000279
10.3205/000279
urn:nbn:de:0183-0002795
Guideline
Guidelines for diagnosis and treatment in neurology – Lyme neuroborreliosis
Leitlinien für Diagnostik und Therapie in der Neurologie – Neuroborreliose
Rauer
Rauer
Sebastian
S
Prof. Dr.
Department of Neurology, Medical Center, University of Freiburg, Beisacherstr. 64, 79106 Freiburg, GermanyGerman Society of Neurology (DGN), Berlin, Germany
sebastian.rauer@uniklinik-freiburg.de
author
Kastenbauer
Kastenbauer
Stephan
S
German Society of Neurology (DGN), Berlin, Germany
author
Hofmann
Hofmann
Heidelore
H
German Dermatology Society (DDG), Berlin, Germany
author
Fingerle
Fingerle
Volker
V
German Society for Hygiene and Microbiology (DGHM), Münster, Germany
author
Huppertz
Huppertz
Hans-Iko
HI
German Society of Paediatrics and Adolescent Medicine (DGKJ), Berlin, Germany
German Society of Paediatric Infectology (DGPI), Berlin, Germany
author
Hunfeld
Hunfeld
Klaus-Peter
KP
The German United Society of Clinical Chemistry and Laboratory Medicine (DGKL), Bonn, Germany
INSTAND e.V., Düsseldorf, Germany
author
Krause
Krause
Andreas
A
German Society of Rheumatology (DGRh), Berlin, Germany
author
Ruf
Ruf
Bernhard
B
German Society of Infectious Diseases (DGI), Berlin, Germany
author
Dersch
Dersch
Rick
R
German Society of Neurology (DGN), Berlin, Germany
Cochrane Germany, Faculty of Medicine, University of Freiburg, Germany
author
Consensus group
Consensus group
author
German Medical Science GMS Publishing House
Düsseldorf
610
Borrelia burgdorferi infection
Lyme borreliosis
Lyme disease
Bannwarth’s syndrome
lymphocytic meningoradiculitis
facial palsy
polyradiculitis
meningitis
encephalomyelitis
polyneuropathy
ixodid tick-borne borreliosis
Borrelia-burgdorferi-Infektion
Lyme-Borreliose
Bannwarth-Syndrom
lymphozytäre Meningoradikulitis
Facialisparese
Polyradikulitis
Meningitis
Enzephalomyelitis
Polyneuropathie
Schildzecken-Borreliose
Neurology
20190130
20200227
engl
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License.
Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung).
1612-3174
18
GMS German Medical Science
GMS Ger Med Sci
03
Die Lyme-Borreliose ist die häufigste durch Zecken übertragene Infektionskrankheit in Europa. Eine neurologische Manifestation kommt bei 3–15% der Infektionen vor und kann sich als Polyradikulitis, Meningitis sowie selten als Enzephalomyelitis manifestieren. Die Erkrankung ist durch Antibiotika behandelbar.Diese S3-Leitlinie richtet sich an Ärzte in Praxis und Klinik, die mit der Behandlung der Neuroborreliose bei Kindern und Erwachsenen befasst sind.An der Entwicklung waren 20 AWMF-Mitgliedsgesellschaften, das Robert Koch-Institut, die Deutsche Borreliose-Gesellschaft und 3 Patienteno<![CDATA[rg</PlainText></TextGroup>anisationen beteiligt. Die systematische Literaturrecherche und Literaturbewertung wurden durch das Deutsche Cochrane Zentrum Freiburg (Cochrane Deutschland) durchgeführt.</Pgraph><Pgraph>Hauptziele der Leitlinie sind es, die Krankheit zu definieren und Empfehlungen abzugeben zur Bestätigung der Verdachtsdiagnose mittels Laboruntersuchungen, Antibiotikabehandlung, Differenzialdiagnostik und Prävention.</Pgraph></Abstract>
<Abstract language="en" linked="yes"><Pgraph>Lyme borreliosis is the most common tick-borne infectious disease in Europe. A neurological manifestation occurs in 3–15% of infections and can manifest as polyradiculitis, meningitis and (rarely) encephalomyelitis.</Pgraph><Pgraph>This S3 guideline is directed at physicians in private practices and clinics who treat Lyme neuroborreliosis in children and adults.</Pgraph><Pgraph>Twenty AWMF member societies, the Robert Koch Institute, the German Borreliosis Society and three patient organisations participated in its development. A systematic review and assessment of the literature was conducted by the German Cochrane Centre, Freiburg (Cochrane Germany).</Pgraph><Pgraph>The main objectives of this guideline are to define the disease and to give recommendations for the confirmation of a clinically suspected diagnosis by laboratory testing, antibiotic therapy, differential diagnostic testing and prevention.</Pgraph></Abstract>
<TextBlock linked="yes" name="Preamble">
<MainHeadline>Preamble</MainHeadline><Pgraph>This guideline pertains to the diagnosis and treatment o<TextGroup><PlainText>f n</PlainText></TextGroup>eurological manifestations of Lyme borreliosis in children and adults. In the future it will be integrated as modu<TextGroup><PlainText>le 2</PlainText></TextGroup> of the planned interdisciplinary S3 guideline <Mark1>“Lyme Borreliosis – Diagnosis and Treatment, AWMF Register No. 013-080”</Mark1>.</Pgraph><Pgraph>Twenty AWMF member societies, the Robert Koch Institute, the German Borreliosis Society and three patient organisations participated in its development. A systematic review and assessment of the literature was conducted by the German Cochrane Centre, Freiburg (Cochrane Germany) with significant input from Dr. Rick Dersch.</Pgraph><Pgraph>The interdisciplinary guideline group is currently developing the S2k guideline “Cutaneous Lyme Borreliosis” (AWMF Register No. 013-044) <TextLink reference="1"></TextLink> into an S3 guideline with the aim of modularly integrating it into the interdisciplinary guideline. Part 3 “Lyme Arthritis, Lyme Carditis and Other Rare Manifestations” will then be developed as a further module of the interdisciplinary S3 guideline “Lyme Borreliosis – Diagnosis and Treatment”. The guideline was formally adopted by the boards of the participating organisations with the exception of the DBG and the patient organisations BFBD, BZK and OnLyme-Aktion.org. The DBG and the patient organisations BFBD, BZK and OnLyme-Aktion.org have issued statements o<TextGroup><PlainText>f d</PlainText></TextGroup>issent, which are published in an appendix (<TextGroup><PlainText>Attachment 1 </PlainText></TextGroup><AttachmentLink attachmentNo="1"/>) to the guideline report (Attachment 2 <AttachmentLink attachmentNo="2"/>).</Pgraph><SubHeadline>What’s new?</SubHeadline><Pgraph><UnorderedList><ListItem level="1">The previous S1 guideline on Lyme neuroborreliosis (AWMF Register No. 030-071) <TextLink reference="2"></TextLink> has been developed into an S3 guideline on Lyme neuroborreliosis according to the methodological guidelines of the Association of Scientific Medical Societies (AWMF).</ListItem><ListItem level="1">The validity of the guideline has been extended to i<TextGroup><PlainText>nc</PlainText></TextGroup>lude the diagnosis and treatment of Lyme neuro<TextGroup><PlainText>borreliosi</PlainText></TextGroup>s in children based on a systematic review <TextLink reference="3"></TextLink>.</ListItem><ListItem level="1">A systematic review of antibiotic treatment of Lyme neuroborreliosis in adults <TextLink reference="4"></TextLink> found the following:</ListItem><UnorderedList><ListItem level="2">There is no scientific basis for deviating from the previously recommended treatment duration of 1<TextGroup><PlainText>4 d</PlainText></TextGroup>ays for early and 14–21 days for late Lyme neuroborreliosis.</ListItem></UnorderedList><UnorderedList><ListItem level="2">In the case of early Lyme neuroborreliosis, doxycycline and beta-lactam antibiotics (penicillin G, ceftriaxone and cefotaxime) are equally effective in terms of the regression of neurological symptoms and are tolerated equally.</ListItem></UnorderedList><UnorderedList><ListItem level="2">There are no reliable, analysable study data on the efficacy of combination antibiotic therapy.</ListItem></UnorderedList><UnorderedList><ListItem level="2">There are no study data available on the efficacy of chloroquine, carbapenems and metronidazole.</ListItem></UnorderedList><ListItem level="1">A systematic review has found that the high prevalence of persisting non-specific and/or atypical symptoms following Lyme neuroborreliosis, as reported in many studies, can largely be traced to study artefacts resul<TextGroup><PlainText>tin</PlainText></TextGroup>g from imprecise case definitions <TextLink reference="5"></TextLink>.</ListItem></UnorderedList></Pgraph><SubHeadline>Key recommendations</SubHeadline><Pgraph><UnorderedList><ListItem level="1">A suspected clinical diagnosis of neuroborreliosis (cranial nerve deficits, meningitis/meningoradiculitis, encephalomyelitis) can be confirmed by the detection of inflammatory changes in cerebrospinal fluid linked to Borrelia-specific intrathecal antibody synthesis.</ListItem><ListItem level="1">Serological testing should only be conducted if there is sufficient clinical suspicion. ↑↑ (consensus 10/13)</ListItem><ListItem level="1">The following antibiotics should be used to treat early and late Lyme neuroborreliosis: doxycycline, ceftriaxone, cefotaxime, penicillin G. ↑↑ (consensus 9/13)</ListItem><ListItem level="1">Antibiotic treatment should last 14 days (early Lyme borreliosis) or 14–21 days (late Lyme borreliosis). ↑↑ (strong consensus 13/13)</ListItem><ListItem level="1">Estimation of treatment success should be based on the clinical symptoms. ↑↑ (strong consensus 12/12)</ListItem></UnorderedList></Pgraph><SubHeadline>Preface</SubHeadline><Pgraph>Lyme borreliosis is the most common tick-borne infectious disease in Europe. A neurological manifestation occurs in 3–15% of infections and can manifest as polyradiculitis, meningitis and (rarely) encephalomyelitis. The disease can be treated with antibiotics.</Pgraph><SubHeadline>Target group</SubHeadline><Pgraph>This guideline is directed at physicians in private practices and clinics who treat Lyme neuroborreliosis in children and adults.</Pgraph><SubHeadline>Objectives of this guideline (recommendations)</SubHeadline><Pgraph><UnorderedList><ListItem level="1">Definition of the disease</ListItem><ListItem level="1">Confirmation of a clinical diagnosis</ListItem><ListItem level="1">Differentiation of non-specific complaints</ListItem><ListItem level="1">Antibody testing in serum</ListItem><ListItem level="1">Cerebrospinal fluid (CSF) testing including antibody detection in CSF</ListItem><ListItem level="1">Meaningful use of molecular-diagnostic testing and culture tests</ListItem><ListItem level="1">Therapy</ListItem><ListItem level="1">Differential diagnostic testing</ListItem><ListItem level="1">Prevention</ListItem><ListItem level="1">Observation of the skin area around the tick bite; information sheet for patients</ListItem><ListItem level="1">Diseases caused by relapsing fever Borrelia (e.g. Borrelia recurrentis) are not covered in this guideline</ListItem><ListItem level="1">Questions relating to co-infections linked to diseases transmitted by ticks are not covered in this guideline</ListItem></UnorderedList></Pgraph></TextBlock>
<TextBlock linked="yes" name="1 Epidemiology, transmission, manifestations, phrophylaxis">
<MainHeadline>1 Epidemiology, transmission, manifestations, prophylaxis</MainHeadline><SubHeadline>1.1 Epidemiology</SubHeadline><SubHeadline2>1.1.1 Definition</SubHeadline2><Pgraph>Lyme borreliosis is a multisystem inflammatory disease that is caused by an infection with the spirochete <Mark2>Borrelia burgdorferi</Mark2> sensu lato and transmitted through the bite of the Ixodes ricinus tick.</Pgraph><SubHeadline2>1.1.2 Distribution and species</SubHeadline2><Pgraph>It is the most prevalent vector-borne disease in the temperate climate zones of the northern hemisphere and is endemically widespread. In North America, Lyme borreliosis is only caused by the Borrelia species <Mark2>Borrelia burgdorferi </Mark2>sensu stricto, while in Europe <Mark2>B. afzelii</Mark2>, <Mark2>B. bavariensis</Mark2> and <Mark2>B. garinii</Mark2> have also been identified as human pathogens. The newly identified species <Mark2>Borrelia spielmanii</Mark2> also has the potential of being pathogenic to humans. It was detected in 4 of 160 skin isolates (all from erythema migrans) but has yet to be linked to Lyme neuroborreliosis (72 CSF isolates) in Germany <TextLink reference="6"></TextLink>. The pathogenic potential of the various <Mark2>Borrelia burgdorferi</Mark2> species varies <TextLink reference="7"></TextLink>. After <Mark2>B. garinii</Mark2> OspA-type 4 was reclassified as the new species <Mark2>Borrelia bavariensis</Mark2> <TextLink reference="8"></TextLink>, a re-evaluation of 242 human isolates from Germany <TextLink reference="6"></TextLink> found that the 72 CSF isolates comprised 21% <Mark2>B. afzelii</Mark2>, 22<TextGroup><PlainText>% </PlainText><Mark2>B. b</Mark2></TextGroup><Mark2>avariensis</Mark2> and 29% <Mark2>B. garinii</Mark2>, and the 160 skin isolates comprised 67% <Mark2>B. afzelii</Mark2>, 12% <Mark2>B. bavariensis</Mark2> and 12% <Mark2>B. garinii</Mark2>. In other words, only the skin isolates showed a clear prevalence of one species, namely <Mark2>B</Mark2><TextGroup><Mark2>. a</Mark2></TextGroup><Mark2>fzelii</Mark2>.</Pgraph><Pgraph>Currently no reliable figures are available on the rate of occurrence of Lyme borreliosis in individual European countries. An evaluation of population registers from six eastern German states found a strongly fluctuating rate of 34.9 cases per 100,000 inhabitants in 2009, and 19.54 cases per 100,000 inhabitants in 2012 <TextLink reference="9"></TextLink>. Secondary data analyses of health insurance data based on ICD 10 code A 69.2 (G) found significantly higher case numbers, although the authors cannot rule out an overestimation of case numbers due to clinical misdiagnosis or miscoding <TextLink reference="10"></TextLink>.</Pgraph><Pgraph>In summary, the available epidemiological data are inconclusive. Data published in Germany to date suggest an incidence of Lyme borreliosis ranging from 60,000 to >200,000 cases per year.</Pgraph><SubHeadline2>1.1.3 Incidence of various manifestations</SubHeadline2><Pgraph>Acute Lyme neuroborreliosis (3.3%) was the second most frequent clinical manifestation after Erythema migrans (95.4%) <TextLink reference="9"></TextLink>. In a prospective, population-based study conducted in the Würzburg area, 313 cases of Lyme borreliosis were identified over a period of 12 months. This corresponds to a significantly higher incidence rate of 111 per 100,000 inhabitants and results in the following frequencies of manifestations <TextLink reference="11"></TextLink>:</Pgraph><SubHeadline3>Early manifestations</SubHeadline3><Pgraph><UnorderedList><ListItem level="1">89% erythema migrans (erythema migrans related to another organ manifestation in a further 3%)</ListItem><ListItem level="1">3% Lyme neuroborreliosis (stage II)</ListItem><ListItem level="1">2% Borrelia lymphocytoma</ListItem><ListItem level="1"><1% carditis</ListItem></UnorderedList></Pgraph><SubHeadline3>Late manifestations</SubHeadline3><Pgraph><UnorderedList><ListItem level="1">5% Lyme arthritis</ListItem><ListItem level="1">1% acrodermatitis chronica atrophicans</ListItem><ListItem level="1">Late Lyme neuroborreliosis (stage III) was not identified.