HIV and the Brain Chris Farnitano, MD Noon Conference Friday, October 31, 2008.

HIV and the BrainHIV and the Brain

Chris Farnitano, MDChris Farnitano, MD

Noon ConferenceNoon Conference

Friday, October 31, 2008Friday, October 31, 2008

Learning ObjectivesLearning Objectives

-Review the differential diagnosis, workup and treatment of three common presentations of central neurologic disease in AIDS:*Dementia*Dementia

*Headache*Headache

*focal neuro signs*focal neuro signs

FormsForms

Case Study #1: R.D.Case Study #1: R.D.

R.D. is a 44 y.o. male with AIDSR.D. is a 44 y.o. male with AIDS Hx of non-adherence to meds and Hx of non-adherence to meds and

clinic visitsclinic visits brought to clinic 2/03 by teenage brought to clinic 2/03 by teenage

daughter who has been caring for daughter who has been caring for himhim


c/o incontinence, increased c/o incontinence, increased confusion, trouble walkingconfusion, trouble walking

requiring help with bathing, requiring help with bathing, dressing, feedingdressing, feeding

Sx developed over monthsSx developed over months T cells 15, Viral load 16,000T cells 15, Viral load 16,000 What could his diagnosis be?What could his diagnosis be?


exam shows MMSE 14/30exam shows MMSE 14/30 CSF: protein 324, glucose 8CSF: protein 324, glucose 8 CSF WBC 24: 90% lymphs, 7% CSF WBC 24: 90% lymphs, 7%

monosmonos

CT scan Patient R. D.CT scan Patient R. D.

Diffuse low attenuation Diffuse low attenuation periventricularperiventricular white matter disease, no mass white matter disease, no mass effecteffect

MRI Patient R.D.MRI Patient R.D.


What is no longer in your What is no longer in your differential?differential?


Toxo titer negToxo titer neg India ink prep negativeIndia ink prep negative CSF Smears bacteria, AFB negCSF Smears bacteria, AFB neg CSF PCR HSV, MTB negCSF PCR HSV, MTB neg serum and CSF crypo antigen low serum and CSF crypo antigen low

titer positivetiter positive


Diagnosis?Diagnosis?


Diagnosis?Diagnosis?– Cryptococcal meningitis (CRAG)Cryptococcal meningitis (CRAG)– Progressive Multifocal Progressive Multifocal

Leukencephalopathy (clinical picture, Leukencephalopathy (clinical picture, imaging studies)imaging studies)

– AIDS dementia complex (clinical AIDS dementia complex (clinical picture)picture)

AIDS Dementia ComplexAIDS Dementia Complex

Also known as HIV associated Also known as HIV associated cognitive-motor complexcognitive-motor complex

Occurs in 1/3 of adults with AIDSOccurs in 1/3 of adults with AIDS


Pathogenesis: Pathogenesis: – Neurons not directly infectedNeurons not directly infected– CNS macrophages overrespond to CNS macrophages overrespond to

infection with release of neurotoxic infection with release of neurotoxic substancessubstances


process is slowly progressive over process is slowly progressive over monthsmonths

T cells usually <200 (median = 18)T cells usually <200 (median = 18)


Symptoms: Symptoms: – 1) Declining mental acuity (difficulty 1) Declining mental acuity (difficulty

in memory, concentration, in memory, concentration, mathematical calculations)mathematical calculations)

– 2) Preservation of alertness(even a 2) Preservation of alertness(even a patient with advanced dementia can patient with advanced dementia can be aroused to a level of alertness. be aroused to a level of alertness. This is an important distinction This is an important distinction between this and other CNS etiologiesbetween this and other CNS etiologies


Neuro exam:Neuro exam:– non-focalnon-focal


Neuro exam: CognitionNeuro exam: Cognition– Early: Inattention, decr. Early: Inattention, decr.

concentration, forgetfulness, slowing concentration, forgetfulness, slowing of thought processesof thought processes

– Late: Global DementiaLate: Global Dementia


Neuro exam: MotorNeuro exam: Motor– Early: Slowed movements, Early: Slowed movements,

clumsiness, ataxiaclumsiness, ataxia– Late: paraplegiaLate: paraplegia


Neuro exam: BehaviorNeuro exam: Behavior– Early: apathy, blunting of personality, Early: apathy, blunting of personality,

agitationagitation– Late: mutismLate: mutism


CSF findingsCSF findings– normal vs. mild pleocytosis, incr. normal vs. mild pleocytosis, incr.

