Lyme Neuroborreliosis

Background: The new German S3 guideline on Lyme neuroborreliosis is intended to provide physicians with scientifically based information and recommendations on the diagnosis and treatment of this disease.

Methods: The scientific literature was systematically searched and the retrieved publications were assessed at the German Cochrane Center (Deutsches Cochrane Zentrum) in Freiburg in the 12 months beginning in March 2014. In addition to the main search terms “Lyme disease,” “neuroborreliosis,” “Borrelia,” and “Bannwarth,” 28 further terms relating to neurological manifestations of the disease were used for the search in the Medline and Embase databases and in the Cochrane Central Register of Controlled Trials.

Results: In the treatment of early Lyme neuroborreliosis, orally administered doxycycline is well tolerated, and its efficacy is equivalent to that of intravenously administered beta-lactam antibiotics (penicillin G, ceftriaxone, and cefotaxime) (relative risk [RR]: 0.98, 95% confidence interval [CI]: [0.68; 1.42], P = 0.93). 14 days of treatment suffice for early Lyme neuroborreliosis, and 14–21 days of treatment usually suffice for late (chronic) Lyme neuroborreliosis.

Conclusion: Lyme neuroborreliosis has a favorable prognosis if treated early. The long-term administration of antibiotics over many weeks or even months for putative chronic Lyme neuroborreliosis with nonspecific symptoms yields no additional benefit and carries the risk of serious adverse effects.

The scientists and physicians involved in research on Lyme neuroborreliosis agree that this disease can be reliably diagnosed and permanently stopped with a two- to three-week course of antibiotic treatment. There nonetheless exists a widespread fear that Lyme disease (as it is also called) can lead to a wide variety of nonspecific symptoms, such as chronic pain, fatigue, and difficulty concentrating, despite antibiotic treatment. This view often leads to repeated courses of antibiotic treatment being given for several months at a time, sometimes with serious adverse effects; there have even been a few deaths (e1–e3). The objective of the S3 guideline on Lyme neuroborreliosis issued by the German Society of Neurology (Deutsche Gesellschaft für Neurologie) is, therefore, to provide clear recommendations on the diagnosis and treatment of this disease which are based on a structured evidence and consensus process.

Epidemiology

Lyme borreliosis is an infectious disease that manifests itself primarily on the skin, in the nervous system, and in the joints. Five species of Borrelia burgdorferi that are pathogenic for human beings have been identified as the responsible organisms in Europe; they are transmitted by the bite of Ixodes ricinus, a species of hard tick. The number of new cases in Germany each year is variably estimated from 60 000 to over 200 000 (e4, e5), in the absence of precise figures. The seroprevalence of Borrelia-specific antibodies in healthy persons ranges from 5% to 20%, depending on their age and place of residence (e6–e8). According to German surveys, tick bites lead to seroconversion in 2.6%–5.6% of cases, and to overt disease in 0.3–1.4% (e9–e11).

Method

The first step in the creation of the guideline was a search for, and an assessment of, already existing guidelines on the subject, of which eight were found. Structured evaluation revealed that all of them had low quality scores, with the result that none of their recommendations could be adopted without further investigation (1). To assess the various proposed modes of antibiotic treatment, systematic literature searches were carried out in three databases:

• Medline (via Ovid),
• Embase (via Scopus),
• and the Cochrane Central Register of Controlled Trials.

Each included study was assessed in structured fashion (2, 3). The results for all of the included studies (reported as stipulated by the PRISMA statement, i.e., Preferred Reporting Items for Systematic Reviews and Meta-Analyses) are shown in the Figure (4). Further procedural details are described in the eMethods section.

Figure

Flowchart of the included studies

Clinical features

Neurological manifestations in adults

Polyradiculitis, i.e., inflammation that affects multiple spinal nerve roots and/or cranial nerves, is the most common clinical manifestation of neuroborreliosis in adults. If the meninges are (latently) involved as well, this is called meningoradiculoneuritis (Garin-Bujadoux-Bannwarth syndrome, or Bannwarth syndrome for short), which, after erythema migrans (EM), is the second most common manifestation of Lyme borreliosis among adults in Europe (5–7). Only 25–50% of patients with Lyme neuroborreliosis have a history of EM, and only a third have a history of tick bite (5–7, e12, e13).

Bannwarth syndrome typically manifests itself with severe, zoster-like segmental pain that is worse at night, responds poorly if at all to common pain-relieving drugs, and has a burning, stabbing, biting, or tearing character. 75% of patients develop neurologic deficits in 1–4 weeks, generally in the form of a flaccid paralysis or a segmental sensory disturbance. Cranial nerve deficits arise in roughly 60% of patients with Bannwarth syndrome. In more than 80% of such cases, facial nerve involvement leads to a typical peripheral facial palsy (which is bilateral in one-third of cases). In principle, any of the other cranial nerves could be affected as well, although no case of olfactory nerve involvement has yet been reported (5, 6, 8).