</ListItem></UnorderedList></Pgraph><Pgraph>According to one study, children have a higher risk of developing Lyme neuroborreliosis after a tick bite than adults, most likely because they are more frequently bit on the head <TextLink reference="12"></TextLink>.</Pgraph><SubHeadline2>1.1.4 Seroprevalence of Borrelia-specific antibodies</SubHeadline2><Pgraph>Borrelia-specific antibodies are found in 5–20% of healthy individuals in Germany and Austria depending on endemic region and age group <TextLink reference="13"></TextLink>, <TextLink reference="14"></TextLink>, <TextLink reference="15"></TextLink>. A seroprevalence of 20% was found in 964 (asymptomatic) Swiss orienteers; in asymptomatic blood donors it was 8% <TextLink reference="16"></TextLink>. A cross-sectional German study of children and adolescents aged 1–17 years found an average seroprevalence of 4.8%. The relative probability of a positive result for antibodies depended on age and increased for every year of life by 6% for girls and 11% for boys <TextLink reference="17"></TextLink>. An elevated level of Borrelia-specific IgG antibodies was found in 20% of men >60 <TextLink reference="15"></TextLink>.</Pgraph><SubHeadline2>1.1.5 Infection rates of ticks</SubHeadline2><Pgraph>Studies of ticks in southern Germany showed average infection rates of about 1% for larvae, 10% for nymphs and 20% for adults <TextLink reference="18"></TextLink>. In addition to regional differences in tick-borne infection rates (18–37% for adults and 5–12% for nymphs), there were also significant differences in the regional distribution of the Borrelia species <TextLink reference="6"></TextLink>. Infection rates in Switzerland were 5–7% depending on the area <TextLink reference="19"></TextLink>. The density of infected ticks also varies greatly from region to region, ranging from 2 to 58 per 100 m<Superscript>2</Superscript> in Switzerland. In addition to Lyme borreliosis, other infectious diseases such as TBE, human granuloc<TextGroup><PlainText>yt</PlainText></TextGroup>ic anaplasmosis, rickettsiosis, ehrlichiosis etc. can be transmitted by ticks.</Pgraph><SubHeadline2>Summary</SubHeadline2><Pgraph><UnorderedList><ListItem level="1">Lyme borreliosis is a multisystem disease that is transmitted through the bite of the <Mark2>Ixodes ricinus</Mark2> tick. It primarily affects the skin, nervous system or joints.</ListItem><ListItem level="1">Five Borrelia species pathogenic to humans have so far been identified in Europe.</ListItem><ListItem level="1">There are no reliable figures on the rate of occurrence (incidence from different surveys in Germany 60,000 to >200,0000 cases/year).</ListItem><ListItem level="1">Seroprevalence of Borrelia-specific antibodies is 5–20%. It varies regionally and is age-dependent.</ListItem><ListItem level="1">Infection rates of ticks are area-dependent: 18–37% for adults, 5–12% for nymphs, 1% for larva.</ListItem></UnorderedList></Pgraph><SubHeadline>1.2 Route of infection</SubHeadline><Pgraph>Borrelia are transmitted through the bite of hard-bodied ticks (in Europe through the “castor bean tick” <Mark2>Ixodes r</Mark2><TextGroup><Mark2>icin</Mark2></TextGroup><Mark2>us</Mark2>). According to data from animal experiments, the risk of infection increases with the duration of the blood meal. It is not possible to reliably deduce the earliest point in time that an infection can be expected, especially since the probability of transmission even appears to vary from species to species <TextLink reference="20"></TextLink>. The transmission mechanism of the Borrelia that survived in the tick’s intestine before the blood meal is very complex <TextLink reference="21"></TextLink>. According to German studies, a seroconversion is expected to occur after a tick bite in 2.6–5.6% of those affected, and disease will manifest in 0.3–1.4% <TextLink reference="22"></TextLink>, <TextLink reference="23"></TextLink>, <TextLink reference="24"></TextLink>. A study conducted in western Switzerland found the risk of being infected with Borrelia from a tick bite was just under 5% <TextLink reference="25"></TextLink>.</Pgraph><SubHeadline>1.3 Prophylaxis</SubHeadline><Pgraph>(Cited from DDG S2k Guideline “Cutaneous Lyme Borreliosis”; AWMF Register No. 013-044 <TextLink reference="1"></TextLink>.)</Pgraph><SubHeadline2>1.3.1 Prevention of Lyme borreliosis</SubHeadline2><Pgraph>It is very important to <Mark1>remove ticks early</Mark1> before they become engorged. The risk of transmission of Borrelia increases with the length of time the tick sucks <TextLink reference="26"></TextLink>. Transmission within the first 12 hours has rarely been observed in laboratory animals. The body should be checked in the evening for ticks after spending time in a garden, park, field, forest or meadow, where contact with a tick may have occurred.</Pgraph><Pgraph>Ticks should be removed immediately with a tick tweezer or a tick card in order to prevent the transmission of the Borrelia. If parts of the suction organ remain in the skin, they can be removed later with a needle or a curettage <TextLink reference="27"></TextLink>. If the head or the suction organ remains in the skin, the risk of a Borrelia transfer does not increase. The bodies of nymphs and adult ticks should not be squeezed when they are engorged with blood in order to prevent a possible transfer of the Borrelia. Examination of the skin-removed tick for Borrelia is not useful, as detection of Borrelia in the tick does not provide sufficient predictive value for Borrelia transmission to the host nor for disease development. After the removal of a tick, the patient should be informed about the <Mark1>necessary follow-up of the tick bite site</Mark1> in the following 6 weeks (Appendix 6: “Patient information after a tick bite” in <TextGroup><PlainText>Attachment 3 </PlainText></TextGroup><AttachmentLink attachmentNo="3"/>).</Pgraph><SubHeadline2>1.3.2 Prophylactic treatment after a tick bite</SubHeadline2><Pgraph>According to an American study, the risk of infection after a tick bite can be reduced through a one-time prophylactic administration of 200 mg of doxycycline (87% effectiveness) <TextLink reference="28"></TextLink>, <TextLink reference="29"></TextLink>. The results, however, should be interpreted with caution since only one follow-up was conducted after 6 weeks. Thus, no statement can currently be made as to whether this is sufficient with respect to a late infection.</Pgraph><Pgraph>In view of the low risk of disease, a large number of unn<TextGroup><PlainText>ece</PlainText></TextGroup>ssary doxycycline treatments would have to be accepted in order to prevent one potential infection. According to projections of infection risk in endemic areas, 40–125 prophylaxes would have to be administered in order to prevent 1 disease <TextLink reference="30"></TextLink>. Impacts on the intestinal flora and a possible development of resistance through frequent prophylaxis is conceivable. Therefore, oral doxycycline prophylaxis is not recommended in Europe. The prophylactic application of an antibiotic cream is also controversial. Animal studies with azithromycin cream reveal a good prophylactic efficacy <TextLink reference="31"></TextLink>, <TextLink reference="32"></TextLink>. A placebo-controlled study on its effectiveness in humans identified no prophylactic effect <TextLink reference="33"></TextLink>. Therefore, this treatment is not recommended.</Pgraph><SubHeadline3>Recommendations for preventing infection</SubHeadline3><Pgraph>(Taken from the S2k guideline “Cutaneous Lyme Borreliosis” <TextLink reference="1"></TextLink>).</Pgraph><Pgraph><UnorderedList><ListItem level="1">Clothing that covers the body should be worn to prevent tick bites. ↑</ListItem><ListItem level="1">Using tick repellents can be recommended with some reservations. ↔</ListItem><ListItem level="1">Skin should be inspected in the evening for ticks after being in an outdoor area where there is the possibility of contact with ticks. ↑↑</ListItem><ListItem level="1">Ticks should be removed early in order to prevent Lyme borreliosis. ↑↑</ListItem><ListItem level="1">The site of the bite should be observed for up to six weeks. ↑↑</ListItem></UnorderedList></Pgraph><SubHeadline3>Not recommended</SubHeadline3><Pgraph><UnorderedList><ListItem level="1">Testing the removed tick for Borrelia is not recommended. ↓</ListItem><ListItem level="1">No local or systemic prophylactic antibiotic treatment should be given after a tick bite. ↓</ListItem></UnorderedList></Pgraph><SubHeadline2>1.3.3 Vaccines</SubHeadline2><Pgraph>No vaccine is currently approved for use in humans.</Pgraph><Pgraph>A vaccination with recombinant lipidated Osp A has been evaluated in the USA as part of a major study and has shown to be effective <TextLink reference="34"></TextLink>, <TextLink reference="35"></TextLink>. The vaccine has been approved in the USA since 1999; however, it was taken off the market by its manufacturer. The reason for the withdrawal were economical. Reports on undesired vaccine reactions in individuals with a genetic predisposition were refuted by multiple qualified studies <TextLink reference="36"></TextLink>, <TextLink reference="37"></TextLink>, <TextLink reference="38"></TextLink>. This monovalent vaccine is not suitable for Europe as it only protects against an infection with <Mark2>B. burgdorferi </Mark2>sensu stricto, and not against the genospecies <Mark2>B. afzelii</Mark2> and <Mark2>B. garinii</Mark2> that are frequently found in Europe.</Pgraph><Pgraph>A polyvalent OspA vaccine is currently being developed for Europe <TextLink reference="39"></TextLink>, however approval is not expected in the foreseeable future.</Pgraph></TextBlock>
<TextBlock linked="yes" name="2 Symptoms">
<MainHeadline>2 Symptoms</MainHeadline><SubHeadline>2.1 Possible stages</SubHeadline><Pgraph>Early localised stage: An early Borrelia infection manifests in 80–90% of patients as local erythema migrans (early localised stage) <TextLink reference="9"></TextLink>, <TextLink reference="11"></TextLink>. General symptoms such as feeling ill, arthralgia, myalgia, subfebrile temperatures or night sweats may occur a few days to weeks after a Borrelia infection <TextLink reference="40"></TextLink>.</Pgraph><Pgraph><Mark1>Early disseminated stage:</Mark1> A disseminated infection can occur weeks to months after a tick bite (erythema migrans is only reported in around 25–50% of the acute cases of Lyme neuroborreliosis <TextLink reference="41"></TextLink>, <TextLink reference="42"></TextLink>, <TextLink reference="43"></TextLink>), which predominantly affects the nervous system, joints and heart (early disseminated stage) <TextLink reference="40"></TextLink>.</Pgraph><Pgraph><Mark1>Late manifestations:</Mark1> In rare cases, a late or chronic manifestation with involvement of the skin, the nervous system and the joints (late manifestations) can occur after months or years <TextLink reference="40"></TextLink>, <TextLink reference="44"></TextLink>, <TextLink reference="45"></TextLink>, <TextLink reference="46"></TextLink>.</Pgraph><Pgraph>Information about a tick bite does not help determine the time of infection, since unnoticed tick bites lead to infection in about two thirds of cases <TextLink reference="41"></TextLink>, <TextLink reference="47"></TextLink>, <TextLink reference="48"></TextLink>. For the classification of neuroborreliosis, therefore, the disease duration is increasingly used in addition to the clinical picture <TextLink reference="49"></TextLink>.</Pgraph><SubHeadline>2.2 Neurological manifestations in adults</SubHeadline><Pgraph><Mark1>Garin-Bujadoux-Bannwarth syndrome (meningoradiculoneuritis)</Mark1> is the most common manifestation of acute Lyme borreliosis in adults in Europe after erythema migrans <TextLink reference="41"></TextLink>, <TextLink reference="47"></TextLink>, <TextLink reference="50"></TextLink>.</Pgraph><Pgraph>In Europe, isolated <Mark1>meningitis</Mark1> (without radicular symptoms) is mainly observed in children <TextLink reference="12"></TextLink>, <TextLink reference="41"></TextLink>, <TextLink reference="43"></TextLink>, <TextLink reference="51"></TextLink>, <TextLink reference="52"></TextLink> .</Pgraph><Pgraph><TextGroup><PlainText>The symptoms of </PlainText><Mark1>radiculitis</Mark1><PlainText> develop on average 4–6 w</PlainText></TextGroup>eeks (maximum 1–18) after the tick bite or after the erythema migrans <TextLink reference="41"></TextLink>, <TextLink reference="53"></TextLink>. Segmental pain occurs first, which intensifies at night and whose localisation can change. Often the pain is initially localised in the extremity where the tick bite or erythema migrans was first observed <TextLink reference="41"></TextLink>, <TextLink reference="54"></TextLink>. The patient experiences pain that is burning, nagging, stabbing or tearing in nature and responds only slightly to conventional analgesics. It often peaks within a few hours or days. Three-quarters of patients develop neurological deficits after 1–4 weeks, and pareses are more frequent than sensory disorders <TextLink reference="41"></TextLink>, <TextLink reference="53"></TextLink>.</Pgraph><Pgraph>About 60% of patients with Bannwarth’s syndrome have <Mark1>cranial nerve deficits</Mark1>.</Pgraph><Pgraph><UnorderedList><ListItem level="1">All cranial nerves may be involved with the exception of the olfactory nerve.</ListItem><ListItem level="1">The facial nerve is affected in over 80% of cases where there is cranial nerve involvement <TextLink reference="41"></TextLink>, <TextLink reference="55"></TextLink>. There is frequently a bilateral manifestation (approximately 1/3 of the cases) <TextLink reference="41"></TextLink>, <TextLink reference="47"></TextLink>, <TextLink reference="56"></TextLink>. The sense of taste may not be affected. In unilateral cases, it can be difficult to differentiate from idiopathic facial nerve paresis; however, sometimes symptoms or anamnestic data (e.g. erythema migrans, radicular pain) can help to indicate Lyme neuroborreliosis. CSF testing can bring clarity here. In most cases, a complete regression is observed within 1–2 months regardless of the severity of the facial paralysis. Residual symptoms or partial recovery with facial synkinesia (pathological movement) are observed in about 5–10% of patients <TextLink reference="56"></TextLink>, <TextLink reference="57"></TextLink>, <TextLink reference="58"></TextLink>.</ListItem><ListItem level="1">Furthermore, Lyme neuroborreliosis may affect the abducens nerve and very rarely the vestibulocochlear nerve, the optic nerve (optic neuritis, papilloedema), the oculomotor system (NN III, IV), the trigeminal nerve and the caudal cranial nerves (NN IX–XII) <TextLink reference="41"></TextLink>, <TextLink reference="47"></TextLink>, <TextLink reference="53"></TextLink>, <TextLink reference="59"></TextLink>. It is questionable whether isolated damage to the vestibulocochlear nerve occurs in the context of an acute Borrelia infection.