EncephalitisEncephalitisin thein the

immunocompromised hostimmunocompromised host

Dr Nicole GilroyStaff Specialist, Infectious DiseasesWestmead Hospital and BMT Network NSW

Viral encephalitisViral encephalitisin the immunocompromisedin the immunocompromised

Human Human HerpesvirusesHerpesvirusesHSV1, HSV2, VZV, EBV, CMV, HHV6 ,HHV7, HHV8HSV1, HSV2, VZV, EBV, CMV, HHV6 ,HHV7, HHV8

PolyomavirusesPolyomavirusesJC VirusJC Virus

EnterovirusesEnteroviruses

HIVHIV

Transplantation (Transplantation (ZoonoticZoonotic))

Risk factorsRisk factors

Impaired cell mediated immunity (CMI)Impaired cell mediated immunity (CMI)HIV/HIV/AIDsAIDsLymphoreticular Lymphoreticular malignancies (malignancies (eg eg HodgkinHodgkin’’s lymphoma)s lymphoma)Chemotherapy (Chemotherapy (eg Purineeg Purine analoguesanalogues--fludarabinefludarabine))Transplantation (Solid, Stem Cell)Transplantation (Solid, Stem Cell)Chronic corticosteroid use (Chronic corticosteroid use (eg eg collagen vascular disease, collagen vascular disease, vasculitisvasculitis, Chronic renal failure, rheumatoid arthritis), Chronic renal failure, rheumatoid arthritis)

Hereditary (Hereditary (eg eg SCID)SCID)Primary infection/rePrimary infection/re--infectioninfection

PersonPerson--PersonPersonTissue transplant (solid, stem cell)Tissue transplant (solid, stem cell)Blood productsBlood productsOtherOther

Reactivation latent infectionReactivation latent infection

Encephalitis in the Encephalitis in the immunocompromisedimmunocompromised

Primary infection severePrimary infection severeReactivation latent infection Reactivation latent infection ⇒⇒CNS CNS DxDxSingle or multiple pathogens (simultaneous, Single or multiple pathogens (simultaneous, sequential)sequential)Atypical clinical presentationAtypical clinical presentationAtypical clinical courseAtypical clinical courseTreatment refractory (resistance)Treatment refractory (resistance)Unusual pathogenesisUnusual pathogenesisDifferential diagnoses wide (infectious, non Differential diagnoses wide (infectious, non infectious)infectious)

Clinical historyClinical history

Immune impairment: depth, duration, qualityImmune impairment: depth, duration, qualityExposures Exposures LatencyLatencyAntiviral (and other) prophylaxisAntiviral (and other) prophylaxisDifferentialsDifferentials

PostinfectiousPostinfectiousAcute Disseminated Encephalomyelitis Acute Disseminated Encephalomyelitis (ADEM)(ADEM)

EncephalopathyEncephalopathyReyes, drugs, toxins, vascular, Reyes, drugs, toxins, vascular, inflammatory, malignancyinflammatory, malignancy

Symptoms, signsSymptoms, signs

Prodromal Prodromal symptoms (+/symptoms (+/--rash)rash)FeverFeverHeadacheHeadacheAltered MentalAltered Mental State, personality, State, personality, behaviourbehaviourSeizuresSeizuresFocal neurological abnormalitiesFocal neurological abnormalities+/+/-- Meningism Meningism ((meningoencephalitismeningoencephalitis))+/+/-- Peripheral neurology Peripheral neurology ((encephalomyeloradiculopathyencephalomyeloradiculopathy))

Diagnosis (1)Diagnosis (1)Cerebrospinal fluidCerebrospinal fluid

Lymphocytic Lymphocytic pleocytosis:10pleocytosis:10--500/mm500/mm33

Neutrophil Neutrophil pleocytosispleocytosisCMV CMV radiculomyelitisradiculomyelitisWest NileWest Nile virusvirus

No No pleocytosis pleocytosis (early disease)(early disease)Protein elevationProtein elevationNormalNormal--mild depressed glucosemild depressed glucose

