focus on lyme-borreliosis (english).pdf · 1 dr. thomas w. talaska, specialist in microbiology and...

Focus onLyme-Borreliosis

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Medi om

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Dr. Thomas W. Talaska, Specialist in Microbiology and InfectionEpidemiology.Since 1992, his work has been focused on tick-borne diseases,especially on epidemiological and diagnostic projects related toLyme borreliosis and other infections caused by parasites (i.e.babesiosis, ehrlichiosis and rickettsiosis).Dr. Talaska coordinates the Interdisciplinary Consulting Group forLyme borreliosis organized by the Brandenburg Medical Associ-ation. He is the Director of the Institute for Tick-Borne Diseases,whose activity was addressed to the prevention and on inform-ing the population about the possible risks of such insect bites.

Prof. Andreas Krause, Specialist in Internal Medicine and Rheuma-tology, has conducted studies about the pathogenesis of Lymeborreliosis and the immune response of cells related to this dis-ease. He has also worked on studies concerning arthritic diseasesassociated with infections and psychoneuroimmunology. Until2002, Prof. Krause was Director of the Day Clinic for Rheumatol-ogy at the Charité University Hospital. Since then, he has beenHead of the department of the Internal Medicine/Rheumatologyand Clinical Immunology Department, Rheumatology Institute,Immanuel-Krankenhaus, Berlin-Wannsee, and since October 2005he has also been Head of the department of the RheumatologyClinic, Berlin-Buch.

Prof. Elisabeth Aberer is specialized in dermatology and venerealdiseases. She has a Master’s Degree in Dermohistopathology. SinceApril 1995 she has been Senior Consultant of the DermatologyClinic, University of Graz. Her studies have mainly focused on clin-ical signs and symptoms, treatment and diagnostic issues relatedto Lyme borreliosis. Prof. Aberer has formed a research center spe-cialized in Lyme borreliosis at the Vienna General Hospital. She hasdirected two projects designed to promote scientific research: “Diepathogenetische Bedeutung von B. burgdorferi in der Haut” (Thepathogenic meaning of B. burgdorferi on the skin, 1989-1992) and“Harn - PCR zur Routinediagnose der Lyme-Borreliose” (Urine PCRin routine screening for Lyme borreliosis, 1999-2002). She is theDirector of the Research Center specialized in General and Self-Immune Pathology and, Director of the Quality Control Depart-ment, University Clinic of Dermatology and Venereology, Graz.Laboratory diagnostics mainly focus on immunodiagnostics inautoimmune dermatological and primary systemic diseases and onspecialized diagnostics for Lyme borreliosis.

● Authors

Elisabeth Aberer

Thomas Talaska

Andreas Krause

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Since July 2000 Prof. Reinhard Kaiser has been the Director ofthe Neurology Clinic, Pforzheim Hospital. After following exper-imental training at the Institute of Virology and Immunology,University of Würzburg, Professor Kaiser has been involved, since1989 in the diagnostics, treatment and clinical observation ofpatients suffering from neuroborreliosis and tick-borne menin-goencephalitis (FSME). His clinical studies have focused on dif-ferential diagnostics, on the treatment of patients with acuteand chronic inflammation of the nervous system and of thosesuffering from neurological disorders who are serologically pos-itive for borreliosis, even in absence of evident symptoms of neu-rological form.

Dr. Volker Fingerle - Specialist in Microbiology and Infectious Epi-demiology - has worked at the Max von Pettenkofer Institute ofHygiene and Medical Microbiology, Ludwig Maximilians Univer-sität (LMU), Munich, since 1990. He works at the National Refer-ence Center (NRZ) for Borreliae and oversees the consiliary labfor Ehrlichea. His studies have mainly focused on training andconsulting activities targeted at colleagues and dealing with theepidemiology, diagnostics and treatment of Lyme borreliosis andof anaplasmosis (ehrlichiosis). His fields of research are epidemiol-ogy, diagnostics and pathogenesis of Lyme borreliosis and gran-ulocytic anaplasmosis in humans.

Prof. Bettina Wilske is Microbiologist at the Max von Pettenkofer-Institute of Hygiene and Medical Microbiology, Ludwig Maxim-ilians Universität (LMU), Munich. She is also the head of the Nation-al Reference Center (NRZ) for Borreliae and carries out medicalconsulting assignments on the prophylaxis, diagnostics and treat-ment of Lyme borreliosis. She has been studying Lyme borrelio-sis since the early ‘80s, especially focusing on the microbiology,diagnostics, epidemiology and analysis of the pathogenic agent’santigen structure. She has authored the MiQ 12 Lyme borreliosis(quality standard for the microbiological diagnosis of Lyme borrelio-sis) edited by the DGHM (German Association for Hygiene and Micro-biology), whose English version can be found on the homepage ofthe DGHM (http://www.dghm.org/red/index.html?cname=MIQ).

Bettina Wilske

Authors

Reinhard Kaiser

Volker Fingerle

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● Index

Epidemiological, biological, and ecologicalaspects of Lyme borreliosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5• Thomas Talaska

Rheumatological and other internalmanifestations of Lyme borreliosis . . . . . . . . . . . . . . . . . . . . . . 25• Andreas Krause

Dermatological manifestations of Lyme borreliosis . . . . . . . . . 37• Elisabeth Aberer

Neuroborreliosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51• Reinhard Kaiser

Lyme borreliosis diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67• Volker Fingerle, Bettina Wilske

Contacts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

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As the science of disease pre-vention, epidemiology plays a

significant role in the planning andevaluation of public health and healthpolitics. It is used in conjunction withlaboratory research to identify riskfactors for disease, elucidate themechanisms by which they develop, andfinally to formulate preventionstrategies. In Germany, the instrumentfor epidemiological evaluation ofinfectious diseases is the InfectiousDiseases Control Law (IfSG), whichcame into force on January 1, 2001;however, this law applies only toinfections transmitted directly fromperson to person or food-borne, anddoes not, cover Lyme borreliosis, by farthe most common vector-borne diseasein central Europe. However, all of theformer East German states and Berlinhave laws regarding registration of bothoccurrence and positive laboratoryresults of the disease. An effective,affordable, regionally tailoredprevention programme includingimmunisation schemes cannot be

realised without knowledge of diseaseprevalence, incidence, and risk factors.Such epidemiological information isalso essential to gauging the success ofany preventive measures. AlthoughLyme borreliosis has an extremely lowmortality rate, its frequency alone has asignificant economic effect. This“economical impact” is defined by theWorld Health Organisation (WHO) asthe total cost of visits to physicians,laboratory diagnostics, drugs, hospitalstay, lost work time, additional healthcare and, in certain cases, invalidity [5].Personal suffering, reduced quality oflife and ability to perform should notbe ignored, even though these aredifficult to quantify. In occupations withhigh exposure rates, Lyme borreliosishas considerable significance as a work-related disease.The WHO European regional office inCopenhagen published a report in 2004on vector-borne diseases, including tick-borne diseases, and their significance inEurope.The incidence of such illness issignificantly higher than has been

Epidemiological, biological,and ecological aspectsof Lyme borreliosis● Thomas Talaska

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Epidemiological, biological,and ecological aspects of Lyme borreliosis

assumed by medical practitioners andpublic health departments – oftendiagnoses are not made and treatmentis delayed. This requires action! In theabsence of the public interest associatedwith dramatic outbreaks, the need forsurveillance and control of not only thedisease but also its vectors is easilyoverlooked, resulting in insufficientsupport for epidemiological research,even by the public health authorities [4].

Borrelia: ticks – hostsThe epidemiology of Lyme borreliosisin humans is closely associated with thetick’s life cycle, its habitat, and theinteraction between tick, host –including humans – and the particularspecies of Borrelia involved. Thus it isnecessary here to make a shortexcursion into the world of ticks inorder to understand this zoonosis.Borrelia are obligate parasites with nofree-living stages, and their propagationrelies on complex zoonotic transmissioncycles involving rodents as the mainreservoir hosts and ticks as vectors.In Europe there are three speciesconfirmed pathogenic to humans:- Borrelia afzelii- Borrelia garinii- Borrelia burgdorferi sensu strictoTwo other species show evidence ofpathogenicity:- Borrelia valaisana- Borrelia lusitaniaeRecently an additional Borreliaburgdorferi genospecies was isolated

from erythema migrans lesions [7]:- Borrelia spielmanii (also designated

A14S).For Borrelia, humans are dead-endhosts.The main vector of Lyme borreliosis incentral Europe is Ixodes ricinus (Fig. 1).This tick species has a very broadspectrum of vertebrate hosts (reptiles,birds, especially migratory species, andmammals), compared with other nativetick species, and is thus well suited fortransmitting pathogens to a wide varietyof species.

How does a tick bite?Once a tick finds a suitable attachmentsite on a host, it uses its mouthparts, thechelicerae, to cut through the host’sskin. The tick pushes its hypostome, achitin tube with recurved teeth, into thesmall wound created. In effect, the tickstabs or pricks its host. The tickhypostome is however not a completely

Fig. 1. A mouse with Ixodes ricinus larvaeand nymphs

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closed tube, as in insects, and tofacilitate suction, the hypostome mustbe cemented into the skin by a salivarysecretion at the site of penetration.While feeding, the tick is stuck fast tothe host – thus the generic name Ixodes(from Greek ixos, meaning “glue” [13]).

Transmission of Borrelia to ticks isrequired for human infection and cantake place in various ways.Trans-ovarialtransmission to offspring in systemicallyinfected ticks is relatively uncommon,affecting less than 5% of Ixodes ricinuslarvae. A more common route oftransmission occurs when larvae areinfected by feeding on blood, usuallyfrom infected forest mice.Trans-stadialtransmission is then possible to nymphsand finally adult ticks. This cross-stagetransmission is highly dependent on theBorrelia species involved, thedistribution of Borrelia in the tick(midgut only or systemic, includingsalivary glands), and on the host species.It also depends on the sensitivity ofBorrelia species to the lytic action ofthe host’s innate immune defences, thecomplement system.If a tick infected with Borrelia afzeliidraws a bird’s blood, the complementsystem in this liquid “meal” is able todestroy the Borrelia in the tick’s midgut.If the tick is infected only in the midgut,then the Borrelia can neither betransferred to the next tickdevelopmental stage nor to the host (anonpermissive system). If, however, the

tick is systemically infected, deactivationin the midgut occurs, but the tickremains infected and trans-stadialtransmission occurs, while the bird hostis protected by its complement system(a semipermissive system).The bird hasno reservoir competence for this strain.Reservoir-incompetent host species canhave a zooprophylactic effect throughwhich the dissemination of Borrelia canbe hindered. Nuncio et al. describe anexample of this effect on the Portugueseisland of Madeira, where the nativehosts are lizards (Madeira wall lizard,Teira dugesii) in either non- or semi-

permissive systems (Fig. 2) [12, 15].The circulation of Borrelia on Madeiracan be maintained by introduced miceand rats [16].

Co-feeding is an additional transmissionroute between ticks. Borrelia can betransmitted through cofeeding whenticks are infected systemically.Ticks are

Fig. 2. Teira dugesii, Funchal, Madeira(photo: Robert Klose)

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pool feeders, meaning that their bitingand the activity of enzymes secreted intheir saliva cause a pool of blood toaccumulate at the base of thehypostome, from which the blood mealis drawn. This “washing” of the tick’sfeeding apparatus with saliva leads tothe transfer of Borrelia into the wound.Ticks have preferred attachment siteswhere they congregate close together tofeed. In the process, Borrelia can betransferred to neighbouring ticks withoutthe host becoming infected or needingto be reservoir-competent (Fig. 3).The above transmission mechanismsare responsible for the local and lifestage-dependent variations in infectionrates of Ixodes ricinus. An extremelyhigh prevalence was found in a part ofCroatia, with 45% of ticks infected withBorrelia, while ticks in a Prague citypark showed a low prevalence of 4.9%over a four-year period.Although some

risk of contracting Lyme borreliosis bytick bite exists throughout Germany,with the exception of vegetation-freeareas in the mountains and Baltic andNorth Sea beaches, the risk variesdramatically within regions anddepends strongly on local conditions.From the many studies in Germanstates, we find mean prevalences of7.7% in Hessen, 14.4% in Baden-Wuerttemberg, 14% in Bavaria, 15.11%in Thuringia, 16.5% in Saxony, and 22%in Brandenburg. However, theincidence of infection in a whole statecannot be used to predict the actual riskin a particular part of that state. In areaswith optimal tick habitat, localprevalence can approach 40%, a factthat is not obvious if only the meanprevalence is considered.Optimal tick habitats have two essentialrequirements: sufficient moisture tomaintain the ticks’ sensitive waterbalance and a mixture of sufficientlynumerous hosts for tick larva, nymphs,and adults. It is interesting to note thattick behaviour is also influenced byBorrelia. Such phenomena are wellknown from other host-parasite systems(e.g. trypanosomes and tsetse flies, ratfleas and Yersinia pestis, Leishmaniaand Phlebotomus sandflies). Drs Perretand Guerin and Prof. Gern of theUniversity of Neuchatel in Switzerlanddemonstrated that, in dry atmosphericconditions, infected ticks move fartherand more often from their originallocation than uninfected ticks. This

Fig. 3. White-tailed deer with a heavy tick infestation (photo:USDA Northeast Area-Wide Tick Control Project, USA)

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increases the likelihood of finding newhosts on which to feed – and thus ofnew infections with Borrelia [10].Prevalence rates also vary according totick life stage; for example in Thuringiaa study of ticks found attached topatients showed infection in 0% oflarvae, about 15% of nymphs, and about19% of adult females [6].

The diversity of interactions betweenBorrelia, ticks, and hosts outlined heredemonstrates the need for sophisticatedbiological and epidemiological analysesof Lyme borreliosis. In addition, onemust also include ecological factors suchas vegetation, geology, hydrology,temperature, and rainfall. At present,we are only able to give a descriptiveaccount of the epidemiology of Lymeborreliosis in humans.

Factors influencing the epidemiologyof Lyme borreliosis in humans- Tick species- Borrelia species- Presence/density of reservoir-

competent hosts- Presence/density of tick habitats

which humans enter- Use of forest and agricultural land- Forest structure and kinds of biotopes- Seasonal changes in temperature,

sunshine, and rainfall- Ground moisture and geological

characteristics- Long-term temperature develop-

ments

- Risk and recreational behaviour ofhumans

- Certainty of the diagnosis of Lymeborreliosis

EpidemiologyWorldwide, epidemiological data onLyme borreliosis as an “emerginginfectious disease” are inadequate, withthe exception of those from the USA(Centers of Disease Control, or CDC,and the Division of Vector-BorneDiseases). In Europe there are currentlyvery few national notification orregistration systems.The epidemiologicaldata available for Germany are basedmostly on studies aimed at only a singleclinical manifestation or are limited tovery small regions within a German state.Other countries have regionalregistration systems, such as in Austriaand France. Russia has the beginnings ofa regional notification system based on ahighly centralised diagnosis of Borrelia.Slovenia probably has the oldestepidemiological databank in Europe,based on a notification system for Lymeborreliosis originating in 1998 [21].What actually is borreliosis? Borreliaare not new pathogens – typical clinicalcases were described as early as the endof the 1800s (acrodermatitis chronicaatrophicans, erythema chronicummigrans, Bannworth’s syndrome). In1996 Ohlenbusch confirmed thepresence of Borrelia in ticks more than100 years old from museum collectionsin Berlin and Vienna (Borrelia

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burgdorferi sensu stricto, Borreliagarinii, Borrelia afzelii [17]). Thesignificant increase in borreliosis,considered a rarity with unknownaetiology but well-defined symptomsas recent as 20 years ago, is surprising.The establishment of clinical casedefinitions of Lyme borreliosis was animportant requirement for collectingvalid data. Those created by the CDCwere very stringent and developedspecifically for epidemiologicalpurposes. However, a number ofEuropean manifestations of the diseasewere not included because they arepractically unknown in the USA. In1996 the European Union forConcerted Action on Risk Assessmentin Lyme Borreliosis (EUCALB)established valid case definitions forEurope that allow standardisation ofregistered, defined clinical cases [20].The existence of yet undefined andhence unregistered clinical manifes-tations must be considered.The possibility of simultaneoustransmission of multiple tick-borndiseases necessitates differentialdiagnosis. In fact, simultaneous infectionwith Borrelia and the pathogens causinghuman granulocytic ehrlichiosis (HGE),Anaplasma phagocytophilum, orBabesia spp. are documented. Thesepresent a clinical picture that differsfrom the course typical for Lymeborreliosis.The significance of infectionwith Rickettsia slovaca and Rickettsiahelvetica is still largely unclear.

What explains the increase in Lymedisease? Socio-ecological factors areimplicated in a study of an area withendemic Lyme disease in thenortheastern USA where the movementof large numbers of people frompopulated urban centres to forestedrural areas increased the risk ofexposure to tick bites [8]. At the sametime, this area experienced a decreasein agricultural land use, and an increasein bushes and trees abutting directly toinhabited areas, with a concomitantincrease in tick hosts.The WHO Reporton Europe also describes massiveecological changes that have taken placesince the end of the Second World War.In particular, intensive reforestation hasbrought (and continues to bring)changes in the flora and fauna. Thepopulation densities of wild boar anddeer have increased, leading to greatertick density. Similar developments canalso be seen in Germany, but specificstudies on this problem are lacking.It is probable that continued climaticchange will influence the frequency ofvector-borne diseases.The distributionand seasonality of diseases transmittedby ectothermic insects and ticks areparticularly sensitive to globaltemperature changes. Warmer wintersfavour tick survival and movement intonew areas where they were previouslyrare or absent. Global warming alsoleads to longer active periods for ticksin spring and autumn and probablyincreases human recreational activities

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in these periods, resulting in higher riskof exposure to ticks. Examples includeSweden, where the distribution of tick-borne encephalitis (TBE) has expandednorthward, and the Czech Republic,where (TBE) expansion has occurredover the last 30 years into higher areasof the Bohemian Forest [25]. How thesituation with Lyme borreliosis willdevelop remains to be determined,although it is likely to follow the patternof TBE. The first data confirming thiscame from the Czech Republic [5].A temperature-related lengthening ofthe tick season in the presence of a largenumber of reservoir-competent hostscan also lead to faster tick develop-mental cycles and thus greater tickdensity; transit from egg to adult canbe shortened from 54 to 18 months.In November of 2004, the EuropeanUnion project “Emerging Diseases in aChanging European Environment” wasstarted. Prof. Sarah Randolph of OxfordUniversity is leading the “Tick-BorneDiseases” section. Its aim is to explainthe increase in tick-borne diseases on aEuropean scale and to create predictivestatistical and biological models.

The development of borreliosisepidemiology in BrandenburgThe first studies on the epidemiology ofLyme borreliosis in Germany began inthe state of Brandenburg under theauspices of the 1994 WHO Consultationon the Development and Application ofGeographical Methods in the

Epidemiology of Zoonoses [3]. In thatyear, the “Geographical Epidemiologyof Borreliosis in Brandenburg” projectwas started, in which a voluntarynotification schedule was introduced andthe Lyme Disease Case Report Formadapted from the American CaseReport Questionnaire in conjunctionwith the CDC. Starting in November1996 the German Federal InfectiousDiseases Law was extended to requirethat all clinical occurrences of Lymeborreliosis in Brandenburg be reportedusing the notification schedule and allpositive laboratory results to beregistered.This was the first opportunityto collect and analyse a data set coveringan entire German state. In the same year,the Lyme Borreliosis InterdisciplinaryAdvisory Group was established by theBrandenburg State Medical Board toadvise medical practitioners, patients andself-help groups. In 2001, theBrandenburg State Ministry for Work,Social Affairs, Women, and Healthfounded the Regional CounsellingCentre for Tick-Borne Diseases. Inaddition to its advisory role, this servicecoordinates and carries out studies,evaluates tests, and makes additionalanalyses of registered cases of Lymeborreliosis. In addition, issues involvingHGE, Rickettsia helvetica, and babesiosisare considered there in cooperation with,among others, the Robert Koch Institute(RKI) in Berlin, the WHO in Geneva,the CDC Division of Vector-BorneDiseases at Fort Collins, the University

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of Frankfurt/Main, and TulaneUniversity in New Orleans.