</ListItem></UnorderedList></Pgraph><Pgraph><Mark1>Polyneuropathy/polyneuritis</Mark1> is linked to a Borrelia infection in European patients only in association with acrodermatitis chronica atrophicans (ACA) in 48–64% of the cases <TextLink reference="60"></TextLink>, <TextLink reference="61"></TextLink>. Isolated polyneuropathies/polyneuritis without other clear symptoms of Lyme borreliosis have been identified in 39–52% of American patients with Lyme borreliosis <TextLink reference="62"></TextLink>, <TextLink reference="63"></TextLink>. However, in 284 US-American patients with etiologically unexplained polyneuropathy, Lyme borreliosis was identified as the cause of the polyneuropathy in only one case (0.3%) after diagnostic re-evaluation <TextLink reference="64"></TextLink>. In contrast, few instances of distally symmetrical polyneuropathies or polyneuritis not associated with ACA have been identified in Europe. A causal link between neurological symptoms and a Borrelia infection cannot easily be made for patients with polyneuropathy/polyneuritis whose blood tests positive for Borrelia <TextLink reference="65"></TextLink> since Borrelia-specific antibodies are found in approximately 5–20% of healthy individuals depending on the endemic region and age group <TextLink reference="13"></TextLink>, <TextLink reference="15"></TextLink>, <TextLink reference="66"></TextLink>. Occupationally exposed risk groups, such as forestry workers, even have seroprevalences of over 50% <TextLink reference="67"></TextLink>. In these cases, the probability of a causal link depends on whether further clinical symptoms of Lyme borreliosis are present and whether other common causes of polyneuritis have been identified.</Pgraph><Pgraph><Mark1>Involvement of the central nervous system</Mark1> is rare and occurs in only around 4% of Lyme neuroborreliosis cases <TextLink reference="41"></TextLink>, <TextLink reference="47"></TextLink>. Its onset is gradual and it is frequently chronic. The most common manifestation is myelitis with spastic atactic gait disturbance and bladder dysfunction <TextLink reference="41"></TextLink>, <TextLink reference="50"></TextLink>. Symptoms can develop over days or several months. Some patients suffer from severe tetra- or paraparesis. Approximately 60% of patients with myelitis have additional signs of encephalitis and around 40% have cranial nerve involvement. Encephalitis has no clinical properties specific to the pathogen.</Pgraph><Pgraph>Encephalitis can lead to <Mark1>psychiatric diseases</Mark1> or <Mark1>organic brain syndromes</Mark1>. Cases of acute psychosis <TextLink reference="47"></TextLink>, <TextLink reference="68"></TextLink>, <TextLink reference="69"></TextLink>, <TextLink reference="70"></TextLink>, <TextLink reference="71"></TextLink>, <TextLink reference="72"></TextLink> or Tourette’s syndrome <TextLink reference="73"></TextLink> have been reported.</Pgraph><Pgraph>In very rare cases cerebral symptoms (e.g. ischemic stroke) can be caused by Borrelia-induced <Mark1>vasculitis</Mark1> <TextLink reference="74"></TextLink>, <TextLink reference="75"></TextLink>. According to a non-systematic review, only 62 cases had been reported by 2015 <TextLink reference="74"></TextLink>. Another very rare manifestation of Lyme borreliosis is <Mark1>myositis</Mark1>, for which only individual case reports exist <TextLink reference="76"></TextLink>, <TextLink reference="77"></TextLink>. Clinical symptoms include focal pain and paresis.</Pgraph><SubHeadline>2.3 Neurological manifestations in children </SubHeadline><Pgraph>In Europe, <Mark1>Lymphocytic meningitis</Mark1> (approximately 30%) and <Mark1>facial paresis</Mark1> (approximately 55%) are the most frequent manifestations of Lyme neuroborreliosis in children <TextLink reference="12"></TextLink>, <TextLink reference="41"></TextLink>, <TextLink reference="51"></TextLink>, <TextLink reference="52"></TextLink>, <TextLink reference="78"></TextLink>. The symptoms of meningitis are often very discrete and can be overlooked in the absence of cranial nerve involvement <TextLink reference="79"></TextLink>. The facial nerve and the nerves of the outer eye muscles are most frequently affected. In principle, all cranial nerves can be affected with the exception of the olfactory nerve. Radicular symptoms in the spinal nerves are rare. However, there are reported cases of early Lyme neuroborreliosis with myelitis <TextLink reference="80"></TextLink>, acute hemiparesis <TextLink reference="81"></TextLink>, opsoclonus-myoclonus syndrome <TextLink reference="82"></TextLink> and ataxia <TextLink reference="83"></TextLink>. <Mark1>Late Lyme neuroborreliosis</Mark1> is very rare in children. Clinical pictures include seizures, neurological deficits with paralysis and excretory disorders. Cognitive impairment and mood disorders can also occur <TextLink reference="81"></TextLink>.</Pgraph><SubHeadline>2.4 Clinical course</SubHeadline><Pgraph><Mark1>Early Lyme neuroborreliosis:</Mark1> symptoms last for weeks to months <TextLink reference="41"></TextLink>, <TextLink reference="47"></TextLink>, <TextLink reference="50"></TextLink>.</Pgraph><Pgraph><UnorderedList><ListItem level="1">Presumably over 98% of cases <TextLink reference="11"></TextLink>, <TextLink reference="43"></TextLink></ListItem><ListItem level="1">Neurological symptoms appear several weeks to several months after a tick bite</ListItem><ListItem level="1">Typical manifestations: painful meningopolyradiculitis of the spinal nerves linked to a unilateral or bilateral facial paresis (Bannwarth’s syndrome); also meningitis in children</ListItem><ListItem level="1">Frequently: radicular pain</ListItem></UnorderedList></Pgraph><Pgraph></Pgraph><Pgraph><Mark1>Late Lyme neuroborreliosis</Mark1> (also termed chronic <Mark1>Lyme neuroborreliosis</Mark1>): symptoms last for months to years <TextLink reference="41"></TextLink>, <TextLink reference="47"></TextLink>, <TextLink reference="50"></TextLink>.</Pgraph><Pgraph><UnorderedList><ListItem level="1">Presumably less than 2% of cases <TextLink reference="11"></TextLink>, <TextLink reference="43"></TextLink></ListItem><ListItem level="1">Neurological symptoms develop slowly over months to years</ListItem><ListItem level="1">Typical manifestations: encephalomyelitis with spastic atactic gait disturbance and bladder dysfunction</ListItem><ListItem level="1">Isolated meningitis is very rare</ListItem><ListItem level="1">Rarely any pain</ListItem></UnorderedList></Pgraph><Pgraph>Erythema migrans (EM) is indicated in the medical histories of 34–46% of patients with Lyme neuroborreliosis <TextLink reference="41"></TextLink>, <TextLink reference="47"></TextLink>, <TextLink reference="50"></TextLink>.</Pgraph><SubHeadline>2.5 Symptoms that should lead to clarification of Lyme neuroborreliosis</SubHeadline><Pgraph>(Hansen & Lebech 1992 <TextLink reference="41"></TextLink>; Kaiser 1994 <TextLink reference="50"></TextLink>; Oschmann et al. 1998 <TextLink reference="47"></TextLink>) (Appendix 7 in <TextGroup><PlainText>Attachment 3 </PlainText></TextGroup><AttachmentLink attachmentNo="3"/>)</Pgraph><Pgraph><UnorderedList><ListItem level="1">Radiculitis of the spinal nerves (typical for early stages) (frequency 70–75%): initially severe, nocturnal, radicular or segmentally distributed pain, persisting without treatment for weeks, later development of paresis > paraesthesia</ListItem><ListItem level="1">Radiculitis of the cranial nerves II–XII (frequency 47–56%): facial nerve paresis most frequent (83–92%), bilateral in about one third; ocular muscle paresis (abducens nerve) (frequency 4–9%). Very rare (individual case reports): paresis of the oculomotor and trochlear nerves, optic neuritis, papilloedema, hearing loss, dizziness (vestibulocochlear nerve), paresis of the hypoglossal nerve</ListItem><ListItem level="1">Meningitis (in children [frequency of around 30%] more frequent than in adults [frequency 4–5%]): headache, meningism, photophobia, nausea, vomiting, fatigue, emotional instability; rarely chronic</ListItem><ListItem level="1">Neuritis of the peripheral nerves (extremely rare), probably only in the context of acrodermatitis chronica atrophicans/axonal polyneuropathy with predominantly sensory symptoms</ListItem><ListItem level="1">Encephalitis (mostly late Lyme neuroborreliosis) (older case series indicate a frequency of 4–5% for encephalomyelitis) <TextLink reference="41"></TextLink>, <TextLink reference="47"></TextLink>: paresis, speech and language disorders, coordination disorders, occasional epileptic seizures; rarely organic brain syndrome with lack of concentration, loss of consciousness and hallucinations</ListItem><ListItem level="1">Myelitis (mostly late Lyme neuroborreliosis) (frequency similar to encephalitis, see above): transverse sensory dysfunction, central and peripheral paresis, voiding disorders; often in association with encephalitis</ListItem><ListItem level="1">Borrelia-induced cerebral vasculitis: rare, mainly ischemic events in different areas of the bloodstream with corresponding neurological symptoms <TextLink reference="74"></TextLink></ListItem><ListItem level="1">Borrelia-induced myositis: extremely rare <TextLink reference="76"></TextLink>, <TextLink reference="77"></TextLink></ListItem></UnorderedList></Pgraph></TextBlock>
<TextBlock linked="yes" name="3 Diagnostic testing">
<MainHeadline>3 Diagnostic testing</MainHeadline><SubHeadline>3.1 Overview</SubHeadline><Pgraph>Typical clinical symptoms are an indication of Lyme neuroborreliosis which must be underpinned by subsequent laboratory tests (serum and cerebrospinal fluid tests) <TextLink reference="84"></TextLink>, <TextLink reference="85"></TextLink>. The diagnostic algorithm is illustrated in Figure 1 <ImgLink imgNo="1" imgType="figure"/> and Figure 2 <ImgLink imgNo="2" imgType="figure"/>.</Pgraph><SubHeadline>3.2 Inflammatory CSF changes</SubHeadline><Pgraph>Inflammatory cerebrospinal fluid (CSF) changes (pleocytosis, blood-CSF barrier dysfunction and intrathecal immunoglobulin synthesis) can be expected for every Lyme neuroborreliosis (possible exceptions: very early stage of the disease or distal symmetric polyneuropathy).</Pgraph><Pgraph>The CSF typically exhibits <Mark1>lymphocytic pleocytosis</Mark1> with plasma cells, activated lymphocytes and a significant <Mark1>increase in the total protein</Mark1> or albumin ratio (blood brain barrier disorder) <TextLink reference="50"></TextLink>, <TextLink reference="55"></TextLink> (Table 1 <ImgLink imgNo="1" imgType="table"/>). The average cell count is between 170 and 220/µl with a range from <TextGroup><PlainText>6 c</PlainText></TextGroup>ells/µl <TextLink reference="50"></TextLink> up to 1,100 cells/µl <TextLink reference="47"></TextLink>. In addition, <Mark1>intrathecal IgM synthesis</Mark1> occurs in 80–100% of early manifestations and <Mark1>IgG synthesis</Mark1> in about 60% of patients <TextLink reference="50"></TextLink>, <TextLink reference="86"></TextLink>. If intrathecal IgG synthesis is determined qualitatively by isoelectric focusing (detection of oligoclonal IgG bands), results will be positive in 70–80% of patients <TextLink reference="50"></TextLink>, <TextLink reference="55"></TextLink>. Late Lyme neuroborreliosis has more frequent and higher <Mark1>intrathecal IgG and IgA synthesis rates</Mark1> than early Lyme neuroborreliosis (Table 1 <ImgLink imgNo="1" imgType="table"/>).</Pgraph><Pgraph><Mark1>Lactate levels in the cerebrospinal fluid</Mark1> are only slightly elevated in patients with Lyme neuroborreliosis. O<TextGroup><PlainText>nly 5 o</PlainText></TextGroup>ut of 118 patients with early Lyme neuroborreliosis showed significantly elevated CSF-lactate levels (=3.<TextGroup><PlainText>5 m</PlainText></TextGroup>mol/l) and the mean CSF lactate concentration for the entire cohort was not elevated (2.1±0.6 mmol/l) (Table 1 <ImgLink imgNo="1" imgType="table"/>) <TextLink reference="55"></TextLink>.</Pgraph><SubHeadline3>Recommendations</SubHeadline3><Pgraph><UnorderedList><ListItem level="1">If Lyme neuroborreliosis is clinically suspected, CSF and serum testing (simultaneous collection) should be performed. ↑↑</ListItem><ListItem level="1">The CSF analysis should include cytological, protein chemical and serological testing (AI calculation, see below). ↑↑ (both recommendations have a strong consensus 13/13)</ListItem></UnorderedList></Pgraph><SubHeadline>3.3 Indirect pathogen detection in serum</SubHeadline><SubHeadline2>3.3.1 Serodiagnosis, antibody detection</SubHeadline2><Pgraph>In the case of early Lyme borreliosis, Borrelia-specific IgM antibodies can be detected starting week 3 p.i. and IgG antibodies starting week 6 p.i. <TextLink reference="85"></TextLink>. However, the use of VlsE or C6 peptide as a test antigen means that IgG antibodies can now often be detected as early as IgM antibodies <TextLink reference="85"></TextLink>. High IgG antibody concentrations are usually found in late manifestations of Lyme borreliosis (<TextGroup><PlainText>Table 2 </PlainText></TextGroup><ImgLink imgNo="2" imgType="table"/>) <TextLink reference="85"></TextLink>, <TextLink reference="87"></TextLink>. A detectable humoral immune response does not always follow the usual course known from other infectious diseases: the measurable antibody response may (still) be absent in an early, localised manifestation (erythema migrans) <TextLink reference="85"></TextLink>. At the same time, there may be no measurable IgM response, for example in the case of reinfections <TextLink reference="85"></TextLink>, <TextLink reference="88"></TextLink>. In the context of very early antib<TextGroup><PlainText>iot</PlainText></TextGroup>ic treatment, a measurable humoral immune reaction may also fail to appear <TextLink reference="89"></TextLink>. On the other hand, the positive detection of borrelia-specific IgM and/or IgG antibodies alone is not an indication of an illness from <Mark2>Borrelia burgdorferi</Mark2> since</Pgraph><Pgraph><OrderedList><ListItem level="1" levelPosition="1" numString="1.">Borrelia infections with asymptomatic seroconversion can occur <TextLink reference="23"></TextLink> and</ListItem><ListItem level="1" levelPosition="2" numString="2.">elevated IgG and IgM antibody titres (in serum and/or cerebrospinal fluid) are not uncommon in healthy individuals for years following sufficiently treated Lyme borreliosis <TextLink reference="90"></TextLink>, <TextLink reference="91"></TextLink>, <TextLink reference="92"></TextLink>. </ListItem></OrderedList></Pgraph><Pgraph>Borrelia serology is not suitable for monitoring antibiotic treatment of Lyme borreliosis and follow-up testing is therefore not recommended <TextLink reference="85"></TextLink>, <TextLink reference="93"></TextLink>.</Pgraph><Pgraph>The <Mark1>serodiagnosis</Mark1> of a systemic Borrelia infection includes a 2-step process: first a screening test (enzyme immunoassay) followed by a confirmation test (immunoblot) <TextLink reference="85"></TextLink>, <TextLink reference="93"></TextLink>.