and in vivo against the causative agent of Lyme neuroborreliosis (LNB), Borrelia burgdorferi. These antibiotics are routinely used clinically to treat LNB, but their relative efficacy is not clear.On 25 October 2016 we searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase. We searched clinical trial registers on 26 October 2016. We reviewed the bibliographies of the randomized trials identified and contacted the authors and known experts in the field to identify additional published or unpublished data. There were no language restrictions when searching for studies.
Randomized clinical trials of antibiotic treatment of LNB in adults and children that compared any antibiotic treatment, including combinations of treatments, versus any other treatment, placebo, or no treatment. We excluded studies of entities considered as post‐Lyme syndrome.
Data collection and analysis
We used standard methodological procedures expected by Cochrane.
We identified seven randomized studies involving 450 European participants with LNB for inclusion in this systematic review. We found no trials conducted in the United States. Marked heterogeneity among these studies prevented meta‐analysis. None of the studies included a placebo control on the initial antibiotic treatment, and only one was blinded. None were delayed‐start studies. All were active comparator studies, and most were not adequately powered for non‐inferiority comparison. The trials investigated four antibiotics: penicillin G and ceftriaxone in four studies, doxycycline in three studies, and cefotaxime in two studies. One study tested a three‐month course of oral amoxicillin versus placebo following initial treatment with intravenous ceftriaxone. One study was limited to children. The trials measured efficacy using heterogeneous physician‐ or patient‐reported outcomes, or both. In some cases cerebrospinal fluid analysis was included as an indirect biomarker of disease and outcome. None of the studies reported on our proposed primary outcome, 'Improvement in a measure of overall disability in the long term (three or more months).' None of the trials revealed any between‐group differences in symptom resolution in response to active treatment. In general, treatment was tolerated well. The quality of adverse event reporting, however, was low.
There is mostly low‐ to very low‐quality clinical evidence from a limited number of mostly small, heterogeneous trials with diverse outcome measures, comparing the relative efficacy of central nervous system‐penetrant antibiotics for the treatment of LNB. The few existing randomized studies have limited power and lack consistent and well‐defined entry criteria and efficacy endpoints. It is not possible to draw firm conclusions on the relative efficacy of accepted antibiotic drug regimens for the treatment of LNB. The majority of people are reported to have good outcomes, and symptoms resolve by 12 months regardless of the antibiotic used. A minority of participants did not improve sufficiently, and some were retreated. These randomized studies provide some evidence that doxycycline, penicillin G, ceftriaxone, and cefotaxime are efficacious in the treatment of European LNB. No evidence of additional efficacy was observed when, in one study, an initial antibiotic treatment with intravenous ceftriaxone was followed by additional longer treatment with oral amoxicillin. There is a lack of evidence identified through our high‐quality search strategy on the efficacy of antibiotics for treatment of LNB in the United States.
Treatment for the neurological complications of Lyme disease
Are antibiotics effective for the treatment of Lyme disease affecting the nervous system?
In humans, a bacterium called Borrelia burgdorferi causes Lyme disease. People become infected when bitten by ticks carrying the bacterium. The person may experience symptoms in the joints, skin, muscles, and nervous system (peripheral nerves (nerves outside the brain and spinal cord), the brain, and the spinal cord). Without antibiotic treatment, neurological Lyme disease either may resolve or cause long‐term problems. Neurological Lyme disease differs between Europe and the United States, probably because of differences in B. burgdorferi. Limited information exists about which antibiotics are better for the treatment of neurological Lyme disease.
We found seven trials studying antibiotic treatments for neurological Lyme disease. All but one trial compared different antibiotics. The other trial compared the treatment effects of oral amoxicillin to placebo following initial ceftriaxone treatment. The trials included 450 Europeans. The antibiotics tested were penicillin G, doxycycline, ceftriaxone, and cefotaxime. One of the trials involved children only, while the others included mostly adults. We only selected studies in which treatment allocation was determined by chance (randomly), as such studies provide the best information for comparing the effects of different treatments. Most studies were not blinded (meaning that those taking part and the study staff knew the treatment being given). We could not find any studies of antibiotic treatments for neurological Lyme disease from the United States. No studies assessed the effects of delaying the start of treatment.
The seven studies were too different for their results to be combined, so we analyzed them individually.
None of the studies provided clear evidence that one antibiotic was better than another. One study failed to find evidence that a second and longer treatment with an oral antibiotic (amoxicillin) offered any extra benefit following initial intravenous treatment with ceftriaxone. As none of the other studies used a dummy treatment (placebo), the extra benefit offered by antibiotic treatment over recovery that occurs naturally is unknown. In general, the treatment was tolerated well, although the quality of adverse event reporting in most studies appeared to be low.
The results indicate that treatment with any of the four antibiotics produced similarly good outcomes for treatment of neurological Lyme disease in Europe. A second treatment with amoxicillin does not appear to provide added benefit to ceftriaxone. We found no trials of antibiotics for treatment of neurological Lyme disease in the United States.
For early disseminated (acute or stage II) Lyme neuroborreliosis (LNB), low‐ to very low‐quality evidence suggests that the majority of people with LNB respond to antibiotics with known brain penetration and appropriate activity spectra, namely penicillin G, ceftriaxone, cefotaxime, and doxycycline, either oral or intravenous. There is no accurate estimate of the absolute efficacy of these antibiotics, as there were no appropriate studies from which to infer this. None of the included trials had a placebo control for initial antibiotic treatment, and most had limited power and lacked consistent and well‐defined efficacy endpoints, study duration, and entry criteria. Also, the studies employed a range of treatment duration, from 10 to 21 days. All studies were conducted in Europe and none in the United States, thus no direct conclusion can be drawn on the effect of antibiotic treatment for LNB in the United States. The number of participants with late disseminated (chronic or stage III) LNB in the included trials was very low, and no useful separate conclusions can be drawn about its treatment with antibiotics. We observed no evidence of additional efficacy in a trial extending initial ceftriaxone treatment with amoxicillin. No firm conclusions can be drawn on the relative efficacy of the four antibiotics we reviewed. In the majority of cases reported in the seven included studies, European LNB was treatable with antibiotic regimens recommended in national guidelines, with marked improvement from baseline impairment. A minority of people do not improve after initial treatment.
