Encephalitis

Encephalitis:

1. Einführung(Symptome,ErregerübersichtundpathophysiologischeProzesse)

2. EncephalitisdurchdirektenVirusbefalldesZNS(Bsp.Herpessimplex)

3. GleicherErregeraberverschiedenepathogenetischeMechanismen(Bsp.Masern)

4. ImmunologischbedingteEncephalitiden: Auslöser?(Viren,andereMechanismen)

5. WennderSpaziergangdurchdenWaldgefährlichwird:durchInsektenübertrageneEncephalitis(Bsp.Zeckenencephalitis)

Vortragsübersicht

ViraleInfektedesZNSWegederNeuroinvasion:

- Neuraler Wege Rabies VirusHerpes simplex VirusVaricella-Zoster Virus

- Olfaktorischer Weg Herpes simplexArboviren

- Hämatogener Weg EnterovirenCytomegalievirusEpstein Barr VirusMumps, MasernAdenoviren, FilovirenLymphocytäre ChoriomeningitisArboviren, HIV, HTLV

ViraleEncephalitis

Hauptsymptome:- Bewusstseinsstörungen- FokaleneurologischeAusfälle- EpileptischeAnfälle- Übelkeit,Erbrechen- Temperaturinstabilität- ev.Diabetesinsipidus- ev.inadaequate ADH– Sekretion- ev.HirnstammbeteiligungmitAtaxie,Hirnnervenausfällen,Nystagmus,pyramidalenSymptomen

Prodromi:- Fieber- Kopfschmerzen- Merkfähigkeitsstörungen

Krankheitspektrum undTherapieeinigerneurotroper VirenErreger Encephalitis Myelitis Vaskulitis Therapie(Evidenzstärke)

Adenovirus + + - -

HSV-1 + + + Aciclovir (Ia),Famciclovir,Foscarnet (Ib)

VZV + + + Aciclovir (1a)

EBV + + + Ganciclovir (V)

CMV + + Foscarnet,Ganciclovir (Ib)

HHV6 + + + Foscarnet (V)

Parvovirus B19 + + +

FSME + +

Mumps-Virus + + +

Masern-VirusSSPE

++

Ribavirin (V)Inosiplex +aIFN (Ib)

Echo-/Rotavirus + +

InfluenzaA + + + Amantadine (V)

Encephalitis

Erreger(Virus)

Ak gegenneuraleMembranproteine

undJonenkanäle

Tumore+andereendogene

Immunmechanismen

PersistenzMutation

desErregers

Pathogenese

HerpessimplexEncephalitis

DerKlassikermitverschiedenen

Problemen

Symptome:- Bewusstseinsstörungen 96 -100%- Fieber 78 - 95%- Kopfschmerzen und Meningismus 74 - 81%- Epileptische Anfälle 59 - 67%- Persönlichkeits-, Verhaltensstörungen 68 - 87%- Fokale neurologische Ausfälle 26 - 79%- Ein Teil der Patienten

mit Operculum Syndrom(Gesichtslähmung, Dysarthrie und Dysphagie)

mit Choreathetosemit Klüver-Bucy Syndrom (fehlende Empathie und Angstreaktion,

orale Automatismen)- Aphasie, Sprechstörungen 12 - 65%- Meningismus 13 - 38%

Herpessimplex Encephalitis

Gnann JWundWhitley RJ2017

HerpesEncephalitisDiagnostische Untersuchungen:1. Liquor: Zellzahl, Granulocyten < Lymphocyten

+ Erythrocyten (abnorm > 95%)Liquoreiweiss é > 80%Antikörper auf HSVPCR auf Herpesviren (gold standard)sensitiv 98% und spezifisch 94%Cave! falsch negativ Resultate währendden ersten Krankheitstagen, LP nach 3 – 4 Tagen wiederholen

2. EEG: sensitiv aber nicht spezifisch3. MRI: sensitiv mit Signal Anhebung

(T2, DWI und Flair)4. Hirnbiopsie nur in Ausnahmesituationen

Liquorbefunde beiHerpessimplex Encephalitis

CSF is very insensitive, with HSV detected by culture in fewerthan 5% of patients with biopsy-proven HSE.