</Pgraph><Pgraph>Improvements in serodiagnosis include screening tests (ELISAs) that contain the preferably in vivo-expressed protein VIsE or the conserved immunodominant C6 region of this protein <TextLink reference="85"></TextLink>, <TextLink reference="94"></TextLink>. In confirmation tests (immunoblot) for diagnosing acute Lyme neuroborreliosis, the recombinant line immunoblot was reported to have a significantly higher sensitivity than the conventional immunoblot combined with an equally high specificity (95%) <TextLink reference="85"></TextLink>, <TextLink reference="95"></TextLink>. This was partly due to the new line immunoblot technique and partly to the widening of the antigen spectrum to include proteins only expressed by the Borrelia <Mark2>in vivo</Mark2> (in the host and not in the culture).</Pgraph><SubHeadline2>3.3.2 Diagnostically relevant Borrelia antigens</SubHeadline2><Pgraph><Mark2>Borrelia burgdorferi</Mark2> has a large number of immunol<TextGroup><PlainText>ogicall</PlainText></TextGroup>y relevant antigens which, depending on the stage, can be detected with varying degrees of sensitivity and which sometimes have different levels of specificity. Knowing these proteins is important when interpreting serological tes<TextGroup><PlainText>t r</PlainText></TextGroup>esults (detailed description in MiQ Lyme borreliosis <TextLink reference="85"></TextLink>).<LineBreak></LineBreak><LineBreak></LineBreak><Mark1>Early immune response</Mark1> (primarily IgM)<LineBreak></LineBreak><TextLink reference="95"></TextLink>, <TextLink reference="96"></TextLink>, <TextLink reference="97"></TextLink>, <TextLink reference="98"></TextLink></Pgraph><Pgraph><UnorderedList><ListItem level="1">Flagellar protein (Flagellin, p41)</ListItem><ListItem level="1">OspC (associated with outer membrane)</ListItem><ListItem level="1">VlsE</ListItem></UnorderedList></Pgraph><Pgraph><LineBreak></LineBreak><Mark1>Late immune response</Mark1> (primarily IgG)<LineBreak></LineBreak><TextLink reference="96"></TextLink>, <TextLink reference="99"></TextLink>, <TextLink reference="100"></TextLink></Pgraph><Pgraph><UnorderedList><ListItem level="1">p83/100, p58, p43, p39, p30, p21, DbpA (Osp17) and p14 (generally reactive with around 80% of the sera <TextLink reference="99"></TextLink>)</ListItem><ListItem level="1">VlsE (detectable in more than 90% of the sera) <TextLink reference="95"></TextLink></ListItem></UnorderedList></Pgraph><Pgraph><LineBreak></LineBreak><Mark1>Non-specific antigens</Mark1></Pgraph><Pgraph><UnorderedList><ListItem level="1">Flagellin</ListItem><ListItem level="1">Heat shock proteins</ListItem></UnorderedList></Pgraph><SubHeadline3>Summary</SubHeadline3><Pgraph><UnorderedList><ListItem level="1">Positive antibody detection is not evidence for a clinical case of Lyme borreliosis. </ListItem><ListItem level="1">Negative antibody detection largely rules out Lyme borreliosis in immune-healthy patients with prolonged disease. </ListItem><ListItem level="1">An isolated positive IgM detection does not support a late manifestation of Lyme borreliosis.</ListItem></UnorderedList></Pgraph><SubHeadline3>Recommendations</SubHeadline3><Pgraph><UnorderedList><ListItem level="1">Serological testing should only be requested if there is sufficient clinical suspicion. ↑↑</ListItem><ListItem level="1">Testing should be done in stages (screening test and confirmation test) ↑↑ (consensus of both recommend<TextGroup><PlainText>ation</PlainText></TextGroup>s 10/13) </ListItem></UnorderedList></Pgraph><SubHeadline>3.4 Intrathecal antibody synthesis – Borrelia-specific antibody index (AI)</SubHeadline><SubHeadline2>3.4.1 Overview</SubHeadline2><Pgraph>In most patients with Lyme neuroborreliosis the suspected clinical diagnosis can be confirmed by detecting Borrelia-specific intrathecal antibody synthesis related to inflammatory changes in their cerebrospinal fluid <TextLink reference="85"></TextLink>, <TextLink reference="101"></TextLink>, <TextLink reference="102"></TextLink>, <TextLink reference="103"></TextLink>. The production of specific intrathecal antib<TextGroup><PlainText>od</PlainText></TextGroup>ies is detected by determining the Borrelia-specific CSF/serum antibody index (Borrelia-specific AI) <TextLink reference="41"></TextLink>, <TextLink reference="104"></TextLink>, <TextLink reference="105"></TextLink>.</Pgraph><SubHeadline2>3.4.2 Determination method</SubHeadline2><Pgraph>Methods used to <Mark1>determine the AI</Mark1> should take into account the blood/CSF barrier function, as otherwise false negative results may be produced <TextLink reference="85"></TextLink>. The determination of the antibody index according to Reiber is a proven method that is recommended <TextLink reference="85"></TextLink>, <TextLink reference="101"></TextLink>, <TextLink reference="106"></TextLink>, <TextLink reference="107"></TextLink>. The following formula is used to calculate the Borrelia-specific AI (the formula is illustrated with IgG. It can also be used to calculate IgM and IgA): Antibody index =<LineBreak></LineBreak><ImgLink imgNo="1" imgType="inlineFigure"/></Pgraph><Pgraph>If intrathecal immunoglobulin synthesis is present in the Reiber diagram (i.e. the total IgG ratio relative to the albumin ratio is above the norm), the total IgG ratio must be replaced by the Q-Lim ratio (empirical limit value for the maximum IgG fraction derived from the serum as a fun<TextGroup><PlainText>ction of the albumin ratio). In this case: Antibody index =</PlainText></TextGroup> <LineBreak></LineBreak><ImgLink imgNo="2" imgType="inlineFigure"/></Pgraph><Pgraph>A value of =1.5 is recommended as the <Mark1>cut-off</Mark1> for a positive AI, unless otherwise evaluated <TextLink reference="85"></TextLink>, <TextLink reference="86"></TextLink>, <TextLink reference="106"></TextLink>, <TextLink reference="108"></TextLink>; previously recommended higher limit values of 2.0 <TextLink reference="109"></TextLink> are considered less sensitive when a reliable test performance can be ensured <TextLink reference="86"></TextLink>. Quantitative measuring methods are usually used to determine the AI and are implemented in commercial, EDP-supported systems <TextLink reference="85"></TextLink>.</Pgraph><Pgraph>It is important to note that there can be considerable fluctuations in the determination of AI (both interrater-dependent for the same method and when comparing different methods) <TextLink reference="86"></TextLink>. Hence antibody testing and AI determination should be conducted in accredited microbiology laboratories.</Pgraph><SubHeadline2>3.4.3 AI throughout the course of the disease</SubHeadline2><Pgraph>Intrathecal <Mark2>Borrelia burgdorferi</Mark2>-specific antibody production develops in untreated patients from around week 2 and is detectable in over 99% of patients after 6–8 weeks <TextLink reference="41"></TextLink>, <TextLink reference="101"></TextLink>, <TextLink reference="102"></TextLink>, <TextLink reference="103"></TextLink>, <TextLink reference="110"></TextLink>. During the course of the disease (short duration of disease), elevated CSF-Borrelia antibodies can sometimes be detected despite negative Borrelia antibodies in serum <TextLink reference="55"></TextLink>, <TextLink reference="110"></TextLink>, <TextLink reference="111"></TextLink>. Conversely, Borrelia-specific AI can remain inconspicuous when the duration of the disease is short or in children with facial paresis <TextLink reference="101"></TextLink>, <TextLink reference="110"></TextLink>, <TextLink reference="111"></TextLink>. Furthermore, very early antibiotic treatment can prevent the development of a measurable humoral immune response and cause the Borrelia-specific AI to remain negative <TextLink reference="112"></TextLink>.</Pgraph><Pgraph>After the Lyme neuroborreliosis has resolved, the Borrelia-specific AI can remain positive for months or years in symptom-free patients <TextLink reference="50"></TextLink>, <TextLink reference="113"></TextLink>, <TextLink reference="114"></TextLink>. Borrelia-specific AI is not suitable for monitoring treatment success and should be interpreted in relation to clinical symptoms and inflammatory changes in cerebrospinal fluid (pleocytosis, blood CSF barrier disorder).</Pgraph><SubHeadline3>Summary</SubHeadline3><Pgraph><UnorderedList><ListItem level="1">A clinically suspected diagnosis of Lyme neuroborreliosis can be confirmed by the detection of intrathecal Borrelia-specific antibody synthesis (positive Borrelia-specific antibody index [AI]) in connection with inflammatory changes in cerebrospinal fluid.</ListItem><ListItem level="1">Intrathecal Borrelia-specific antibody synthesis starts in about the second week of the disease and is detectable after 6–8 weeks in over 99% of patients.</ListItem><ListItem level="1">A Borrelia-specific AI without accompanying inflammatory changes in CSF may remain positive for years after Lyme neuroborreliosis has resolved.</ListItem></UnorderedList></Pgraph><SubHeadline3>Recommendations</SubHeadline3><Pgraph><UnorderedList><ListItem level="1">The Borrelia-specific AI should be determined if Lyme neuroborreliosis is suspected. ↑↑</ListItem><ListItem level="1">The Borrelia-specific AI should not be used to monitor treatment success. ↑↑ (strong consensus for both recommendations 13/13)</ListItem></UnorderedList></Pgraph><SubHeadline>3.5 Chemokine CXCL13</SubHeadline><Pgraph>In recent years, the chemokine CXCL13 has been shown to increase significantly in the CSF of almost all patients with acute Lyme neuroborreliosis – even before a specific antibody response is generated. Once antibiotics are administered, chemokine levels immediately drop very quickly, long before CSF pleocytosis regresses <TextLink reference="115"></TextLink>, <TextLink reference="116"></TextLink>, <TextLink reference="117"></TextLink>. A prospective study of 179 patients with suspected Lyme neuroborreliosis showed a sensitivity/specificity of 100%/99% and positive and negative predictive values of 88% and 100% respectively <TextLink reference="118"></TextLink>. Hence, the parameter can be helpful in ambiguous cases of very early Lyme neuroborreliosis <TextLink reference="43"></TextLink>, <TextLink reference="85"></TextLink>. It should be noted that CXCL13 is not specific to Lyme neuroborreliosis; increased CSF values have also been found with neurosyphilis, tubercular meningitis and CNS lymphomas <TextLink reference="116"></TextLink>, <TextLink reference="119"></TextLink>, <TextLink reference="120"></TextLink>, <TextLink reference="121"></TextLink>, <TextLink reference="122"></TextLink>. Furthermore, determinatio<TextGroup><PlainText>n –</PlainText></TextGroup> including cut-off – has yet to be generally standardised.</Pgraph><SubHeadline2>Summary</SubHeadline2><Pgraph><UnorderedList><ListItem level="1">CXCL13 levels in the cerebrospinal fluid correlate with the “disease activity” (indication of existing infection) of Lyme neuroborreliosis and can be diagnostically helpful in individual cases. </ListItem><ListItem level="1">CXCL13 determination has yet to be generally standardised.</ListItem><ListItem level="1">Elevated CXCL13 values in CSF also occur in conjunction with other diseases.</ListItem></UnorderedList></Pgraph><SubHeadline2>Recommendation</SubHeadline2><Pgraph><UnorderedList><ListItem level="1">CXCL13 can be determined in CSF when early Lyme neuroborreliosis is clinically suspected and the CSF cell count and/or Borrelia-specific AI are (still) inconspicuous. ↔ (strong consensus 12/13)</ListItem></UnorderedList></Pgraph><SubHeadline>3.6 Direct detection of the pathogen using molecular biological detection methods and culture</SubHeadline><Pgraph>In exceptional cases (e.g. immunosuppressed patients (e.g. insufficient antibody production due to primary immunodeficiency or B-cell depletion)), a Borrelia infection can be underpinned by pathogen detection in CSF <TextLink reference="85"></TextLink>, <TextLink reference="123"></TextLink>. However, for acute Lyme neuroborreliosis, the sensitivity of the pathogen detection in CSF through culture or a PCR test is only 10–30% <TextLink reference="85"></TextLink>, <TextLink reference="87"></TextLink>. Pathogen detection is expected to have a higher sensitivity when the duration of the disease is short (where patients may still be seronegative) than in prolonged cases. For example, 50% of patients with acute Lyme neuroborreliosis tested positive with PCR compared to only 13% of patients with a prolonged course of the disease <TextLink reference="124"></TextLink>. Detection in the cerebrospinal fluid using a PCR test is generally preferred because results can be provided faster than for cultures. If the results are positive, a species diagnosis should be made by analysing the PCR products. Detection of the pathogen in blood is not recommended because this method is even less sensitive <TextLink reference="85"></TextLink>. The specificity of the PCR test depends to a large extent on the quality of the laboratory performing it. Therefore, the investigation should be explicitly limited to special, designated reference laboratories, especially as further molecular biological confirmation tests are required when the results are positive <TextLink reference="85"></TextLink>. In every case, the PCR result must be interpreted in relation to the symptoms and the serology results. For example, positive PCR test results for patients with a prolonged disease and negative serology are very likely to be false positive <TextLink reference="85"></TextLink>.</Pgraph><SubHeadline2>Recommendations for direct detection using molecular biological methods and culture</SubHeadline2><Pgraph><UnorderedList><ListItem level="1">Molecular biological detection and direct detection in culture using cerebrospinal fluid should only be employed for the differential diagnosis of ambiguous cases (e.g. insufficient antibody production when there is a primary immunodeficiency or B-cell depletion). ↑ (consensus 11/13)</ListItem><ListItem level="1">Molecular biological detection and the cultivation of <Mark2>Borrelia burgdorferi</Mark2> sensu lato should be restricted to specialist laboratories. ↑ (strong consensus 13/13)</ListItem><ListItem level="1">Positive culture results should be confirmed using suitable molecular biological methods. ↑↑ (strong consensus 13/13)</ListItem><ListItem level="1">Molecular biological detection or direct detection in culture should not be used as a screening test if Lyme borreliosis is suspected. ↑↑ (strong consensus 13/13)</ListItem><ListItem level="1">Lyme neuroborreliosis should not be ruled out if the results of the molecular biological test or culture are negative for the pathogen. ↓↓ (strong consensus 13/13)</ListItem><ListItem level="1">Positive results for molecular biological detection or detection in culture should be confirmed by further molecular biological testing methods and the detected genospecies should be reported in the findings. ↑↑ (strong consensus 13/13)</ListItem><ListItem level="1">No additional treatment should be carried out if detection results are positive following antibiotic treatment conducted in accordance with the guidelines and without typical clinical manifestation. ↓↓ (strong consensus 13/13)</ListItem></UnorderedList></Pgraph><SubHeadline>3.7 Routine laboratory parameters in blood</SubHeadline><Pgraph>In the routine laboratory, patients with Lyme neuroborreliosis have normal or slightly elevated values for ESR, CRP, leukocytes and transaminases that indicate a systemic infection (Table 3 <ImgLink imgNo="3" imgType="table"/>). When diagnosing Lyme neuroborreliosis, the routine laboratory results only play a role in differential diagnosis.