Protein Protein – similar to asymptomatic HIV+ similar to asymptomatic HIV+

individualsindividuals


CT/MRICT/MRI– usually normal in early diseaseusually normal in early disease– atrophy can be seen in late diseaseatrophy can be seen in late disease

HIV DementiaHIV Dementia

Note widened sulci and enlarged Note widened sulci and enlarged ventriclesventricles


TreatmentTreatment– Antiviral therapy useful in preventing Antiviral therapy useful in preventing

as well as reversing dementiaas well as reversing dementia– importance of CSF penetration of importance of CSF penetration of

various antivirals not clearvarious antivirals not clear– Case P.J. –complete reversal of severe Case P.J. –complete reversal of severe

dementia with Combivirdementia with Combivir

Headache in AIDSHeadache in AIDS

Differential Diagnosis - with any T Differential Diagnosis - with any T cell countcell count– medications (especially zidovudine)medications (especially zidovudine)– aseptic HIV meningitisaseptic HIV meningitis– bacterial meningitis (usuals plus bacterial meningitis (usuals plus

increased risk of Listeria)increased risk of Listeria)– TB meningitisTB meningitis– Syphilitic meningitis - may have focal Syphilitic meningitis - may have focal

neuro findings, i.e. cranial nerve palsiesneuro findings, i.e. cranial nerve palsies


Differential Diagnosis - with any T Differential Diagnosis - with any T cell countcell count– bacterial sinusitis - occurs in 1/3 to bacterial sinusitis - occurs in 1/3 to

2/3 of adults with AIDS2/3 of adults with AIDS xray: 79% have air fluid levelxray: 79% have air fluid level 60% recur or fail to respond to ABT Rx60% recur or fail to respond to ABT Rx refer to ENT for antral puncture and Cx if refer to ENT for antral puncture and Cx if

fail to respondfail to respond


Differential Diagnosis - with T cells Differential Diagnosis - with T cells <100<100– Above plus Fungal meningitisAbove plus Fungal meningitis

most common is Cryptococcus (most have most common is Cryptococcus (most have T cells <50)T cells <50)

also consider Coccidiomycosis (Sonoran also consider Coccidiomycosis (Sonoran life zone including all of California Central life zone including all of California Central Valley) and Histoplasmosis (Missisipi Valley) and Histoplasmosis (Missisipi Valley and Central America) in endemic Valley and Central America) in endemic areas.areas.

Endemic Areas ForEndemic Areas ForHisto and CocciHisto and Cocci

Cryptococcal MeningitisCryptococcal Meningitis

Sx: Sx: – Subacute meningitis w/ fever, HA, Subacute meningitis w/ fever, HA,

malaisemalaise Clinical exam:Clinical exam:

– Stiff neck in 1/4Stiff neck in 1/4– focal neuro exam in 1/5 (often cranial focal neuro exam in 1/5 (often cranial

nerve palsy), altered mental status (ie nerve palsy), altered mental status (ie encephalitis) in someencephalitis) in some

– skin lesions resembling molluscum in 3-skin lesions resembling molluscum in 3-10%10%

Cutaneous CryptococcusCutaneous Cryptococcus

Note similar appearance to molluscumNote similar appearance to molluscum


Diagnosis:Diagnosis:– Serum CRAG >99% positive. Serum CRAG >99% positive.

Excellent screening test. Not useful Excellent screening test. Not useful for monitoring response to therapy.for monitoring response to therapy.

– CT scan: always do in AIDS patient CT scan: always do in AIDS patient before LP to rule out mass lesion, before LP to rule out mass lesion, given the increased frequency of given the increased frequency of space occupying lesions in AIDS pts space occupying lesions in AIDS pts with HA even without focal neuro with HA even without focal neuro findings.findings.


Diagnosis:Diagnosis:– LP opening pressure >200 in 60%LP opening pressure >200 in 60%– Cell counts low (mean 4 Cell counts low (mean 4

lymphs/mm3)lymphs/mm3)– india ink prep positive in 75%india ink prep positive in 75%– Blood Cx positive in 75%Blood Cx positive in 75%– Serum CRAG positive in 95%Serum CRAG positive in 95%– CSF CRAG positive in >90%CSF CRAG positive in >90%


Increase intracranial pressure:Increase intracranial pressure:– associated with obtundation, cranial nerve associated with obtundation, cranial nerve

palsies, papilledema, blindness and incr. palsies, papilledema, blindness and incr. Mortality Mortality

– 13/14 deaths in one trial with opening 13/14 deaths in one trial with opening pressure (OP)>250pressure (OP)>250

– In observational studies, aggressive In observational studies, aggressive management of increased pressure often management of increased pressure often led to survival without permanent neuro led to survival without permanent neuro sequellae.sequellae.