The diagnostic test of choice for HSE is demonstrationof HSV DNA in CSF using a polymerase chain reaction(PCR) assay [61–63]. In HSE caused by HSV-1, the sensi-tivity of PCR is estimated to be 98% with specificity 94–99%. The Simplexa™ HSV-1 and 2 Direct kit (FocusDiagnostics) is FDA-approved for detection of HSVDNA in CSF [64]. However, many laboratories continueto utilize PCR assays that were developed in-house andmay have variable sensitivity and specificity. Use of type-specific primers allows discrimination between HSV-1 andHSV-2. CSF positive for HSV-2 by PCR is indicative ofeither HSE caused by HSV-2 (rare) or HSV-2 meningitis(more common), although the two syndromes are usuallyclinically distinguishable.

PCR is usually positive within 24 h of symptom onset andremains positive during the first week of acyclovir therapy.Negative CSF PCR has been reported in HSE patients whowere tested very early in their clinical course [65, 66]. If theclinical presentation is strongly suggestive of HSE, but theinitial CSF PCR is negative, acyclovir therapy should be

continued and the patient should undergo a second lumbarpuncture; the PCR is usually positive when the patient isretested. False-negative PCR results may also occur as a resultof a suboptimal assay or due to the presence of an inhibitorysubstances in CSF (e.g., blood). False positive results are rare,but occasionally occur (as with any PCR-based assay), mostlikely due to laboratory cross-contamination.

The duration of PCR positivity in the setting of acyclovirtherapy has not been well-defined but is at least 7 days [62].After 10–14 days of acyclovir therapy, the HSV DNA in CSFwill usually become undetectable (although detection of HSVDNA beyond 2 weeks has been described) [62, 67]. Thismeans that there is a wide window for repeat PCR testing ifthe original CSF is negative, even if acyclovir therapy hasbeen initiated. A longer duration of CSF PCR positivity hascorrelated with poor outcome in some reports [68].

The availability of PCR has largely eliminated the need forbrain biopsy, which was previously the definitive diagnostictest. Brain biopsy may still be necessary in unusual caseswhen the clinical and radiographic evidence suggest HSE,but the PCR is repeatedly negative. HSV can be identified inbiopsied brain tissue by PCR, viral culture, in situ hybridiza-tion, or immunohistochemical staining. Assays for detectionof HSV antigens and anti-HSV antibodies in CSF have beendescribed but have been replaced by PCR. These tests mayoccasionally be useful as an alternative to brain biopsy inunusual cases where HSE is strongly suspected, but the PCRis nondiagnostic [69, 70].

Quantitative PCRmethodology has been utilized in a smallnumber of HSE cases and demonstrates a decline in CSF viralload over the course of acyclovir therapy [30, 67, 71].Whether the magnitude of the CSF viral load predicts out-come is uncertain. Several investigators have found no corre-lation between quantitation of HSV DNA in CSF and severityof clinical disease and prognosis [67, 68, 72–74]. Other stud-ies have demonstrated a positive correlation between higherCSF viral load and poorer clinical outcome [71, 75].

Table 2 Cerebrospinal fluid findings in patients with herpes simplexencephalitis

Laboratory test Typical finding

Leukocytes 25–75/mm3 (range 0–>500)

Percent lymphocytes 75–90% (range 60–98%)

Glucose 60–75 mg/dL (about 25% of patients will haveCSF glucose <50% of serum glucose level)

Protein 65–85 mg/dL (about 60–70% of patients willhave elevated CSF protein)

Not every finding was reported for every patient. Compiled from 302reported HSE cases [16–19, 77, 139]

Table 1 Presenting signs andsymptoms in patients with herpessimplex encephalitis

Finding Percentage of patients Reported range

Fever 80% 70–97%

Confusion/disorientation 72% 54–81%

Personality changes/behavioral disturbances 59% 42–92%

Headache 58% 42–70%

Altered mental status/impaired consciousness 58% 54–100%

Seizures 54% 35–65%

Focal neurological deficits 41% 26–79%

Nausea and vomiting 40% 19–46%

Aphasia/altered speech 40% 12–65%

Coma 33% 4–48%

Meningismus 28% 13–38%

Not every finding was reported for every patient. Compiled from 388 reported HSE cases [16–20, 77, 139, 140]

13 Page 4 of 12 Curr Infect Dis Rep (2017) 19: 13

Gnann JWundWhitley RJ2017

Herpes simplex Encephalitis:Therapie

Acyclovir 20mg/kg/8h während 21 TagenCave! Bei kürzerer Therapiedauer

Rezidivgefahr!!