</Pgraph><SubHeadline>3.8 Diagnostic imaging – MRI</SubHeadline><Pgraph>Magnetic resonance imaging (MRI), including MR angiography, is indispensable in diagnosing Borrelia-induced vasculitis; MR tomography can detect both cerebral ischemia and intracranial vascular stenosis <TextLink reference="47"></TextLink>, <TextLink reference="74"></TextLink>, <TextLink reference="75"></TextLink>. Inflammatory lesions that show gadolinium enhancement in MRI have been detected in individual cases of encephalomyelitic manifestations <TextLink reference="47"></TextLink>, <TextLink reference="43"></TextLink>. However, there are no controlled studies on the diagnostic value of MRI in Lyme neuroborreliosis. In most cases of early Lyme neuroborreliosis, inconspicuous findings are expected due to the very rare involvement of the brain and spinal cord; here, MRI is primarily used for differential diagnosis.</Pgraph><SubHeadline>3.9 Testing</SubHeadline><Pgraph>The following tests should be conducted if Lyme neuroborreliosis is clinically suspected (for symptoms see Section 2.4):</Pgraph><Pgraph><UnorderedList><ListItem level="1">Targeted anamnesis with questions related to tick bites, visits to endemic areas, early symptoms (erythema migrans, multiple erythema migrantia, Borrelia lymphocytoma [lymphadenosis cutis benigna], general symptoms), psychosocial anamnesis if necessary </ListItem><ListItem level="1">Neurological state, inspection of the skin (erythema migrans may still be detectable at the time of neurological symptoms)</ListItem><ListItem level="1">Basic lab tests with inflammation parameters</ListItem><ListItem level="1">CSF analysis: cell count, differential cell count, total protein, immunoglobulins, lactate </ListItem><ListItem level="1">Borrelia serology including Borrelia-specific CSF/serum antibody index (AI)</ListItem></UnorderedList></Pgraph><SubHeadline>3.10 Diagnostic criteria for Lyme neuroborreliosis</SubHeadline><Pgraph>Depending on the constellation of the clinical findings and laboratory data, the diagnosis of Lyme neuroborreliosis can be classified as possible, probable and definite (see below) <TextLink reference="84"></TextLink>, <TextLink reference="125"></TextLink>.</Pgraph><SubHeadline3>Possible neuroborreliosis</SubHeadline3><Pgraph><UnorderedList><ListItem level="1">Typical clinical picture (cranial nerve deficits, meningitis/meningoradiculitis, focal neurological deficits; cf. Section 2.4)</ListItem><ListItem level="1">Borrelia-specific IgG and/or IgM antibodies in serum (<Mark2>The serology may [still] be negative in very early stages of the disease</Mark2>)</ListItem><ListItem level="1">CSF findings not available/spinal tap not performed</ListItem><ListItem level="1">Differentiation from other causes</ListItem></UnorderedList></Pgraph><SubHeadline3>Probable Lyme neuroborreliosis</SubHeadline3><Pgraph>As with “possible Lyme neuroborreliosis”, however additionally</Pgraph><Pgraph><UnorderedList><ListItem level="1">Inflammatory cerebrospinal fluid syndrome with lymphocytic pleocytosis, blood-CSF barrier dysfunction and intrathecal immunoglobulin synthesis</ListItem></UnorderedList></Pgraph><SubHeadline3>Definite Lyme neuroborreliosis</SubHeadline3><Pgraph>As with “probable Lyme neuroborreliosis”, however additionally</Pgraph><Pgraph><UnorderedList><ListItem level="1">Intrathecal synthesis of Borrelia-specific antibodies (positive IgG and/or IgM antibody index) in CSF or</ListItem><ListItem level="1">Positive culture or nucleic acid detection (PCR) in cerebrospinal fluid</ListItem></UnorderedList></Pgraph><SubHeadline>3.11 Testing methods not suitable for diagnosing Lyme neuroborreliosis</SubHeadline><Pgraph>There are no prospective controlled studies available for the following methods that would prove useful for the diagnosis of Lyme neuroborreliosis.</Pgraph><Pgraph>Therefore, these methods should not be used in diagn<TextGroup><PlainText>osin</PlainText></TextGroup>g Lyme neuroborreliosis ↓↓ (consensus 10/12) <TextLink reference="85"></TextLink>:</Pgraph><Pgraph><UnorderedList><ListItem level="1">Antigen detection in bodily fluids</ListItem><ListItem level="1">PCR in serum and urine</ListItem><ListItem level="1">Lymphocyte transformation tests (LTT) <TextLink reference="126"></TextLink>, <TextLink reference="127"></TextLink>, <TextLink reference="128"></TextLink>, <TextLink reference="129"></TextLink></ListItem><ListItem level="1">Enzyme-linked immunospot assay (ELISPOT) <TextLink reference="130"></TextLink></ListItem><ListItem level="1">“Xenodiagnosis” – hard tick larvae suck blood from suspected Lyme borreliosis patients; the larvae are subsequently tested for Borrelia <TextLink reference="131"></TextLink>, <TextLink reference="132"></TextLink></ListItem><ListItem level="1">Visual contrast sensitivity test (VCS test or grey scale test): By measuring the detection of shades of gray, a lipophilic neurotoxin from Borrelia is to be detected indirectly <TextLink reference="133"></TextLink></ListItem><ListItem level="1">Detection of so-called L forms or spheroplasts <TextLink reference="134"></TextLink></ListItem><ListItem level="1">Detection of immunocomplexes as markers of disease activity</ListItem><ListItem level="1">CD57 positive/CD3 negative lymphocyte subpopulation <TextLink reference="135"></TextLink></ListItem><ListItem level="1">Commercially available serological rapid tests (insufficient sensitivity (18–32%) <TextLink reference="136"></TextLink></ListItem></UnorderedList></Pgraph><Pgraph><Mark1>Note:</Mark1> The DBG and the patient organisations BFBD, BZK and OnLyme-Aktion.org have issued dissenting opinions on this topic, which are published in an appendix (Attachment 1 <AttachmentLink attachmentNo="1"/>) to the guideline report (Attachment 2 <AttachmentLink attachmentNo="2"/>).</Pgraph></TextBlock>
<TextBlock linked="yes" name="4 Chronic and atypical symptoms linked to Lyme neuroborreliosis">
<MainHeadline>4 Chronic and atypical symptoms linked to Lyme neuroborreliosis</MainHeadline><SubHeadline>4.1 Introduction</SubHeadline><Pgraph>In addition to the confirmed early and late manifestations of Lyme neuroborreliosis (such as radiculitis, meningitis or encephalomyelitis and/or their clinical residuals), there is a broad range of persisting symptoms in which a causal link to Lyme neuroborreliosis is suspected without an inflammatory-infectious process being detectable on the basis of generally accepted criteria <TextLink reference="43"></TextLink>, <TextLink reference="137"></TextLink>, <TextLink reference="138"></TextLink>, <TextLink reference="139"></TextLink>, <TextLink reference="140"></TextLink>, <TextLink reference="141"></TextLink>, <TextLink reference="142"></TextLink>. The terms used for these chronic symptoms include “post-treatment Lyme disease syndrome” (PTLDS), “(post-)Lyme encephalopathy” or simply “chronic Lyme (neuro)borreliosis” and are often used with no clear delineation between them. Characteristic for all three illnesses is that general symptoms predominate. It is questionable whether it makes sense to administer repeated doses of antibiotics as no studies have provided reliable evidence for this <TextLink reference="142"></TextLink>, <TextLink reference="143"></TextLink>.</Pgraph><Pgraph>The frequency and range of persistent symptoms following antibiotic treatment in patients with Lyme neuroborreliosis have been systematically investigated <TextLink reference="5"></TextLink>. Forty-four studies published between 1986 and 2014 were identified (8 RCTs, 17 cohort studies, 2 case-control studies and 17 case series), of which 38 studies (n=1,469 patients) reported patients with residual symptoms. A total of 28% of patients (95% CI 23–34%, n=34 studies) had persistent or residual symptoms. In studies in which the inclusion criteria (case definition) were a “probable or definite” case of Lyme neuroborreliosis (inflammatory changes in CSF), the prevalence of persistent symptoms was 24% (95% CI 0.16–0.33; n=547) – significantly lower (p=0.0048) than with patients whose inclusion criterion was only a “possible” case of Lyme neuroborreliosis (CSF findings inconspicuous or unavailable) (31% [95% CI 0.25–0.37]; n=922). Furthermore, the type of persistent symptoms also differed between the two patient groups. The non-specific complaints typically reported for PTLDS (see Section 4.3) were statistically more prevalent in patients with “possible” Lyme neuroborreliosis than in patients with “probable/definitive” Lyme neuroborreliosis: fatigue (5.13% vs. 0%), cognitive disorders (16.67% vs. 1.6%), general pain (18.75% vs. 2.77%), headaches (8.33% vs. 1.75%) (Table 4 <ImgLink imgNo="4" imgType="table"/>). Even though a study bias or the presence of different disease stages in the cohorts studied cannot be definitively ruled out, the authors conclude that the significant prevalence of persistent atypical symptoms for Lyme neuroborreliosis, as reported in the studies, is largely due to study artefacts as a result of blurred case definitions.</Pgraph><SubHeadline>4.2 Presumptive chronic Lyme neuroborreliosis</SubHeadline><SubHeadline2>4.2.1 Introduction</SubHeadline2><Pgraph>The terms “chronic Lyme borreliosis” or “chronic Lyme neuroborreliosis” are confusingly used in an overlapping sense with very different meanings and correspondingly different therapeutic consequences. They mostly refer to non-specific symptoms such as fatigue, musculoskeletal pain, cognitive disorders and depression <TextLink reference="140"></TextLink>, <TextLink reference="141"></TextLink>, <TextLink reference="142"></TextLink>, <TextLink reference="143"></TextLink>, <TextLink reference="144"></TextLink>, <TextLink reference="145"></TextLink>, <TextLink reference="146"></TextLink>, <TextLink reference="147"></TextLink>, <TextLink reference="148"></TextLink>. In terms of the pathophysiology of presumptive “chronic Lyme disease” or “chronic Lyme neuroborreliosis”, current systematic reviews have not found a scientific basis for the assumption of a persistent latent infection caused by <Mark2>Borrelia burgdorferi</Mark2> <TextLink reference="140"></TextLink> or its morphological variants <TextLink reference="134"></TextLink>. Likewise, no evidence has been found for chronic co-infections transmitted by tick bites in patients with non-specific symptoms <TextLink reference="149"></TextLink>. Feder et al. have described 4 clinical categories to which patients with presumptive “chronic Lyme borreliosis” can be assigned (for complete criteria according to Feder see Appendix 1 in <TextGroup><PlainText>Attachment 3 </PlainText></TextGroup><AttachmentLink attachmentNo="3"/>) <TextLink reference="142"></TextLink>.</Pgraph><Pgraph><UnorderedList><ListItem level="1"><Mark1>Category 1</Mark1> includes patients with symptoms of an unknown cause without evidence of an infection with <Mark2>Borrelia burgdorferi</Mark2>.</ListItem><ListItem level="1"><Mark1>Category 2</Mark1> includes patients with symptoms of a known, well-defined illness without evidence of an infection with <Mark2>Borrelia burgdorferi</Mark2>. Here the original diagnosis is presumed to be false.</ListItem><ListItem level="1"><Mark1>Category 3</Mark1> describes patients with symptoms of an unknown cause when the Borrelia serology tests positive but there is no objective clinical finding of Lyme borreliosis.</ListItem><ListItem level="1"><Mark1>Category 4</Mark1> refers to patients with PTLDS-like symptoms (PTLDS see Section 4.3 and Appendix 2 in <TextGroup><PlainText>Attachment 3 </PlainText></TextGroup><AttachmentLink attachmentNo="3"/>).</ListItem></UnorderedList></Pgraph><SubHeadline2>4.2.2 Present study situation</SubHeadline2><Pgraph>Older studies, in which patients with presumptive “chronic Lyme borreliosis” were re-evaluated at speci<TextGroup><PlainText>alis</PlainText></TextGroup>ed academic centres, primarily featured category 1 and 2 illnesses according to Feder <TextLink reference="150"></TextLink>, <TextLink reference="151"></TextLink>, <TextLink reference="152"></TextLink>. Later studies on this topic examined 240 US-American patients <TextLink reference="153"></TextLink>, 29 Norwegian patients <TextLink reference="154"></TextLink>, 95 German patients <TextLink reference="155"></TextLink> and 200 Dutch patients <TextLink reference="156"></TextLink>. In summary, Lyme borreliosis was confirmed in a smaller percentage of patients (13–24%). PTLDS was presumed in 6–20% of patients, with no proven causal link to Lyme borreliosis and no indication for antibiotic treatment (see above). <TextGroup><PlainText>A d</PlainText></TextGroup>iagnosis remained undetermined in 18–52% of cases. All in all, these studies suggest that if “chronic Lyme borreliosis” is suspected, it is imperative that an intensive differential diagnosis of both organic and psychosocial disease factors be conducted <TextLink reference="156"></TextLink>, <TextLink reference="157"></TextLink>. Furthermore, in light of the very broad distribution of the study results cited here, further research is regarded as necessary.</Pgraph><SubHeadline2>4.2.3 Practical approach</SubHeadline2><Pgraph>There is no rationale behind administering antibiotics to categorie<TextGroup><PlainText>s 1</PlainText></TextGroup> and 2 according to Feder. Based on current data (see Section 4.3), antibiotic treatment of categor<TextGroup><PlainText>y 4</PlainText></TextGroup> is also not indicated. In patients with category 3 symptoms according to Feder <TextLink reference="142"></TextLink> probatory (oral) antibiotic treatment may be considered. However, these patients should be advised that the diagnosis of Lyme borreliosis is very uncertain in their situation, as the predictive value of Borrelia serology is very low when symptoms are non-specific <TextLink reference="158"></TextLink>, <TextLink reference="159"></TextLink> and temporary “treatment effects” may be caused by both the placebo effect <TextLink reference="160"></TextLink> and by the anti-inflammatory side effects of antibiotics <TextLink reference="161"></TextLink>, <TextLink reference="162"></TextLink>, <TextLink reference="163"></TextLink>.</Pgraph><Pgraph> </Pgraph><SubHeadline2>Summary</SubHeadline2><Pgraph><UnorderedList><ListItem level="1">None of the 4 categories according to Feder <TextLink reference="142"></TextLink> correspond to a disease entity.