Diagnosis (2)Diagnosis (2)NeuroimagingNeuroimaging

CT scanCT scanScout for problems that may preclude lumbar punctureScout for problems that may preclude lumbar punctureMay be useful in HSV encephalitis (but ~40% nonMay be useful in HSV encephalitis (but ~40% non--diagnostic)diagnostic)

MRIMRITest of choiceTest of choiceVarious sequences assist with diagnosisVarious sequences assist with diagnosis

Diffusion weighted imagesDiffusion weighted imagesT1 (with contrast)T1 (with contrast)T2 prolongationT2 prolongationFLAIRFLAIR

PET scanPET scan

Diagnosis (3)Diagnosis (3)Electroencephalography (EEG)Electroencephalography (EEG)

Detect CNS dysfunctionDetect CNS dysfunction

Temporal lobe Temporal lobe localisation localisation with slow waves, spikes, spike waves with slow waves, spikes, spike waves associated with HSV encephalitisassociated with HSV encephalitis

80% biopsy proven HSV will have focal abnormalities EEG80% biopsy proven HSV will have focal abnormalities EEG

Low Specificity for HSELow Specificity for HSE in some geographic contextsin some geographic contextsSimilar patterns with Eastern Equine EncephalitisSimilar patterns with Eastern Equine EncephalitisCalifornian EncephalitisCalifornian Encephalitis

Severe depression of background wave activitySevere depression of background wave activity-- poor prognostic poor prognostic signsign

Diagnostics (4)Diagnostics (4)PCRPCR

Pretest probability (clinical, imaging)Pretest probability (clinical, imaging)

TimingTiming

Quality of specimenQuality of specimen

Viral identification=productive infection?Viral identification=productive infection?

Diagnostics (5)Diagnostics (5)SerologySerology

Serological testsSerological testsSerumSerumCSFCSF

Important to document baseline serology in Important to document baseline serology in donors/recipients to assess risk donors/recipients to assess risk primary/reactivated disease post transplantprimary/reactivated disease post transplant

May be useful in documenting acute infectionMay be useful in documenting acute infection

CSF serologyCSF serology for retrospective diagnosisfor retrospective diagnosis

Human Human HerpesvirusesHerpesviruses

Encephalitis in the immunocompromised host

Herpes Simplex VirusHerpes Simplex Virus90% acute sporadic cases of encephalitis90% acute sporadic cases of encephalitis

ImmunocompetentImmunocompetentTemporoparietal Temporoparietal diseasedisease> 90% HSV1 (30% primary; 70% reactivation)> 90% HSV1 (30% primary; 70% reactivation)Peaks in >60yrsPeaks in >60yrs

ImmunocompromisedImmunocompromisedDisseminated disease (pneumonitis, Disseminated disease (pneumonitis, hepatitis,encephalitis)hepatitis,encephalitis)Skin, eye , mouth (neonates)~20% will Skin, eye , mouth (neonates)~20% will progress to CNS disease without therapyprogress to CNS disease without therapyAtypical distributionAtypical distribution-- brainstem (AIDS)brainstem (AIDS)HSV1/HSV2 (neonates, AIDS)HSV1/HSV2 (neonates, AIDS)Disease mitigated with prophylaxisDisease mitigated with prophylaxis

HSV EncephalitisHSV EncephalitisNeuroimaging Neuroimaging (1)(1)

T2W-normal brain Inferior temporal lobe

T2W-hyperintensityInferior-medial temporal lobe

• Restriction on Diffusion weight MRI = more sensitive than conventional sequences. Mimics infarct

HSV EncephalitisHSV EncephalitisNeuroimaging Neuroimaging (2)(2)

HSV EncephalitisHSV EncephalitisPCRPCR

In brain biopsy proven HSVIn brain biopsy proven HSV

PCR Sensitivity 98%PCR Sensitivity 98%

PCR Specificity 94%PCR Specificity 94%

Lakeman Lakeman FD et al FD et al J Infect J Infect DisDis 1995;171:8571995;171:857

HSVHSV-- CSF PCRCSF PCR

Days antiviral Days antiviral PCR +PCR +vevetherapytherapy

00--7 7 100%100%88--14 47%14 47%>15 >15 21%21%

Lakeman Lakeman FD FD J Infect J Infect DisDis 1995; 171:8571995; 171:857

Limitations HSV CSF PCRLimitations HSV CSF PCR

False positiveFalse positiveCross contaminationCross contaminationNested PCRNested PCR