Geographic information systems andLyme disease Computer-based geographic in-

formation systems (GIS) represent amodern tool for analysing risk factorsand producing risk maps for theepidemiology of infectious diseases,particularly tick-borne diseases [3].Thisin turn can provide the basis for locallyadapted prevention strategies similarto the time-tested methods used inveterinary medicine and veterinarydisease control. The GIS systems arebased on area-related databases withparameters that include cases ofinfection, geographic coordinates,administrative structures, andpopulation density.They contain digitalcoordinate reference maps showing, forexample, administrative boundaries,biotopes, geology, hydrology, weather,and other relevant factors [14, 18, 19].

The computer programme “EpiInfo”,freeware for epidemiologicalsurveillance originally developed by theCDC, includes databases, analyticaltools, and EpiMap, a componentprogram that can produce cartographicrepresentations of epidemiological data.The databases are compatible with theGIS system ArcView, which allowscoordinates from study areas or newdistribution areas to be recorded locallyusing global positioning systems (GPS)and precisely located on coordinatereference maps. Other geographicparameters such as vegetation andwatercourses can be superimposed onthese maps for analysis (Fig. 4).EpiInfo is also useful for evaluating

Fig. 4. Distribution of borreliosis cases inBrandenburg 2003 (database: EpiInfo 3.3;created using ArcView 3.2 [23])

Fig. 5. Example of satellite-supported biotope cartography– alder sections (marked blue) in the Spree forest (photos:Landsat TM; processed with ArcView 3.2; A. Ober 2003)

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satellite photographs, in which forexample different vegetation typesproduce different patterns of reflectionspectra. The ability to preciselysuperimpose satellite photographs ontodigital maps permits on-site biotopesearching and analysis using GPS.Computer searches for biotypes withsimilar characteristics are also facilitated(Fig. 5).Areas with a potentially higher risk ofLyme borreliosis can be located on thecomputer screen and related to datafrom regions with a higher incidence ofborreliosis – a major prerequisite forthe development of risk maps.

Epidemiological data on Lymeborreliosis in BrandenburgThe first incidence data on Lymeborreliosis in Brandenburg werecollected on a volunteer basis from 1994to 1996, i.e. until introduction of thenotification requirement.The incidencewas ten cases per 100,000 inhabitantsbut with marked regional differences,which may, however, have been stronglyrelated to notification behaviour. In1997, 400 clinical cases were registered.Two studies in Maryland andConnecticut, USA shortly after theintroduction of a notificationrequirement showed that only 10–15%of cases fitting the CDC case definitionwere actually registered. Applying thisfactor optimistically to Brandenburg(ignoring undiagnosed cases and thosenot presenting erythema migrans, as

these can only be speculated) wouldpredict 4,000 clinically relevant cases ofborreliosis. Developments in the USAshow that the number of registeredcases increased markedly in the yearsfollowing introduction of thenotification system, especially when the

1997 1998 1999 2000 2001 2002 2003 2004

350

300

250

200

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� Cases

Fig. 6. Lyme borreliosis in Brandenburg – registered clini-cal cases per month until 31.12.2004 (graphic: T. Talaska)

* preliminary data

1995

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� Cases1,981

1,823

1,4101,3551,240

783819

451

198164

1996 1997 1998 1999 2000 2001 2002 2003 2004*

Fig. 7. Clinical cases of Lyme borreliosis from 1995 to 2004(graphic: T. Talaska)

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notifying physician was informed onregional epidemiological data. It isassumed that with an establishednotification system, about a third ofinfections are reported (D.T. Dennis,personal communication). If this is thecase, Brandenburg’s 1,240 registered

borreliosis cases in 2000 represent anactual value of about 4,200. Such highestimates suggest that the increasedincidence of borreliosis is probably onlya function of the notification changes,and that the actual estimates for the lastfour years were much lower.Nevertheless, one cannot ignore that

subsequent years have shown a steadyincrease in registered cases of 10–15%annually.This trend has also been foundin other German states with notificationrequirements,as G.Hesse reported at the2004 Thuringia Workshop on Tick-BorneDiseases in Erfurt (Figs. 6, 7, 8, 9, 10).

Regional variability in the stateof BrandenburgAs already indicated, there aresignificant differences between districtsin the registered incidence ofborreliosis. The highest incidence inBrandenburg was reached in 2000 inthe Oder-Spree district (89.3/100,000inhabitants), the Uckermark(89.0/100,000), and the Barnim(74.6/100,000). In general, there hasbeen a trend toward higher incidencein eastern Brandenburg since 1996.Thisappears to depend not on riskbehaviour but rather on the density ofsuitable biotopes for the ticks. It is stillnecessary to determine whether moreand smaller habitat areas with highercontact for humans exist in the easternpart of Brandenburg than the west. Atypical such case is the municipality ofScharmuetzelsee in the Oder-Spree

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West Pomerania

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� Saxony-Anhalt� Berlin

Fig. 8. Borreliosis in individual German states (graphic: G.Hesse, Erfurt 2004)

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01996 1997 1998 1999 2000 2001 2002 2003

Mor

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Fig. 9. Borreliosis morbidity from 1994 to 2003 (graphic:G. Hesse, Erfurt 2004)

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district, a densely forested recreationalcentre for people visiting the lake area.Inhabitants of the town of Bad Saarowstated they are regularly bitten by ticksin their gardens, in which mice are verycommon and visits by wild animals (e.g.roe deer) are not uncommon.Scharmuetzelsee had the highestincidence in Brandenburg in 2000, with237 cases per 100,000 inhabitants. Thisfigure does not include visitors fromBerlin who were affected.This exampleshows considerable similarities toobservations made in the USA [8].Considering the Oder-Spree districtmore closely, one finds immensedifferences in incidence at the locallevel. These ranged from 10/100,000inhabitants in Beeskow to thepreviously mentioned 237/100,000 inadjacent Scharmuetzelsee. Mappingcases in the Oder-Spree district on asatellite photograph, most of theregistered cases were localised close toforested wetlands. Sections with verylow incidence included largeagricultural areas, but even there, thefew registered cases were associatedwith small lakes or water courses.

In general Brandenburg is rich in forestand wetlands, but not all forested landis suitable tick habitat. Ticks require amoist microclimate for survival [11] andprotection from the cold in winter.These are best provided by severalannual layers of slowly decomposingleaf cover, especially beech and oak.

Such deciduous and mixed forest tractstogether comprise less than 5% offorest cover in the state.There are largeareas of commercial pine monoculture.Areas forested in this way are poorhabitats for ticks because pine needle

Age-specific incidence of Lyme Borreliosis in BrandenburgTotal 2001-2003

500

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� Incidence

50Age (years)

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Fig. 10. Registered cases and incidence of borreliosis inthose German states with required notification (graphic:T. Talaska)

Fig. 11. Incidence of borreliosis in 2003 in municipalitiesand communities (database: EpiInfo 3.3 created usingArcView 3.2 [23])

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layers retain less humidity directly overthe soil surface than deciduous leaflayers in the warmer part of the year.Recent changes in forestry practice inthis region have aimed at increasing thedeciduous and mixed forest componentsto 40% over a 10-year period to returnthe forest to its original natural make-up. It is anticipated that the extent ofsuitable tick habitat will also increase,and therefore provisions have beenmade to monitor tick density and thusthe potential risk of Lyme borreliosisin these areas (Fig. 11).

Clinical dataErythema migrans, an early clinicalmanifestation, is the most commonregistered sign of borreliosis in all statesof Germany, and the trend from 1997 to2004 shows that its proportion increasedfrom 61.7% to 84.5% over that period.It is now higher than in Austria (77.7%)

and the USA (76.0%) [24]. It is alsoevident that the growing proportion oferythema migrans cases accompaniessignificant reductions in the proportionsof reported cases of both the moreadvanced disseminated borreliosis(19.2% in 1997 vs 5.6% in 2004) andcases which cannot be clearly clinicallyclassified into the EUCALB casedefinitions (19.1% in 1997 to 8.7% in2004).Given the notification requirementfrom 1996 and continuing educationorganised by the Interdisciplinary LymeBorreliosis Advisory Group, a possibleexplanation for this trend is that the earlystage of borreliosis is more frequentlyand accurately diagnosed and treateddue to increasing physician and patientawareness. This would reduce thenumber of patients developing latemanifestations such as disseminatedborreliosis. However, these cannot becompletely avoided, as a significantproportion of infected individualspresent with the disseminated form atanamnesis. Only 21% of cases of Lymearthritis registered in 1999 and 2000 hadbeen previously diagnosed witherythema migrans. The decreasingproportion of “unclear” cases is anindication that Lyme borreliosis isgenerally being diagnosed with morecertainty. However, it is still necessaryto analyse these ambiguous clinicalcases and if possible expand the currentcase definitions. When analysing casesfrom 2003 and 2004, it is necessary toconsider a certain bias in registered

1997 1998 1999 2000 2003 2004

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� Other� K/L� ACA� NB� LA� EM

K/L = Karditis/Lymphadenosis cutis benigna;ACA = Acrodermatitis chronica atrophicans;NB = Neuroborreliosis; LA = Lyme arthritis; EM = Erythema migrans

Fig. 12. Different clinical manifestations in percentages

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manifestations toward erythemamigrans due to the RKI case definitionof Lyme borreliosis (Fig. 12).Considering the conservatively estima-ted cost of 10,000 Euro per case of dis-seminated borreliosis and the relativelycertain relationship between erythemamigrans and development of dis-seminated borreliosis in the absence ofintervention, the economic importanceof information distribution and con-tinuing education is evident.According to this very simplified model,about 1 million Euros could have beensaved by the prevention campaign inBrandenburg over the last few years.(Fig. 13).

Model system in theOder-Spree districtThe Oder-Spree district was chosen asa study area to analyse risk factors forborreliosis and the prevalence ofBorrelia in ticks due to the highincidence of Lyme borreliosis foundthere. The study was carried out inconjunction with the RKI from June toDecember 1999. In addition, thegeographic distribution of cases wascalculated to determine whether it wasrandom or there were indeed high-riskareas within the district (which, asindicated previously, is very hetero-geneous).One significant risk factor, as predicted,was activity in private gardens,particularly those bordering the forest(Fig. 14).

This is probably due to a lack ofawareness of the risk, which mostindividuals seem to associate only withactivities in the woods. Light clothingis often worn while gardening and, ifnobody search for ticks follows, there

1997EM-Cases

2000Disseminated Borreliosis

1000

800

600

400

200

0

� EM� LA� LA/Prev� NB� NB/Prev

-260,000Euro

-820,000Euro

250

200

150

100

50

0

EM = Erythema migrans; LA = Lyme arthritis; NB = Neuroborreliosis

Fig. 13. Estimates of borreliosis occurrence in Brandenburgwith and without preventive measures (highest estimates)for 1997 and 2000

Fig. 14. Typical “tick biotope” in the Oder-Spree district: agarden adjacent to the forest kept close to natural condition

18


is a distinct risk of infection. Unfor-tunately it was also determined that, inspite of familiarity with personal pre-vention measures, they were actuallycarried out by only 40% of those que-stioned. This requires action by thehealth authorities and additionalprevention strategies directed not onlyat individual activities. It showed thatpersonal prevention can be veryeffective, when actually carried out. Ourexperience from the Oder-Spreewalddistrict shows that it is frequentlyignored [2, 9].In the USA a comprehensive analysis ofpractical prevention methods requiring

Fig. 15. Registered cases of Lyme borreliosis in 1998 and1999 in the Oder-Spree district showing the proportion ofmunicipalities on the cluster index (Borreliosis Study, Oder-Spree District; A. Ammon, RKI 1999)

Table 1. Model system in the Oder-Spree district: incidence of registered Lyme borreliosis 2003(Compare with incidence in Old Lyme municipality, USA 2001, 297, and 2002, 391)

Municipality Mean age N clinical cases IncidenceCases/100,000 inhabitantsBeeskow 34 9 100Brieskow-Finkenheerd 55 26 311Eisenhüttenstadt 53 62 149Erkner 38 2 16Friedland 63 5 146Fürstenwalde 51 25 73Grünheide 54 13 184Neuzelle 55 8 111Odervorland 47 4 68Rietz-Neuendorf 52 5 109Scharmützelsee 49 25 298Schlaubetal 54 5 58Schöneiche bei Berlin 57 11 45Spreenhagen 44 11 142Steinhöfel 24 1 24Storkow 51 12 127Tauche 63 1 23Woltersdorf 39 4 59

19

minimal effort was done. From thepoint of view of practicability, acaricide-impregnated feeding stations for wildanimals, like those used in the USA, area realistic alternative.Their applicationrequires minimal administrative effort,and the case reduction achieved inmodels is very good. Unfortunately, atpresent this is not possible in Germanydue to the difficulty in coordinating theareas of responsibility of the variousauthorities involved.The geographic distribution shows aclear aggregation of cases in the Oder-Spree district in particular, andBrandenburg as a whole (Fig. 15).Analyses of notification records showthat differences in notification beha-viour by physicians can be eliminatedas a possible cause.Thus we can assumethat the geographic factors previouslydiscussed are responsible for thisvariation in risk (Table 1) [2].

Forestry workers: a risk groupThe seroprevalence of tick-bornediseases in forestry workers wasexamined in a study carried out inBerlin and Brandenburg [22]. Forestryworkers, hunters, and forest managersare more commonly exposed to suchdiseases than the general population;however, they are also better informedon the risks and their prevention andhence their typical working clothing isusually well-suited to preventing tickbites.Our study was carried out on a volunteer

basis and included immunoglobulin-G(IgG) examinations for seroprevalenceagainst Borrelia burgdorferi sensu lato,as well as the pathogens causing HGE(human granulocytic ehrlichiosis):Anaplasma phagocytophilum, Babesiamicrotii and Rickettsia helvetica.The risk group as a whole showed 29%Borrelia burgdorferi prevalence,although borreliosis was allegedlydiagnosed and treated in only 10.2%of cases. This discrepancy indicates asignificant number of asymptomaticand previously undiagnosed cases. Infact, a questionnaire filled out afterserodiagnosis showed that anadditional 24% of seropositive subjectsdescribed symptoms compatible withLyme borreliosis.

A significant aggregation of sero-positive cases occurred in the Barnimregion northeast of Berlin. Thispopulation showed 6.2% positivity forIgG antibodies to Anaplasma phago-cytophilum (FAT,Western blot). In thesubsequent case control study, nostatistical relationship could be foundbetween HGE-positive cases andpotential symptoms. Thus there isevidence of contact with the pathogen,but the course of infection appears tobe either asymptomatic or mild.There are only limited data on thefrequency of Babesia microtii antibodiesin humans in Europe. Our studyshowed a 1.4% IgG-positive prevalence(FAT, Western blot). Only one indi-

20


vidual complained at anamnesis ofsymptoms consistent with babesiosisafter a tick bite, but we found noantibodies against HGE or Borrelia.Rickettsia helvetica has been found in

ticks from Switzerland, Sweden, France,and Slovenia. Clinical cases withprolonged fever, weakness, and myalgiawere recorded in France. In Scandinavia,the deaths of two young athletes wereattributed to perimyocarditis fromtraining during Rickettsia helveticainfection. A sample from the forestryworker group was therefore tested forRickettsia helvetica IgG using an in-house FAT (Raoult, Rolain, MarseillesUniversity). A total of 28.3% ofindividuals tested were IgG-positive.Infection with other Rickettsia specieswere found in only two cases. Theseresults are in agreement with Swedishstudies; Rickettsia helvetica is apparentlyendemic and dominant in central andnorthern Europe. In a current study, weare examining the prevalence ofRickettsia helvetica IgG in children andthe elderly. Our results to date show 0%prevalence for children less than10 years old (without borreliosis). Thisincreases to 25% in the elderly(>65 years, without borreliosis) (Figs. 16,17). In a third group of patients withclinically and serologically provenborreliosis, this level increased to 27.7%,with co-infections probable.The clinicalsignificance of these results still needsclarification.

OutlookConsidering the borreliosis situationover the past 8 years, it is apparent thatinterest in this illness, originallyconsidered a “fashionable disease” in

Fig. 17. Map showing HGE and babesiosisseropositivity in Brandenburg

Rickettsia helvetica IgG seroprevalencein Brandenburg

30

25

30

25

20

15

0

� Children� Blood donors� Elderly� Patients with borreliosis� Forestry workers

0

IgG seroprevalence in %, n = 217

13,3

2527,7

28,3

Fig. 16. Rickettsia helvetica IgG seroprevalence in Bran-denburg (study from 2005)

21

Europe, has increased markedly andthat the problem of vector-associateddiseases in general is being taken moreseriously. Collection of the epidemio-logical data from Brandenburg, whichaccording to the CDC are among thebest available worldwide for Lymeborreliosis, would not have beenpossible without the active help ofphysicians, public health officials, andthe Brandenburg state Department ofPublic Health and Ministry of Health.We hope the German federal govern-ment will also become active in theprevention of Lyme borreliosis.A posi-tive signal can be see in the publicationin 2002 of the RKI Bulletin of casedefinitions for this disease conformingto the new IfSG. However, the inclusionof only erythema migrans and what waspreviously termed neuroborreliosisremains an obstacle to effective epide-miological work. Lyme arthritis, Borrelia-related lymphocytoma, chronic neuro-borreliosis, acrodermatitis chronicaatrophicans, and Lyme carditis were notincluded, in contrast with both the CDCand EUCALB definitions. We knowfrom our own epidemiological data thatabout 15–20% of cases fall outside ofthe RKI definitions. This biases theactual picture. For example, erythemamigrans is found in only 21.5% of Lymearthritis cases. Cranial nerve paralysis,such as facial nerve paralysis, bydefinition requires registration under

neuroborreliosis only in cases whereintrathecal antibodies are present, eventhough it is known that these are notfound in all cases because centralnervous system involvement is notnecessary. Accurate analyses of theclinical spectrum of Lyme borreliosisand the efficiency of preventionprograms are not possible using thepresent case definitions. Since these arestill under discussion, it is hoped thatmore inclusive versions will be forth-coming. In 2004, the RKI wrote in apublication on zoonoses in humans:“Animproved database on the frequency ofLyme borreliosis in Germany is to bestrived for.A contribution to improvedepidemiological data collection wouldbe achieved by including Lyme borre-liosis in the list of pathogens requiringofficial registration according to theIfSG” [1]. We hope this will not remainonly a dream.Another unsolved problem is thedevelopment of a safe, efficaciousvaccine against Lyme borreliosis. Themonovalent OspA vaccine approvedfor use in the USA showed good immu-nogenicity, but was later removed fromthe market.A polyvalent OspC vaccinefailed to gain approval due to problemswith side effects. The development oftherapeutically useful polyvalentvaccines based on chimeric antigens iscurrently underway. However, it will besome time before they are available.

22


Legal bases in thoseGerman states withnotification requirementsfor Lyme borreliosis- Thuringia:Thuringian Decree on the

Adjustment of Notification Requi-rements for Infectious Diseases(Thüringer Infektionskrankhei-tenmeldeverordnung, or ThürIfKr-MVO) of 15 February 2003

- Saxony: Decree of the Saxon StateMinistry for Social Affairs on theExtension of the Notification Requi-rements for Transmissible Diseasesand Pathogens According to theInfectious Diseases Control Law(IfSGMeldeVo) of 3 June 2002

- Saxony-Anhalt: Decree on theExtension of Notification Requi-rements for Transmissible Diseasesin the State of Saxony-Anhalt of 24April 1997

- Mecklenburg-West Pomerania: StateDecree on the Extension of the Noti-fication Requirements for TransmissibleDiseases According to the FederalEpidemic Law of 5 February 1992 (anew version for protection againstinfection is currently being produced)

- Berlin:Decree on the Extension of Noti-fication Requirements for TransmissibleDiseases according to the FederalEpidemic Law of 13 January 1997

- Brandenburg: Decree on theExtension of Notification Require-ments for Infectious Diseases (Infek-tionskrankheitenmeldeverordnung,or InfKrankMV) of 14 December2001 (succeeding the SeuchMV of 1November 1996)

There is no notification requirement forLyme borreliosis or positive laboratoryresults in the other German states.