Clinical research on the treatment of LNB lacks standardization of diagnostic, entry, and efficacy outcome criteria. There is a need for randomized and blinded controlled trials of adequate size and power and with proper study design to compare relative efficacy of antibiotics, in terms of route of administration, treatment duration, safety and tolerability, and the need for retreatment. A multiple‐treatments meta‐analysis may be possible in the future if adequate data are generated. It is unlikely that a standard placebo arm can be ethically included in any future trial designs, and novel trial designs with delayed start or add‐on therapy designs will be required. Future research would benefit greatly from standardization of diagnostic and outcome criteria and treatment failure criteria. Diagnostic research criteria should be sensitive enough to include an acceptable range of patients with different presentations, but also be specific enough to include only patients with Lyme disease—in clinical practice the findings of a trial can be broadened. The assessment of trial outcomes is equally important, as trial‐based diagnosis and these outcomes should have both internal and external validity. Assessment of subjective complaints and cognitive impairment is feasible and should be included. It is important to address not only impairment and derivative biomarkers, but also to measure patient‐reported disabilities and activity and participation measures. Rasch‐built outcome measures should be preferred over those based on classical test theory.
There is an absence of trials in some important areas. Controlled trials of antibiotic treatment of chronic LNB and also including participants with non‐European LNB are required, as current epidemiological and clinical studies suggest different disease courses and etiologic agents of LNB in Europe and the United States. More studies in children are also needed.
Lyme neuroborreliosis (LNB) is a group of diseases that can affect the central nervous system (CNS) and the peripheral nervous system (PNS), or both, as a result of infection with or the postinfectious consequences of different species of the spirochete bacterium Borrelia burgdorferi. These organisms are transmitted by ixodid ticks in endemic areas in the United States and Europe. Although a multitude of clinical manifestations of LNB have been reported, the most common are radicular pains, facial paralysis, and meningitis, referred to as Bannwarth's syndrome in Europe (Bannwarth 1941; Bannwarth 1944). It was not until 1981 that entomologist Willy Burgdorfer and colleagues in the United States suspected that the cause of Lyme disease was a tick‐borne spirochete (Burgdorfer 1982). In the decades since the identification of B. burgdorferi, it has become clear that LNB is one of the most common and important complications of Lyme disease. The diagnosis of LNB requires confirmation of infection with B. burgdorferi plus evidence of involvement of the CNS, the PNS, or both. According to the Centers for Disease Control and Prevention, from the 154,405 cases of Lyme disease reported during 2001 to 2010 in the United States, 14% were identified with facial palsy, radiculoneuropathy, meningitis, or encephalitis (CDC 2011a). Looking at Lyme disease occurring in Europe, others have estimated that up to 12% of cases have neurological manifestations (Koedel 2015), and that approximately 5% of individuals with an untreated erythema migrans will develop LNB (Hansen 2013).
Knowledge of the natural course and prognosis of untreated LNB is limited, and both increases in severity of disease and spontaneous remissions may occur. A random review of medical records from the original Lyme disease investigation among people from Connecticut, United States, who were not treated with antibiotics because they were diagnosed before the infectious cause of the disease was known, revealed that when left untreated, LNB can result in long‐term sequelae (Kalish 2001). In this report, 31 people who had presented with facial palsy and meningism frequently went on to develop more disseminated manifestations of LNB, with two‐thirds being formally diagnosed with lymphocytic meningitis, radiculoneuritis, or both, and 1 in 5 developing atrioventricular block. In a German retrospective study of 72 people with untreated LNB, only 59 went into full remission, whereas 13 developed mild‐to‐moderate sequelae during 5 to 27 years of follow‐up. Importantly, all those participants were eventually judged as “having been cured without antibiotics” (Kruger 1989).
The incidence of LNB varies widely among European countries, with the highest incidences in central European and Scandinavian countries. Population‐based annual incidence rates of LNB in central Europe are 30 to 50 per million for acute LNB and less than 0.4 per million for chronic LNB (Hansen 2013).
People with the characteristic skin lesion of Lyme disease, erythema migrans, followed by manifestations of infection of the nervous system, referred to as LNB, were successfully treated with antibiotics (penicillin) as early as 1948 (Hollstrom 1951). Treatment with antibiotics capable of crossing the blood‐brain barrier is now the standard of care for people diagnosed with LNB. However, no placebo‐controlled trials have ever been performed, and the antibiotic of choice, route of administration, dose, and length of treatment for LNB remain controversial.
At the time that the protocol for this review was conceived, there had been several attempts at producing treatment guidelines for Lyme disease and no high‐quality systematic evidence reviews to synthesize the available evidence to feed those reviews. Guidelines have now been produced by the American Academy of Neurology (AAN) (Practice Parameter) (Halperin 2007), the European Federation of Neurological Societies (EFNS) (Mygland 2010), the German Neurological Society (Rauer 2012), and the International Lyme and Associated Diseases Society (ILADS) (Cameron 2014). American Academy of Neurology/American College of Rheumatology/Infectious Diseases Society of America as well as the German Neurological Society are currently working on updated guidelines. This review will continue to synthesize the evidence for the antibiotic treatment of LNB.