False negativeFalse negativeEarly disease (<72 hrs)Early disease (<72 hrs) Weil A et al Weil A et al Clin Clin Infect Infect DisDis 2002;34:11542002;34:1154

⇑⇑Days antiviral therapyDays antiviral therapy Lakeman Lakeman FD FD J Infect J Infect DisDis 1995; 171:8571995; 171:857

Inhibitors (Inhibitors (eg Haemeg Haem))Less sensitiveLess sensitive testtest

HSV EncephalitisHSV EncephalitisSerologySerology

Positive >2 weeks after onsetPositive >2 weeks after onsetRetrospective diagnosisRetrospective diagnosis

Serum Serum AbAb: CSF : CSF Ab Ab ((≤≤ 20)20)

Serum: CSF albumin (control)Serum: CSF albumin (control)

HSV EncephalitisHSV EncephalitisDiagnostic issues in immunocompromisedDiagnostic issues in immunocompromised

Prophylactic, Preemptive, Empiric antiviral use commonProphylactic, Preemptive, Empiric antiviral use common

Lumbar punctures often risky Lumbar punctures often risky espespThrombocytopenia (<50,000)Thrombocytopenia (<50,000)

Increased risk of bloody tapsIncreased risk of bloody tapsHaem Haem contamination CSFcontamination CSFTechnical difficultiesTechnical difficulties

** Bloody taps and antiviral may decrease sensitivity of ** Bloody taps and antiviral may decrease sensitivity of PCR in this settingPCR in this setting

Volume required for a single test small but often a battery Volume required for a single test small but often a battery of investigations requestedof investigations requested

Dual pathologies not uncommonDual pathologies not uncommon

Varicella Varicella Zoster Virus(VZV)Zoster Virus(VZV)encephalitis encephalitis (1)(1)

Immunocompetent Immunocompetent Kleinschmidt Bk Kleinschmidt Bk et al et al Arch Path Lab Arch Path Lab MedMed 2001 ; 127:7702001 ; 127:770

Acute Acute meningoencephalitismeningoencephalitisReyes syndromeReyes syndromeAcute Disseminated Encephalomyelitis (ADEM)Acute Disseminated Encephalomyelitis (ADEM)Large vesselLarge vessel ((granulomatous vasculitisgranulomatous vasculitis))

Varicella Varicella Zoster Virus(VZV)Zoster Virus(VZV)encephalitisencephalitis(2)(2)

Immunocompromised Immunocompromised Kleinschmidt Bk Kleinschmidt Bk et al et al Arch Path Lab Arch Path Lab MedMed 2001 ; 127:7702001 ; 127:770

Clinical:Clinical: Herpes Zoster (+/Herpes Zoster (+/--) followed by confusion, ataxia, ) followed by confusion, ataxia, fever , seizures, focal fever , seizures, focal neuro neuro deficitsdeficits

Pathology:Pathology:•• Ventriculitis Ventriculitis ((Ependymal Ependymal cells)cells)•• Multifocal leukoencephalopathy Multifocal leukoencephalopathy (Small vessel (Small vessel

vasculopathy vasculopathy + + oligodendrocyte oligodendrocyte invasion)invasion)•• Meningoencephalitis Meningoencephalitis ((Meningeal Meningeal Cells)Cells)

VZV encephalitisVZV encephalitisSmall vessel Small vessel vasculopathyvasculopathy

• Cortical infarction, white matter lesions and lesions at junction of grey-white matter on MRI

= Mulifocal leukoencephalopathy

• Less coalescent than lesions seen in PML

Gilden DH et al, NEJM, 2000;342:635-646

VZV encephalitisVZV encephalitisDiagnosisDiagnosis

VZV PCRVZV PCRSensitivity and specificitySensitivity and specificity >95%>95%Can be seen in CSF in uncomplicated ZosterCan be seen in CSF in uncomplicated Zoster--lesslessspecific if LP performed Close to time of Shingles specific if LP performed Close to time of Shingles eruptioneruption (dorsal root ganglia proximity to (dorsal root ganglia proximity to subarachnoid subarachnoid space)space)Useful for monitoring response, guiding length of Useful for monitoring response, guiding length of therapy in HIVtherapy in HIV Gilden Gilden DH et al DH et al J J Neurol SciNeurol Sci 1998; 159: 1401998; 159: 140