23

● References1. Alpers K, Stark K, Hellenbrandt W,

Ammon A (2004) Zoonotische Infektionenbeim Menschen – Übersicht über dieepidemiologische Situation in Deutschland.Bundesgesundheitsbl-Gesundheitsforsch-Gesundheitsschutz 47:611-622

2. Ammon A (2001) Risikofaktoren für Lyme-Borreliose: Ergebnisse einer Studie ineinem Brandenburger Landkreis. RKIEpidemiol Bull 21:147-149

3. Anonymous (1994) WHO Consultation ondevelopment and application ofgeographical methods in the epidemiologyof zoonoses. WHO/CDS/VPH/94.139

4. Anonymous (2004) The vector-bornehuman infections of Europe – theirdistribution and burden on public health.WHO Regional Office for Europe,Copenhagen

5. Danielova V (2005) The risk of tick-bornediseases rises in higher altitudes in centralEurope (Czech Republik). Abstract. VIIIInternational Potsdam symposium on tick-borne diseases, Jena, March 2005

6. Dorn W, Flügel C, Grübner I (2002) Dataon human-biting Ixodes ricinus ticks in aregion of Thuringia (Germany). Abstract.Int J Med Microbiol 291 [Suppl 33]:219

7. Fingerle V, Schulte-Spechtel U, Göttner G,Hizo-Teufel C, Hofmannn H, Pfister K,Leonhard S, Weber K, Wilske B (2005)Detection of a new Borrelia burgdorferi s.l.genospecies A14S from patient materialand ticks. Abstract. VIII InternationalPotsdam symposium on tick-borne diseases,Jena, March 2005

8. Fish D (1997) Ecoepidemiology of tick-borne pathogens (Borrelia burgdorferi,Ehrlichia) in the northeastern United States:implications for Europe? In: Süss J, Kahl O(eds) Tick-borne encephalitis and Lymeborreliosis. Pabst Science Publishers,pp 15-20

9. Fitzner J, Ammon A, Baumann I, TalaskaT, Schönberg A, Stöbel K, Fingerle V,WilskeB, Petersen L (2001) Risk factors in Lyme-borreliosis: a German case-control study.

Poster. VII. International Postdamsymposium on tick-borne diseases

10. Gern L, Humair P-F (2002) Ecology ofBorrelia burgdorferi sensu lato in Europe.In: Gray JS, Kahl O, Lane RS, Stanek G(eds) Lyme borreliosis – biology,epidemiology and control. CABIInternational 149-174

11. Kahl O (1995) Betrachtungen zur Ökologieder Lyme-Borreliose in der Region Berlin-Brandenburg. In:Talaska T (ed) Borreliosenin Brandenburg. Tagung BerufsverbandMed Mikrobiol. Brandenburg, pp 6-7

12. Kahl O, Gern L, Eisen L, Lane RS (2002)Ecological research on Borrelia burgdorferisensu lato: terminology and somemethodological pitfalls. In: Gray JS, KahlO, Lane RS, Stanek G (eds) Lymeborreliosis – biology, epidemiology andcontrol. CABI International 29-46

13. Kimmig P (2000) Biologie von Zecken. In:Kimmig P, Hassler D, Braun R (eds)Zecken – Kleiner Stich mit bösen Folgen.Ehrenwert, Munich, pp 11-21

14. Kistemann T, Schweickart J, Exner M(2003) Geographische Information-ssysteme. In: Krämer A, Reintjes R (eds)Infektionsepidemiologie. Springer, BerlinHeidelberg, pp 109-116

15. Kurtenbach K, Schäfer SM, Michaelis S de,Etti S, Sewell H-S (2002) Borreliaburgdorferi sensu lato in the vertebratehost. In: Gray JS, Kahl O, Lane RS, StanekG (eds) Lyme borreliosis – biology,epidemiology and control. CABIInternational pp 117-148

16. Nuncio MS, Schouls LM, Pool I van de,Almeida V, Filipe AR (2002) Ecoe-pidemiology of Borrelia spp. on MadeiraIsland, Portugal. Abstract. Int J MedMicrobiol 291 [suppl 33]:212

17. Ohlenbusch A (1996) Beiträge zurDiagnostik und Pathogenese der Lyme-Borreliose und zur Transmission desErregers Borrelia burgdorferi. Cuvillier,Göttingen

18. Schöder W (2005) GIS, geostatistics,metadatabanking and tree-based models

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for data analysis and mapping inenvironmental and epidemiology.Abstract.VIII International Potsdam symposium ontick-borne diseases, Jena, March 2005

19. Schweickart J, Kistemann T, Leisch H(1998) Der Arbeitskreis “MedizinischeGeographie”. Eine interdisziplinäreAntwort auf gesundheitsrelevanteFragestellungen. HHG-J 12:245-250

20. Stanek G, O’Connell S, Cimmino M,AbererE, Kristoferitsch W, Granström M, Guy E,Gray J (1996) European Union concertedaction on risk assessment in Lymeborreliosis: clinical case definitions for Lymeborreliosis. Wiener Klin Wochenschr106:741-747

21. Strle F (1999) Lyme borreliosis in Slovenia.Zentralbl Bakteriol 289:643-652

22. Talaska T, Bätzing-Feigenbaum J (2001)

Waldarbeiterstudie Berlin-Brandenburg2000 zu zeckenübertragenen und anderenZoonosen. RKI Epidemiol Bull 16:109-110

23. Talaska T, Ober A, Hoffmann C,Schweickart J, Pieper J, Dreissig M (2005)Epidemiological analysis of Lymeborreliosis in the Federal LandBrandenburg with GIS. Abstract. VIIIInternational Potsdam symposium on tick-borne diseases, Jena, March 2005

24. Tylewska-Wierzbanowsk S (1995) CountryReports/WHO Workshop on Lymeborreliosis – diagnosis and surveillance.WHO/CDS/VPH/95.141-1

25. Zeman P, Benes C (2004) A tick-borneencephalitis ceiling in central Europe hasmoved upwards during the last 30 years:possible impact of global warming? Int JMed Microbiol 293 [suppl 37]:48-54

25

Rheumatological and other internalmanifestations of Lyme borreliosis● Andreas Krause

Lyme arthritis is one of the mostcommon and clinically important

manifestations of Lyme borreliosis. Itwas discovered and first described about30 years ago due to a local aggregationof cases in children in the municipalitiesof Lyme and Old Lyme in Connecticut,USA. In addition, systemic infectionwith Lyme borreliosis can lead tonumerous other rheumatological andgeneralised internal symptoms,knowledge of which is of particularimportance for differential diagnosis ofthe various clinical pictures.

All three species of Borrelia burgdorferisensu lato known to be human patho-gens (Borrelia burgdorferi sensu stricto,Borrelia garinii, Borrelia afzelii) cancause internal symptoms. Whether theother Borrelia species recently isolatedfrom patients with Lyme borreliosis(e.g. Borrelia valaisiana, Borrelialusitaniae, Borrelia bissettii) are patho-gens remains unclear.

The most important cause of Lyme

arthritis is Borrelia burgdorferi sensustricto. The fact that this is the onlyspecies known to cause Lyme borre-liosis in the USA explains why Lymearthritis occurs more frequently therethan in Europe or Asia. AlthoughBorrelia garinii and Borrelia afzelii areconsiderably more common in Europethan Borrelia burgdorferi sensu stricto,various studies of patients with Lymearthritis have found either comparablefrequencies of all three species orpredominantly Borrelia burgdorferisensu stricto. These data confirm theparticularly athritogenic significance ofBorrelia burgdorferi sensu stricto whileindicating that Borrelia garinii andBorrelia afzelii play an important role incausing Lyme arthritis in Europe [1, 3,4, 9, 10, 15].

Clinical pictureIt is impractical to divide the clinicalcourse of Lyme borreliosis into threestages, as was previously common, asthis incorrectly suggests that victimsmust go through all these stages and

26

Rheumatological and other internalmanifestations of Lyme borreliosis

that chronic infections become moredisseminated with the involvement ofmore and more organ systems. In truth,Lyme borreliosis follows a variablecourse with a wide variety of symptoms.It can spontaneously heal at any phaseor be arrested through the action ofantibiotics. Except for the earlycutaneous manifestation, erythemamigrans, Lyme borreliosis usually affectsa single organ system, presumingantibiotic treatment has followed thediagnosis. Thus for example a patientsuffering from acute neuroborreliosisusually does not get Lyme arthritis, and

Lyme arthritis patients with antibiotictreatment need not fear developingchronic neuroborreliosis. A possibleexplanation for this is the organspecificity of the different Borreliaburgdorferi species, which attack organsystems preferentially.It has proven clinically valuable,however,to divide Lyme borreliosis into an earlyor acute stage (with the pathogenic stagesof local and disseminated infection), anda late or chronic stage (persistentinfection) showing different clinicalpictures and variable degrees of responseto antibiotic treatment (Table 1).

Table 1. Rheumatological and other internal manifestations of Lyme borreliosis (from [3, 8])

Organ system/phase Symptoms Comments

General symptomsEarly phase Feeling of illness, headache, Can be pronounced, no respiratory

subfebrile temperatures, or gastrointestinal symptomslymph node swelling

Chronic phase As in the acute phase Mostly less distinct

HeartEarly phase Perimyocarditis Uncommon, typical AV block with

changing grade, usually completerecovery

Chronic phase Dilated cardiomyopathy, Questionable, individual casesventricular extrasystoles

Musculoskeletal systemEarly phase Arthralgia and myalgia Rarely fleeting arthritisChronic phase Arthritis, myositis, Intermittent, uncommon chronic

bursitis, enthesitis persistent arthritis, mainly in theknee joint, not the axis skeleton,myositis is uncommon

OtherEarly phase Hepatomegaly, hepatitis, Practically never clinically relevant

splenomegalyChronic phase Vasculitis Uncommon, can lead to ischaemia

27

Particularly in the early phase, manypatients have the feeling of being ill.Swollen lymph nodes and subfebriletemperatures are also possible. Thesesymptoms can be especially evident atthe beginning of the infection.Respiratory or gastrointestinal symp-toms, however, are not part of thesymptomatology of Lyme disease andare therefore helpful in differentiating itfrom other infectious diseases. Duringthe chronic phase, these unspecific signsof infection are less common and weaker.

Lyme carditis is rare, occurring in lessthat 5% of patients. As heart invol-vement is often subclinical or onlyaccompanied by unspecific symptoms,it is possible for transitory rhythmdisturbances or partial atrioventricular(AV) block to go unnoticed if they arenot consciously sought. Dramatic andpotentially lethal complete AV blocks,which can require temporary pace-maker treatment, are rare and usuallyare rapidly cured with antibiotic andsteroid therapy.Whether Lyme borreliosisleads to dilated cardiomyopathy (DCMP)in the late phase is still controversial. Onthe one hand, sporadic borrelia-likestructures have been detected inmyocardial biopsies, while on the other,serological studies do not suggest anassociation between dilated cardio-myopathy and Lyme borreliosis.

The involvement of other internalorgans is possible but is usually not

clinical significant. Hepato- and spleno-megaly, increased hepatic enzymelevels, and pathological urine results inLyme borreliosis patients have beendescribed, but relevant functionaldisturbances of the correspondingorgans have not been documented.

Rheumatological symptoms can occurrelatively early in the course of thedisease (within weeks), with arthralgia,myalgia, or mild short-term arthritidesof individual joints. The typicalmanifestation of Lyme arthritis occurshowever in the chronic phase (severalweeks to months after infection). Due toits variable latency, there is no seasonalaggregation of new cases. Arthritisusually manifests as mono- or oligo-arthritis, with 85% of cases involving atleast one knee joint.The ankle and elbowjoints can also be involved, whileinvolvement of finger joints, especiallyas polyarthritis, has only rarely beenrecorded. Individual exceptions are thearthropathies that appear in associationwith acrodermatitis chronica atrophicansand often involve toe or finger joints.Due to the frequency with which theseoccur together, they are commonlyreferred to as arthrodermatitis.The course of Lyme arthritis is usuallysporadic, with recurring inflammationinterrupted by intervals in which theintensity of symptoms is reduced orthey disappear completely. Over time,these intervals may shorten and thearthritis becomes chronic. Synovial

28


analysis shows acute arthritis withdramatically increased white cell countsof up to 50,000/µl, predominantlyneutrophils. Histological findings forthe synovial membrane in chronic Lymeborreliosis cannot be distinguished fromthose in rheumatoid arthritis.Accompanying manifestations relatedto the musculoskeletal system are bursitisand tenosynovialitis. Important for thedifferentiation from other, clinicallysimilar spondylarthritides is that the axialskeleton, as for example in sacroiliitis, isnot involved in Lyme arthritis.Moreover,there are no typical symptoms clearlydifferentiating Lyme arthritis from otherinflammatory joint diseases.In addition to the myalgia frequentlyfound in the early phase, chronic Lymearthritis can on rare occasions developinto manifest, proximally accentuatedmyositis leading to muscle weaknessand atrophy.With early diagnosis and treatment,Lyme arthritis has good prognosis andusually heals without further con-sequences. Erosive courses with chronicarthritis have been reported but arerare. For some patients with Lymearthritis, cure is not achieved even aftermultiple antibiotic treatments. In theUSA this proportion is estimated at10% of patients; the epidemiologicaldata for Europe are not adequate forsuch an estimate. Evidence suggests thatthese antibiotic-resistant cases involveinfection-triggered immunopathologicalmechanisms [1, 3, 5, 14].

So-called post-Lyme syndromerepresents a special rheumatologicalproblem. In spite of regression ofinflammatory manifestations withantibiotic therapy, some patients showpersistent unspecific symptoms such asarthralgia, myalgia, sleep disturbances,and fatigue,while others report headacheas well as memory and concentrationdisturbances. Some patients show onlytransient symptoms in the previouslyinflamed joints. In children, bothcognitive and psychiatric changes suchas fear and depression have beenrecorded. Late start of therapy is a riskfactor associated with these problems.Many patients with post-Lyme syndromeare severely handicapped by thecontinuing symptoms and suffer fromsignificantly reduced quality of life.Thecourse is similar in many ways to that ofchronic fatigue syndrome and fibro-myalgia.Recent studies have shown that,contrary to the fear nourished byuncertainty and information from lessauthoritative sources, the risk ofcontracting this syndrome is very low.Acomparison of previous Lyme borreliosispatients and an age-matched controlgroup showed good health in bothgroups and similar frequency of commonunspecific symptoms.Only those patientswith, for example, neuroborreliosis whohad received inadequate or late antibiotictreatment were more likely to suffer fromresidual neurological symptoms and pain.Patients with Lyme arthritis at anamnesiscomplained more of knee pain.

29

In two placebo-controlled studies,symptoms showed a variable coursethat was not influenced by antibiotictherapy. It is hypothesised that Borreliainfection triggers autoimmune orneurohormonal processes whichcontinue some time after the pathogenitself has been eradicated, and which inturn cause the symptoms experienced.Thus, although an optimal pathogen-oriented treatment is still lacking,irrational use of antibiotic therapy, withits potentially severe side effects shouldbe avoided [1, 2, 3, 6, 7, 15].

Diagnosis and differentialdiagnosisGeneral symptoms, fever and lymphnode swelling, are not specific to Lymedisease, opening up a range ofdifferential diagnoses which must beeliminated through anamnesis andlooking for more specific manifestationsof the disease.Any myocarditis can be a manifestationof Lyme borreliosis, especially when ahigh-grade AV block is present. Asadditional specific symptoms are lacking,anamnesis with tick bite, erythemamigrans, and Lyme serology are ofparticular diagnostic importance. Othercauses of myocarditis must be eliminatedas well, since positive Borrelia serologycannot prove the presence of Lymeborreliosis (see below).Lyme arthritis must be considered inthe differential diagnosis of new casesof mono- or oligoarthritis.The diagnosis

must be based on clinical findings andanamnesis, and corroborated by positiveserology. Because direct detection ofthe pathogen is uncommon, generallyLyme arthritis can be diagnosed withcertainty only after the elimination ofmany differential diagnoses.

Differential diagnosis for Lymearthritis (most important examples)includes:- Gout- Pseudogout- Septic arthritis- Löfgren’s syndrome- Reactive arthritis- Psoriatic arthritis- Enteropathic arthritis- Rheumatoid arthritis (atypical onset)

Typical for Lyme arthritis is uni- orbilateral involvement of the knee jointwith synovialitis and usually voluminouseffusion (Fig.1).This frequently leads to

Fig. 1. Lyme arthritis of the right knee

30


extended Baker’s cysts, which oftenrupture. In addition, there is also afrequent discrepancy between pro-nounced local findings and only limitedpain. Other large joints of the upper andlower extremities are less commonlyinvolved. In contrast to infection-reactivearthritides, isolated hand and arm jointinvolvement is quite possible in Lymearthritis.Otherwise, the symptoms of thisdisease are ambiguous and unspecificwhen considered alone. Polyarthritis ofsmaller joints suggests either a viral orautoimmune-based disease, andinvolvement of the axis skeleton indicatesone of the spondylarthritides.Important anamnestic clues to thepresence of Lyme arthritis includeincreased risk of exposure to ticks(occupational or especially recreationalgardening), previous tick bite, andobviously, a recent untreated orinadequately treated erythema migrans.It is highly unlikely that Lyme arthritiswill develop after adequately treatederythema migrans,however if anamnesisindicates exposure to ticks and increasedrisk of tick bites, the possibility of a newinfection should be taken intoconsideration. Unfortunately, less than50% of Lyme arthritis patients remembera tick bite,and decidedly fewer,a previouserythema migrans. Previously untreatederythema migrans and neuroborreliosisare now less common due to increasedknowledge of the disease and therefore ofadequate antibiotic therapy.Occasionallythe association of arthritis with

acrodermatitis chronica atrophicans canbe diagnostically suggestive. Lymearthritis, however, is often the first andonly manifestation of Borrelia infectionand it is precisely these cases that makediagnosis so difficult [1, 4].

The diagnostic gold standard for aninfectious disease is demonstration of thepathogen’s presence. Due to thispathogen’s characteristics and its lowdensity, determining the presence ofBorrelia burgdorferi using culturemethods is difficult, time-consuming,and,with Lyme arthritis,of low sensitivity andhence unsuitable for clinical diagnostics.Therefore, polymerase chain reaction(PCR) is increasingly used for directdetermination of the pathogen. Thismethod can detect the presence ofBorrelia DNA in synovia and synovialmembrane from untreated patients witha sensitivity approaching 80% (Table 2)[9,12,13,16]. Information on its sensitivitywith muscle biopsies from myositispatients is not available. False positiveresults are uncommon, so this test hashigh specificity. It is important to notehowever that PCR does not demonstratethe presence of viable pathogens, onlypathogen DNA. Nevertheless, a positivePCR result is now interpreted as ademonstration of the presence of thepathogen and thus as an indication fortherapy. Various protocols and testsystems are now available;however, theirsuitability to routine diagnostics needs tobe validated. PCR is fast becoming an

31

established component of laboratorydiagnostics,particularly for Lyme arthritis[9, 11, 12, 16].

The most common laboratory methodfor routine diagnosis is serology, i.e.determining the presence of specificantibodies against Borrelia burgdorferi(see the relevant chapter in this book).In the early phase of infection, Borreliaserology is often still negative, asmeasurable concentrations of anti-bodies develop slowly over weeks.Given continued clinical suspicion, ashort-term serological examination ofdisease progression demonstratingseroconversion will confirm thediagnosis. In chronic phases of theillness such as Lyme arthritis, serologyis less problematic, as in general thereare clearly positive antibody values fora whole series of Borrelia antigens.Significantly elevated IgG levels can befound but, in spite of pathogenpersistence, specific IgM antibodies areseldom detected. In other cases, IgMantibodies can persist for years aftersuccessful treatment and thus cannotbe used as an indication for therapy orevidence of persistence of the infection.