Acyclovir + Corticosteroide Þ bessere Resultate?nur Einzelfälle, keine prospektive Studie,erfolgreich bei erhöhtem IKD

(Kamel S. et al: J Neurol Neurosurg Psychiatr 2005Gnaham J.W. und Whitley RJ: Curr Infect Dis Rep 2017)

HerpessimplexEncephalitis:Outcome

Normal 62 (42%)Geschädigt:Mittelschwer 45 (29%)Schwer 33 (23%)Exitus 9 ( 6%)

Hsieh et al 2007Elbers et al 2007Lahat et al 1999Ito et al 2000Uren et al 1993Wang et al 1994Kimura et al 1992

HSV Infektion im ZNS

CytokineChemokine Aktiviert durch Gliazellen

Neuroimmunantwort

Sekundäre Schädigung

RezidivnachHSVEncephalitisVirusbedingtesRezidivderHSE

NichtVirusbedingtePost-HSE

ZeitpunktdesHSERezidivs

Variabel 4-6WochennachHSEBeginn

NeurologischeSymptome FokaleneurologischeAusfälle,epileptischeAnfälle,Verhaltensstörungen

Kinder:AbnormeBewegungen(Choreathetose,Ballismus)Adoleszente:Verhaltensstörungen

HSVPCRimLiquor positiv negativNeuenekrotischeLäsionenimMRI

ja nein,ev.Befallderweissen Substanz

AnsprechenaufantiviraleTherapie

ja nein

Aetiologie HSV Infektion Autoimmun,NMDARoderDR2Antikörper,

Armangue Tetal:Curr Opin Neurol 2014

ungenügendesAnsprechenaufantiviraleTherapie+klinischeZeicheneinerNMDAREncephalitis?

BestimmungderNMDAR-Ak imSerumundLiquorHSVPCRimLiquor+/- imBlut

ErneutHSVTherapie(Acyclovir)

„Firstline“Immuntherapie:IVIGoderPlasmapherese

HSVKontrolle(PCR)+Monitorisierung derNMDAR–AKTiter

„Secondline“Immuntherapie:Steroide+/- Rituximab +/- CyclophosphamidKontrollenHSV(PCR)undNMDAR-Ak Titer

TherapieschemafürRezidivnachHSEoderprolongiertemHSEVerlauf

0714211369136912

Tage

MasernNeurologischeKomplikationen

PIE

Exanthem

Masernvirus-infektion

ME: MasernencephalitisPIE: PostinfektiöseEncephalitisMIBE: MasernEinschlusskörperchen

(inclusion body)EncephalitisSSPE: Subakutesklerosierende

PanencephalitisMIBE

Monate

SSPE

Jahre

ME

Praevalenz:Akute primäre Masernencephalitis 1 : 1000Akute Postmasernencephalitis 1 : 1000Akute Postvaccinationsencephalitis 1 : 1000000Masern Einschlusskörperchen Encephalitis 1 : ?Akute disseminierte Encephalomyelitis (ADEM) 1 : 1000ADEM nach MMR Impfung 1-2 : 100000 Subakute sklerosierende Panencephalitis (SSPE) 1 : 25000SSPE nach Masern bei Kindern < 2 Jahre 1 : 5000SSPE nach Masernimpfung < 1 : 1000000Letalität:Akute Masernencephalitis 15 - 20%Akute Postmasernencephalitis 5 – 25%Masern Einschlusskörperchen Encephalitis 75%SSPE > 90%

NeurologischeKomplikationenvonMasern

NeurologischeKomplikationenvonMasernKlinik,EEG,Bildgebung

PrimäreMasern-encephalitis

Akutepost-infektiöseMasernenc.

Einschluss-körperchenEncephalitis

SSPE

Voraus-setzungZeitspanne

AktiveMasern Masernvor1– 6Monaten

Immundefekt,innerhalb1JahresnachMasern

M. währenderster2LJ,3– 20JahrenachM

Klinik Fieber,Kopf-schmerzen,Epi-Anfälle, mentaleStörungen,Ausschlag

allg.Schwäche,mentaleStörungenSensibilitätsstö-rungen

mentaleStö-rungen,refraktäreEpi-Anfälle,MotorischeAusfälle

Verhaltensstö-rung, Demenz,Myoklonienprogredient

EEG DiffusDeltaw.fokaleod.gene-ralisierte Epi-Entladungen

normaloderunspezifischabnorm

DiffuseDeltaw.fokaleodergene-ralisierte Epi-entladungen

PeriodischeKomplexe,Burstsuppression.