VZV antibodies CSFVZV antibodies CSFVasculopathy Vasculopathy may result in may result in extravasation extravasation VZVVZVantibodies into the CSF (circumstantial evidence to antibodies into the CSF (circumstantial evidence to support diagnosis)support diagnosis)

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Clinical vignette (1)Clinical vignette (1)

40+ yr old male40+ yr old maleDiagnosis: AML Diagnosis: AML --Dx Dx 2005, 2005, relapsedrelapsed 20062006 , , Cx Pulm aspergillusCx Pulm aspergillusTransplant : Transplant : Unrelated peripheral cellUnrelated peripheral cell Tx Tx 2007 (Cy/2007 (Cy/TBI/ATGTBI/ATG))SerologySerology

CMV CMV Neg Neg (Donor (Donor NegNeg))HSV HSV IgGIgG++EBV EBV IgG IgG ++VZV VZV IgG IgG ++HHV6 IgG+HHV6 IgG+HIV /HIV /HepBHepB//Hep Hep C C Neg Neg

Clinical vignette (1)Clinical vignette (1)

Clinical courseClinical courseDay +12Day +12 Acute GVHDAcute GVHD (skin, grade 2)(skin, grade 2)-- steroidssteroidsDay +16Day +16 Neutropenic Neutropenic sepsis, ICUsepsis, ICUDay+21Day+21 Neutrophil engraftmentNeutrophil engraftmentDay >28Day >28 Platelet transfusion dependentPlatelet transfusion dependentDay +70Day +70 High fevers, High fevers, diplopiadiplopia, drowsy, drowsy

HRCTHRCT chest patchy ground glass changechest patchy ground glass changeCT brain (nonCT brain (non--contrast):NADcontrast):NADCSF Glucose normal, protein 1.22CSF Glucose normal, protein 1.22

monos 29, monos 29, neut neut 4 red cells 194 red cells 19Cytology atypical mononuclear cellsCytology atypical mononuclear cells

MRB ? T2 intensity posterior MRB ? T2 intensity posterior ponsponsNeck massNeck mass-- right cervical right cervical adenopathy adenopathy (failed(failed

biopsy)biopsy)

Clinical vignette (1)Clinical vignette (1)

Bone MarrowBone Marrow-- hypocellularhypocellular, no malignant cells seen, no malignant cells seenCSFCSF-- no bacterial growth, crypto Ag negative, flow no bacterial growth, crypto Ag negative, flow cyto cyto PCR negativePCR negative

CMVCMVHSVHSVVZVVZVAdenovirus Adenovirus EnterovirusEnterovirusHHV6HHV6ToxoplasmosisToxoplasmosisM.TBM.TB

PCR positivePCR positiveEBVEBV

DECEASEDDECEASED Day+87Day+87

EBVEBVCNS CNS PathologyPathology

ImmunocompetentImmunocompetentMononucleosis, with CNS disease (1Mononucleosis, with CNS disease (1--5%)5%)Isolated EBV Isolated EBV meningoencephalitismeningoencephalitisPostPost--infectious (ADEM)infectious (ADEM)

ImmunocompromisedImmunocompromisedMeningoencephalitisMeningoencephalitisPrimary CNS Lymphoma, NHL (AIDS)Primary CNS Lymphoma, NHL (AIDS)Post transplant Post transplant Lymphoproliferative Lymphoproliferative disorder (PTLD) disorder (PTLD) with CNS involvementwith CNS involvement

EBV encephalopathyEBV encephalopathyPathogenesisPathogenesis

Direct CNS Infection?Direct CNS Infection?MRI /pathology support MRI /pathology support postinfectious postinfectious syndromesyndrome

Endothelial Endothelial AbAb--Ag complexesAg complexesDemyelination Demyelination (ADEM)(ADEM)