Due to the high sensitivity of the test, afalse negative serology for Lymearthritis is very unlikely. However, thelack of IgM antibodies does not excludea current infection or active illness.Themain problem here lies in theinterpretation of serological findings:positive IgG values in the chronic phaseof Lyme borreliosis are indistin-guishable from positive titres after anacute illness or infection (so-calledserum scar). This means that thebanding pattern on immunoblot doesnot allow determination of the time ofinfection or inference of a possibleongoing infection. Immune responsesare individual, in part geneticallydetermined and dependent on, forexample, extruded pathogen antigens.The antibody response is therefore alsovariably strong and in some casesnonexistent. The value of a positiveBorrelia serology is thus dependent onthe clinical symptoms. Only in caseswith sufficient clinical evidence doespositive serology have high diagnosticvalue. In those with unspecificsymptoms however, positive serologyis of limited diagnostic value. Due tothe high sensitivity of the test, negative

Table 2. Sensitivity of methods for direct proof of B. burgdorferi (from [16])

Material Sensitivity

Skin biopsy (erythema migrans, acrodermatitis) 50–70% in culture or PCRLiquor (acute neuroborreliosis) 10–30% in culture or PCRSynoviaa 50–70% in PCR

aEven higher sensitivity (up to 80%) by examination of the synovial tissue

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serology practically eliminates thediagnosis of Lyme arthritis.Given the slowness of changes inimmune response during the chronicphase, successive examinations overtime are seldom helpful, as theyproduce significant findings only atintervals of several months. In suchcases, chronic borreliosis can often besurmised with only a limited probabilitybut seldom proven [3, 5, 13, 16].An additional difficulty stems from thefact that serological tests are notstandardised; tests performed in differentlaboratories often provide different results,which could be mistakenly interpreted asthe titre course or an effect of therapy.This commonly leads to false diagnosis,unnecessary fears of continued diseaseprogression, and unnecessary treatment.Thus Lyme arthritis can be diagnosedwith sufficient certainty either by standardanamnesis and clinical symptoms togetherwith positive serology or, in case of lesstypical symptoms, by demonstrating thepresence of the pathogen. A carefulrheumatological differential diagnosis isalso always necessary.

Criteria for the diagnosis of Lymearthritis- Association with pathognomonic

extra-articular manifestations- Typical pattern of joint involvement- Exclusion of possible differential

diagnoses- IgG antibodies against Borrelia

burgdorferi

- Positive Borrelia PCR for the synoviaor synovial membrane

Depending on the constellation offindings, it is possible to distinguishbetween certain, probable, and possibleLyme arthritis. This also helps indicatethe possible need for critical re-examination of the diagnosis during thecourse of the disease. If the first fourcriteria are fulfilled,e.g.,when the arthritisis associated with obvious acrodermatitischronica atrophicans in a patient withhighly positive Borrelia serology, then thefindings are unequivocal and allowdefinite diagnosis. The same is true forgonarthritis patients with positiveserology,and positive Borrelia PCR resultfrom synovial fluid once the differentialdiagnoses have been excluded.In practicehowever, the suspected diagnosis is basedonly on criteria 2 and 4, leaving diagnosticuncertainty, and even after eliminatingother possible diagnoses, one can onlyspeak of a probable diagnosis; or, forexample, if there is also psoriasis thatcannot be excluded by other cause, onlya diagnosis of possible Lyme arthritisremains [2, 4, 8, 10].

TherapyAntibiotic therapy should be started assoon as possible after diagnosis in orderto shorten the course of the disease,cure it, and prevent progression or thedevelopment of chronic disease.Treatment is stage- and symptom-oriented, with doxycycline, amoxicillin,

33

and ceftriaxone being the drugs ofchoice.The current internationally validstandard treatment recommendationsare listed in Table 3.

The success rate of antibiotic therapy ishigh, and therapy-resistant cases are rare.In the acute phase, a single treatmentcycle almost invariably leads to a cure,although general, unspecific symptomssometimes take a long time to disappear.The success rate of the first therapy forLyme arthritis is about 80%. If patientsstill have symptoms after several weeks,a second and later at most a thirdtreatment with parenteral antibioticsshould be carried out. Recent studieshave shown that further antibiotictreatment is inefficacious, as are long-term therapies, high-dose pulse therapies,

combination treatment, and the use ofantibiotics other than those listed [6,7].Therapy-resistant Lyme arthritis occursin about 10% of patients in the USA butis probably less common in Europe.Useful treatment can include intra-articular steroid injections (only afterantibiotic therapy!), radiosynoviorthesis,and synovectomy. Otherwise, symptom-oriented treatment is recommendedtogether with an explanation to thepatient that the disease will not spreadand usually improves slowly over time,possibly many months. The generalprognosis for Lyme arthritis and theother forms of Lyme borreliosisdiscussed is very good [1, 2, 3, 4, 17].Early studies on Lyme arthritis haveshown that 10% of cases healspontaneously within a year, and that

Table 3. Therapy for Lyme borreliosis [1, 2, 3, 4, 10, 17]

Manifestation Drug Dose/day Duration(dose for childrena) (days)

General symptoms, Doxycycline 1x200 mg or 2x100 mg orally 14-21acute phase Amoxicillin 3x500-750 mg or 2x1,000 mg orally 14-21(corresponds to (50 mg/kg)therapy for Azithromycinb 2x500 mg orally 1erythema migrans) 500 mg 2-5

Cefuroxime Axetilb 2x500 mg orally 14-21Carditisc Ceftriaxone 1x2 g i.v. 14

Cefotaxim 3x2 g i.v. 14Penicillin G 4x5 million U i.v. 14

Arthritis, myositis Doxycycline 1x200 mg or 2x100 mg oral 30 (-40)Amoxicillin 3x500-750 mg or 2x1,000 mg oral 30 (-40)Ceftriaxone 1x2 g i.v. 14-21Cefotaxim 3x2 g i.v. 14-21

aAdult dose corresponds to maximum dosebOnly in case of allergies or contraindications against doxycyline and amoxicillincIn patients with 1st grade AV Block, the oral therapy (14-21 days) is indicated

34


antibiotic therapy initiated even severalyears after disease onset is effective [14].

Case studiesFirst case descriptionA 38-year-old male patient hadcomplained for 4 months of painfulswelling in the right knee. As thisproblem first occurred after a skiingholiday, trauma was suspected, althoughthe patient could not remember suchincident. Magnetic resonance imagingshowed minor chondropathy anddegenerative changes to the outermeniscus. Symptomatic treatment withdiclofenac led to only short-termimprovement. Further anamnesisshowed no significant previous illness.About a year previously, the patient hadbeen bitten on the left side of the chestby a tick probably while working in thegarden.The tick had been removed witha tweezers. Shortly thereafter, erythemaoccurred which lasted 1 day and thenspontaneously disappeared. Indicationsfor another cause of the arthritis,additional rheumatological symptoms,and extra-articular manifestations wereneither reported nor found on clinicalexamination. The latter was unre-markable with the exception of florid,left-sided gonarthritis with substantialsynovitis.Arthrosonography confirmedthis finding and showed partlyedematous, partly proliferativesynovialitis, and joint swelling with apoor echo (estimated volume 50 ml) butno popliteal cyst.

Laboratory findings showed limitedhumoral inflammatory activity withincreased erythrocyte sedimentationrate and elevated C-reactive protein(CRP). All other routine parameterswere normal. The patient was humanleukocyte antigen (HLA)-B27-negative.Borrelia serology was highly positivefor IgG antibodies against Borreliaburgdorferi using enzyme-linkedimmunosorbent assay (ELISA).Immunoglobulin-M antibodies were notpresent. These results were confirmedby immunoblot using antibodies against,among others, the proteins OspC, p39,flagellin,VlsE, and p83/100.Analysis ofsynovial fluid from the right knee jointshowed a highly inflamed knee effusionwith 10,000 leukocytes/mm3 (90%neutrophils). Probable Lyme arthritiswas diagnosed that likely resulted fromthe reported tick bite. Whether theerythema following the tick bite waserythema migrans remains unclear. Itsregression after only 1 day suggests thatthis was not the case, although erythemamigrans is sometimes very pale and cango unnoticed by patients. Oral treatmentwith 200 mg/day of doxycycline wasinitiated. Acemetacin (60 mg) asrequired was given as an anti-inflammatory in addition to coldtreatment and physiotherapy. Thearthritis healed slowly under thistreatment, with symptomatic treatmentcontinuing 4 weeks after the antibiotictherapy was finished. The patient wassymptom-free after 3 months.

35

Second case descriptionA 55-year-old, obese female hadcomplained for several months of pain inthe right knee.Additionally, she had hadlumbar back pain for “as long as shecould remember”. Anamnesis indicatedpsoriasis vulgaris from early adulthoodand typical erythema migrans on the leftupper thigh 6 years previously that hadbeen treated for 2 weeks with anunknown antibiotic. She suffered tickbites every year. Having changed hergeneral practitioner shortly before, thenew physician conjectured that herrheumatological problems were causedby Lyme arthritis. A serologicalexamination was positive.From the clinical rheumatological pointof view, both iliosacral joints weremarkedly swollen and painful whenmoved, and the right knee joint showedmalposition of the valgus with lightinflammation. Subsequent anamnesisindicated, at least for earlier years, aninflammatory character to the back painwith a distinct maximum in the earlymorning and reduction with movement.Radiology showed bilateral sacroiliitisand right-sided gonarthritis.Laboratory findings showed increasedvalues for erythrocyte sedimentationrate and CRP. Human leukocyteantigen-B27 was present. Borreliosisserology was positive, with low titres ofIgG against OspC, flagellin, p58, and p60.Analysis of synovial fluid from the kneeshowed less than 1,000 leukocytes/mm3,as seen in arthritic irritation.

A diagnosis of active right-sided valgusgonarthritis was made, with probablepsoriatic spondylarthritis associatedwith HLA-B27, and Lyme borreliosiswith erythema migrans 6 yearspreviously. There was no evidence offlorid Lyme disease.Sacroiliitis does not manifest in Lymearthritis. Synovial analysis clearlyshowed that the knee problems, whichcould also be related to psoriaticarthritis in differential diagnosis, did notresult from Lyme arthritis but, takentogether with the other clinical andradiological findings, were apparentlycaused by active arthritis.The serologicalfindings also speak against Lymearthritis, as the typical clearly positiveIgG antibody response againstnumerous Borrelia proteins, e.g. VlsEand p38/100, was not present. Thefindings suggest a serum scar after Lymeborreliosis some years previously. Theerythema migrans 6 years earlier helpsto explain this serological result. Anassociation between Borrelia and thecurrent rheumatological problems couldnot be made due to the time spaninvolved. In addition, the developmentof a disease course involving an organcannot be expected after adequateantibiotic treatment of erythemamigrans. This case shows how carefullya serological finding must be interpretedin relation to clinical symptoms andother results.

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● References1. Burmester GR, Kamradt T, Krause A

(2004) Lyme disease. In: Isenberg DA,Maddison PJ, Woo P, Glass D, BreedveldFC (eds) Oxford textbook of rheumatology.pp 613-620,

2. European Union concerted action on Lymeborreliosis (EUCALB). http://www.dis.strath.ac.uk/vie/LymeEU/index.htm

3. Franz JK, Krause A: Lyme disease (Lymeborreliosis). Best Practice & ResearchClinical Rheumatology 17: 241-264, 2003

4. Herzer P, Krause A. Lyme-Borreliose. In:Classen M et al. (Hrsg.) RationelleDiagnostik und Therapie in der InnerenMedizin, Urban&Fischer, München, 2006, inpress

5. Huppertz HI, Krause A. Lyme-Borreliose.Internist 44: 175-183, 2003

6. Kalish RA, et al. Evaluation of studypatients with Lyme disease, 10-20-yearfollow-up. J Infect Dis 183: 453-460, 2001

7. Klempner MS, et al. Two controlled trialsof antibiotic treatment in patients withpersistent symptoms and a history of Lymedisease. N Engl J Med 34: 85-92, 2001

8. Krause A, Herzer P. Frühdiagnostik derLyme-Arthritis. Z f Rheumatol 2005 (inpress)

9. Lünemann J, et al. Rapid typing of Borreliaburgdorferi sensu lato species in specimensfrom patients with different manifestationsof Lyme borreliosis. J Clin Micrbiol 39:1130-1133, 2001

10. Nationales Referenzzentrum für Borrelienam Max von Pettenkofer-Institut München.http://pollux.mpk.med.uni-muenchen.de/alpha1/nrz-borrelia/lb/frame-lb.html

11. Nocton JJ, Dressler F, Rutledge BJ, Rys N,Persing DH, Steere AC. Detection of B.burgdorferi DNA by polymerase chainreaction in synovial fluid in Lyme arthritis.N Engl J Med 330: 229-234, 1999

12. Priem S, et al. Detection of Borreliaburgdorferi by polymerase chain reactionin synovial membrane, but not synovial fluidfrom patients with persisting Lyme arthritisafter antibiotic therapy. Ann Rheum Dis57: 118-121, 1998

13. Quality standards for the microbiologicaldiagnosis of infectious diseases“: Lyme-Borreliose (MiQ 12 2000 LymeBorreliosis).http://pollux.mpk.med.uni-muenchen.de/alpha1/nrz-borrelia/miq-lyme/frame-miq-lyme.html

14. Steere AC, Schoen RT, Taylor E. Theclinical evolution of Lyme arthritis. AnnIntern Med 107: 725-731, 1987

15. Steere AC, Coburn J, Glickstein L. Theemergence of Lyme disease. J Clin Invest113: 1093-1101, 2004

16. Wilske B. Diagnosis of Lyme borreliosisin Europe. Vector-Borne Zoonotic Dis 3:215-227, 2003

17. Wormser GP, et al. Practice guidelines forthe treatment of Lyme disease. Clin InfectDis 31: 1-14, 2000

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As the organ contacting theenvironment, the skin is exposed

to many external influences. It is alsoa point of entry for pathogens, whichspread via the skin if the barrierfunction or immune system is no longerintact. In contrast, the transmission ofpathogens such as Borrelia spp. byarthropods can occur in fully healthyindividuals.Whether Lyme borreliosis (LB)manifests, leading to a specific clinicalpicture, depends on the geneticdisposition of the patient, duration ofthe tick bite and virulence of thepathogen [20, 22, 26, 28].Cutaneous symptoms of LB werealready recognized many decadesbefore discovery of the pathogen,Borrelia burgdorferi, by W. Burgdorferin 1983. It has also been known sincethe 1950s that erythema migrans (EM),Borrelia lymphocytoma (BL), andacrodermatitis chronica atrophicans(ACA) can be successfully treated withpenicillin [19, 21].

What happens after a tick bite?The transmission of Lyme borreliosisby ticks, in Europe predominantly bythe Ixodes ricinus species, is reportedin only about 60% of patients [30].Studies have shown that insects such asmosquitoes, horse flies, sandflies, gnats,and wasps have no organ suitable forsurvival of the Borrelia pathogen asexists in the tick gut [13].

Unspecific arthropod reactionsAfter a tick has attached to the skin foran extended time, a local immunereaction occurs that, however, may gounnoticed.An itchy swelling or lump maythen form at the site of the bite, fromwhich a tick granuloma can develop.Aninflamed patch several centimetres indiameter can also develop and thendisappears over a number of days.

Classic cutaneous symptomsof Lyme borreliosis (Table 1)Erythema migransErythema migrans can develop from

Dermatological manifestationsof Lyme borreliosis● Elisabeth Aberer

38

Dermatological manifestationsof Lyme borreliosis

an unspecific reaction to a tick bite afteronly 1–2 days. It is characterised by aslowly expanding inflamed patch. Inmost cases however there is a latentphase of 4–20 days before the formationof this patch. If not treated, it canincrease to 50 cm or more in diameter.The erythema can vary in form fromround to oval to irregular. Subjectivelyit can lead to slight itching. Local lymphnode swelling is possible [11, 28].

Clinical forms of erythema migrans- The color can be bluish in the center

while the edge is bright red. Thereare often streaky or patchy radialbranches at the periphery (Fig. 1).

- A bright red, moving ring can form,with healing in the center (Fig. 2).

- A small vesiculous variant canappear (Fig. 3).

- A homogenous erythema without amarked border can form (Fig. 4).

Children often show a unilateralreddening of a cheek or a stripe that isonly visible on some days. Temporarydisappearance followed by reappearanceof the erythema has been reported.Rubbing a suspect location with awooden spatula can lead to re-appearance of the erythema.

Fig. 1. Fig. 3.

Fig. 2.

39

Disseminated early infectionWhile only about two thirds of patientshave only cutaneous infection (erythemamigrans minor), the remaining third havesimultaneous, generalised symptoms asa sign of haematogenic dissemination[34]. Patients with this EM major formreport flu-like symptoms, light fever,headache, joint and muscle pain, swollenlymph nodes, and fatigue. Occasionally,rapid heartbeat and cardiac rhythmdisturbances are observed [23]. MultipleEM lesions can also result from haema-togenic dissemination as well as from

Fig. 4.

Table 1. Differential diagnosis of Lyme borreliosis

Cutaneous manifestation Differential diagnosis

Erythema migrans

Bluish center Fixed drug eruptionMorphea

Homogenous reddening Fixed drug eruptionErysipeloidSubacute cutaneous lupus erythematosus

Vesicular form Contact dermatitisHerpes simplex

Multiple erythemata Urticaria

Borrelia lymphocytoma

On the ear OthaematomaErysipelasRelapsing polychondritis

On the mamilla Breast cancer

In other places Malignant lymphoma

Acrodermatitis chronica atrophicans

Light red discoloration of the distal extremities Stasis dermatitis

Diffuse livid discoloration Chronic venous insufficiencyVenous thrombosis of the leg

Acral form: fingers/toes Acrocyanosis

Livid reticular discoloration on the extremities Phospholipid antibody syndromeLivedo reticularis/racemosa

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simultaneous infection from multipletick bites.

Erythema chronicum migransIf not treated, EM can last several weeksor months while growing continuously.Spontaneous healing is possible, but itsfrequency is difficult to determine.

Borrelia lymphocytomaBorrelia Lymphocytoma (BL) was firstdescribed as lymphadenosis cutis benigna(Bäfverstedt’s disease),a pseudolymphomawith mixed polyclonal B and T cell proli-feration [6].After a latent period of severalweeks, BL most commonly manifests inchildren as a reddish to bluish node inthe area of the earlobe (Fig. 5), lividreddish discoloration or swelling in thearea of the helix, and a flat node one or

more centimetres in size in the scrotalarea. BL may also occur on onemammilla or areola mammae as anenlargement or nodular lesion (Fig. 6).These nodes can start in an expandingEM that the patient may or may notremember. As EM often occurs on theheads of children, the redness frequentlygoes unnoticed and a lymphocytomaon the ear is the first recognisedsymptom.

Acrodermatitis chronicaatrophicansAcrodermatitis chronica atrophicansbegins as an inconspicuous, poorlydefined reddening of the skin (Fig. 7),subjectively without symptoms, whichbecomes slowly darker. It occurs on thedistal extremities, elbows, extensor sides

Fig. 5. Fig. 6.

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of the upper arms, back of the hand,and upper and lower legs.

Case reportsThe development of ACA withneuropathy. A 57-year-old femaleobserved an EM on her lower leg aftera tick bite. Correct diagnosis was notmade, and the erythema spread to theupper thigh and buttocks over the next2 years. After 3 years an enlargedlymph node was removed from theright inguinal area which showedunspecific lymphadenitis. The patientreported intermittent redness on thebuttocks. Two years later, left-sidedbartholinitis appeared and laterdisappeared.Twelve years after the tick

bite, the patient noted a burningsensation and weakness in both thighsas well as a bright red discolorationwith undefined borders and lightswelling in the left ankle region. Thisled her to visit a dermatologist, wherefinally ACA was diagnosed clinicallyand verified with a biopsy and serology(Fig. 7). The dermatological changeshealed under antibiotic treatment with2 g of ceftriaxone daily for 15 days.Theaccompanying neuropathy improvedslowly.

CommentsThe clinical course of ACA can rarelybe studied so clearly. This patientdistinctly shows the clinical persistenceof the disease as described in theliterature [14, 29]. Reactivation ofBorrelia burgdorferi and thedevelopment of ACA were also foundin two other patients, one injured on arose thorn while gardening and theother on a metal spike at home. Thisindicates that latent infections occur inthe extremities where temperature islower, the optimum Borrelia growthtemperature being 33–34°C.Bluish, cushion-like swellings alsodevelop in ACA. Sometimes individualfingers are swollen and discolored blue(Fig. 8). Swelling of the feet can lead tothe patient’s requiring a larger shoe size.More reticulate discoloration can occuron the extensor sides of the upper armsand thighs.The skin gradually becomesthin and wrinkled, and the bluish

Fig. 7.

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discoloration decreases. A thin, almosttransparent skin remains, with bloodvessels visible underneath (Fig. 9).The neuropathy often reported bypatients does not respond to antibioticsas well as the dermatological changesdo [12]. Solid, extra-articular (fibrous)nodes form over the elbows, knees, andfinger joints. These can easily be liftedin a fold of the skin and, unlike rheu-matic nodes, are not painful.Skin sclerosis is possible in shin andunderarm extensor regions (tibial andulnar bands) where ACA is present.This can be differentiated from linearscleroderma by its undefined edges. Inaddition to classic ACA, anetodermiclesions can occur also.