MRI T2fokaleHyper-intensitäten,Hirnoedem

T2multifokaleHyperintensitätHirn+RM

normal,OedemspäterAtrophien,Ventrikulomegalie

FokaleLeuko-dystrophie,diffusekortikaleAtrophie

NeurologischeKomplikationenvonMasernLaborbefunde

PrimäreMasern-encephalitis

Akutepost-infektiöseMasernenc.

Einschluss-körperchenEncephalitis

SSPE

Masernvirus nachweisbar nichtnachweisbar

nachweisbarpersistierend

defekter Masern-Virus

Masern-AkimSerum

+/- + ++, Titeransteigend

+++

Masern-AkimLiquor

+/- + ++, Titeransteigend

+++.

MyelinbasischesProtein

keines +++ keines keines

Liquorbefund(Zellen,Eiweiss,Glucose)

LymphocytenéEiweisséGlucose normal

LymphocytenéEiweisséGlucosenormal

normal normal

MasernEinschlusskörperchen Encephalitis

- PatientenmitImmundefizienz (z.B.beilymphatischerLeukämieoderandernmalignenTumoren)

- AuftretennachMasernundMasernimpfung,aberauchohneersichtlichenGrund

- NurgeringesExanthemwegengestörterT-ZellFunktion- Hauptsymptome:EpileptischeAnfälle(fokalodergeneralisiert,meistTherapieresistent),Bewusstseins- undVerhaltensstörungen

- Gelegentlich:fokalemotorischeAusfälle,visuelleSymptomeinklusivekortikaleErblindungundDysphagie

- Diagnose:PCRaufMasernviren- Prognose:Mortalitätca.75%

Stadium KlinischeSymptome

StadiumI Persönlichkeitsveränderungen,Schulprobleme,Verhaltensstörungen

StadiumII Massive,häufigerepetitivemyoklonischeZuckungen,epileptischeAnfälleundDemenz

StadiumIII Rigor,extrapyramidaleSymptome,progressiveAbnahmederAnsprechbarkeit

StadiumIV AkinetischerMutismus,vegetativerZustand,Coma,autonomeStörungen

Subakutesklerosiende Panencephalitis(SSPE)KlinischeStadien

AkutedisseminierteEncephalomyelitis (ADEM)KlinischeSymptomeundLiquorbefunde

UnspezifischeProdromi:- Kopfschmerzen,Myalgien,leichtesFieberundÜbelkeitFokaleneurologischeAusfälle:- Hemiparese,Tetraparese,seltenAphasie- AtaxieVeränderungendesmentalenStatus:- Schläfrigkeit,StuporundComaWeitereSymptome:- HirnnervenAusfälleundN.opticus neuritis- SymptomeeinerMyelopathie- unwillkürlicheBewegungen

Liquor:- Lymphocytäre Pleocytose,Protein↑,- oligoklonale Bandenin0-29%nachweisbar

Infectious agents associated with ADEM

normal and lipid-ladenmacrophages are not seen (Poweret al., 1993). However, rare cases of HIV encephalopathypresenting as an ADEM-like illness, with demyelinationand relative sparing of axons, have been reported (Joneset al., 1988; Gray et al., 1991; von Giesen et al., 1994).HTLV-I infection causes slowly progressive myelopathyand is associated with demyelination, but through a dif-ferent mechanism than ADEM. HTLV-I does not infectoligodendrocytes or neurons but preferentially infectsCD4þ and CD8þ T cells, which, when activated by thevirus, could lead to demyelination (Hollsberg, 1997;Kannian et al., 2012). It may also infect microglia, whichmay become activated and release cytokines toxic tomyelin (Hollsberg, 1997).

Other forms of encephalitis that may also causedemyelination but distinct from ADEM include sub-acute sclerosing panencephalitis, a chronic progressivemeasles infection of the brain, rubella panencephalitis,varicella-zoster virus (VZV) encephalitis, and humanherpesvirus-6 (HHV-6). In panencephalitis caused byrubella, prominent white-matter changes with axonalfragmentation are seen (Townsend et al., 1975, 1976).VZV encephalitis in AIDS patients can produce demye-lination. In addition to inflammatory demyelination,

VZV may also directly infect oligodendrocytes, sinceviral inclusion bodies can be seen in these cells (Grayet al., 1991, 1994; Amlie-Lefond et al., 1995). HHV-6can produce demyelination also by directly infectingoligodendrocytes (De Bolle et al., 2005). HHV-6 is alsoone of several hypothesized etiologic agents for MS(Challoner et al., 1995).