</ListItem></UnorderedList></Pgraph><SubHeadline2>Recommendations</SubHeadline2><Pgraph><UnorderedList><ListItem level="1">As with Lyme neuroborreliosis, patients in categorie<TextGroup><PlainText>s 1</PlainText></TextGroup>, 2 and 4 according to Feder <TextLink reference="142"></TextLink> should not be treated with antibiotics. Instead a differential diagnosis should be performed based on the symptoms and treatment should be prescribed based on the primary symptoms. ↑↑ (consensus 9/11)</ListItem><ListItem level="1">In exceptional cases, a single round of antibiotics lasting 14–21 days may be considered for category 3 patients following a detailed differential diagnosis and taking into account the fact that it is an unconfirmed diagnosis. ↔ (10/14 majority consensus)</ListItem></UnorderedList></Pgraph><Pgraph> </Pgraph><SubHeadline>4.3 Symptoms following treatment: “Post-Treatment Lyme Disease Syndrome” (PTLDS)</SubHeadline><SubHeadline2>4.3.1 Diagnostic criteria</SubHeadline2><Pgraph>PTLDS is a syndrome that has not yet been scientifically defined and therefore not uniformly accepted. It is to be diagnostically differentiated from confirmed late manifestations of Lyme borreliosis, symptoms caused by the persistence of reproducing pathogens, and symptoms caused by partial recovery.</Pgraph><Pgraph>In the case of Lyme neuroborreliosis, objective neurological deficits and inflammatory changes in the cerebrospinal fluid usually respond well to antibiotic treatment <TextLink reference="41"></TextLink>, <TextLink reference="43"></TextLink>, <TextLink reference="137"></TextLink>, <TextLink reference="138"></TextLink>, <TextLink reference="139"></TextLink>, <TextLink reference="140"></TextLink>. However, some patients are reported to have developed non-specific symptoms of fatigue, paraesthesia, muscle and joint pain as well as concentration and memory issues despite antibiotic treatment <TextLink reference="164"></TextLink>, <TextLink reference="165"></TextLink>, <TextLink reference="166"></TextLink>, <TextLink reference="167"></TextLink>. If the non-specific symptoms last more than 6 months, some authors refer to this as post-treatment Lyme disease syndrome (PTLDS) <TextLink reference="27"></TextLink>, <TextLink reference="142"></TextLink>. Predictors for the development of fatigue 30 months after treatment have been described as the delayed onset of antibiotic treatment, severe neurological symptoms before treatment, and incomplete regression of neurological symptoms 4 months after treatment <TextLink reference="166"></TextLink>.</Pgraph><Pgraph>In 2006, the Infectious Diseases Society of America (IDSA) proposed the following diagnostic criteria for PTLDS <TextLink reference="27"></TextLink>. The main criteria for this definition are: a previous, confirmed case of Lyme borreliosis which has improved or stabilised under a generally accepted antibiotic treatment regimen, and the occurrence of subjective symptoms within 6 months after diagnosis of Lyme borreliosis without any indication of another aetiology despite thorough differential diagnosis, which persist for at least <TextGroup><PlainText>6 m</PlainText></TextGroup>onths after completion of the antibiotic treatment (see Appendix 2 in Attachment 3 <AttachmentLink attachmentNo="3"/> for the full definition). So far, these criteria have seldom been used in clinical studies. This would require the establishment of practical and reliable tools to assess these subjective symptoms and their influence on the patient’s quality of life and professional and general performance <TextLink reference="139"></TextLink>, <TextLink reference="168"></TextLink>.</Pgraph><SubHeadline2>4.3.2 Frequency</SubHeadline2><Pgraph>In a non-systematic review, it was reported that 0–20% of patients being treated for Lyme borreliosis with antib<TextGroup><PlainText>iotic</PlainText></TextGroup>s had symptoms of so-called PTLDS; after treatment of Lyme neuroborreliosis the percentage was between <TextGroup><PlainText>5 a</PlainText></TextGroup>nd 54% <TextLink reference="43"></TextLink>.</Pgraph><SubHeadline2>4.3.3 Subjective symptoms in case-control studies</SubHeadline2><Pgraph>The frequency of subjective symptoms was investigated in case-control studies comparing cohorts of patients that previously had Lyme borreliosis and persons that did not have Lyme borreliosis. Since PTLDS-like symptoms are non-specific and also common among the general population <TextLink reference="169"></TextLink>, <TextLink reference="170"></TextLink>, classifying them as Lyme neuroborreliosis in the sense of a causal secondary disease is very problematic. This problem is also reflected in very heterogeneous data: compared to control subjects, German adults as well as Swedish and US-American children did not exhibit an increased frequency of non-specific symptoms at long-term follow up after the treatment of Lyme neuroborreliosis <TextLink reference="171"></TextLink>, <TextLink reference="172"></TextLink>, <TextLink reference="173"></TextLink>, <TextLink reference="174"></TextLink>. The same applied to European patients following the treatment of erythema migrans <TextLink reference="175"></TextLink> and American patients after various manifestations of Lyme borreliosis <TextLink reference="176"></TextLink>, <TextLink reference="177"></TextLink>. Other case-control studies found a significant accumulation of non-specific symptoms in children and adults after the treatment of Lyme neuroborreliosis <TextLink reference="148"></TextLink>, <TextLink reference="178"></TextLink>, <TextLink reference="179"></TextLink> or after any manifestation of Lyme borreliosis <TextLink reference="180"></TextLink>, <TextLink reference="181"></TextLink>, <TextLink reference="182"></TextLink>. A meta-analysis examined five of the studies cited above <TextLink reference="173"></TextLink>, <TextLink reference="177"></TextLink>, <TextLink reference="179"></TextLink>, <TextLink reference="180"></TextLink>, <TextLink reference="181"></TextLink> and concluded that there is an overriding link between the chronic symptoms of PTLDS and a previous case of Lyme borreliosis <TextLink reference="183"></TextLink>. This meta-analysis is countered by the fact that it includes various retrospective studies whose diagnostic criteria and antibiotic treatment no longer meet current standards <TextLink reference="184"></TextLink>.</Pgraph><Pgraph>According to another study, fatigue and depression lead to physical and psychological impairment in patients with PTLDS-like symptoms <TextLink reference="185"></TextLink>, which is why the authors recommend targeted symptomatic treatment of these primary symptoms.</Pgraph><SubHeadline2>4.3.4 Neuropsychological symptoms in case-control studies</SubHeadline2><Pgraph>The current study situation is contradictory in terms of the frequency of neuropsychological symptoms. In addition to subjective symptoms, objective neuropsychological impairments (verbal and visual memory, attention, executive functions) ≥30 months after treatment of Lyme neuroborreliosis are described as possible consequences of the disease <TextLink reference="186"></TextLink>, <TextLink reference="187"></TextLink>. However, these reports could not be confirmed by another study <TextLink reference="174"></TextLink> nor in children who had previously had Lyme neuroborreliosis (facial paresis) <TextLink reference="179"></TextLink>. In addition, further studies – at least in subgroups – revealed limited memory performance, mainly in verbal tasks, compared to healthy controls or patients who had fully recovered <TextLink reference="180"></TextLink>, <TextLink reference="188"></TextLink>, <TextLink reference="189"></TextLink>, <TextLink reference="190"></TextLink>, <TextLink reference="191"></TextLink>, <TextLink reference="192"></TextLink>, <TextLink reference="193"></TextLink>. However, there are also resu<TextGroup><PlainText>lts tha</PlainText></TextGroup>t contradict these studies <TextLink reference="176"></TextLink>, <TextLink reference="181"></TextLink>, <TextLink reference="194"></TextLink>, <TextLink reference="195"></TextLink>.</Pgraph><SubHeadline2>4.3.5 Studies on antibiotic treatment</SubHeadline2><Pgraph>Three randomised, placebo-controlled studies have examined the therapeutic benefit of antibiotic treatment over 28 to 70 days in patients with PTLDS <TextLink reference="193"></TextLink>, <TextLink reference="195"></TextLink>, <TextLink reference="196"></TextLink>, <TextLink reference="197"></TextLink>. None of the studies identified a sustained improvement in neuropsychological performance. </Pgraph><Pgraph>The most extensive of the three studies (N=129), in which antibiotics were administered for the longest period o<TextGroup><PlainText>f t</PlainText></TextGroup>ime (2 g/d of ceftriaxone for 30 days followed by 20<TextGroup><PlainText>0 m</PlainText></TextGroup>g/d of doxycycline for 60 days), was negative for all endpoints (especially health-related quality of life and cognitive functions) <TextLink reference="195"></TextLink>, <TextLink reference="196"></TextLink>.</Pgraph><Pgraph>A study by Fallon et al. <TextLink reference="193"></TextLink> (N=37, 2 g/d of ceftriaxone over 70 days) found a temporary improvement in cognitive performance after 12 weeks, but this was not confirmed after 24 weeks. There was no significant difference between the fatigue scales of the placebo and verum groups.</Pgraph><Pgraph>A study by Krupp et al. (N=55, 2 g/d of ceftriaxone over 28 days) showed a slight but significant improvement in the fatigue score of the verum group compared to the placebo group after 6 months <TextLink reference="197"></TextLink>. Critics state that</Pgraph><Pgraph><OrderedList><ListItem level="1" levelPosition="1" numString="1.">the effect is very marginal (score improvement in FS<TextGroup><PlainText>S-1</PlainText></TextGroup>1: 22% versus 9% verum/placebo [p<0.01]);</ListItem><ListItem level="1" levelPosition="2" numString="2.">patients in the verum group still had very severe fatigue (mean FSS-11=4.4) even after treatment, so that they continued to meet the inclusion criteria of the study;</ListItem><ListItem level="1" levelPosition="3" numString="3.">the results of a second fatigue scale (Fatigue-VAS) were insignificant and</ListItem><ListItem level="1" levelPosition="4" numString="4.">the improvement was not perceived by the patients themselves on a scale of health-related quality of life (first question of SF-36) <TextLink reference="198"></TextLink>.</ListItem></OrderedList></Pgraph><Pgraph>In light of the very low effects and based on the fact that there was a critically high number of protocol drop-outs (33% of placebo patients) in the study <TextLink reference="199"></TextLink>, the validity of this study is questionable from a methodological point of view <TextLink reference="198"></TextLink>. In addition, the study results are contradicted by two negative studies <TextLink reference="193"></TextLink>, <TextLink reference="195"></TextLink>, <TextLink reference="196"></TextLink>.</Pgraph><Pgraph>In all three studies, side effects – some of which are life-threatening – are reported at a rate of 25%–43%. Based on a risk-benefit analysis, none of the three author groups recommends treating so-called PTLDS with any of the investigated antibiotic regimens <TextLink reference="193"></TextLink>, <TextLink reference="195"></TextLink>, <TextLink reference="196"></TextLink>, <TextLink reference="197"></TextLink>.</Pgraph><SubHeadline2>4.3.6 Pathophysiology</SubHeadline2><Pgraph>The pathophysiology of so-called PTLDS is unclear. An autoimmune process has not been proven <TextLink reference="142"></TextLink>, <TextLink reference="200"></TextLink>, <TextLink reference="201"></TextLink>. In light of the negative or marginal effects of repeated antibiotic treatments (see Section 5), a chronic infection is unlikely. This assumption is further supported by the following arguments <TextLink reference="142"></TextLink>: no accompanying, objective clinical signs of the disease and/or inflammation with progression <TextLink reference="196"></TextLink>, <TextLink reference="202"></TextLink>, persistence of symptoms irrespective of a positive Borrelia serology <TextLink reference="196"></TextLink>, <TextLink reference="202"></TextLink>, <TextLink reference="203"></TextLink>, no pathogen detection by culture and/or PCR <TextLink reference="196"></TextLink>, <TextLink reference="204"></TextLink>, no proven resistance of <Mark2>Borrelia burgdorferi </Mark2>sensu lato to the commonly used antibiotics <TextLink reference="138"></TextLink>, <TextLink reference="205"></TextLink>.</Pgraph><SubHeadline2>Summary</SubHeadline2><Pgraph><UnorderedList><ListItem level="1">Due to inconsistent data, so-called PTLDS cannot be defined as a disease entity.</ListItem><ListItem level="1">There are no controlled studies on the frequency of so-called PTLDS.</ListItem><ListItem level="1">The data refute the assumption of a chronic infection with <Mark2>Borrelia burgdorferi</Mark2> or an autoimmune process in patients with symptoms of so-called PTLDS (strong consensus for all 3 statements of 13/13).</ListItem></UnorderedList></Pgraph><SubHeadline2>Recommendations</SubHeadline2><Pgraph><UnorderedList><ListItem level="1">In the case of PTLDS-like symptoms, symptom-based differential diagnosis and treatment should be carried out. ↑↑ (consensus 11/13)</ListItem><ListItem level="1">If a so-called PTLDS is assumed, antibiotic treatment should not be prescribed. ↓↓ (consensus 11/12)</ListItem></UnorderedList></Pgraph><SubHeadline2>Further guidelines exist for PTLDS-like symptoms</SubHeadline2><Pgraph><UnorderedList><ListItem level="1">DEGAM S3 guideline on fatigue, AWMF Register N<TextGroup><PlainText>o. 0</PlainText></TextGroup>53-002 <TextLink reference="206"></TextLink></ListItem><ListItem level="1">DIVS S3 guideline on fibromyalgia syndrome, AWMF Register No. 041-004 <TextLink reference="207"></TextLink></ListItem><ListItem level="1">DEGAM S1 guideline on chronic pain, AWMF Register No. 053-036 <TextLink reference="208"></TextLink></ListItem><ListItem level="1">National Disease Management Guideline (S3) “Unipolar Depression”, AWMF Register No. nvl-005 <TextLink reference="209"></TextLink></ListItem><ListItem level="1">DGN guideline (S2e) on the diagnosis and treatment of memory disorders, AWMF Register No. 030-124 <TextLink reference="210"></TextLink></ListItem><ListItem level="1">DGPM S3 Guideline “Management of Patients with Non-specific, Functional and Somatoform Physical Complaints”, AWMF Register No. 051-001 <TextLink reference="211"></TextLink></ListItem></UnorderedList></Pgraph><SubHeadline>4.4 Lyme encephalopathy</SubHeadline><Pgraph>The term “Lyme encephalopathy” was originally coined in the 1980s when some clinical manifestations of Lyme disease were first described. At the time, patients frequently suffered from an undiagnosed, detectably active Borrelia infection (e.g. arthritis or ACA) for months or even years and reported cognitive complaints including memory disorders, which usually regressed after antibiotic treatment <TextLink reference="189"></TextLink>, <TextLink reference="212"></TextLink>, <TextLink reference="213"></TextLink>, <TextLink reference="214"></TextLink>. In these case series, encephalitis was identified in only a small subset of patients who exhibited focal neurological deficits, abnormalities in cerebrospinal fluid or in imaging <TextLink reference="213"></TextLink>. The majority of these patients suffered from “toxic-metabolic” encephalopathy as described in systemic (non-neurological) infections or inflammatory diseases (sepsis, pneumonia, urinary tract infections, active rheumatoid arthritis, etc.) <TextLink reference="201"></TextLink>, <TextLink reference="215"></TextLink>, <TextLink reference="216"></TextLink>. Since this is a non-specific reaction of the brain to a systemic inflammatory process, the term “Lyme encephalopathy” should only be used in connection with the historical publications cited above.</Pgraph><Pgraph>Other authors use the term Lyme encephalopathy in connection with cognitive complaints in PTLDS patients <TextLink reference="185"></TextLink>, <TextLink reference="193"></TextLink>. Since it is not possible to differentiate the term “Lyme encephalopathy” from its more historical use in the 1980s as outlined above, this designation should currently not be used as a diagnosis or syndrome designation.</Pgraph><SubHeadline2>Recommendation</SubHeadline2><Pgraph><UnorderedList><ListItem level="1">The term Lyme encephalopathy should not be used due to its unclear definition and contradictory use in diagnoses. ↓↓ (strong consensus 13/13)</ListItem></UnorderedList></Pgraph></TextBlock>