Genospecies-specific coursesof Lyme borreliosisThe species Borrelia burgdorferi sensulato is subdivided into threegenospecies: Borrelia burgdorferi sensustricto, Borrelia afzelii, and Borreliagarinii; all three of these can cause EM.Various genospecies-specific courses ofEM have been reported [7]. Of these,only Borrelia burgdorferi sensu strictois found in the USA.This species causesthe least number of Borrelia infectionsin Europe. In our study in the Viennaarea, Borrelia burgdorferi sensu latowas isolated from the skin of 28patients. Of these, 23 had Borrelia afzelii(17 with EM, six with ACA), three hadBorrelia garinii (all with EM), and twohad Borrelia burgdorferi sensu stricto

Fig. 8.

Fig. 9.

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infection (one with EM, one positiveblood culture in disseminated LB). Inand around the city of Graz,Austria 11strains were isolated, of which five wereBorrelia garinii from EM and sixBorrelia afzelii (four EM, one ACA,one morphea). A similar pattern hasbeen found in other studies [25]. Forthe other cutaneous symptoms, BL ismost commonly caused by Borreliaafzelii (eight of nine cases) [18] andACA almost exclusively by Borreliaafzelii [24], with mixed infections alsopossible. This explains why nosecondary cutaneous clinical courses(e.g. BL or ACA) of LB have beenfound in the USA, with the exception ofpatients who were infected in Europe.Differences between EM caused byBorrelia burgdorferi sensu stricto andEM caused by Borrelia afzelii are:shorter incubation time (4 days vs 14),more frequent localisation in the trunkarea (50% vs 27%), central lighteningof colour in only a third of patientscompared with two thirds of Borreliaafzelii infections, and more frequentsystemic signs and seropositivity (89%vs 30%) [30]. In addition, EM caused byBorrelia afzelii differs from that causedby Borrelia garinii–infections with theformer occurring more often in June andwith Borrelia garinii in September, whileBorrelia afzelii EM appears more oftenon the extremities and less often on thetrunk. Growth of the reddened area byBorrelia afzelii reaches 3 cm/day and byBorrelia garinii 12.5 cm/day. Generalised

and local symptoms occur in threequarters of Borrelia garinii patients butonly a third of Borrelia afzelii patients[5, 17].

Symptoms aftererythema migransA case of EM is clinically cured with2–3 weeks of antibiotic treatment,sometimes within a few days andsometimes towards the end of thetherapy period. Occasionally there is stilla livid erythema after 3 weeks that fadesseveral weeks later. If severe symptomsexist at the start of therapy, they maycontinue after the end of medication andcompletely disappear several weekslater. Severe symptoms can also ariseduring therapy (Herxheimer-likereaction) and should not be interpretedas treatment failure. The prescribedantibiotic must not be stopped. Durationof therapy should be increased to3 weeks if originally set at 2 weeks basedon apparently localised EM.About 7%of patients suffer relapse in the followingweeks (for up to 6 months) withrepeated wandering joint and musclepain and headaches that can last for days.These symptoms also disappear afterseveral weeks. In severe cases, anadditional course of antibiotics is usuallyprescribed. The occurrence of arthritisor neuroborreliosis has not beenobserved in LB patients with correctlytreated EM over an observation periodof 20 years. In two patients, erythemanodosum (EN) accompanied the EM.

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Case report of erythema migrans witherythema nodosum (EN)A 34-year-old male had a 7 x 5 cm annularerythema on the right leg for 2 monthsand painful, bright red nodes on bothshins for a week. He could notremember being bitten by a tick. He alsocomplained of joint pain that had lastedfor a year. X-ray of the thorax showedbilateral lymphadenopathy (Löfgren’ssyndrome). Pathological findingsincluded C-reactive protein of 89,erythrocyte sedimentation rate of 44,and angiotensin-converting enzyme of57.4 U (normal range 18.0–55.0 Units).Immunoblot for Borrelia antibodies wasnegative before and after therapy.Polymerase chain reaction (PCR) forBorrelia in the urine was positive on fiveoccasions from the 5th to 150th day oftreatment but negative on days 210 and360 [2]. Anti IgM and IgG antibodiesspecific for Ehrlichia were positive (1:64)over 5 months without a change in titre,but PCR for Ehrlichia in the blood wasnegative. A pulmonary specialistdiagnosed pulmonary sarcoidosis I.Bronchoscopy and bronchoalveolarlavage showed no evidence ofpulmonary involvement. A doubletherapy cycle of 200 mg of doxycylinefor 3 weeks and glucocorticosteroidtreatment led to cure of the EM, EN,and lymph node swelling.

CommentsDue to the steady titre values andnegative PCR, ehrlichiosis could be

eliminated as a cause of the EN andbilateral lymphadenopathy. There werealso no fever or unusual laboratoryvalues such as leukopenia.The conclusionis that the EN is associated with the EM.Arthralgia,myalgia,memory disturbances,fatigue syndrome, conjunctivitis, febrileperiods,headache, tinnitus,and acute lossof hearing are referred in the literature assymptoms of post-Lyme syndrome.Seltzeret al. [27] examined the symptom profilesof 212 patients 1–11 years after LB andcompared them to a group withequivalent age and place of residence.Nodifferences were found between thegroups. It is still unclear how to classifythis clinical picture.Perhaps the symptomsare overrated and were influenced byfear of further organ involvement fromthe LB.

Culture and polymerasechain reaction confirmedatypical formsClinical observations have shown thatthe potency of Borrelia burgdorferiinfection lies in immune stimulation ofB cells and the induction of cutaneoussclerosis.

Cutaneous lymphomaThe role of Borrelia burgdorferi inatypical cutaneous proliferation,pseudolymphoma, and malignantlymphoma has been confirmed in manypublications. As a cause of malignantlymphoma, it acts similarly toHelicobacter pylori or Epstein-Barr

45

virus. A targeted antibiotic (virostatic)therapy can lead to cure in some cases.Comparative studies with lymphomapatients in the USA or Asia showed noassociation with Borrelia burgdorferi[16, 32], while those in Austria, France,Scotland, Denmark, and Germanyclearly did [9, 15].

Circumscribed scleroderma(morphea) and lichen sclerosis Starting in 1985, an association betweenBorrelia infection and the developmentof morphea was described in Switzerland,Germany,and Austria by various authorsfrom Basel, Munich, Berlin, and Vienna.According to PCR results and positiveBorrelia cultures from skin biopsies andtheir typing, aggregation of Borrelia-induced morphea cases was geographicin nature [4, 10]. Only Borrelia afzeliicould be isolated from both morpheaand lichen sclerosis.

Diagnostic and therapeuticmanagement of these patients In principle, circumscribed sclerodermahas a variety of causes. It can occur afterinsect bites, immunisations, and trauma.Independently of this, a childhood andearly adolescent form exists which islocalised to the lines of Blaschko (e.g.linear forms, morphea en coup de sabre)and therefore could be induced duringembryonal development. Congenitalatrophic morphea has been cured bytreatment with ceftriaxone [1]. Thesignificance of Borrelia to the emergence

of this disease is not yet clear.Borrelia serology using immunoblot andBorrelia PCR of a skin biopsy arerecommended for diagnosis. The IgGELISA titres are often negative,but specificbands appear on immunoblot.In Borreliaassociated skin sclerosis it is likely thatcellular immune reactions predominate,asshown by lymphocyte proliferation tests.Stimulation of lymphocytes by Borreliaburgdorferi was also observed inseronegative patients with morphea andACA patients with fibrous nodules [3].Patients with morphea react better tosystemic therapy with ceftriaxone (for20 days) than to oral treatment; the samehas been observed in seronegative patients.This is the treatment of choice for allpatients with progressive morphea anddistinct lilac rings, particularly in children.

Dermatoses in which Borreliaburgdorferi infection mustbe consideredAll patients with unexplained sclerosis[31], myositis, and especiallydermatomyositis must be examined forthe presence of Borrelia burgdorferiinfection. In the literature this infectionhas also been associated with cases oflivid erythema with myopathy, relapsingfebrile panniculitis, annular erythema,trigger-finger, Schönlein-Henoch andthrombocytopenic purpura, granu-lomatous thrombophlebitis, temporalarteritis, sarcoidosis, pityriasis rosea,pityriasis lichenoides, anetoderma,Buschke’s scleroderma, eosinophilic

46


fasciitis (Shulman’s syndrome), facialhemiatrophy, granuloma annulare, andinterstitial granulomatous dermatitis.

Diagnosis of Lyme borreliosisConsult the European Union forConcerted Action on Risk Assessmentin Lyme Borreliosis guidelines athttp://www.oeghmp.at/eucalb/.

Erythema migransErythema migrans is usually diagnosedon purely clinical criteria! Anamnesisof a growing red patch is the mostimportant feature; patients frequentlydo not remember a bite. This patchshould be >5 cm.The patch may have tobe observed over the course of a week,with a control examination sometimesrequired. Histological examination isunspecific, showing perivascularlymphohistiocytic infiltrate with sparseeosinophils. Biopsy is needed only whenthe clinical picture is unclear.Serological examination can showpositive IgM antibodies, which shouldhowever be confirmed by immunoblot.Depending on the duration of theerythema, IgG antibodies may also bepresent.These could also result from anearlier infection of known or unknownorigin (seroprevalence in healthyindividuals 10–30%). Since only 50% ofpatients have antibodies, serologicalexamination is not required for diagnosis.

Borrelia lymphocytomaThe clinical diagnosis is also decisive here.

Biopsy shows polyclonal B and T cellproliferation. In children, biopsy can beavoided if there is a classic manifestation.In cases of lymphocytoma of themammilla or other localised areas, a skinbiopsy should be carried out. In about70% of patients, antibodies can bedemonstrated. Healing after antibiotictherapy can be slow, taking several weeks.

Acrodermatitis chronicaatrophicansPositive IgG titre, typical clinical picture,and histological examination are crucialto diagnosing this manifestation of LB.Histology shows atrophy of theepidermis and dermis, telangiectasia,and occasionally band-like lympho-histiocytic infiltrates with plasma cells.The cure by therapy is very slow,requiring months. Follow-up after a yearis recommended, possibly also a repeatbiopsy to determine whetherinflammatory infiltrates are present.

SerologyBorrelia serology will be dealt with indetail in the chapter on diagnosis. Hereonly a possible serological picture forEM is presented (Table 2).

TherapyTreatments of LB with oral penicillin,tetracycline, cefuroxime axetil, andazithromycin are equally effective(Table 3). With antibiotic treatment,EM with or without accompanyingsymptoms heals without complications

47

in >90% of cases. If treatment fails,headaches, joint and muscle pain, andfatigue can occur for a period of6 months but usually disappear withina few weeks. Secondary manifestationsare extremely rare after appropriatetreatment.The most recent publicationson duration of therapy show that post-Lyme syndrome occurs in 5-10% ofpatients independently of whethertreatment lasts 2 or 3 weeks [33].Three-week treatment is recommended

if the erythema lasts >2 months and incase of severe symptoms. The choice ofantibiotic depends on patient compa-tibility and possible allergies.Tetracyclinesshould be avoided if exposure to sun islikely,and are also contraindicated duringpregnancy, while breast-feeding, and forchildren <8 years old. In casesaccompanied by fever, severe generalsymptoms, or when co-infection withehrlichiosis is suspected, tetracycline isthe treatment of choice (Table 3).

Table 2. Serological picture in erythema migrans (Borrelia antibodies)

ELISA IgM ELISA IgG IB IgM IB IgG Interpretation

- - - - EM/no borreliosis?+ - - - EM/unspecific+ - + - EM Confirmation/antibody

persistence from older infections+ + + +/- EM Confirmation/reinfection- + - + Older infections+/- - + + EM Confirmation/older infections

Table 3. Antibiotic therapy for Lyme borreliosis

Erythema migransPenicillin V 3x1 1,5 Mio 14-20 daysAmoxicillin 3x1 500-750 mg 14-20 daysDoxycycline 1x1 200 mg 14-20 daysAzithromycin 2x1 500 mg 1st day

1x1 500 mg 7 days

Borrelia lymphocytomaOral therapy 20 days

Acrodermatitis chronica atrophicansOral therapy 30 daysOr ceftriaxone 1x1 2g 20 days

A second treatment with an alternative antibiotic is recommended for the following findings:Positive serology Severe sufferingand unspecific symptomsEM Continuing arthralgia, headaches for >3 monthsBL No cure within 3 monthsACA Histologically verified infiltrate after 1 year

48


PrognosisPathogen persistence was found in threeof 48 patients with late symptoms [29].Re-infection is possible. It is noteworthythat chronic Borrelia infections stimulatelymphocytes, with the possibility ofmonoclonal lymphocytic proliferation.Persistent, severe disease courses couldbe due to infection with exceptionallypathogenic Borrelia burgdorferi clones(RST1 isolate [8]). In addition tointerspecies variation, additional geneticfactors can lead to organ-specificmanifestations. In general, there is no

danger of developing LB when EM isproperly treated. Therapy can failhowever, when less efficacious antibioticssuch as first-generation cephalosporins,roxithromycin, or erythromycin are usedin an irregular manner; for example iftherapy is interrupted on weekends, assometimes happens with ceftriaxonetherapy. Uncertainty concerningserology remains, as the variableprevalence in the population andpersistence of antibodies after therapycomplicate the assessment of serologyresults, making diagnosis difficult.

49

● References1. Aberer E, Weissenbacher G (1997)

Congenital anetoderma induced byintrauterine infection? Arch Dermatol133(4):526-527

2. Bergmann AR, Schmidt BL, Derler AM,Aberer EJ (2002) Importance of samplepreparation for molecular diagnosis of lymeborreliosis from urine. J Clin Microbiol40(12):4581–4584

3. Breier P, Klade H, Stanek G, Poitschek C,Kirnbauer R, Dorda W, Aberer E (1996)Lymphoproliferative responses to Borreliaburgdorferi in circumscribed scleroderma.Br J Dermatol 134(2):285–291

4. Breier FH,Aberer E, Stanek G, KhanakahaG, Schlick A,Tappeiner G (1999) Isolationof Borrelia afzelii from circumscribedscleroderma. Br J Dermatol 140(5):925–930

5. Carlsson SA, Granlund H, Jansson C, NymanD, Wahlberg P (2003) Characteristics oferythema migrans in Borrelia afzelii andBorrelia garinii infections. Scand J Infect Dis35(1):31–33

6. Colli C, Leinweber B, Müllegger R, ChottA, Kerl H, Cerroni L (2004) Borreliaburgdorferi-associated lymphocytoma cutis:clinicopathologic, immunophenotypic, andmolecular study of 106 cases. J Cutan Pathol31(3):232–240

7. Dam AP van, Kuiper H, Vos K,Widjojokusumo A, Jongh BM de, SpanjaardL, Ramselaar AC, Kramer MD, Dankert J(1993) Different genospecies of Borreliaburgdorferi are associated with distinctclinical manifestations of Lyme borreliosis.Clin Infect Dis 17(4):708–717

8. Dolan MC,Piesman J,Schneider BS,SchrieferM,Brandt K,Zeidner NS (2004) Comparisonof disseminated and nondisseminated strainsof Borrelia burgdorferi sensu stricto in micenaturally infected by tick bite. Infect Immun72(9):5262–5266

9. Fouchardiere A de la,Vandenesch F, BergerF (2003) Borrelia-associated primarycutaneous MALT lymphoma in anonendemic region. Am J Surg Pathol27(5):702–703

10. Fujiwara H, Fujiwara K, Hashimoto K,Mehregan AH, Schaumburg-Lever G,Lange R, Schempp C, Gollnick H (1997)Detection of Borrelia burgdorferi DNA (Bgarinii or B afzelii) in morphea and lichensclerosus et atrophicus tissues of Germanand Japanese but not of US patients. ArchDermatol 133(1):41–44

11. Hengge UR,Tannapfel A,Tyring SK, ErbelR, Arendt G, Ruzicka T (2003) Lymeborreliosis. Lancet Infect Dis 3(8):489-500;Erratum in: Lancet Infect Dis 3(12):815

12. Kindstrand E, Nilsson BY, Hovmark A,Pirskanen R, Asbrink E. Peripheralneuropathy in acrodermatitis chronicaatrophicans - effect of treatment. ActaNeurol Scand. 2002 Nov;106(5):253

13. Kosik-Bogacka D, Kuzna-Grygiel W,Bukowska K (2004) The prevalence ofspirochete Borrelia burgdorferi sensu latoin ticks Ixodes ricinus and mosquitoesAedes spp. within a selected recreationalarea in the city of Szczecin. Ann AgricEnviron Med 11(1):105–108

14. Kuiper H, Dam AP van, Spanjaard L, JonghBM de,Widjojokusumo A, Ramselaar TC,Cairo I, Vos K, Dankert J (1994) Isolationof Borrelia burgdorferi from biopsyspecimens taken from healthy-looking skinof patients with Lyme borreliosis. J ClinMicrobiol 32(3):715–720

15. Leinweber B, Colli C, Chott A, Kerl H,Cerroni (2004) Differential diagnosis ofcutaneous infiltrates of B lymphocytes withfollicular growth pattern. Am JDermatopathol 26(1):4–13

16. Li C, Inagaki H, Kuo TT, Hu S, Okabe M,Eimoto T (2003) Primary cutaneousmarginal zone B-cell lymphoma: a molecularand clinicopathologic study of 24 asian cases.Am J Surg Pathol 27(8):1061–1069

17. Logar M, Ruzic-Sabljic E, Maraspin V,Lotric-Furlan S, Cimperman J, Jurca T, StrleF (2004) Comparison of erythema migranscaused by Borrelia afzelii and Borreliagarinii. Infection 32(1):15–19

18. Maraspin V, Cimperman J, Lotric-Furlan S,Ruzic-Sabljic E, Jurca T, Picken RN, Strle F

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(2002) Solitary borrelial lymphocytoma inadult patients. Wien Klin Wochenschr31;114(13-14):515–523

19. Miescher G, Storck H (1951) Successfulpenicillin therapy of acrodermatitisatrophicans. Dermatologica 102(4-6):370–371

20. Nahimana I, Gern L, Blanc DS, Praz G,Francioli P, Peter O (2004) Risk of Borreliaburgdorferi infection in western Switzerlandfollowing a tick bite. Eur J Clin MicrobiolInfect Dis 23(8):603–608

21. Paschoud JM (1958) Lymphadenosisbenigna cutis as a communicable disease.IV. Discussion of study results. Part B:penicillin therapy; lymphadenosis benignacutis & erythema chronicum migrans,connections & etiology; summary. DerHautarzt 9(7):311–315

22. Piesman J (1993) Dynamics of Borreliaburgdorferi transmission by nymphalIxodes dammini ticks. J Infect Dis167(5):1082–1085

23. Pikelj-Pecnik A, Lotric-Furlan S, MaraspinV, Cimperman J, Logar M, Jurca T, Strle F(2002) Electrocardiographic findings inpatients with erythema migrans.Wien KlinWochenschr 31;114(13-14):510–514

24. Rijpkema SG,Tazelaar DJ, Molkenboer MJ,Noordhoek GT, Plantinga G, Schouls LM,Schellekens JF (1997) Detection of Borreliaafzelii, Borrelia burgdorferi sensu stricto,Borrelia garinii and group VS116 by PCRin skin biopsies of patients with erythemamigrans and acrodermatitis chronicaatrophicans. Clin Microbiol Infect3(1):109–116

25. Schaarschmidt D, Oehme R, Kimmig P,Hesch RD, Englisch S (2001) Detection andmolecular typing of Borrelia burgdorferisensu lato in Ixodes ricinus ticks and indifferent patient samples from southwestGermany. Eur J Epidemiol 17(12):1067–1074

26. Seinost G, Dykhuizen DE, Dattwyler RJ,Golde WT, Dunn JJ,Wang IN,Wormser GP,Schriefer ME, Luft BJ (1999) Four clones ofBorrelia burgdorferi sensu stricto cause

invasive infection in humans. Infect Immun67(7):3518–3524

27. Seltzer EG, Gerber MA, Cartter ML,Freudigman K, Shapiro ED (2000) Long-term outcomes of persons with Lymedisease. JAMA 2;283(5):609–616

28. Stanek G, Strle F (2003) Lyme borreliosis.Lancet 15;362(9396):1639–1647

29. Strle F, Cheng Y, Cimperman J, MaraspinV, Lotric-Furlan S, Nelson JA, Picken MM,Ruzic-Sabljic E, Picken RN (1995)Persistence of Borrelia burgdorferi sensulato in resolved erythema migrans lesions.Clin Infect Dis 21(2):380–389

30. Strle F, Nadelman RB, Cimperman J,Nowakowski J, Picken RN, Schwartz I,Maraspin V,Aguero-Rosenfeld ME,VardeS, Lotric-Furlan S, Wormser GP (1999)Comparison of culture-confirmed erythemamigrans caused by Borrelia burgdorferisensu stricto in New York State and byBorrelia afzelii in Slovenia.Ann Intern Med5;130(1):32–36

31. Wackernagel A, Bergmann AR, Aberer E(2005) Acute exacerbation of systemicscleroderma in Borrelia burgdorferiinfection. J Eur Acad Dermatol Venereol19(1):93–96

32. Wood GS, Kamath NV, Guitart J, Heald P,Kohler S, Smoller BR, Cerroni L (2001)Absence of Borrelia burgdorferi DNAin cutaneous B-cell lymphomas fromthe United States. J Cutan Pathol28(10):502–507

33. Wormser GP, Ramanathan R, NowakowskiJ, McKenna D, Holmgren D, Visintainer P,Dornbush R, Singh B, Nadelman RB (2003)Duration of antibiotic therapy for earlyLyme disease.A randomized, double-blind,placebo-controlled trial. Ann Intern Med6;138(9):697–704

34. Wormser GP, McKenna D, Carlin J,Nadelman RB, Cavaliere LF, Holmgren D,Byrne DW, Nowakowski J (2005) Briefcommunication: hematogenous dissemi-nation in early Lyme disease. Ann InternMed 3;142(9):751–755

51

For laymen the terms Borreliainfection, borreliosis, and neuro-

borreliosis are commonly used assynonyms.The reason for this confusion isthe incorrect assumption that unspecific,generalised symptoms are usually causedby a disease of the nervous system, andthat a borrelial infection discovered bychance during examination is causingthese symptoms. Here the uncriticalrequest for Borrelia serology analysis inresponse to unspecific symptoms has ahigh a priori chance of returning positiveresults due to the high seroprevalence inthe population.Even using an optimal testmethod, such as ELISA usingrecombinant proteins from three Borreliaspp.,only a negative result provides usefulinformation. The following is a criticaldiscussion of the typical neurologicalsymptoms of neuroborreliosis, theproblem of unspecific symptoms,and post-Lyme syndrome.