Increase intracranial pressure:Increase intracranial pressure:– if opening pressure >300, urgently Rx with if opening pressure >300, urgently Rx with

drainage of enough CSF to decrease OP by drainage of enough CSF to decrease OP by 50% (at least 10-20 ml)50% (at least 10-20 ml)

– follow up with daily LP drainage until OP follow up with daily LP drainage until OP normal x 2 daysnormal x 2 days

– Consider placement of lumbar drain if Consider placement of lumbar drain if OP>400 or daily LP fails to control SxOP>400 or daily LP fails to control Sx

– No proven benefit to dexamethasone , No proven benefit to dexamethasone , diamox or mannitol.diamox or mannitol.


Treatment:Treatment:– Amphotericin B associated with less Amphotericin B associated with less

mortality than initial treatment with mortality than initial treatment with FluconazoneFluconazone

– Adding Flucytosine to Ampho B gave Adding Flucytosine to Ampho B gave significantly higher rate of CSF significantly higher rate of CSF sterilization and lower relapse rate sterilization and lower relapse rate than Ampho alonethan Ampho alone


Treatment:Treatment:– Amphotericin B IV and Flucytosine PO Amphotericin B IV and Flucytosine PO

x 2 weeks (or until afebrile, HA, N/V x 2 weeks (or until afebrile, HA, N/V resolved)resolved)

– then Fluconazole 400mg PO qd x 8 then Fluconazole 400mg PO qd x 8 weeksweeks

– then Fluconazole 200 mg PO qd until then Fluconazole 200 mg PO qd until Tcells >100 for six monthsTcells >100 for six months


Treatment:Treatment:– If normal mental status, >20 WBC in If normal mental status, >20 WBC in

CSF, and CSF CRAG <1:32, can use CSF, and CSF CRAG <1:32, can use fluconazole alonefluconazole alone


Treatment:Treatment:– High failure rate and high mortality High failure rate and high mortality

(often weeks after Tx started) in pre-(often weeks after Tx started) in pre-combo antiviral eracombo antiviral era

Focal Brain Dysfunction in Focal Brain Dysfunction in AIDSAIDS

Presenting Signs or symptoms:Presenting Signs or symptoms:– Focal neuro complaint or examFocal neuro complaint or exam– New onset seizureNew onset seizure


Differential Diagnosis - Abrupt Differential Diagnosis - Abrupt onset:onset:– CVACVA– TIATIA


Differential Diagnosis - subacute onset Differential Diagnosis - subacute onset (days):(days):– ToxoplasmosisToxoplasmosis– Primary CNS lymphomaPrimary CNS lymphoma– Tubercular brain abcessTubercular brain abcess– CryptococcomaCryptococcoma– Varicella encephalitisVaricella encephalitis– CMVCMV– Herpes Simplex EncephalitisHerpes Simplex Encephalitis


Differential Diagnosis - insidious Differential Diagnosis - insidious onset (weeks):onset (weeks):– Progressive Multifocal Progressive Multifocal

Leucoencephalopathy (PML)Leucoencephalopathy (PML)


Workup:Workup:– CT with and without contrastCT with and without contrast– MRIMRI– LP if no midline shift or other signs of LP if no midline shift or other signs of

herniation: send for fungal and AFP herniation: send for fungal and AFP smears and Cx, VDRL, cytology, CRAGsmears and Cx, VDRL, cytology, CRAG


Workup:Workup:– Serum Toxo IgGSerum Toxo IgG– Serum CRAGSerum CRAG– CSF for PCRCSF for PCR

Toxoplasmosis:Toxoplasmosis:

– almost all have positive Toxo IgG (this is a almost all have positive Toxo IgG (this is a reactivation disease)reactivation disease)

– Toxo acquired from undercooked meat or Toxo acquired from undercooked meat or cysts in cat fecescysts in cat feces

– 15% US adults Toxo IgG+, 50-75% in 15% US adults Toxo IgG+, 50-75% in EuropeEurope

– In advanced AIDS, if Toxo IgG+ and not on In advanced AIDS, if Toxo IgG+ and not on prophylaxis, 12 mo. incidence of Toxo prophylaxis, 12 mo. incidence of Toxo encephalitis is 33% encephalitis is 33%

– rare if adherent to Septra prophylaxisrare if adherent to Septra prophylaxis

Toxo Encephalitis:Toxo Encephalitis:

80% have T cells <10080% have T cells <100– Clinical: altered MS (70%), focal signs Clinical: altered MS (70%), focal signs

(60%), HA (50%), fever(60%), HA (50%), fever– CT/MRI: multiple ring enhancing CT/MRI: multiple ring enhancing

lesionslesions

Cerebral ToxoplasmosisCerebral Toxoplasmosis

CT with contrast: Note ring CT with contrast: Note ring enhancement and surrounding edemaenhancement and surrounding edema


Note lesions on medial surface of both Note lesions on medial surface of both hemisphereshemispheres


Recurrent Sx 6 mo later: CT shows only Recurrent Sx 6 mo later: CT shows only old calcified lesionold calcified lesion