<TextBlock linked="yes" name="5 Treating Lyme neuroborreliosis">
<MainHeadline>5 Treating Lyme neuroborreliosis</MainHeadline><SubHeadline>5.1 Introduction</SubHeadline><Pgraph>A current systematic review <TextLink reference="4"></TextLink>, <TextLink reference="217"></TextLink> found that there is limited evidence concerning drug treatment for Lyme neuroborreliosis. Eight randomised controlled trials (RCT) and eight non-randomised studies (NRS) were selected for the evaluation after screening 5,779 reports from three databases. The authors state that the conclusions for medical practice must be weighed against the low number of studies – some of which had small cohorts – and the relevant risk for diverse study biases (Appendi<TextGroup><PlainText>x 8</PlainText></TextGroup> in Attachment 3 <AttachmentLink attachmentNo="3"/>) <TextLink reference="4"></TextLink>.</Pgraph><Pgraph>Only three studies examined patients who did not undergo antibiotic treatment <TextLink reference="218"></TextLink>, <TextLink reference="219"></TextLink>, <TextLink reference="220"></TextLink>. Two studies compared these with patients who received antibiotic treatment <TextLink reference="219"></TextLink>, <TextLink reference="220"></TextLink>. The studies used heterogeneous methods and produced contradictory findings with a low degree of precision. Therefore, a meta-analysis of these data is not justified (Appendix 8 in Attachment 3 <AttachmentLink attachmentNo="3"/>) <TextLink reference="4"></TextLink>. Nevertheless, when the benefits are weighed against the risks, antibiotic treatment is indicated beyond doubt, especially as this can accelerate the regression of symptoms and counteract the development of late manifestations <TextLink reference="41"></TextLink>, <TextLink reference="42"></TextLink>, <TextLink reference="174"></TextLink>, <TextLink reference="221"></TextLink>, <TextLink reference="222"></TextLink>.</Pgraph><SubHeadline>5.2 Early Lyme neuroborreliosis</SubHeadline><SubHeadline2>5.2.1 Duration of treatment</SubHeadline2><Pgraph>Eight RCTs and eight prospective cohort studies predo<TextGroup><PlainText>mi</PlainText></TextGroup>nantly examined patients with early Lyme neurobo<TextGroup><PlainText>rr</PlainText></TextGroup>eliosis. The duration of antibiotic treatment in the RCTs was 14–21 days (with one exception of 100 days <TextLink reference="223"></TextLink>. Treatment duration in the NRSs varied from 10 to 30 days, if specified at all. No studies compared different treatment durations. The treatment effect on the primary endpoint (neurological residual symptoms) varied considerably in both the 8 RCTs (10–66%) and the 2 prospective cohort studies (7–44%) (Appendix 3 in Attachment 3 <AttachmentLink attachmentNo="3"/>). The main reasons for this broad range of results are non-standardised survey methods (neurological status, score system, patient self-assessment) as well as different assessment timeframes, including wide-ranging assessment times within the individual studies themselves (3 RCTs: 3–12 months; 3 RCTs 12 months; 2 RCTS >3 months) <TextLink reference="4"></TextLink>.</Pgraph><Pgraph>When comparing different treatment durations, there is, in fact, indirect evidence based on a prospective controlled study that examined 152 patients with disseminated Lyme disease (80% with predominantly early Lyme neuroborreliosis [43% confirmed, 37% possible]) <TextLink reference="223"></TextLink>. Patients were initially treated with 2 g of ceftriaxone i.v. per day for 3 weeks. This was followed by further treatment carried out on a randomised basis for 100 days during which the patient received either 1 g of amoxicillin p.o. per day or a placebo. After 1 year, about 90% of the patients in both groups exhibited excellent or very good results. This study therefore is an indication that there i<TextGroup><PlainText>s n</PlainText></TextGroup>o benefit to extending treatment beyond 3 weeks (Clas<TextGroup><PlainText>s I</PlainText></TextGroup>b). A lack of study evidence for longer treatment times and the existence of a controlled study with indirect evidence reveal that there is no scientific basis for deviating from the previously recommended treatment duration of 14 days <TextLink reference="109"></TextLink>, <TextLink reference="224"></TextLink> for early Lyme neuroborreliosis.</Pgraph><SubHeadline2>5.2.2 Choice of antibiotics and side effects</SubHeadline2><Pgraph>Due to their good CSF penetration, controlled clinical trials have evaluated beta-lactam antibiotics (penicillin G, ceftriaxone and cefotaxime) and doxycycline in treating Lyme neuroborreliosis. According to a meta-analysis, the orally administered doxycycline and the intravenously administered beta-lactam antibiotics show no statistically significant difference with regard to the regression of neurological symptoms after an investigation period o<TextGroup><PlainText>f 4</PlainText></TextGroup>–12 months (RR 1.27, 95% confidence interval 0.98–1.63, P=0.07) and after more than 12 months (R<TextGroup><PlainText>R 0</PlainText></TextGroup>.98, 95% confidence interval 0.68–1.42, P=0.93) and are therefore of similar efficacy (Class Ia) <TextLink reference="4"></TextLink>. These findings confirm an earlier meta-analysis conducted by American authors <TextLink reference="225"></TextLink>. Secondary endpoints, such as quality of life and fatigue, were investigated in an RCT follow-up study <TextLink reference="178"></TextLink>, <TextLink reference="226"></TextLink>. No significant difference was found after 30 months between patients treated with beta-lactam antibiotics and those receiving doxycycline (Class Ib). Two RCTs showed that these two antibiotic treatment regimens did not differ with regard to cerebrospinal fluid pleocytosis <TextLink reference="4"></TextLink>, <TextLink reference="221"></TextLink>, <TextLink reference="226"></TextLink> (Class Ib). Based on two RCTs <TextLink reference="223"></TextLink>, <TextLink reference="227"></TextLink> there was also no statistically significant difference (RR 0.82, 95% CI 0.54–1.25, P=0.35) (Class Ia) in terms of reported side effects. The following side effects were reported: diarrhoea, nausea, constipation, redness of the skin, dizziness, and thrombophlebitis. Severe side effects such as cholecystitis, stomatitis, allergic reactions and duodenal ulcers were not reported frequently enough in the studies to make valid comparisons (Appendices 4 and 5 in Attachment 3 <AttachmentLink attachmentNo="3"/>) <TextLink reference="4"></TextLink>.</Pgraph><Pgraph>There are currently no studies that investigate doxycycline doses higher than 200 mg/d, which is why no statement can be made in regard to higher dosages of doxycycline <TextLink reference="4"></TextLink>.</Pgraph><Pgraph>A comparison of cefotaxime and penicillin in two RCTs <TextLink reference="228"></TextLink>, <TextLink reference="229"></TextLink> revealed cefotaxime had a significant advantage in terms of fewer neurological residual symptoms after 4–12 months (RR 1.81, 95% CI 1.10–2.97, P=0.02). In contrast, patients treated with penicillin had significantly fewer side effects (RR 0.54, 95% CI 0.35–0.83, P=0.005). Mild diarrhoea and Herxheimer-like reactions were found to be the most common side effects (41%) (Appendices 4 and 5 in Attachment 3 <AttachmentLink attachmentNo="3"/>). Since serious side effects such as colitis, shock and allergic reactions (3%) were not reported enough for comparative analysis <TextLink reference="229"></TextLink> and both studies are also subject to a significant risk of bias (Appendix 8 in Attachment 3 <AttachmentLink attachmentNo="3"/>), no recommendation can be derived from these data with regard to a preference of either substance over the other <TextLink reference="4"></TextLink>.</Pgraph><Pgraph>There is currently no valid analysable study data on the efficacy of antibiotic combination treatments and no study data are available on the efficacy of chloroquine, carbapenems and metronidazole <TextLink reference="4"></TextLink>.</Pgraph><SubHeadline2>5.2.3 Course following antibiotic treatment</SubHeadline2><Pgraph>Most studies report a significant improvement in neurological symptoms several weeks to a few months following antibiotic treatment lasting 10–14 days. In a prospective study of 77 patients with Bannwarth’s syndrome, 88% of patients had good results 12 months after antibiotic treatment (Class IIa) <TextLink reference="230"></TextLink>. The reported frequency of residual neurological symptoms is consistent with previous cohort studies in which 78/86 (90.6%) of patients were symptom-free 3 months after antibiotic treatment <TextLink reference="42"></TextLink>, and 178/187 patients exhibited very good results after 4–72 (median 33) months <TextLink reference="41"></TextLink>. Another cohort study found that the daily activities of 100/114 (88%) patients with predominantly early Lyme neuroborreliosis were not impaired after an observation period of 5 years <TextLink reference="164"></TextLink>. A systematic review examined the residual symptoms in 687 patients with Lyme neuroborreliosis confirmed through the diagnostic testing of CSF (probable/definitie Lyme neuroborreliosis) <TextLink reference="5"></TextLink>. The following rates of neurological residual symptoms were found after antibiotic treatment: sensory disorders 5.24%; cranial nerve paresis 3.6%; extremity paresis 2.33%, pain 2.77%; unsteady gait/dizziness/ataxia 2.62% (Appendix 6 in Attachment 3 <AttachmentLink attachmentNo="3"/>).</Pgraph><SubHeadline>5.3 Late Lyme neuroborreliosis</SubHeadline><Pgraph>There are no controlled studies that explicitly investigate antibiotic treatment of late manifestations of Lyme neuroborreliosis (myelitis, encephalitis, encephalomyelitis). In the 16 systematically analysed treatment studies (RCTs and cohort studies) <TextLink reference="4"></TextLink> only 15 patients reportedly had late Lyme neuroborreliosis (Appendix 3 in <TextGroup><PlainText>Attachment 3 </PlainText></TextGroup><AttachmentLink attachmentNo="3"/>). A separate evaluation of this form of manifestation is not possible due to a lack of data in the primary studies. However, neurological residual symptoms appear to occur more frequently than with early Lyme neuroborreliosis (Class III). In a case series examining 15 patients, only 3 patients (20%) were symptom-free 6 months after antibiotic treatment <TextLink reference="42"></TextLink>. In another cohort study, 8/<TextGroup><PlainText>8 p</PlainText></TextGroup>atients with encephalomyelitis caused by late Lyme neuroborreliosis had neurological residuals after 4–7<TextGroup><PlainText>2 m</PlainText></TextGroup>onths (median 33), whereby 5/8 (62%) had severely disabling residual symptoms <TextLink reference="41"></TextLink>.</Pgraph><Pgraph>The controlled studies and cohort studies <TextLink reference="4"></TextLink> as well as the larger case series <TextLink reference="41"></TextLink>, <TextLink reference="42"></TextLink> have shown no evidence of treatment failure when beta-lactam antibiotics or doxycycline (Class III) are administered for 2–3 weeks. No further studies show any benefits of receiving antib<TextGroup><PlainText>ioti</PlainText></TextGroup>c treatment for more than 3 weeks. Therefore, a risk-benefit analysis finds that there is no scientific basis for deviating from the previous recommendation of administering antibiotics for 2–3 weeks to patients with late manifestations.</Pgraph><Pgraph>Moreover, doxycycline has also been shown to be equally effective in reducing CSF pleocytosis in 26 patients with Lyme encephalitis and/or myelitis compared to 115 patients with radicular manifestation (Bannwarth’s syndrome) (Class Ib) <TextLink reference="231"></TextLink>. Based on the data, doxycycline is assumed to be effective regardless of the severity of the symptoms – as the authors conclude – however this has not been proven.</Pgraph><Pgraph>Polyneuritis associated with ACA improves clinically – albeit slowly – after antibiotic treatment, while electrophysiological abnormalities do not change significantly after a mean follow-up period of 18.5 months (range 11–50 months) <TextLink reference="232"></TextLink>. The authors regard this finding to be a partial recovery rather than an indication of a persistent infection.</Pgraph><SubHeadline>5.4 Cerebral vasculitis resulting from Lyme borreliosis</SubHeadline><Pgraph>There are no controlled studies on the treatment of – very rare – cerebral vasculitis resulting from Lyme borreliosis. Case reports, case series and narrative reviews have reported that early antibiotic treatment with ceftriaxone and/or doxycycline has very good results <TextLink reference="74"></TextLink>, <TextLink reference="75"></TextLink>, <TextLink reference="231"></TextLink>, <TextLink reference="233"></TextLink>, <TextLink reference="234"></TextLink>, <TextLink reference="235"></TextLink>, <TextLink reference="236"></TextLink> (Class IV). Several authors administer steroids in addition to antibiotics <TextLink reference="235"></TextLink>, <TextLink reference="237"></TextLink>, <TextLink reference="238"></TextLink>, <TextLink reference="239"></TextLink> (Class IV). Despite antibiotic and steroid administration, clinical stabilization was achieved in 2 casuistics only after a subsequent immunosuppressive cyclophosphamide treatment (Class IV); two cases involving the basilar artery were lethal <TextLink reference="240"></TextLink>, <TextLink reference="241"></TextLink>. In summary, in the case of cerebral vasculitis due to Lyme borreliosis, the earliest possible antibiotic treatment is in the foreground; whether the addition of steroids and/or prophylactic platelet function inhibition with ASA 100mg, in analogy to the recommendations in autoimmune mediated cerebral vasculitis, results in an advantage is unclear (DGN S1 guideline on cerebral vasculitis, AWMF Register No. 030-085 <TextLink reference="242"></TextLink>).