PathogenesisLaboratory investigations have shownthat Borrelia burgdorferi sensu lato has

a natural affinity for cells of the centraland peripheral nervous systems,where itconcentrates in the region of themeninges and nerve roots. This becausethese cells have surface proteoglycansand galactocerebrosides, which providebinding sites for the outer surface proteinOsp A of Borrelia burgdorferi sensu lato[2]. The OspA lipoprotein is also ofparticular importance in the pathogenesisof neuroborreliosis. Initially it inducesproliferation of astrocytes and lym-phocytes via the synthesis of pro-inflammatory cytokines (e.g. IL-1, IL-6,and IL-8). Later however, it causes theirapoptosis from increased production oftumour necrosis factor alpha [30]. Thegeneral feeling of illness and, in cases ofacute neuroborreliosis, frequently paincan be explained by the increasedsynthesis of immunotransmitters and theirattachment to neuronal receptors,but themechanisms leading to the disturbanceof neurological function in chronic formsare not yet known.Antibodies and auto-reactive T lymphocytes specific forneuronal and glial proteins are commonly

Neuroborreliosis● Reinhard Kaiser

52

Neuroborreliosis

found, but their significance is alsounclear.A correlation between these la-boratory findings and the clinical courseand prognosis of the disease has not beenestablished [14, 18].

Clinical pictureBorrelia infection of the nervous systemis usually acute, and seldom chronic.Symptoms lasting for ≥6 months arecriteria for the chronic form.

Diseases affecting theperipheral nervous systemMeningopolyradiculoneuritis(Bannwarth’s syndrome)After erythema migrans, meningopoly-radiculoneuritis (Bannwarth’s syndrome)is the second most common mani-festation of acute Borrelia infection inEurope [19, 34]. Diagnosis is charac-terised by the effects of Borrelia-inducedinflammation in the meninges (menin-gitis), spinal cord root (radiculitis), andcranial nerves, which may occur concur-rently or consecutively but also alone.

MeningitisMeningitis is relatively uncommon inadult Europeans but can be a majorproblem in children [4, 7]. Headachesoften are only moderately pronounced,however their intensity can fluctuatesubstantially within a few days or weeks.Meningitis, fever, nausea, vomiting, andvertigo are uncommon.Suspected diagnosis is confirmed bydemonstrating pleocytosis in the CSF

and an elevated Borrelia-specificantibody index.

RadiculitisThe symptoms of radiculitis develop onaverage within 4–6 weeks (range1–12 weeks) after the tick bite. The firstsymptoms are predominantly night timeradicular pain in the extremities andcircling pain in the trunk that do notrespond to simple analgesics. Maximumpain is often reached within a few hoursor days. It reaches an intensity thatpatients report not having previouslyexperienced, is constantly present, andoften prevents sleep.As there is usually nodemonstrable neurological deficit duringthis phase, the possibility of borreliosis isoften not considered. Most patientshowever show sensory neurologicalirritation and neurological deficits withina few weeks: symptoms involvingsensitivity to stimulus are commonlyreported although corresponding deficitsare rare. Occasionally the segment withthe most intense pain later becomesnumb. Paresis is more common thansensitivity disturbances and is typicallydistributed asymmetrically, morecommonly affecting the limb bitten bythe tick or where the erythema migransoccurred. In cases of radiculitis, the painusually decreases within a few days afterbeginning antibiotic treatment.Differential diagnoses for such extremepain and pleocytosis are Varicella zostervirus reactivation and carcinomatousmeningitis. Pathological findings on

53

magnetic resonance imaging areuncommon for radiculitis.

Cranial nerve paresisAbout 60% of patients with Bannwarth’ssyndrome have cranial nerve paresis.With the exception of the olfactory nerve,reports indicate that any brain region canbe affected. In most cases, the paresisoccurs within a few weeks after theerythema migrans. The facial nerveparesis is by far the most common,affecting about 80% of cases, and isbilateral in 40% of these (acute > chroniccourse).Facial paresis in neuroborreliosisis occasionally isolated, in which case itcannot be differentiated from idiopathiccases. Clarification is best made byanalysis of the CSF. If pleocytosis isabsent–even with the presence ofBorrelia-specific IgG antibodies in theserum–an idiopathic case is most likely.If Borrelia-specific IgM antibodies arefound in the serum, it is not possible toexclude borreliosis as a cause of theparesis,even in the absence of pleocytosisand antibodies in the CSF. In such cases(particularly if there are also Borrelia-specific IgG antibodies in the serum), a14-day oral course of antibiotics (e.g.1x200 mg doxycycline or 3x750 mgamoxicillin per day) is recommended.Aswith idiopathic facial paresis, about5–10% of patients suffer fromsubsequent disturbances [5, 17].Second in frequency after facial paresis isabducens paresis, which is bilateral inabout 10% of cases.All the other cranial

nerves are affected much less often.Thesignificance of Borrelia infection investibulocochlear nerve or vestibularorgan diseases is still unconfirmed. Anumber of large epidemiological studieswere unable to show a definite causalrelationship between acute vertigo andserologically determined borreliosisinfection [27]. Only in a single study ofpatients with acute hearing loss didanalysis of CSF by lumbar puncture revealinflammatory changes. It is noteworthythat patients with such inflammatory CSFsigns and positive Borrelia serologyresponded better to treatment and/or hadbetter prognoses than those with acuteidiopathic hearing loss [13].These findingssuggest a recommendation not only forBorrelia serology but also for lumbarpuncture in cases of acute hearing loss.Chronic neuroborreliosis can occasionallyalso be associated with a significant lossin hearing.

Polyneuritis/polyneuropathyThe term polyneuritis is used to describecases in which there is evidence of aninflammatory cause of a polyneuropathy(PNP). In PNP, disturbances inneurological function or dysaesthesiaare usually distal, affecting theextremities. In European patients distalpolyneuritis resulting from Borreliainfection is almost always found inassociation with acrodermatitis chronicaatrophicans (ACA) [16].All other casesof Borrelia-induced polyneuritis shouldbe considered with scepticism, as most

54

Neuroborreliosis

publications on the subject lacksufficient proof and an adequatedifferential diagnosis is not defined.Themajor hindrances to collecting evidenceare the large number of possible causesof PNP combined with the very highseroprevalence of Borrelia antibodiesin the general population (between 10%and 30% depending on region).Additionally, only a small proportion ofBorrelia infections (<5%) manifestclinically. Thus the association of PNPand serum Borrelia antibodies is morecoincidental than causal in mostpatients. Only with additional evidenceof pathological CSF changes cancausality be accepted. This however,would suggest a diagnosis of radiculitis,because CSF involvement is notgenerally associated with thepredominantly distal changes seen in atypical PNP. Using such diagnostic andtherapeutic methods, we have beenunable to find a proven Borrelia-induced PNP in the last 15 years.

Diseases of the centralnervous systemEncephalitisClinical symptoms of borreliosisinvolving the central nervous systemhave seldom been observed. Whenpresent, they occur more frequently inthe chronic than the acute course. Casesof encephalitis involving Borrelia showno characteristics pointing to suchaetiology. Reported disturbances haveincluded quantitatively and qualitatively

reduced states of consciousness, focal andgeneralised seizures, mono- andhemiparesis, hemianopsia, aphasia,dysarthria and coordination disturbances.Individual cases have presented withchoreiform and dystonic motordisturbances, transitory Parkinson’sdisease-like symptoms, pseudotumourcerebri in association with autoimmunethyroiditis, obstructive hydrocephalus,temporary organic brain syndrome withmemory and concentration disturbances,opsoclonus, and cerebral “pseudo-lymphoma” (lymphocytic infiltrate as aconsequence of local collection ofBorrelia in the cerebrum).

MyelitisThe clinical symptoms of the rare, acuteBorrelia myelitis include transversesensory and motor symptoms as well asbladder disturbances, usually accompa-nied by fever. These cannot bedifferentiated from myelitis of viralaetiology. Chronic myelitis, which wasdiagnosed more frequently in the past, isnow relatively rare and usually developsslowly over months to years.At first, thepatients notice increased fatigue whilewalking, more frequent stumbling,progressive reduction in walkingdistance and finally the development ofa spastic-ataxic gait disorder and urinarydysfunction.Two thirds of such patientswith para- or tetraparesis described inthe literature showed severe clinicalsymptoms [1, 9]. In about 60% ofpatients with myelitis, there were also

55

signs of encephalitis, and of these, 40%had additional cranial nerve paresis.Magnetic resonance imaging seldomshowed signal changes in the spinal cord.Borrelia-induced inflammation of thespinal cord and nerve roots (myelora-diculitis) can sometimes be painless orlack changes in sensitivity such as thosein a motor neuron illness. The causalrelationship between Borrelia infectionand the development of amyotrophiclateral sclerosis suggested by someauthors is based only on seroprevalence,and no case has been confirmed usingappropriate diagnostic tests.

Cerebral vasculitisIn rare cases, cerebral symptoms arecaused by Borrelia-induced cerebralvasculitis. More than a third of thereported cases occur in patientsyounger than 30 [24, 32]. Its course isusually acute, involving an infarct in theposterior basin (thalamus, brainstem)(Fig. 1), and can be fatal.Autopsies haverevealed obliterative vasculitis withsubstantial intima swelling and onlydiscrete fibrosis of the media butmarked thickening of the adventitiawith numerous lymphocytic infiltrates.Additionally, chronic lymphocyteinfiltration of the meninges was present.Diagnosis is based on positive serology,pathological CSF findings, MRI, andmagnetic resonance angiography. Dueto its rare aetiology, regular checks forantibodies in cases of cerebral insultare not necessary.

MyositisMyositis is considered a very rare mani-festation of borreliosis affecting themusculoskeletal system. The pain andparesis are usually focal, and muscleenzyme levels are seldom elevated.Histopathology shows nodular orinterstitial myositis with little degene-ration of the muscle fibres and fewmacrophage but many CD4-positive T-lymphocytes [31]. This findingdifferentiates Borrelia myositis fromother inflammatory myopathies in whichB-lymphocytes usually predominate.Diagnosis is supported by electromyo-graphy, clinical symptoms conforming tothe serology, and immunological andmolecular demonstration of Borreliaburgdorferi sensu lato in the biopsy.

Problem cases in clinical practiceBorrelia encephalopathyThis diagnosis comes predominantlyfrom the American literature and showsvarious unspecific symptoms such asreduced performance, increased fatigue,

Fig. 1. Brainstem infarct as a result of cerebral vasculitisdue to Borrelia

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Neuroborreliosis

irritability,emotional instability,as well asdisturbances in sleep, concentration, andmemory [22]. A causal relationshipbetween these symptoms andserologically determined Borreliainfection is hardly conceivable withoutevidence of inflammatory signs in theCSF and the persistence of symptomsafter antibiotic therapy. The positiveBorrelia serology in patients lackinginflammatory changes in the CSF, shouldbe interpreted instead as resulting froma clinically unapparent past infection(seroprevalence), and possible causes forthese symptoms other that Borrelia mustbe sought in the differential diagnostic.When, a positive Borrelia serology isassociated with inflammatory changes inthe CSF and other neurological deficits,all of these indications, singly or incombination, can be interpreted assymptoms of neuroborreliosis.

Post-Lyme syndromePost-Lyme syndrome (PLS) was definedin 1996 as a complex of symptoms thatpersist more than 6 months afterappropriately treated Lyme disease [6].Two groups of 23 patients of comparableage and gender who had receivedantibiotic treatment were compared,one group without persistent symptomsand the other without. Fibromyalgia wasdiagnosed in seven patients with PLS,three had chronic fatigue syndrome, andten had “other” mild symptoms. Patientswith PLS showed conspicuous deficitsin concentration and memory tests and

complained more frequently of sleepdisturbances and mood changes thanthe control population. It was concludedfrom these results that Lyme borreliosiscould lead to persistent complaints in aproportion of patients despite antibiotictreatment. It was not possible to showwhat factors, other than the Borreliainfection, were responsible fordevelopment of these symptoms.Elkins et al. examined 30 patients withPLS using psychological andneuropsychological tests [12]. Unlikeother authors, they could not findrelevant deficits compared with a normalgroup.The only feature observed was areduced proportion of positive emotions.However, such conspicuous emotionalfeatures are also found in chronic fatiguesyndrome patients with no history ofLyme borreliosis, calling into questionthe credibility of PLS as a cause.Klempner et al. examined 78 Borreliaantibody-positive and 51 antibody-negative patients with a history ofborreliosis and PLS in a double-blind,placebo-controlled study to test the valueof long-term antibiotic therapy (2 gceftriaxone for 30 days plus 200 mgdoxycycline for 60 days or placebo).Thestudy had to be stopped prematurely,as aninterim analysis showed that symptomssuch as muscle pain, fatigue, anddysaesthesia could not be eliminated bysuch treatment [25]. Similar results werefound in two other large-scale antibioticstudies,of which neither showed a positiveeffect on the unspecific symptoms [23,26].

57

A critical review of this literature showsno plausible evidence for a chronicLyme disease or PLS without proof ofpresence of the pathogen. In particular,immunological and microbiologicalfindings that could explain thepersistence of these unspecificsymptoms are lacking.

Fibromyalgia syndromeThe diagnostic criteria of fibromyalgiaare:- Generalised pain by anamnesis (i.e.

left- and right-sided, upper and lowerbody, axis skeleton)

- Pain on at least 11 of 18 tender pointswith finger pressure (nine on eachbody side)

- Insertion point of the cisternal muscles- Transverse processes of the spine

C5–7- Central upper edge of the M.

trapezius and M. supraspinatus- Cartilage/bone boundary of the

second rib- Radial epicondyle- Regio glutaea lateralis- Trochanter major- Medial fat pad of the knee proximal

to the line of the joint

In 1992 Dinerman and Steere describedthe appearance of fibromyalgicsymptoms during acute Lyme arthritisor up to 5 months after acute Lymedisease [10].Additional antibiotic therapyled to temporary improvement thatlasted only a few months. The authors

attributed this temporary success to asuggestive or placebo effect of theantibiotic, since sleep deficit, lack oftraining,and changed muscle metabolismcan act as trigger functions, as caninfections with various pathogens, headtrauma, and emotional factors. Steerediscussed the clinical differentiationbetween Lyme arthritis and fibromyalgiain his 1995 review article. Local jointinflammation predominates in Lymearthritis; whereas patients withfibromyalgia show generalised symptomssuch as increased fatigue, head, joint, andmuscle pain, diffuse paraesthesia, andconcentration disturbances [35]. Theappearance of fibromyalgia weeks ormonths after Lyme disease will bediscussed in a subsequent article by apanel of experts who are however quitecritical of any causal relationship toprevious Borrelia infection.A retrospective study conducted byShadick et al. compared the long-termresults of 186 patients with clinicallyprobable Lyme disease with those of167 control individuals with no evidenceof earlier Borrelia infection [33]. Sixyears after the acute illness, thefrequency of neurological and cognitivedeficits in the Lyme disease patientswas not higher than that of the controls.During the initial illness, patients in theborreliosis group complained mostly offever, headache, photophobia, and neckstiffness (symptoms of meningitis).Theauthors deduce from their results thatthe long-term prognosis for borreliosis

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Neuroborreliosis

is usually good and that fibromyalgia isnot a typical residual effect.As neither the pathogenesis noraetiology of fibromyalgia is known, thecause of the syndrome by some earlierevent, e.g. a Borrelia infection, cannotbe determined. This needs to be takeninto consideration when expert opinionis given. Most authors agree thatadditional antibiotic treatment does notlead to a cure of the symptoms. Aproportion of patients do howeverbenefit from anti-depressive therapywith serotonin re-uptake inhibitors.

Chronic fatigue syndromeDiagnostic criteria for chronic fatiguesyndrome (CFS).The main criterion of CFS is persistentfatigue or rapid tiring for at least6 months which:- Cannot be explained by another

illness and is recent- Does not result from a chronic stress

situation and can not be significantlyimproved by bed rest

- Is so pronounced that averageperformance is distinctly reduced

At least four secondary criteria of CFSmust be present at or after the onset offatigue and for diagnosis must persistfor at least 6 months:- Neck pain- Painful cervical or axillary lymph

nodes- Muscle pain- Wandering,noninflammatory arthralgia- Newly developed headaches

- Concentration problems anddisturbances in short-term memory

- No recovery after sleep- Increased, generalised fatigue

persisting >24 h after a previouslytolerated activity

Coyle et al. (1994) questioned theimportance of Borrelia infection to thedevelopment of CFS. They examined13 patients who had had borreliosis and12 controls without previous clinicalevidence of such disease [8]. The onlyremarkable result was notablevariations in the cerebrospinal fluid ofone third of subjects in both groups;however, a specific influence of Borreliainfection on the cerebrospinal fluidcould not be found.A similar result wasfound by Pollark et al., who examined138 CFS patients for antibodies toBorrelia burgdorferi sensu lato in a riskarea for this disease [29]. Only eightserum samples were borderline positive,but using immunoblot they werenegative. In various case control studiesa large number of pathogens, includingBorrelia burgdorferi sensu lato, andvarious other factors (gender, numberof childbirths, silicon implants, tendencyto depression) have been investigatedas possible causes of CFS, however noaetiology has been identified.To summarise, the aetiology andpathogenesis of CFS as well asfibromyalgia are still unknown, and acausal relationship with previous Borreliainfection has not been demonstrated.

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Pain syndromePain of unknown origin. Such pain, withno cause found by differential diagnosis,could indicate the beginning of Borreliaradiculitis if Borrelia antibodies arepresent in the serum. The next step islumbar puncture in order to test thispossible diagnosis. If the CSF findingsare normal, it is highly unlikely that thepain is related to a Borrelia infection,and the search for other causes must beintensified.Borrelia infections can cause, in rarecases, a complex regional pain syndrome(previously called Sudeck’s dystrophy).Treatment involves eliminating theinfection (e.g. by 1x2 g ceftriaxone/dayfor 14 to 21 days) and symptomatictherapy of the sympathetic nervoussystem-supported pain syndrome.