Infection of the central nervous system is seen in 2–4% of all cases of Lyme neuroborreliosis, typically in the late or chronic stage of the disease (5, 6). Its onset is often insidious, with a tendency to worsen slowly over a period of months to years. The spinal cord is the most commonly affected part of the CNS, with myelitis manifesting itself in a spastic-ataxic gait and bladder dysfunction; the brain is affected (encephalitis) in 60% of cases, with additional cranial nerve involvement in 40% (6, 7).

In European patients, polyneuropathy/polyneuritis is generally seen only in association with acrodermatitis chronica atrophicans (ACA) as a manifestation of borreliosis (9, 10). The mere fact that a patient has polyneuropathy/polyneuritis and positive Borrelia serology in the blood does not, in itself, imply a causal relationship between the neurological manifestations and a putative Borrelia infection (11), as Borrelia-specific antibodies can be found in 5–20% of normal individuals, depending on the endemic area and age group (e6, e8, e13).

Rarely, encephalitis manifests itself as a mental illness or organic brain syndrome (5, 12, e14 – e17) with inflammatory changes in the cerebrospinal fluid that resolve under treatment with antibiotics.

Stroke has also been described in case reports and small case series, as a result of Borrelia-induced cerebral vasculitis (e18, e19). Another very rare manifestation is Borrelia-induced myositis, which has only been described in older single-case reports (e20, e21).

Neurological manifestations in children

Among children in Europe, the most common manifestations are facial nerve palsy (ca. 55%) and lymphocytic meningitis (ca. 30%) (13, 14). Meningitis, when present, often has only very mild symptoms; it can easily be missed unless cranial nerve deficits are present at the same time (15). Late (chronic) Lyme neuroborreliosis is very rare in children (e22).

Diagnostic evaluation

If the clinical manifestations arouse the suspicion of Lyme neuroborreliosis, the serum and the CSF should be examined (16–18) (↑↑). Inflammatory changes in the CSF (pleocytosis, disruption of the blood-CSF barrier, intrathecal immunoglobulin synthesis) are to be expected in every case of Lyme neuroborreliosis. Normal CSF is seen only in very early stages of the disease, or else in patients with distal symmetric polyneuropathy in association with ACA.

Borrelia-specific IgM antibodies are detectable in the blood from the third week after exposure, and IgG antibodies from the sixth. In late (chronic) Lyme neuroborreliosis, high Borrelia-specific IgG antibody concentrations should, in principle, always be found, as long as the patient is immune-competent (17, 19). However, antibody generation does not always take the typical course seen in other infectious diseases. For example, both IgG and IgM antibodies can persist for several years despite a clinically healed infection (17, 19). In consequence, a positive serological finding alone does not establish the presence of an infection. Serological testing should be ordered only if there is adequate clinical suspicion of active borreliosis, as its predictive value will otherwise be low (↑↑).

In most patients, CSF examination confirms the clinically suspected diagnosis by revealing the intrathecal synthesis of Borrelia-specific antibodies in association with an elevated CSF cell count (17, 20). It is, therefore, recommended that CSF and serum should be obtained simultaneously for serologic testing in any patient with suspected Lyme neuroborreliosis (↑↑). CSF analysis should include cytological, protein-chemical, and serological examinations (determination of the antibody index, AI) (↑↑). The intrathecal production of Borrelia-specific antibodies is demonstrated by measurement of the Borrelia-specific CSF/serum antibody index (Borrelia-specific AI) (7, 21).

If the diagnosis remains unclear, e.g., in an immunosuppressed patient, a suspected infection can be confirmed by detection of the pathogen in the CSF (17). The sensitivity of pathogen detection in the CSF by culture or by the polymerase chain reaction (PCR) in acute Lyme neuroborreliosis is, however, only 10–30% (17, 19).

Diagnostic criteria for Lyme neuroborreliosis

Algorithms for the diagnostic evaluation of early and late Lyme neuroborreliosis are shown in eFigures 1 and 2 (4). Depending on the clinical and laboratory findings, the diagnosis of Lyme neuroborreliosis can be classified as possible, probable, or definite (4, 16, 22) (Box 1).

Box 1

Diagnostic criteria for Lyme neuroborreliosis (4)

eFigure 1

Diagnostic algorithm for early Lyme neuroborreliosis (4) PCR, polymerase chain reaction

eFigure 2

Diagnostic algorithm for late Lyme neuroborreliosis (4)

Unsuitable diagnostic tests

No prospective, controlled trials are available that would support the putative utility of the methods listed in Box 2 in the diagnostic evaluation of Lyme neuroborreliosis. These methods should, therefore, not be used for this purpose (↓↓) (17).