</Pgraph><SubHeadline>5.5 Treating Lyme neuroborreliosis in children</SubHeadline><Pgraph>According to a systematic review <TextLink reference="3"></TextLink>, the current scientific data on the antibiotic treatment of Lyme neuroborreliosis in children is very limited and existing studies are of a low quality. Two RCTs and four NRSs (one prospective and three retrospective cohort studies) were identified as being analysable studies. These are all older studies, some of which are several decades old, and do not meet current standards for clinical trials. The treatment duration was 14 days in the RCTs and 10–30 days in the NRSs. Different treatment durations were not compared. Only one prospective cohort study required a positive CSF finding in the sense of a “probable” case of Lyme neuroborreliosis as an inclusion criterion; all other studies based their inclusion criteria on a “possible” case of Lyme neuroborreliosis, which does not require the detection of inflammatory changes in CSF for a diagnosis and thus carries the risk of recruiting false positive cases. Penicilli<TextGroup><PlainText>n G</PlainText></TextGroup> was investigated most frequently (5 studies), fo<TextGroup><PlainText>llowe</PlainText></TextGroup>d by ceftriaxone (4 studies) and doxycycline (<TextGroup><PlainText>2 s</PlainText></TextGroup>tudies). No studies examined the antibiotics hydroxychloroquine, azithromycin, minocycline or carbapenem antibiotics. Three studies compared several beta-lactam antibiotics, one study compared beta-lactam antibiotics with doxycycline, and two studies investigated various treatment regimens. Apart from one cohort study, all studies showed a critical overall risk for bias. This pertained to the recruitment process, randomisation, blinding, confounding of baseline data and data evaluation and/or data report, so that the results can only be used to a very limited extent for treatment recommendations. When comparing beta-lactam antibiotics with doxycycline, none of the studies showed a statistically significant difference, although the wide confidence intervals place limitations on this statement. The same applies to the comparison of penicillin G with ceftriaxone. In one study no side effects of the penicillin G group were reported, however there was a moderate allergic skin reaction (n=1), increase in liver enzymes (n=2) and asymptomatic gallbladder concrements (n=6) in the ceftriaxone group. The gallbladder concrements were detected by an ultrasound screening conducted on the ceftriaxone group, but not on the penicillin comparison group. The side effects reported in the other studies could not be assigned to the respective interventions and could therefore not be evaluated. Differentiated recommendations for clinical use cannot be derived from the limited study data. However, the prognosis for Lyme neuroborreliosis in children appears to be favourable across all studies. Poor results or an inadequate treatment response were rarely reported regardless of the antibiotic used.</Pgraph><SubHeadline2>Recommendations for treating children and adults</SubHeadline2><Pgraph><UnorderedList><ListItem level="1">Antibiotic treatment should be carried out in the case of Lyme neuroborreliosis with inflammatory cerebrospinal fluid syndrome (probable or confirmed Lyme neuroborreliosis) (Section 3.4). ↑↑ (strong consensus 13/13)</ListItem><ListItem level="1">In the case of a “possible” Lyme neuroborreliosis (CSF not available or inconspicuous) (Section 3.4), antibiotic treatment may be considered after a thorough differential diagnosis and if there is no evidence of another disease. ↔ (13/13)</ListItem><ListItem level="1">Antibiotic treatment should take place over a perio<TextGroup><PlainText>d o</PlainText></TextGroup>f 14 days (early Lyme neuroborreliosis) or 14–21 days (late Lyme neuroborreliosis). ↑↑</ListItem><ListItem level="1">Reference is made to the S2k Guideline “Cutaneous Lyme Borreliosis” (AWMF Register No. 013-044) <TextLink reference="1"></TextLink> for the treatment of polyneuropathy associated with acrodermatitis chronica atrophicans (ACA). (consensus 12/13)</ListItem><ListItem level="1">If a distally symmetrical polyneuropathy is suspected as a manifestation of Lyme neuroborreliosis without accompanying ACA (rare in Europe), the same procedure recommended for “possible” Lyme neuroborreliosis can be used. ↔ (consensus 10/13)</ListItem><ListItem level="1">Cerebral vasculitis resulting from Lyme borreliosis should be treated with antibiotics in accordance with the recommendations for “late Lyme neuroborreliosis”. ↑↑ (strong consensus 12/12)</ListItem><ListItem level="1">Analogous to the recommendations for cerebral vasculitis of another aetiology (DGN S1 guideline on cerebral vasculitis, AWMF Register No. 030-085 <TextLink reference="242"></TextLink>), the additional administration of steroids and/or 100 mg/d of ASS can be considered for cerebral vasculitis resulting from Lyme borreliosis. ↔ (consensus 10/12)</ListItem><ListItem level="1">In addition to antibiotic treatment, symptoms should also be treated (physiotherapy, physical therapy, occupational therapy, speech therapy, neuropsychological training, psychosocial measures, the administration of analgesics, rehabilitative measures). ↑ (strong consensus 13/13) </ListItem></UnorderedList></Pgraph><SubHeadline2>Recommendation for choosing antibiotics for children and adults</SubHeadline2><Pgraph><UnorderedList><ListItem level="1">Antibiotic treatment of early and late Lyme neuroborreliosis should be performed with one of the following substances: doxycycline, ceftriaxone, cefotaxime, penicillin G. The choice of antibiotic should be based on the individual patient (allergies, other tolerability, age, pregnancy, mode and frequency of application, etc.). ↑↑ (consensus 9/13) (Table 5 <ImgLink imgNo="5" imgType="table"/>)</ListItem></UnorderedList></Pgraph><SubHeadline2>Recommendations for monitoring the treatment of children and adults</SubHeadline2><Pgraph><UnorderedList><ListItem level="1">The success of the treatment should be assessed on the basis of the clinical symptoms. ↑↑ (strong consensus 12/12)</ListItem><ListItem level="1">If clinical deterioration occurs during or after treatment, the differential diagnoses should be reviewed on an interdisciplinary basis. ↑ (strong consensus 10/10)</ListItem><ListItem level="1">If a patient continues to have impairing symptoms <TextGroup><PlainText>6 m</PlainText></TextGroup>onths after treatment, the diagnostic testing of CSF should be repeated; if there are doubts about whether the symptoms are improving, an earlier follow-up CSF analysis can be considered; if the pleocytosis persists, a new course of antibiotic treatment should be carried out after review of the differential diagnosis. ↑ (11/13 consensus)</ListItem><ListItem level="1">The following parameters should not be used to monitor treatment ↓↓ (strong consensus 13/13):</ListItem><UnorderedList><ListItem level="2">Borrelia-specific antibody concentrations (and/or titre) in serum</ListItem></UnorderedList><UnorderedList><ListItem level="2">Borrelia-specific CSF/serum antibody index</ListItem></UnorderedList><UnorderedList><ListItem level="2">Oligoclonal bands in CSF</ListItem></UnorderedList><UnorderedList><ListItem level="2">Total protein in CSF</ListItem></UnorderedList><UnorderedList><ListItem level="2">Band pattern in Lyme immunoblot</ListItem></UnorderedList></UnorderedList></Pgraph></TextBlock>
<TextBlock linked="yes" name="Notes">
<MainHeadline>Notes</MainHeadline><SubHeadline>Guideline information</SubHeadline><Pgraph>This is the English version of the German DGN S<TextGroup><PlainText>3 G</PlainText></TextGroup>uideline “Neuroborreliose”, AWMF Register No. 030-071 <TextLink reference="243"></TextLink>.</Pgraph><Pgraph><UnorderedList><ListItem level="1">Development stage: S3</ListItem><ListItem level="1">Lead coordinator: Prof. Dr. Sebastian Rauer</ListItem><ListItem level="1">Deputy coordinator: PD Dr. Stephan Kastenbauer</ListItem><ListItem level="1">Published by the Guideline Commission of the German Neurological Society</ListItem></UnorderedList></Pgraph><SubHeadline2>Version</SubHeadline2><Pgraph><UnorderedList><ListItem level="1">Completely revised: 21 March 2018</ListItem><ListItem level="1">German version online at <Hyperlink href="https://www.awmf.org">https://www.awmf.org</Hyperlink> since: 12 April 2018 <TextLink reference="243"></TextLink></ListItem><ListItem level="1">Valid until: 12 April 2021</ListItem><ListItem level="1">Chapter: Inflammatory and pathogen-causing diseases</ListItem></UnorderedList></Pgraph><SubHeadline2>ICD 10 code</SubHeadline2><Pgraph>A69.2+, G01*, G63.0*</Pgraph><SubHeadline2>Internet</SubHeadline2><Pgraph><Hyperlink href="https://www.dgn.org/">https://www.dgn.org/</Hyperlink></Pgraph><Pgraph><Hyperlink href="https://www.awmf.org">https://www.awmf.org</Hyperlink></Pgraph><SubHeadline>Support/Financing of the guideline</SubHeadline><Pgraph>This guideline was created without the influence or financial support of sponsors.</Pgraph><Pgraph>The funds required to create and to translate this guideline were provided by the Society for Promotion of Quality Assurance in Medical Laboratories (INSTAND e.V.), Düsseldorf.</Pgraph><Pgraph>Travel expenses were provided by the respective expert medical societies.</Pgraph><Pgraph>See Attachment 4 <AttachmentLink attachmentNo="4"/></Pgraph><SubHeadline>Competing interests</SubHeadline><Pgraph>See Attachment 4 <AttachmentLink attachmentNo="4"/></Pgraph><SubHeadline>Dissenting opinions</SubHeadline><Pgraph>The DBG and the patient organisations BFBD, BZK and OnLyme-Aktion.org have issued dissenting opinions, which are published in an appendix (Attachment 1 <AttachmentLink attachmentNo="1"/>) to the guideline report (Attachment 2 <AttachmentLink attachmentNo="2"/>).</Pgraph><SubHeadline>Methods used to develop guideline</SubHeadline><Pgraph>This guideline is based on an update of the S1 guideline “Neuroborreliosis” No. 030-071 issued by a panel of e<TextGroup><PlainText>xper</PlainText></TextGroup>ts in 2012 <TextLink reference="2"></TextLink>. The guideline was created in accordance with the methodological guidelines of the German Association of Scientific Medical Societies (AWMF) fo<TextGroup><PlainText>r th</PlainText></TextGroup>e development and further development of diagnosis and treatment guidelines. It corresponds to an S<TextGroup><PlainText>3 g</PlainText></TextGroup>uideline in accordance with AWMF’s three-stage concept. The composition of the guideline group was interdisciplinary (IDA).</Pgraph><Pgraph>Uniform formulations are used in order to standardise the recommendations of the guideline. The following gradations shall apply here:</Pgraph><Pgraph><UnorderedList><ListItem level="1">Strong recommendation: “shall” ↑↑</ListItem><ListItem level="1">Recommendation: “should” ↑</ListItem><ListItem level="1">Open recommendation: “may be considered” ↔</ListItem><ListItem level="1">Recommendation against an intervention: “should not<TextGroup><PlainText>” ↓</PlainText></TextGroup></ListItem><ListItem level="1">Strong recommendation against an intervention: “shall not” ↓↓</ListItem></UnorderedList></Pgraph><SubHeadline>DGN guideline commission</SubHeadline><SubHeadline2>Chair</SubHeadline2><Pgraph>Prof. Dr. med. Hans-Christoph Diener</Pgraph><Pgraph>Prof. Dr. med. Christian Gerloff (vice chairman)</Pgraph><SubHeadline2>Chief editor</SubHeadline2><Pgraph>Prof. Dr. med. Christian Weimar</Pgraph><SubHeadline2>Members (in alphabetical order)</SubHeadline2><Pgraph>Prof. Dr. med. Peter Berlit (Vertreter der Chefärzte), Prof<TextGroup><PlainText>. D</PlainText></TextGroup>r. med. Claudio L. A. Bassetti (Vertreter der SNG), Dr. med. Uwe Meier (Vertreter der Niedergelassenen), Prof. Dr. med. Jörg R. Weber (Vertreter der ÖGN), Pro<TextGroup><PlainText>f. Dr. m</PlainText></TextGroup>ed. Claudia Sommer (Vertreterin für Schmerzen und PNP), Prof. Dr. med. Dr. h.c. Günther Deuschl, P<TextGroup><PlainText>D Dr. m</PlainText></TextGroup>ed. Karla Eggert, Prof. Dr. med. Christian Elger, Prof. Dr. med. Gereon R. Fink, Prof. Dr. med. Peter U. Heuschmann, Prof. Dr. med. Andreas Hufschmidt, Pro<TextGroup><PlainText>f. Dr. m</PlainText></TextGroup>ed. Thomas Lempert, Prof. Dr. med. Dr. h.c. Wolfgang H. Oertel, Prof. Dr. med. Hans Walter Pfister, Prof. Dr. med. Heinz Reichmann, PD Dr. Christiane Schneider-Gold, Prof. Dr. med. Bernhard J. Steinhoff, Pro<TextGroup><PlainText>f. Dr. m</PlainText></TextGroup>ed. Lars Timmermann, Prof. Dr. med. Claus W. Wallesch, Prof. Dr. med. Christian Weimar, Prof. Dr. med. Michael Weller, Prof. Dr. med. Wolfgang Wick</Pgraph></TextBlock>
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<Media>
<Tables>
<Table format="png">
<MediaNo>1</MediaNo>
<MediaID>1</MediaID>
<Caption><Pgraph><Mark1>Table 1: Cerebrospinal fluid results for early and late manifestations of Lyme neuroborreliosis prior to antibiotic treatment</Mark1></Pgraph></Caption>
</Table>
<Table format="png">
<MediaNo>2</MediaNo>
<MediaID>2</MediaID>
<Caption><Pgraph><Mark1>Table 2: Antibody detection and test sensitivity based on disease stage (modified according to [85])</Mark1></Pgraph></Caption>
</Table>
<Table format="png">
<MediaNo>3</MediaNo>
<MediaID>3</MediaID>
<Caption><Pgraph><Mark1>Table 3: Routine lab parameters for patients with early or late manifestations of Lyme neuroborreliosis [47]</Mark1></Pgraph></Caption>
</Table>
<Table format="png">
<MediaNo>4</MediaNo>
<MediaID>4</MediaID>
<Caption><Pgraph><Mark1>Table 4: Systematic evaluation of the frequency of persistent symptoms following the treatment of Lyme neuroborreliosis in relation to diagnostic certainty (probable/confirmed vs. possible) (modified according to [5])</Mark1></Pgraph></Caption>
</Table>
<Table format="png">
<MediaNo>5</MediaNo>
<MediaID>5</MediaID>
<Caption><Pgraph><Mark1>Table 5: Overview of antibiotic treatment</Mark1></Pgraph></Caption>
</Table>
<NoOfTables>5</NoOfTables>
</Tables>
<Figures>
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<Caption><Pgraph><Mark1>Figure 1: Diagnostic algorithm for early Lyme neuroborreliosis; modified according to [43]</Mark1></Pgraph></Caption>
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<Caption><Pgraph><Mark1>Figure 2: Diagnostic algorithm for late Lyme neuroborreliosis; modified according to [43]</Mark1></Pgraph></Caption>
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