Health disturbancesA whole spectrum of health problemsare attributed to chronic borreliosis bypatients with positive Borrelia serology.This self-diagnosis is supported byappropriate questionnaires patternedafter that of Burrascano. Even whenthere is no doubt about the presence ofchronic Borrelia infection, as with ACAor chronic neuroborreliosis (withappropriate inflammatory indicationsin the CSF), persistent health problemscannot be assumed to stem fromchronic borreliosis in the absence oforgan-specific pathology consistent withthis diagnosis, despite positive Borreliaserology. Cost-benefit analyses speak

against speculative treatment ofunspecific symptoms in cases of positiveBorrelia serology.

Differential diagnosisIn cases of neuroborreliosis it isnecessary, in principle, to consider otherpathogens (bacterial and viral),autoimmunity (multiple sclerosis, lupuserythematosus), and granulomatousdiseases of the nervous system(neurosarcoidosis) in the differentialdiagnosis. In the USA it is necessary, inrare cases of polyneuropathy after atick bite, to consider a toxic or allergicneuropathy caused by tick saliva.

DiagnosticsThe diagnosis of neuroborreliosis isinitially determined clinically, thenconfirmed by serology and CSFanalysis. The probability of correctdiagnosis can be divided into differencegrades depending on clinical andlaboratory findings [19].

Possible neuroborreliosis:- Typical clinical picture (cranial nerve

deficits, meningitis/meningoradiculitis,focal neurological deficits)

- Borrelia-specific IgG and/or IgMantibodies in serum

- CSF findings not available

Probable neuroborreliosis is as “possibleborreliosis” but also with:- Positive CSF findings with lympho-

cytic pleocytosis, blood/CSF barrier

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Neuroborreliosis

disturbances, and/or intrathecalimmunoglobin synthesis and

- Elimination of other possible causesof the symptoms present

Certain neuroborreliosis is as “probableborreliosis” but also includes:- Intrathecal synthesis of Borrelia-

specific antibodies (IgG and/or IgM)in the CSF or

- Positive PCR for the CSF

Typical CSF findings for neuroborreliosisshow lymphocytic pleocytosis withnumerous plasma cells and a definitebarrier disruption (increased albuminand total protein levels). In addition, theacute form also displays pronouncedintrathecal IgM that progresses toinclude synthesis of both IgG and IgAin the chronic form. The diagnosis canbe confirmed by demonstration ofBorrelia-specific intrathecal antibodysynthesis.This can be done most easily bycomparing specific antibody con-centrations in the CSF and serum withrespect to the total immunoglobulinconcentrations in both compartments[21].An antibody concentration at least1.5 times higher per unit of immu-noglobin in the CSF indicates intrathecalsynthesis. Pathogen-specific intrathecalantibody synthesis can also bedemonstrated by different bandingpatterns using immunoblot when theimmunoglobulin concentrations in theCSF and serum are equivalent.Intrathecal Borrelia burgdorferi-specific

antibody production can persist formany years or decades.

TherapyCeftriaxone and cefotaxim, given forsufficient duration, are equally effectivefor treating neuroborreliosis [28]. Theformer shows very good in vitro resultsfor minimum inhibitory concentrationand availability in brain tissue. Bothantibiotics reach CSF concentrations upto ten times higher than required toinhibit bacterial growth, even under thephysiological conditions of the blood/CSFbarrier.The clinical value of ceftriaxonefor the treatment of erythema migrans,Lyme arthritis, and neuroborreliosis hasbeen described in numerous studies andcase reports.As a general rule, a dosageof 1x2 g ceftriaxone/day given over30 min is adequate. If the infusion is toorapid and/or the dose higher, thenprecipitation of a calcium salt ofceftriaxone in the gallbladder may occur(accumulation of biliary sludge). Suchprecipitates usually do not causesymptoms and disappear at theconclusion of therapy. If the therapy lastsmore than 2 weeks, sonography of thegallbladder should be done to check forbiliary sludge. The effect of treatmentduration on outcome has been clearlyshown in several studies. In one case,Borrelia burgdorferi sensu lato could beisolated from the CSF of a patient7 months after a 10-day ceftriaxonetreatment regimen [28,36];while anotherstudy showed a substantial number of

61

patients complaining of unspecificproblems weeks after short durationtreatment. Our own study with 101patients diagnosed with certain neuro-borreliosis showed no such findings orproblems after 14-day–21-day for chronicneuroborreliosis–treatment with ceftria-xone [20]. There are no criteria suppor-ting a longer duration.Thus a minimum14-day treatment should be given.

Although ceftriaxone showed clinicalefficacy equivalent to that of penicillinG in comparative studies, some authorsfind significant advantage in the once-a-day drug application and the higherbactericidal CSF concentrations attainedby the former. Pharmacological data onceftriaxone can be found at www.rxlist.com/cgi/generic3/ceftriax_cp.htm.The advantage of cefotaxim overceftriaxone lies in its lower biliaryexcretion (no accumulation of biliarysludge); its disadvantage is a shorterhalf-life with the resulting need of morefrequent application. Study resultsdemonstrate cefotaxime’s efficiency inboth acute and chronic forms ofborreliosis.Penicillin has a similar efficiency todoxycycline for certain forms of acuteborreliosis. In a Danish prospectivestudy, 170 neuroborreliosis patientswere successfully treated with 2x10mega penicillin G over 10 days [15].Doxycycline is probably the mostcommonly used antibiotic forborreliosis. Studies testing a new

antibiotic normally use doxycycline forcomparison. In most of these studies, itwas as effective as the alternative testsubstances. It has been tested usingvarious doses and durations oftreatment, and it is generally agreed thatthe minimum dose is 200 mg/day, with aminimum duration of 14 days. In casesof uncomplicated meningopolyneuritis,300 mg/day of doxycycline over 21 daysis a possible alternative to 2 g/dayceftriaxone over 14 days [11]. Controlledtests determining the optimal dose ofdoxycycline are not available.

Ophthalmological diseasesClinical pictureIn certain cases, Borrelia infection canalso lead to ophthalmologicalmanifestations: follicular conjunctivitis,interstitial keratitis, vitritis, iridocyclitis,episcleritis, anterior uveitis, choroiditis,and retinal vasculitis [3]. Visualdeterioration in cases of optic neuritisusually develops sub-acutely over severalweeks and only with early treatment cana good prognosis be given.

DiagnosticsAnamnesis, the clinical picture, andevidence of specific IgM and IgGantibodies support the diagnosis.However, they seldom demonstratecausality between Borrelia infection andthe ophthalmological illness. Only in thecase of papillitis can CSF findings confirmthe diagnosis. Culture of the pathogenand PCR do not play a role in confirming

62

Neuroborreliosis

diagnosis.

TherapyProspective studies are lacking due tothe rarity of these diseases. Fortreatment, primarily third-generationcephalosporins are recommended (e.g.2 g/day of ceftriaxone or 3x2 g/day ofcefotaxime) due to their favourablepenetration.

Case reportCase 1: acute neuroborreliosisA 45-year old male programmer firstexperienced mild back pain about3 weeks after a long hike in the BlackForest. Within a few days the pain haddisseminated to include the right leg, andits intensity increased to such an extentthat he visited his local physician. Thepatient showed a positive nerve stretchreflex, but neurological findings wereotherwise normal. The physiciansuspected a slipped disk and orderedMRI of the lumbar spine.A small lateralprotrusion was found at L4/5 but therewas no nerve compression. Primarytherapy therefore included analgesics,physiotherapy, and application ofwarmth. Despite these measures, thepain increased and the patient wasunable to sleep at night. Ten days afterthe pain began, he developed facialparalysis. The physician prescribedcortisone (100 mg prednisolone), whichdid not affect the paralysis, but the othersymptoms improved. Four days afterbeginning this treatment, the pain

increased again, this time to the extentthat the patient was admitted to hospital.Neurological examination showedperipheral, bilateral facial paralysis andmild impairment of foot lifting. Borreliaserology was positive for IgM and IgGantibodies, and CSF analysis showedlymphocytic pleocytosis with 200 cells/µl,an increased albumin quotient of 10x10-3,and intrathecal synthesis of IgM.At 1.3,the Borrelia-specific antibody index wasstill within normal limits. In spite of this,acute neuroborreliosis was suspectedbased on anamnesis and symptoms.Treatment with 2 g/day of ceftriaxonei.v. was started.After 3 days the patientreported marked reduction in pain andat the end of the 14-day treatment it haddisappeared completely. In addition, theleg paralysis was no longer apparent ondischarge from the hospital.The bilateralfacial paralysis disappeared completelyabout 6 weeks after the end oftreatment. Follow-up CSF examinationat 3 months showed normal cell countand an intact blood/CSF barrier,decreasing IgM synthesis, and low IgGsynthesis with evidence of oligoclonalbands.A year later, the Borrelia-specificantibody index was significantly higherat 2.5, indicating previous Borreliainfection of the nervous system, but CSFfindings remain normal.The patient wassymptom-free 6 weeks after the end oftreatment.

Case 2: chronic neuroborreliosisA 40-year-old female resumed jogging

63

in March 2000 after a 3-month winterpause and noticed a considerablereduction in her normal runningdistance. Despite training three times aweek, she remained unable to reach herprevious year’s distance,5 km at a stretch.She also noted an increased tendency tostumble not only in the forest but alsoon any uneven or rough surface. In June2000 she noticed light urinaryincontinence and increased micturition,which could not be explained throughurinalysis. The following August shestumbled over a curb in the darkness, fellto the ground, and broke her lower armafter an evening of dancing, when shehad also noticed a certain “stiffness”. Onadmittance to hospital, she mentionedinstability while walking, so a neurologistwas consulted. Further examination

showed pronounced ataxia whilestanding and walking as well as lightspastic paraparesis in the legs. Magneticresonance imaging of the brain and spinalcord for suspected multiple sclerosis waspathologically unremarkable.Subsequentlumbar puncture showed pleocytosis at100 cells/µl, total protein of 2500 mg/l,and intrathecal IgG synthesis of 70%.Test results for sarcoidosis, vasculitis,neurolysis, and HIV infection werenegative. However, the high Borrelia-specific antibody index of 5.8 wasoccasion for initiating a 3-week treatmentregimen with 2 g of ceftriaxone per day.Control examination of the patient’s CSF1 year later was unremarkable except forthe clear presence of oligoclonal bands,and both general and Borrelia-specificIgG synthesis.

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● References1. Ackermann R, Gollmer E, Rehse-Kupper

B (1985) [Progressive Borreliaencephalomyelitis. Chronic manifestationof erythema chronicum migrans disease ofthe nervous system] Progressive Borrelien-Enzephalomyelitis. ChronischeManifestation der Erythema-chronicum-migrans-Krankheit am Nervensystem.Dtsch Med Wochenschr 110:1039–1042

2. Bay I, Narayan K, Dail D, Sondey M,Hodzic E, Barthold SW, Pachner AR,Cadavid D (2004) Spinal cord involvementin the nonhuman primate model of Lymedisease. Lab Invest 84:160–172

3. Balcer LJ, Winterkorn JM, Galetta SL(1997) Neuro-ophthalmic manifestationsof Lyme disease. J Neuroophthalmol 17:108–121

4. Belman AL, Iyer M, Coyle PK, DattwylerR (1993) Neurologic manifestations inchildren with North American Lymedisease. Neurology 43:2609–2614

5. Berglund J, Stjernber L, Ornstein K,Tykesson-Joelsson K, Walter H (2002) 5-yFollow-up study of patients withneuroborreliosis. Scand J Infect Dis34:421–425

6. Bujak DI, Weinstein A, Dornbush, RL(1996) Clinical and neurocognitive featuresof the post Lyme syndrome. J Rheumatol23:1392–1397

7. Christen HJ (1996) Lyme neuroborreliosisin children. Ann Med 28:235–240

8. Coyle PK, Krupp LB, Doscher C, Amin K(1994) Borrelia burgdorferi reactivity inpatients with severe persistent fatigue whoare from a region in which Lyme disease isendemic. Clin Infect Dis 18 [Suppl1]:S24–S27

9. Depre A, Sindic CJ, Bukasa K, Bigaignon G,Laterre C (1988) [Borrelia burgdorferiencephalomyelitis] Formes encephalo-myelitiques de l’infection a Borreliaburgdorferi.Rev Neurol (Paris ) 144:416–420

10. Dinerman H, Steere AC (1992) Lymedisease associated with fibromyalgia. AnnIntern Med 117:281–285

11. Dotevall L, Hagberg L (1999) Successfuloral doxycycline treatment of Lyme disease-associated facial palsy and meningitis. ClinInfect Dis 28:569–574

12. Elkins LE, Pollina DA, Scheffer SR, KruppLB (1999) Psychological states andneuropsychological performances inchronic Lyme disease. Appl Neuropsychol6:19–26

13. Finizia C, Jonsson R, Hanner P (2001)Serum and cerebrospinal fluid pathologyin patients with sudden sensorineuralhearing loss.Acta Otolaryngol 121:823–830

14. Garcia-Monco JC, Benach JL (1997)Mechanisms of injury in Lyme neuro-borreliosis. Semin Neurol 17:57–62

15. Hansen K, Lebech AM (1992) The clinicaland epidemiological profile of Lymeneuroborreliosis in Denmark 1985–1990.A prospective study of 187 patients withBorrelia burgdorferi specific intrathecalantibody production. Brain 115 (Pt2):399–423

16. Hopf H (1975) Peripheral neuropathy inacrodermatitis chronica atrophicans(Herxheimer). J Neurol Neurosurg 38:458

17. James DG (1997) Differential diagnosis offacial nerve palsy. Sarcoidosis Vasc DiffuseLung Dis 14:115–120

18. Kaiser R (1995) Intrathecal immuneresponse in patients with neuroborreliosis:specificity of antibodies for neuronalproteins. J Neurol 242:319–325

19. Kaiser R (1998) Neuroborreliosis. J Neurol245:247–255

20. Kaiser R (2004) [Clinical courses of acuteand chronic neuroborreliosis followingtreatment with ceftriaxone]. Nervenarzt75:553–557

21. Kaiser R, Lucking CH (1993) Intrathecalsynthesis of specific antibodies inneuroborreliosis. Comparison of differentELISA techniques and calculation methods.J Neurol Sci 118:64–72

22. Kaplan RF, Jones-Woodward L (1997)Lyme encephalopathy: a neuropsycho-logical perspective. Semin Neurol 17:31–37

23. Kaplan RF,Trevino RP, Johnson GM, Levy

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L, Dornbush R, Hu LT, Evans J, WeinsteinA, Schmid CH, Klempner MS (2003)Cognitive function in post-treatment Lymedisease: do additional antibiotics help?Neurology 60:1916–1922 these are out ofalphabetical order

24. Keil R, Baron R, Kaiser R, Deuschl G(1997) [Vasculitis course of neuroborreliosiswith thalamic infarct] VaskulitischeVerlaufsform einer Neuroborreliose mitThalamusinfarkt. Nervenarzt 68:339–341

25. Klempner MS, Hu LT, Evans J, Schmid CH,Johnson GM, Trevino RP, Norton D, LevyL,Wall D, McCall J, Kosinski M,WeinsteinA (2001) Two controlled trials of antibiotictreatment in patients with persistentsymptoms and a history of Lyme disease.N Engl J Med 345:85–92

26. Krupp LB, Hyman LG, Grimson R, CoylePK, Melville P, Ahnn S, Dattwyler R,Chandler B (2003) Study and treatment ofpost Lyme disease (STOP-LD): arandomized double masked clinical trial.Neurology 60:1923–1930

27. Peltomaa M, Pyykko I, Seppala I,ViljanenM (1998) Lyme borreliosis – an unusualcause of vertigo. Auris Nasus Larynx25:233–242

28. Pfister HW, Preac-Mursic V, Wilske B,Schielke E, Sorgel F, Einhaupl KM (1991)Randomized comparison of ceftriaxone andcefotaxime in Lyme neuroborreliosis. JInfect Dis 163:311–318

29. Pollark RJ, Komaroff AL,Telford SR, Gleit,Fagioli L, Brunet LR, Spielman A (1995)Borrelia burgdorferi infection is rarely

found in patients with chronic fatiguesyndrome. Clin Infect Dis 20:467–468

30. Ramesh G, Alvarez AL, Roberts ED,Dennis VA, Lasater BL,Alvarez X, PhilippMT (2003) Pathogenesis of Lymeneuroborreliosis: Borrelia burgdorferilipoproteins induce both proliferation andapoptosis in rhesus monkey astrocytes. EurJ Immunol 33:2539–2550

31. Reimers CD, Koning J de, Neubert U,Preac-Mursic V, Koster JG, Muller-FelberW, Pongratz DE, Duray PH (1993) Borreliaburgdorferi myositis: report of eightpatients. J Neurol 240:278–283

32. Schmiedel J, Gahn G, Kummer R von,Reichmann H (2004) Cerebral vasculitiswith multiple infarcts caused by lymedisease. Cerebrovasc Dis 17:79–81

33. Shadick NA, Phillips CB, Sangha O,Logigian EL, Kaplan RF,Wright EA, FosselAH, Fossel K, Berardi V, Lew RA, LiangMH (1999) Musculoskeletal and neurologicoutcomes in patients with previously treatedLyme disease.Ann Intern Med 131:919–926

34. Stanek G, Flamm H, Groh V, Hirschl A,Kristoferitsch W, Neumann R, SchmutzhardE, Wewalka G (1987) Epidemiology ofborrelia infections in Austria. ZentralblBakteriol Mikrobiol Hyg [A] 263:442–449

35. Steere AC (1995) Musculoskeletalmanifestations of Lyme disease.Am J Med98:44S–48S

36. Treib J, Fernandez A, Haass A, Grauer MT,Holzer G, Woessner R (1998) Clinical andserologic follow-up in patients withneuroborreliosis. Neurology 51:1489–1491

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IntroductionLyme borreliosis is the most commontick-borne disease in the northernhemisphere. It does not occur in thesouthern hemisphere.As a multisystemdisease it affects many organs, inparticular the skin, nervous system,joints, and heart [58, 69, 70]. Due to thewide variety of symptoms, testing forantibodies against Borrelia spp. is themost commonly requested serologicaltest. In Europe, microbiologicaldiagnostics must take into account theheterogeneity of the pathogen.

Heterogeneity of Borreliaburgdorferi sensu lato and itssignificance for thediagnostics of Lyme borreliosisAt least four Borrelia species causeLyme disease in Europe, Borreliaburgdorferi sensu stricto, Borreliaafzelii, Borrelia garinii, and the till nowrarely found Borrelia spielmanii (Fig.1). Up to now, we have found Borreliaspielmanii four times (all from patientswith erythema migrans) after analysing

242 isolates from European patients(Fingerle and Wilske, unpublisheddata). In contrast, Borrelia burgdorferisensu stricto is the only Borrelia spp.pathogenic to humans in the USA [76].The three most important humanpathogenic species in Europe compriseat least seven outer surface protein A

Lyme borreliosis diagnostics● Volker Fingerle, Bettina Wilske

Fig. 1. Heterogeneity of Borrelia burgdorferi sensu lato.Yellow rectangles, known human pathogens; green rec-tangle, human pathogenicity unclear; orange rectanglenonpathogenic for humans

B. spielmanii

B. bissettii

B. japonica

B. andersonii

B. turdi

B. tanukii

B. sinica

B. valaisiana

B. lusitaniae

B. afzelii

B. garinii

B. burgdorferi s.s.

B. burgdorferi s. l. complex

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Lyme borreliosis diagnostics

(OspA) serotypes [83]. Skin isolates arepredominantly Borrelia afzelii (OspAtype 2), particularly those from patientswith acrodermatitis chronicaatrophicans, which incidentally is alsonot found in the USA [10,53,83]. Isolatesfrom CSF and ticks are variable but showa predominance of Borrelia garinii(OspA types 3-7) [18, 72, 79, 83].Sequence analysis of OspA ampliconsusing polymerase chain reaction (PCR)on arthrocentesis from patients withLyme arthritis are distinctlyheterogeneous [17, 73]. Other PCRstudies showed mostly Borreliaburgdorferi sensu stricto (5S/23S rRNAintergenic spacer PCR [48] or flagellinPCR [35, 36]).Borrelia afzelii and Borrelia garinii arethe most common European species.The third most common, Borreliaburgdorferi sensu stricto, is particularlyrare in eastern Europe (see review byHubalek and Halouzka 1997 [32]). Agreat deal of heterogeneity can occureven in very small areas [18, 21, 49, 61,64] however, distinct regionalaccumulations of certain species orsubspecies have also been observed [45,49, 55]. Multispecies infections in tickshave also been reported [32], althoughsuch infections are less commonly foundin humans [14, 73, 79].The heterogeneityof the pathogen (Fig. 1) makes thediagnostics of Lyme borreliosis inEurope substantially more difficult thanin the USA and must be taken into

consideration in the development ofdiagnostic reagents such as PCR primersand antigens.Thus when considering thefrequently used OspA PCR, it isimportant that not only representativesof all human pathogenic species bedetected but also the various OspAtypes of the heterogeneous Borreliagarinii group [18]. In addition, PCRshould also distinguish Borreliavalaisiana and Borrelia lusitaniaebecause both are potential humanpathogens, as indicated by a number ofPCR and culture results [63, 75, 78].Werecently developed a powerful OspAPCR assay to determine anddifferentiate the various Europeanspecies and OspA subtypes [49]. Inserodiagnostic procedures, the strains’hetergeneity must also be taken intoaccount, as certain important diagnosticproteins are decidedly heterogeneousand thus differ in their reactivity withpatient sera. For example, amongrepresentative strains of Borreliaburgdorferi sensu stricto, Borrelia afzelii,and Borrelia garinii (B31, PKo, and PBi),amino acid sequence identities forDbpA (Osp17) are 40–44%, and thosefor OspC are 54–68%. DbpA inparticular has much greater amino acidsequence heterogeneity than DNAheterogeneity, which indicatesimmunoselection. Interestingly, highlyheterogeneous proteins can still showhighly conserved immunogenic epitopes(e.g. the C6 peptide from VlsE) [46, 47].