Box 2

Unsuitable diagnostic tests for Lyme neuroborreliosis (4)

The treatment of Lyme neuroborreliosis

A systematic evaluation of the literature on the pharmacotherapy of Lyme neuroborreliosis yielded only a limited amount of evidence overall (Figure) (2, 3). Conclusions for clinical practice can be drawn from no more than a few studies, some of which involved only a small number of patients, and some of which were vulnerable to bias (3). An update of the systematic literature search (method analogous to [2]) in August 2018 yielded 700 new results, of which only a single publication contained relevant information that met the inclusion criteria established for the current guideline (25). In this study, it was concluded that steroids have a statistically significant, deleterious effect on the regression of facial nerve palsies due to Lyme neuroborreliosis. It must be remarked, however, that this particular study was based on a highly selected group of patients, the treatments and follow-up examinations were not standardized, and the retrospective design rendered the findings vulnerable to recruitment bias. It follows that no additional treatment recommendation can be derived from any data that were published after the initial literature review carried out in the preparation of this guideline.

In general, treatment with antibiotics is recommended for all patients who have neurological manifestations that are typical of Lyme neuroborreliosis, inflammatory CSF changes, and positive Borrelia serology (Table) (↑↑). In “possible” Lyme neuroborreliosis (CSF findings unavailable or normal), treatment with antibiotics can be considered after a thorough differential diagnostic evaluation that h

Table

Any of the drugs listed above can be used; the optimal duration of treatment is unknown.

as not led to the diagnosis of any other condition (↔).

Early Lyme neuroborreliosis—duration of treatment

The systematically evaluated studies mainly included patients with early Lyme neuroborreliosis. The duration of treatment in randomized, controlled trials (RCT) was 7–14 days (with the sole exception of 100 days in reference [26]), while the duration of treatment in the nonrandomized trials (where reported) ranged from 10 to 30 days. No comparative trials of different treatment durations or antibiotic doses were identified (3).

Indirect evidence on the duration of treatment can, however, be drawn from a prospective, controlled trial involving 152 patients with disseminated Lyme borreliosis (80% of whom had early Lyme neuroborreliosis) (26). In this trial, prolongation of the inital antibiotic administration by a further 100 days yielded no clinical advantage over the administration of a placebo.

Late Lyme neuroborreliosis—duration of treatment

The systematic literature search did not yield any controlled trials in which antibiotic treatment for late (chronic) Lyme neuroborreliosis was explicitly studied. As far as was reported, the 17 systematically evaluated therapeutic trials (RCTs and NRS) contained a total of only 15 patients with late (chronic) Lyme neuroborreliosis (3). These cases cannot be separately evaluated, because of their small number and the incompleteness of the data. Although these patients had residual neurologic deficits much more commonly than those with early Lyme neuroborreliosis (class III), none of the reported cases showed evidence of being treatment failures. Thus, a risk/benefit analysis yields no scientifically supported reason to change the current recommendation for two to three weeks of antibiotic treatment for the typical patient with late (chronic) Lyme neuroborreliosis (↑↑).

The choice of antibiotic and side effects

According to a meta-analysis, the efficacy of orally administered doxycycline with regard to the regression of neurological manifestations does not differ, to any statistically significant extent, from that of intravenously administered beta-lactam antibiotics, after a follow-up interval of 12 months (relative risk [RR]: 0.98, 95% confidence interval [CI]: [0.68; 1.42], P = 0.93). They should thus be considered to be of comparable benefit (class Ia) (3). As for side effects, two RCTs (26, 27) did not show any statistically significant difference either (RR: 0.82 [0.54; 1.25], P = 0.35) (class Ia). Serious side effects were reported too rarely overall in these trials to enable any valid comparison (3).

These data do not show any of the substances tested to be preferable to the others. An antibiotic should thus be chosen (Table) in consideration of patient-specific aspects such as allergies, age, pregnancy, and the mode and frequency of application (↑↑).

Clinical course after treatment with antibiotics

In most of the RCTs, a 7- to 14-day course of antibiotic treatment for early Lyme neuroborreliosis led to marked improvement of neurologic manifestations in most patients within a few weeks to months. A year after treatment, approximately 90% of patients were free of symptoms (6, 28–30). Late Lyme neuroborreliosis can likewise be stabilized by one year after treatment, but 60–80% have relevant residual neurologic symptoms (3, 6, 29).

Cerebral vasculitis due to Lyme borreliosis

Good results of early antibiotic treatment are reported in case series and narrative reviews (e18, e19) (class IV) (↑↑). Some authors give steroids and platelet aggregation inhibitors in addition to antibiotics (class IV) (↔).