Infiltration CD8+ cytotoxic cellsInfiltration CD8+ cytotoxic cells

Indirect:Indirect:CNS lymphoma in CNS lymphoma in AIDsAIDsPTLDPTLD-- clonal clonal expansion EBV infected B cells in expansion EBV infected B cells in presence of depleted cytotoxic T cellspresence of depleted cytotoxic T cells

EBV CNS diseaseEBV CNS diseaseImmunocompromisedImmunocompromised

AIDsAIDs20% all CNS lymphomas are primary20% all CNS lymphomas are primary-- majority EBV relatedmajority EBV relatedOther lymphomas with potential secondary CNS involvement Other lymphomas with potential secondary CNS involvement also EBV related (NHL , also EBV related (NHL , HodgkinsHodgkins, , BurkittsBurkitts))CD4<50/mmCD4<50/mm33

EBV DNA +EBV DNA +ve ve CSF high predictive lymphomaCSF high predictive lymphomaEBV DNA may precede onset overt diseaseEBV DNA may precede onset overt disease

TransplantsTransplants95% PTLD EBV associated (10% CNS disease, HSCT>SOT)95% PTLD EBV associated (10% CNS disease, HSCT>SOT)Decreased EBV CTLDecreased EBV CTLMonomorphic Monomorphic ((clonal clonal B cell) B cell) --Tx Tx with with chemotherapy/immunotherapychemotherapy/immunotherapyPolymorphic Polymorphic --decrease immunosuppressiondecrease immunosuppressionHigh association D+/RHigh association D+/R--

Cytomegalovirus encephalitisCytomegalovirus encephalitis

Rare in Rare in immunocompetentimmunocompetent

In immunocompromisedIn immunocompromised-- mitigated with use of primary and mitigated with use of primary and secondary prophylaxis (transplants, HIV) and HAART in HIVsecondary prophylaxis (transplants, HIV) and HAART in HIV

Risk in Risk in AIDs AIDs when CD4 counts <100/mmwhen CD4 counts <100/mm33

In transplantationIn transplantationObserved as late complication HSCT Observed as late complication HSCT Predictors include prior CMV reactivations, steroids, low CD4 Predictors include prior CMV reactivations, steroids, low CD4 countscounts

** often associated with other end** often associated with other end--organ disease (enteritis, organ disease (enteritis, hepatitis, pneumonitis, retinitis)hepatitis, pneumonitis, retinitis)

CMV encephalitisCMV encephalitisDiagnosisDiagnosis

CultureCultureBrain BiopsyBrain BiopsyNeuroimagingNeuroimagingPCR >80% sensitivity >90% specificityPCR >80% sensitivity >90% specificityQ PCR serum, CSFQ PCR serum, CSF-- diagnosis and monitoring diagnosis and monitoring response to therapyresponse to therapyCMV retinitis in CMV retinitis in AIDs AIDs ~42% associated with CMV ~42% associated with CMV encephalitis post mortem series, 75% if retinitis encephalitis post mortem series, 75% if retinitis peripapillary peripapillary Bylsma Bylsma SS et al SS et al Arch Arch ophthalmolophthalmol 1995;113:891995;113:89

CMV encephalitisCMV encephalitisPathologyPathology

Isolated Isolated cytomegalic cytomegalic cellscells

Microglial Microglial nodulesnodules-- occ occ CMV inclusions (assoc CMV inclusions (assoc Dementia)Dementia)

VentriculoencephalitisVentriculoencephalitisDestruction Destruction ependymal ependymal lining with high proportion CMV lining with high proportion CMV infected cellsinfected cellsNecrosis Necrosis periventricular periventricular parenchymaparenchymaHIV patients CD4<100/mmHIV patients CD4<100/mm33

Arribas Arribas JR et al JR et al Ann Intern MedAnn Intern Med 1996;125:577 1996;125:577

CMV encephalitisCMV encephalitis

TW1-coronal ventriculomegaly& ependymal enhancement with gadolinium

TW2- axialVentriculomegalyEpendymal enhancement

Adult-ventriculoencephalitis Congenital CMV

Non-contrast axialCT scanVentricolmegaly &Periventricular calcification

Human Human Herpesvirus Herpesvirus 66EncephalitisEncephalitis

Neurotropic Neurotropic and Tand T lymphotropiclymphotropicAstrocytesAstrocytes? may be latent reservoir? may be latent reservoirImmunomodulatoryImmunomodulatory