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Microbiological diagnosticsQuality standards for themicrobiological diagnosisof Lyme borreliosisThe German Society for Hygiene andMicrobiology (DGHM) has publishedquality standards for the diagnosis ofLyme borreliosis formulated by acommittee of experts (MiQ 12 Lyme-Borreliose) [86].The free English versionis available at http://www.dghm.org/red/index. html?cname=MIQ.Except for the pathognomic clinicalmanifestation of erythema migrans, thediagnosis of Lyme borreliosis normallyrequires microbiological confirmation.For this purpose, determination of thepresence of antibodies is usually used,while demonstration of the pathogenusing culture or PCR is limited to specialcases, for example with ambiguousserological test results or difficult clinicalcases. Demonstration of the pathogen’spresence should be made only inspecialised laboratories.

Detection of the pathogenDetection using cultureCulture using modified Kelly medium

[59, 85], which expends considerabletime and material, can help in specialcases when the clinical picture stronglysuggests Lyme borreliosis despitenegative serology (seronegative Lymeborreliosis) [86]. Such cases may involveatypical erythema migrans, especiallyacute neuroborreliosis with shortdisease duration and no proof ofantibodies in the CSF, or patients withimmunodeficiency. The sensitivity ofpathogen detection in culture isgenerally poor (Table 1).

Detection using PCRCurrently no standard procedures areavailable for either sample preparationor the PCR itself. Borrelia PCR shouldenable diagnosis of the Borrelia species,i.e. the laboratory report should supplyinformation on which humanpathogenic species is present. Thediagnostic sensitivity of PCR isapproximately the same as for culture,whereas it is distinctly easier to detectBorrelia in tissue than in body fluids [2,6, 35, 39, 44, 71, 87]. Only in the case ofsynovial fluid is PCR appreciably betterthan culture (Table 1; [52]).

Table 1. Sensitivity of culture and PCR methods for detecting Borrelia burgdorferi

Sample Sensitivity

Skin (erythema migrans, acrodermatitis) 50–70% with culture or PCRCerebrospinal fluid (acute neuroborreliosis) 10–30% with culture or PCRSynovial fluid* (Lyme arthritis) 50–70% with PCR

(culture is extremely seldom positive)

*higher sensitivity with synovial biopsy compared to synovial fluid

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Detection of antibodiesto Borrelia burgdorferiIt is generally accepted that serologicalexamination should follow a two-stepapproach [12, 37, 85, 86]: (1) serologicalscreening which, only if reactive, shouldbe followed by (2) a confirmatoryexamination. A sensitive screeningprocedure is recommended, e.g.

enzyme-linked immunosorbent assay(ELISA) or a similar procedure suchas chemiluminescence immunoassay(CLIA), which can be confirmed byimmunoblot if reactivity is present.

Screening procedure. At least animproved second-generation test (usingfor example recombinant material as

Table 2. Reactivity of the various homologues of VlsE and DbpA using line immunoblot for early manifestations.Data from Goettner et al. 2005

A. IgG reactivity

DbpA from DbpA VlsE from VlsEQuantity PBie PBr PKo B31e reactive PBie PKoe PKa2 reactive(n) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%)

EMa 15 0 2 4 1 5 12 9 6 12(0,0) (13,3) (26,7) (6,7) (33,3) (80,0) (60,0) (40,0) (80)

NBb 50 19 20 17 6 39 44 41 41 46(38,0) (40,0) (34,0) (12,0) (78,0) (88,0) (82,0) (82,0) (92,0)

Controlsc 110 2 2 0 0 4 1 3 0 4(1,8) (1,8) (0,0) (0,0) (3,6) (0,9) (2,7) (0,0) (3,6)

B. IgM reactivity

DbpA from DbpA VlsE from VlsEQuantity PBie PBre PKoe B31e reactived PBie PKoe PKa2e reactived

(n) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%)

EMa 15 0 0 1 0 1 8 4 3 8(0,0) (0,0) (6,7) (0,0) (6,7) (53,3) (26,7) (20,0) (53,3)

NBb 50 9 13 2 0 22 26 7 6 28(18,0) (26,0) (4,0) (0,0) (44,0) (52,0) (14,0) (12,0) (56,0)

Controlsc 110 0 1 0 0 1 6 0 0 6(0,0) (0,9) (0,0) (0,0) (0,9) (5,4) (0,0) (0,0) (5,4)

aErythema migransbNeuroborreliosiscSera from blood donors were used as controls n=60, patients with syphilis n=10, patients with feverof unknown origin n=30, rheumatic factor-positive sera n=10dAt least one homologous protein reactiveeThe Borrelia strains belong to the following species: PBi to Borrelia garinii OspA type 4, PBR to B. gariniiOspA type 3, PKo to Borrelia afzelii, and B31 and PKa2 to Borrelia burgdorferi

71

antigen) should be used for the screeningprocedure [86] due to possible cross-reactions with other bacteria.The strainsused as a source of antigens shouldexpress OspC, the dominant antigen ofthe IgM immune response, and DbpA,an immunodominant antigen of the IgGresponse [86]. Recently, specificrecombinant antigens (e.g VlsE) orsynthetic peptides (e.g. the C6 peptidederived from VlsE) were usedsuccessfully on samples from American[4, 43, 47] and European patients [20, 22,46, 54]. Moreover, DbpA which, likeVlsE, is often hard to extract fromBorrelia in culture, has also proved tobe a sensitive antigen [22, 54] (Table 2).

Confirmatory test (immunoblot). As aconfirmatory test, immunoblot requiresa high specificity of at least 95%. Usingrecombinant antigens, the identificationof diagnostic bands is substantiallyeasier than with lysate blots.The American immunoblot criteriarecommended by the centers for diseasecontrol cannot be applied in Europe [28,29, 65]. Dressler et al. [16] have shownthat the immune response of Europeanpatients is confined to a markedlynarrower spectrum of Borrelia proteinsthan that of American patients. In a studyusing sera from Germany and anotherusing sera from various Europeancountries, Hauser et al. have shown thatstrain-specific criteria for interpretationmust be defined [28, 29]. Different rulesfor interpretation must therefore be

established in order to achieveequivalent sensitivity and specificityusing different Borrelia strains forimmunoblot antigens. The criteria forinterpreting immunoblots recommendedby the DGHM were published in “MiQ12 Lyme-Borreliose” [86].

Patients with early manifestations havean immune response based on only afew proteins, while those with latemanifestations (acrodermatitis orarthritis) have IgG antibodies againsta broad spectrum of antigens (Fig. 2).Using recombinant antigens has anumber of advantages over the use ofwhole cell lysate antigen: (a) specificantigens can be selected (e.g. p83/100,BmpA), (b) homologous antigens fromvarious strains can be combined (e.g.DbpA [Osp17], OspC, BmpA), (c)truncated antigens with a higherspecificity can be produced (internalflagellin fragment), and (d) antigensexpressed primarily in vivo but not inculture are available (e.g. DbpA and inparticular VlsE [30, 67, 81]). Commercialrecombinant blots can be betterstandardised than whole cell lysate blots.The sensitivity of immunoblots basedon recombinant antigens has beenimproved considerably in the last fewyears by additional antigens and theestablishment of line immunoblots [22,67, 81]. For the first time, this hasallowed significantly higher sensitivitywith recombinant immunoblots thanwith whole cell lysate blots.

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Recombinant immunoblot technology isan essential step towards standardisingand increasing sensitivity, as homologousantigens from various strains (especiallythose with low sequence identity such asDbpA) and antigens that are onlyexpressed in vivo (e.g.VlsE) can be used.

Serological results at variousstages of the diseaseSerological test results must always beinterpreted in relation to the clinicalfindings. For this, case definitions arehelpful [60, 68, 86]. In stage I(erythema migrans), only 20–50% of

patients are seropositive for IgMand/or IgG antibodies [3, 26, 77] (Table3), and IgM antibodies are prevalent.A possible exception is the immuneresponse to VlsE. In American patientswith erythema migrans, VlsE IgGantibodies were detectable before theBorrelia-specific IgM response (44%vs 19% of patients in acute erythemamigrans and 59% vs 43% in convale-scent erythema migrans) [4]. InEuropean patients with erythemamigrans, earlier IgG response againstVlsE was observed in 20 of 23 casesconfirmed by culture (87%). The IgM

Fig. 2. Line immunoblot: IgG immune response in patients with various manifestations of Lymeborreliosis. Late Lyme borreliosis: sera from patients with acrodermatitis chronica atrophicansor Lyme arthritis. The Borrelia strains belong to the species: PBi to Borrelia garinii OspA type4, PBR to Borrelia garinii OspA type 3, 20047 to Borrelia garinii unknown OspA type, PKo toBorrelia afzelii, and B31 and PKa2 to Borrelia burgdorferi sensu stricto

Early LB

Antigen (Strain) Erythema migrans Neuroborreliosis

Late LB Controls

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response was not studied [46]. In stageII (acute neuroborreliosis), the rate ofseropositivity increases (IgM and/or IgGantibodies) to 70–90% [24, 25, 80, 82].In principle, patients with earlymanifestations can be seronegative,particularly those with short-term illness.A check of the serological course shouldbe done in such cases. At 6 weeks ormore after onset of the disease, 100%of stage II neuroborreliosis patients areseropositive [24]. In cases with latemanifestations (stage III, acrodermatisand arthritis), IgG antibodies could bedemonstrated in all patients examined[26, 37, 80, 82]. A negative IgG testtherefore speaks against diagnosis oflate-stage Lyme borreliosis. A positiveIgM test with negative IgG is likewisenot diagnostically relevant for late-stageLyme borreliosis [86].For the diagnosis of neuroborreliosis,evidence of intrathecal antibodyproduction (i.e. in the CSF/serumindex) is particularly important [84].Combined with additional changes inthe CSF such as lymphocytic pleo-cytosis and barrier disturbance, thisprovides decisive diagnostic evidence.

For diagnosing chronic borreliosis ofthe central nervous system, a positiveIgG CSF/serum index is essential (seeEUCALB case definitions [68, 86]),whereas chronic peripheral neuropathyusually displays no intrathecal antibodyproduction [42].As serological results can varysubstantially and antibodies can persistfor a long time even in successfullytreated patients, serological coursecontrols are not suitable fordetermining therapy failure. Untilrecently, a fall in VlsE specificantibodies was considered an indicatorfor the success of therapy [57]. Thiscould not however be confirmed in aEuropean study [56].The presence of specific antibodies doesnot indicate the presence of a clinicalmanifestation. Antibody tests can alsobe positive due to previous clinical orsubclinical infection. The less specificthe patients’ symptoms are, the less isthe positive predictive value. In normal,healthy individuals, seropositivity varieswith age and outdoor activity (e.g. in astudy from Bavaria between 5% and20% [62]).

Table 3. Sensitivity for the presence of antibodies in cases of Lyme borreliosisStage Sensitivity Antibody class

I 20-50% Predominantly IgM

II 70-90% With short-term illness predominantly IgM,with longer-term illness predominantly IgG

III Near 100% Usually only IgGa

aThe presence of IgM antibodies without IgG is not diagnostic for late manifestation

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Methods not recommendedfor the diagnosis of LymeborreliosisEvidence of borreliosis from atick removed from a patientExamination of ticks for the presenceof Borrelia burgdorferi is valuable onlyif (1) with a negative test result thereis sufficient certainty that no infectionwith Borrelia burgdorferi has occurredor (2) with a positive result there issufficient likelihood of a clinicalmanifestation of the infection.The following points must beconsidered for evaluating this methodof examination:1.Not every tick bite is discovered.

Ixodes ricinus larvae and nymphs canhardly be recognised by normal visionand are often unconsciously removedwith a fingernail.Thus, negative resultscan lead to a false sense of security,and infection can be contractedthrough the unrecognised bite.

2.Infected ticks usually do not transmitthe pathogen through biting, and,should an infection result, only somecases become clinically relevant (e.g.Nahimana et al. [51] in which onlythree of 17 individuals who sero-converted became clinically ill).

3.The diagnostic sensitivity andspecificity of the various methods foranalysing ticks is largely unclear.Influencing factors include transporttime, DNA extraction, presence ofinhibitory substances (e.g. haemo-globin or scutum of the tick),

laboratory contamination and thegenetic heterogeneity of Borreliaburgdorferi sensu lato.

4.The great majority of the resultingillnesses are simple to diagnose andefficiently to treat [34].

5.No European study has been able todemonstrate that antibioticprophylaxis or therapy following abite by an infected tick has moreadvantages than disadvantages.

To summarise, examining ticks removedfrom humans for Borrelia burgdorferisensu lato cannot be recommended.Thereasons are the low infection andmanifestation rates, insufficient negativeand positive predictive value of themethod, good disease prognosis, and noevidence of a reasonable prophylactictreatment.Action useful after tick biteshas been proposed by a group ofexperts [38].

Significance of the lymphocytetransformation testIn principle, the lymphocytetransformation test (LTT) measuresproliferation of lymphocytes in patientblood after stimulation with an antigen(e.g. sonicated Borrelia, recombinantBorrelia antigens).The test is thereforean attempt to determine cellularimmunity against specific antigens. In1988, Dattwyler et al. showed that LTTcould be positive even in cases ofseronegative chronic borreliosis thatdeveloped after prompt treatment for

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an early manifestation [13]. However, aseries of studies published since thenhave shown no advantage of LTT overserology in routine Lyme borreliosisdiagnostics [5, 9, 15, 19, 31, 33, 40, 66, 74].Krause et al. used LTT to examine 24patients with various manifestations ofLyme disease and 30 patients witharthritis of unrelated aetiology as acontrol group, including also 20 healthyindividuals [40]. For proof of antibodies,the sensitivity was 83% and specificity92%. For LTT with a specificity of 92%,the sensitivity was 71%, while for asensitivity of 83% the specificity was 72%.Krause recently questioned whether LTTcould contribute to routine clinicaldiagnostics. In addition, due to the test’slow specificity,he re-emphasised the highlikelihood of false positive results andconcluded that LTT should not be usedfor the diagnosis of Lyme borreliosis [41].Dressler et al. examined 42 patientswith chronic Lyme borreliosis and 77control individuals [15]. A sonicatedBorrelia burgdorferi sensu stricto strainwas used as antigen. The sensitivity ofthe test was given at 45% (serology93%) with specificity of 95%. (No datawere provided for serology.) Four ofnine laboratory personnel examinedalso were positive using LTT.In 1996 Huppertz et al. examined 55children with Lyme arthritis and 48control patients [33]. Two unsonicatedBorrelia burgdorferi sensu stricto strainswere used as the antigen source. Thesensitivity of the test was 77% with a

specificity of 78%. For eight of thechildren with Lyme arthritis, thestimulation index was negative beforetherapy but positive after therapy. Inthe authors’ opinion, their studydemonstrates that the test is valuablefor neither prognosis nor control of thedisease course. They concluded:“Lymphocyte proliferation assay willrarely aid in finding the correct diagnosiswhen clinical presentation and anti-borrelial serology do not match.”The studies of LTT to date show that itis not well standardised and, comparedwith serology, is less sensitive andparticularly less specific.Therefore, LTTis not suited for routine diagnosis ofLyme borreliosis.Meanwhile, the ELISPOT test (acommercially available LTT modifi-cation) has been recommended forhuman granulocytic ehrlichiosis,including an indication that co-infectionhas considerable significance for theprognosis and course of infection withBorrelia. Here we would point out thatto date no case of autochthonous humangranulocytic ehrlichiosis in Germanyhas been published and therefore useof this test is already questionable onepidemiological grounds.

The significance of cysticforms of Borrelia burgdorferiSo-called cystic forms, also known asspheroblasts, forms without cell walls, orL forms, can be induced in vitro byvarious stress factors such as culture in

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CFS, extreme changes in pH value, andincreased temperature [1, 7, 8, 50]. PurelyL forms proved infectious to mice [23].Whether these forms are significant forpathogenesis of the disease or todiagnostics is however still unclear. Inthe meantime, assays allegedly specificfor the Borrelia burgdorferi sensu latoform without cell walls are available.However, they have not been adequatelyevaluated and thus cannot berecommended for Lyme borreliosisdiagnostics [11].

The visual contrastsensitivity testThe visual contrast sensitivity test(VCS) has been recommended byHartmann and Müller-Marienburg forchronically ill patients with unspecificsymptoms such as myalgia, muscle

twitching, joint pain, low energy, fatigue,diarrhea, constipation, and similarsymptoms [27].This test is based on thehypothesis that Borrelia burgdorferiproduces a lipophilic neurotoxin which,among other activities, binds to theoptic nerves, making the diseasedetectable using a VCS test due toreduced function, i.e. a deficit inrecognising grey tones [27]. We do notknow of any scientific publication thatsupports the suppositions on which thistest is based. As the neurotoxin issubject to the enterohepatic circulation,it is also recommended that chole-styramine be used to break the toxiccycle.From our point of view, we urgentlyadvise against therapy with cholesty-ramine and the use of VCS tests for thediagnosis of Lyme borreliosis.

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Göbel, UB, Stanek, G unter Mitarbeit vonHW Pfister. MIQ 12 Lyme-Borreliose. InQualitätsstandards in der mikrobiologischinfektiologischen Diagnostik. Edited byMauch H and Lütticken R; im Auftrag derDeutschen Gesellschaft für Hygiene undMikrobiologie (DGHM). Urban & FischerVerlag, München Jena; 2000 (english version:http://www.dghm.org/red/index.html?cname=MIQ)

87. Zore, A.; Ruzic-Sabljic, E.; Maraspin, V.;Cimperman, J.; Lotric-Furlan, S.; Pikelj,A.;Jurca, T.; Logar, M.; Strle, F. Sensitivity ofculture and polymerase chain reaction forthe etiologic diagnosis of erythemamigrans. Wien. Klin. Wochenschr.:114(2002)606-609

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Dr. med. Thomas TalaskaPraxis für Mikrobiologie und Infektionsepidemiologie Rudolf-Breitscheid-Str.1015295 Groß [email protected]

Prof. Dr. med. Andreas KrauseImmanuel Krankenhaus GmbHRheumakliniken Berlin-Wannsee und Berlin-BuchKönigstr.63 Karower Str.1114109 Berlin 13125 [email protected]

Prof. Dr. med. Elisabeth AbererUniversitätsklinik für DermatologieMedizinische Universität GrazA-8036 [email protected]

Prof. Dr. med. Reinhard KaiserNeurologische KlinikKlinikum Pforzheim GmbHKanzlerstraße 2-675175 [email protected]

Dr. med. Volker FingerleMax von Pettenkofer-Institut, LMU MünchenNationales Referenzzentrum für Borrelien Pettenkofer-Strasse 9a80336 [email protected]

Prof. Dr. med. Bettina WilskeMax von Pettenkofer-Institut, LMU MünchenNationales Referenzzentrum für Borrelien Pettenkofer-Strasse 9a80336 [email protected]

● Contacts

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