The treatment of Lyme neuroborreliosis in children

A systematic evaluation of the literature reveals that there is only very limited evidence on the use of antibiotics to treat Lyme neuroborreliosis in children; furthermore, the available studies are of poor quality (31). All of them do, however, appear to document a favorable prognosis of Lyme neuroborreliosis in children. Unfavorable clinical courses under antibiotic treatment are rare, whatever antibiotic is used.

Treatment monitoring

The effect of treatment should be judged from the clinical manifestations. If the clinical situation worsens during or after treatment, the differential diagnosis should be rechecked in an interdisciplinary evaluation; if indicated, the CSF analysis should be repeated (↑↑).

Chronic atypical symptoms and “post-treatment Lyme disease syndrome”

It has been debated for decades whether properly treated Lyme neuroborreliosis can transform itself into a chronic disease state with nonspecific symptoms, even in the absence of any inflammatory or infectious process that can be demonstrated by generally accepted methods of laboratory testing (32–34). Terms such as “post-treatment Lyme disease syndrome” (PTLDS), “(post-) Lyme encephalopathy,” or simply “chronic (neuro-)borreliosis” have been used to describe such putative cases, without any clear differentiation in meaning from each other.

The frequency and symptom spectrum of chronic manifestations after antibiotic treatment for Lyme neuroborreliosis were systematically studied in a meta-analysis (35). Persistent general symptoms were found to be more common, to a markedly statistically significant extent, in patients whose initial diagnosis was not confirmed by CSF examination. This suggests that the high prevalence of nonspecific long-term symptoms found in earlier studies is perhaps best explained as an artifact induced by loose inclusion criteria.

The putative therapeutic benefit of antibiotics for patients with persistent nonspecific symptoms after (a correct or incorrect diagnosis of) chronic Lyme borreliosis—i.e., patients with so-called PTLDS or PTLDS-like symptoms—was studied in three randomized, placebo-controlled trials (36–39). No lasting improvement of neuropsychological test results was found in any trial. In two trials, no benefit was found with respect to either of two endpoints (fatigue and quality of life) (36, 37); in one trial, there was a slight, but statistically significant improvement of the fatigue score (38), but the clinical relevance of this finding seems questionable (e29) in view of the two negative trials (36, 37) and methodological considerations. Antibiotic side effects arose in all three trials, in 25–43% of the subjects. These included (among others) diarrhea, allergic reactions, cholecystitis, thromboembolism, and gastrointestinal bleeding. In three cases, antibiotic complications were life-threatening. None of the authors, in their risk/benefit analyses, recommended treating patients with so-called PTLDS or PTLDS-like symptoms with the antibiotic regimen that had been used in their own trial (36–39).

The evidence suggests that chronic infection with Borrelia burgdorferi should not be assumed in patients with so-called PTLDS or PTLDS-like symptoms. Thus, these patients should not be treated with antibiotics (↓↓). Rather, it is recommended that they undergo a symptom-oriented differential diagnostic evaluation and, where indicated, a corresponding, symptom-oriented treatment (↑↑).

Note
The German Borreliosis Society (Deutsche Borreliose Gesellschaft, DBG) and three patient organizations (the German Borreliosis and FSME League - Borreliose und FSME Bund Deutschland [BFBD], The National Tick-Borne Disease Association - Bundesverband Zecken-Krankheiten e. V. [BZK], and the Action Committee against Tick-Borne Infections in Germany - Aktionsbündnis gegen zeckenübertragene Infektionen Deutschland e. V. [OnLyme-Aktion.org]) have issued dissenting statements, which are published as an appendix to the original guideline report. These four organizations did not approve the final version of the guideline.

Conflict of interest statement
Prof. Rauer owns stock in the ravo Diagnostik company (Freiburg), which manufactures serologic tests for the diagnosis of Lyme borreliosis. He has received payment from various judicial bodies and insurance companies for independent medical evaluations relating to the topic of this article. He has also received a lecture honorarium from Biogen.

Dr. Fingerle has received payment for three medicolegal evaluations relating to the topic of this article, honoraria and travel expenses for medical meetings from the Mikrogen, Diasorin, Seramun, and Pfizer companies, and travel expenses from Quality Control for Molecular Diagnostics.

Prof. Hunfeld has received payment for a medicolegal evaluation relating to the topic of this article.

The remaining authors state that they have no conflict of interest.

Manuscript submitted on 15 June 2018, revised version accepted on
19 July 2018.

Translated from the original German by Ethan Taub, M.D.

Corresponding author
Prof. Dr. med. Sebastian Rauer
Universitätsklinikum, Neurologie
Breisacher Str. 64,
9106 Freiburg, Germany

►Supplementary material

For eReferences please refer to:
www.aerzteblatt-international.de/ref4518

eMethods, eFigures:
www.aerzteblatt-international.de/18m0751

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