ImmunocompetentImmunocompetentHHV6 associate with 31% febrile convulsions in <2 yr oldsHHV6 associate with 31% febrile convulsions in <2 yr oldsCase Reports of encephalitis in children and adults Case Reports of encephalitis in children and adults (diagnosis on PCR, (diagnosis on PCR, immunohistochemistry immunohistochemistry brain tissue)brain tissue)

ImmunocompromisedImmunocompromisedHSCT limbic encephalitisHSCT limbic encephalitis (somnolence, short term (somnolence, short term memory loss)memory loss)

Case reports Case reports immunstainimmunstain+brain tissue + CSF PCR+brain tissue + CSF PCRQ PCR correlates with disease Q PCR correlates with disease Ogata M Ogata M JIDJID 2006; 193; 682006; 193; 68

Case reports SOT (Case reports SOT (esp esp liver, cardiac)liver, cardiac)AIDs AIDs associations less clearassociations less clear-- demyelination demyelination autopsy autopsy specimensspecimens

Human Human Herpesvirus Herpesvirus 77EncephalitisEncephalitis

CD4 CD4 lymphotropiclymphotropic

Viraemia Viraemia in post transplant settingin post transplant settingHSCT 57% HSCT 57% Wang FZ Wang FZ BloodBlood 1996; 88:36151996; 88:3615

Renal transplant 39% Renal transplant 39% Osman Osman HK HK J Med J Med VirolVirol 1996;48:2951996;48:295

? Cofactor in CMV pathogenesis? Cofactor in CMV pathogenesis

Case report in 8 yr old SCT recipient of fatal brainstem Case report in 8 yr old SCT recipient of fatal brainstem encephalitis encephalitis Chan PKS et al Chan PKS et al J Med J Med VirolVirol 2002;66:4932002;66:493

++ve ve PCR HHV7 in CSFPCR HHV7 in CSF++ve ve HHV7 from brain stem tissue (HSV1/2, VZV, CMV,HHV7 from brain stem tissue (HSV1/2, VZV, CMV,

EBV, HHV6, HHV8 all negative)EBV, HHV6, HHV8 all negative)Prior Prior CSFs CSFs (for chemo)(for chemo) negativenegative

Human Human Herpesvirus Herpesvirus 88EncephalitisEncephalitis

Detected in brain biopsies HIV , dorsal root ganglia of Detected in brain biopsies HIV , dorsal root ganglia of KaposiKaposi’’s patients and in brain tissue of s patients and in brain tissue of immunocompetent immunocompetent hostshosts

Associations with Associations with castlemans castlemans syndrome and effusionsyndrome and effusion--related related lymphomas, lymphoma without effusions (Brain, GIT)lymphomas, lymphoma without effusions (Brain, GIT)

Small vessel Small vessel vasculopathyvasculopathy/encephalitis in/encephalitis in cases (2 HIV, one cases (2 HIV, one immunocompetentimmunocompetent) ) Said J Said J AIDSAIDS 1997;11:11191997;11:1119

Non Herpesviruses

Encephalitis in the immunocompromised host

Clinical vignette (2)Clinical vignette (2)

4747 yr old femaleyr old femaleLymphoma 1995, relapsed x2Lymphoma 1995, relapsed x2Sibling peripheral blood stem cell Sibling peripheral blood stem cell Tx Tx 1999,1999,reduced intensity conditioning (reduced intensity conditioning (FludarabineFludarabine, , cyclophosphamidecyclophosphamide))cGVHDcGVHD-- steroids, steroids, cyclosporincyclosporin

SerologySerologyCMV D+/R+CMV D+/R+HSV +HSV +EBV+EBV+VZV+VZV+HIV/HIV/HepHep B/B/HepC negHepC neg

Clinical vignette (2)Clinical vignette (2)

Presents in 2006 Presents in 2006 I week left sided weakness, few days slurred speech, I week left sided weakness, few days slurred speech, afebrileafebrile