Another form of demyelinating disease seen inHIV isprogressive multifocal leukoencephalopathy (PML),which is caused by infection of oligodendrocytes bythe JC virus, a polyomavirus. PML is seen underconditions that impair immunity, such as acquiredimmunodeficiency syndrome (AIDS), posttransplant,lymphoma, and autoimmune diseases receiving treat-ment with chemotherapy or immunomodulators suchas natalizumab, rituximab, or efalizumab (Carsonet al., 2009). PML lesions usually occur in the deep whitematter and are typically solitary, but they can rarely bemultifocal (Astrom et al., 1958). Also, cortical demyelin-ation from PML has been described (Sweeney et al.,1994; Shintaku et al., 2000;Moll et al., 2008). The frontaland parieto-occipital regions are usually affected, butdeep graymatter, brainstem, cerebellum, and spinal cordcan be involved (von Einsiedel et al., 1993; Bienfait et al.,1998; Kastrup et al., 2002; Bernal-Cano et al., 2007). Thedemyelinating lesions seen in PML lack inflammatoryreaction and necrosis, but have accompanying reactiveastrocytes and oligodendroglial nuclear inclusions(Astrom and Stoner, 1994; Aksamit, 2006). However,upon immune reconstitution, as may occur in AIDSpatients after highly active antiretroviral therapy or inautoimmune diseases once immunosuppression isstopped, PML lesions once containing little inflamma-tion now develop intense inflammatory reaction withedema and necrosis (Tan et al., 2009). This immunereconstitution inflammatory syndrome can producediffuse white-matter changes, as seen on magnetic res-onance imaging (MRI), even in areas initially devoidof any pathology, for example in MS after cessationof natalizumab therapy (Tan et al., 2011; Gheuenset al., 2012).

PATHOGENESIS

The pathogenesis of ADEMhasmost resemblance to theanimal model experimental autoimmune encephalomy-elitis (EAE), which is an acute demyelinating diseaseinduced by immunization of animals with myelin proteinproducts (Rivers et al., 1933). After immunization withCNS antigens emulsified in Freund’s complete adjuvant,animal recipients present with amonophasic illness caus-ing tetraparesis and incontinence. Histologic analysisshows inflammatory demyelinating lesions typically inthe spinal cord and in some animal strains in the brain.

Table 35.1

Infectious agents associated with acute disseminatedencephalomyelitis

Viruses Vaccinations Bacterial

Measles Measles StreptococcusMumps Mumps Borrelia

burgdorferiRubella Rubella LegionellaCoxsackie Rabies

(Semple-type)Mycoplasmapneumoniae

Coronavirus Tetanus SalmonellaHerpes (HSV, HHV-6,VZV, EBV, CMV)

Oral polio Rickettsiarickettsii

Influenza A and B Influenza ChlamydiaHepatitis A and B Pertussis CampylobacterHTLV-1 Hepatitis B LeptospiraHIV Japanese

encephalitisvirus

Dengue virus Tick-borneencephalitis

Smallpox Yellow fever

Adapted from Garg (2003); Bennetto and Scolding (2004); Menge

et al. (2005); Tenembaum et al. (2007).

HSV, herpes simplex virus; HHV, human herpesvirus; VZV, varicella-zoster virus; EBV, Epstein–Barr virus; CMV, cytomegalovirus; HTLV-

1,humanT-lymphotropicvirus-1;HIV,human immunodeficiencyvirus.

706 A. JAVED AND O. KHAN

AkutedisseminierteEncephalomyelitisTherapie

1. Acyclovir 20mg/kg/d(meistinitialeingesetztwegendiagnostischerUnsicherheit)

2. Cortison20– 30mg/kg/Tagwährend3-5TagenoderDexamethason 1mg/kg/Tag

3. IVIg 2g/kgüber5Tage4. Plasmapherese,wennkeinAnsprechenaufSteroide

5. WennkeinAnsprechenaufTh 1– 4:Cyclophosphamid und/oderMitoxantron

WennderSpaziergangimWaldgefährlichwerdenkann

FrühsommerMeningo – Encephalitis

(FSME)

Fig. 9. Distribution of I. ricinus, mapped as points according to the coordinates of the site of collection. This differs from map in Fig. 8 in which actual coordinates ofcollections, instead of the complete administrative divisions, are included as ‘‘positive’’ to the tick, allowing a finer mapping of the tick’s range. It is observed that thedistribution of I. ricinus in western Palearctic is larger than the distribution of TBEV. Map originally published by Estrada-Peña et al. (2013a,b,c,d).