CT head:NADCT head:NADCSF glucose normal, protein 2.67 g/CSF glucose normal, protein 2.67 g/dLdL, no, no white cells, 33 RBCwhite cells, 33 RBCCSF bacterial cultures negative, crypto Ag CSF bacterial cultures negative, crypto Ag negnegPCR PCR NegNeg

HSVHSVVZVVZVHHV6HHV6ToxoToxoM.TBM.TBJC virusJC virus

DECLINE IN NEUROLOGICAL STATUSDECLINE IN NEUROLOGICAL STATUSMRIMRIBrain biopsy JCV +Brain biopsy JCV +Bone Marrow Bone Marrow BiospyBiospy/ flow / flow cytometrycytometry

Viral inclusionsViral inclusionsoligodendrocyteoligodendrocyte

White matter degenerationWhite matter degeneration-- Multiple foamyMultiple foamyhistiocyteshistiocytes

OligodendrocyteOligodendrocyteWithWith ground glassground glassnucleusnucleus

Perivascular Perivascular Lymphocytic Lymphocytic InfiltrateInfiltrate

JC VirusJC VirusDiagnosisDiagnosis

PolyomavirusPolyomavirusRapidly progressive focal neurologyRapidly progressive focal neurology

Ataxia, visual fields,Ataxia, visual fields,paraesthesiaparaesthesia, cognitive, cognitivePoor prognosis (death within 4Poor prognosis (death within 4--6 months of onset)6 months of onset)

MRIMRICSFCSF

PCR JCVPCR JCVBrain BiopsyBrain Biopsy

Viral inclusions in Viral inclusions in oligodendrocytesoligodendrocytesImmunoperoxidase Immunoperoxidase ++veveEM+EM+veve

• Asymmetric area T2signal (white matter)

• Therapy– * limited data in

transplant– Immune

reconstitution (HAART) +CDV

– IL2 (anecdotal)– AraC (HIV)

JC VirusJC Virus

EnterovirusesEnteroviruses

Persistent fatal infections in host with hereditary, Persistent fatal infections in host with hereditary, acquired defects in acquired defects in B lymphocytesB lymphocytes

X linked X linked agammaglobulinaemiaagammaglobulinaemiaCommon variable Common variable immunodeficeincyimmunodeficeincyHSCTHSCT

Heightened risk ofHeightened risk of Vaccine associated paralytic Vaccine associated paralytic poliopolioChronic hepatitis, Chronic hepatitis, dermatomyositisdermatomyositis, , papilloedemapapilloedema, encephalitis +, encephalitis +--//meningismmeningismLethargy, seizures, tremor ataxiaLethargy, seizures, tremor ataxiaRecurrent isolation Recurrent isolation enterovirus enterovirus from CSFfrom CSF

Zoonotic Zoonotic Encephalitis from transplantation Encephalitis from transplantation and transfusionand transfusion

Keeping an open mindKeeping an open mind……

•• West Nile VirusWest Nile Virus (MMWR Sept 2002)(MMWR Sept 2002)

2002:2002: WNV in Transplants WNV in Transplants from infected donor or from infected donor or infected blood productsinfected blood products

•• RabiesRabies (MMWR July 2004)(MMWR July 2004)

2004: 3 deaths2004: 3 deaths(liver, 2 kidneys)(liver, 2 kidneys)

All fatalAll fatalInfected donor, Infected donor, unrecognised unrecognised exposureexposure

•• Lymphocytic Lymphocytic choriomeningitis choriomeningitis (MMWR May 2005)(MMWR May 2005)

2005:2005: 44 transplants, 3 deathstransplants, 3 deathsHepatitic Hepatitic failurefailure

DiagnosisDiagnosis

Neuroimaging Neuroimaging (CT, MRI, PET)(CT, MRI, PET)Electro encephalography (EEG)Electro encephalography (EEG)CSFCSFPCRPCRQPCRQPCRMultiplex PCR (Multiplex PCR (herpesvirusesherpesviruses, EV, EV--HSV, HSV, polyomavirusespolyomaviruses))Serology (serum:CSF)Serology (serum:CSF)Brain BiopsyBrain Biopsy