Fig. 10. Schematic cycle of transmission of the tick-borne encephalitis flavivirus. It shows the importance of some species of rodents on which the larva and nymph may feedtogether, that may produce a back-transmission of the virus from the infected nymphs to the co-feeding larvae, without systemic circulation of the virus in the host. The largehosts for adults are necessary only for the completion of the life cycle of the tick, but have been not reported as important in the transmission of the virus in the nature. Thecourse of the tick life cycle is indicated by blue arrows. The possible transmission of the virus between ticks and mammals or directly between ticks is marked by red arrows.Figure prepared with material originally created by Alex McAuley.

116 A. Estrada-Peña, J. de la Fuente / Antiviral Research 108 (2014) 104–128

LebenszyklusderZeckeÜbertragungsmöglichkeitendesFSMEVirusaufdenMenschen

Estrada-PenaAundDelaFuente J2014

InfizierteHuftiere

NachZeckenstichInfizierungderLangerhanszellen derHaut→ InfektionderLymphknoten(Lymphocyten und

Makrophagen→ Virämie Phase→InfektiondesNS

ZielzellenimNS:EpithelzellenderHirnhäute,Purkinjezellen,motorischeKerneimHirnstammundRM,NeuroneimThalamus,Diencephalen undMesencephalon(Neuronenzerstörung)

PathogenesederZeckenencephalitits

KlinikderFSME:

• NachInkubationszeitvonca 10TagenSymptomeeinerSommergrippe:Fieber,Kopfschmerzen,HustenundgastrointestinaleBeschwerden

• SpontanerRückgangderSymptome• EinigeTagespätererneuterFieberanstieg:• 50%isolierteMeningitis• 40%Meningiencephalitis• 10%Myelitis

SymptomebeiFrühsommerMeningoencephalitis

Meningitis Encephalitis Myelitis

Allgemeinsymptome AZ↓Fieber AZ↓Fieber AZ↓Fieber

Häufig Kopfschmerzen Bewusstsein↓(Sopor,Coma)Bewusstseinveränderung(Delir, Halluzinationen)KognitionsstörungenAtaxie,Paresen

SchlaffeParesenMiktions-störungen

Gelegentlich NeuritisderHirnnerven

Tremor,mimischesBeben,zentraleAtemstörungen,Dysphagie,epileptischeAnfälle

SpasmenderBlasenmuskulatur,Schmerzen(RumpfundExtremitäten)

KaiserR.2016

CME

Abb. 28 FSME-RisikogebieteinDeutschland,StandMai2015([20];Grafik:Pfitzer;mitfreundl.Genehmigung,www.zecken.de). FSME Frühsommermeningoenzephalitis

Erwachsenen ca. 10-mal seltener auftreten [28, 29, 32, 34, 41, 42, 49, 50, 51, 52, 53, 54, 55, 56,57]. Letale Verläufe sind bei Kindern und Jugendlichen eine absolute Ausnahme.

Das jüngste Kind mit einer FSME-Virusinfektion war 17 Tage alt [50]. Klinisch imponiertezunächst ein Anfall mit nachfolgender Hemiparese, die sich nach 2Monaten nicht zurückgebildethatte. Die Magnetresonanztomographie (MRT) des Gehirns zeigte zunächst ein Hirnödem dergesamten linken Hemisphäre und nach 2 Monaten eine Atrophie in diesem Bereich. Klinisch botder Säugling fokale Anfälle, der weitere Verlauf ist nicht bekannt.

Doppelinfektionenmit dem FSME-Virus und Borrelia burgdorferi s. l. verlaufen meist schwer-wiegend [58, 59].

Diagnostik

Die Diagnose der FSME stützt sich auf:4 eine Exposition in einem Risikogebiet,4 einen Zeckenstich innerhalb der letzten 1 bis 3 Wochen (fakultativ),4 die klinische Symptomatik mit Kopfschmerzen, Fieber und ggf. neurologischen Funktionsstö-

rungen,4 einen entzündlichen Liquorbefund sowie4 den Nachweis FSME-spezifischer Immunglobulin-M(IgM)- und IgG-Antikörper im Serum,4 den Nachweis eines erhöhten FSME-spezifischen Antikörperindexes im Liquor (bei Unsicher-

heiten).

Der Nervenarzt 6 · 2016 671

FSMEDiagnose