Recurrent Sx 6 mo later: MRI shows Recurrent Sx 6 mo later: MRI shows multiple new lesionsmultiple new lesions

Primary CNS lymphoma:Primary CNS lymphoma:

– Used to occur in up to 10% of AIDS pts.Used to occur in up to 10% of AIDS pts.– T cells almost always <50T cells almost always <50– CSF cytology pos in <15%, CSF PCR for EBV CSF cytology pos in <15%, CSF PCR for EBV

high specificity and sensitivityhigh specificity and sensitivity– median survival 10-18 months (used to be median survival 10-18 months (used to be

<3 mo)<3 mo)– whole brain radiation improves survival by 5 whole brain radiation improves survival by 5

monthsmonths– cases of remission with antiviral induced cases of remission with antiviral induced

immune reconstitutionimmune reconstitution

Primary CNS lymphomaPrimary CNS lymphoma

Note edema and mass effect, similar Note edema and mass effect, similar radiographic appearance to Toxoradiographic appearance to Toxo

Progressive Multifocal Progressive Multifocal Leucoencephalopathy Leucoencephalopathy

(PML):(PML): caused by JC virus caused by JC virus Most humans infected early in life; 70% of Most humans infected early in life; 70% of

adults are Ab+adults are Ab+ MRI: multiple non-enhancing fluffy lesions in MRI: multiple non-enhancing fluffy lesions in

sub-cortical white mattersub-cortical white matter no mass effectno mass effect CSF PCR for JC 58% sens, 92-100% specificCSF PCR for JC 58% sens, 92-100% specific No specific treatmentNo specific treatment death usual within 6 monthsdeath usual within 6 months prolonged survival and remission with antivirals prolonged survival and remission with antivirals

reportedreported

Progressive Multifocal Progressive Multifocal LeukoencephalopathyLeukoencephalopathy

Note vague hypodense region Note vague hypodense region suggestive of strokesuggestive of stroke


T2-weighted MRIT2-weighted MRI


Note extensive white matter Note extensive white matter degeneration in parietal lobedegeneration in parietal lobe

Focal Brain Lesion Rx Focal Brain Lesion Rx AlgorithmAlgorithm

If Toxo IgG pos and not on If Toxo IgG pos and not on prophylaxis:prophylaxis:– Treat for Toxo, Bx if no response in Treat for Toxo, Bx if no response in

10-14 d or worsens10-14 d or worsens

Focal Brain Lesion Rx Focal Brain Lesion Rx AlgorithmAlgorithm

If Toxo IgG neg or Toxo IgG pos but If Toxo IgG neg or Toxo IgG pos but on prophylaxis:on prophylaxis:– Consider sending CSF for PCR for EBV, Consider sending CSF for PCR for EBV,

JC virus, CMV; also CSF Toxo IgGJC virus, CMV; also CSF Toxo IgG

Focal Brain Lesion in AIDSFocal Brain Lesion in AIDS

– PCR EBV pos = lymphoma, Bx to confirmPCR EBV pos = lymphoma, Bx to confirm– PCR JCV pos = PML Bx to confirm only if PCR JCV pos = PML Bx to confirm only if

there is mass effect as this is atypical of there is mass effect as this is atypical of PML, likely have more than one diagnosisPML, likely have more than one diagnosis

– PCR CMV pos =Treat for CMV encephalitisPCR CMV pos =Treat for CMV encephalitis– If CSF Toxo IgG pos then treat for Toxo, Bx if If CSF Toxo IgG pos then treat for Toxo, Bx if

no response in 7-10 d or worsensno response in 7-10 d or worsens– If all tests negative proceed with brain bxIf all tests negative proceed with brain bx

Role of Brain BiopsyRole of Brain Biopsy

– Definitive diagnosis reached in 93-Definitive diagnosis reached in 93-96% of AIDS patients with focal CNS 96% of AIDS patients with focal CNS lesionslesions

– 0 to 3.1 percent mortality0 to 3.1 percent mortality– 0.5 to 9 percent major morbidity0.5 to 9 percent major morbidity– 2 to 4 percent minor morbidity2 to 4 percent minor morbidity

Return to Case R.D.Return to Case R.D.

Treated with Ampho B/Flucytocine Treated with Ampho B/Flucytocine followed by high dose Fluconazonefollowed by high dose Fluconazone

Triple drug anti-HIV therapy Triple drug anti-HIV therapy initiatedinitiated

Case R.D.: 6 weeks later:Case R.D.: 6 weeks later:

T cells improve 15 -> 25, viral load T cells improve 15 -> 25, viral load 16,000 -> 60016,000 -> 600

Despite this lab response, clinical Despite this lab response, clinical status deterioratesstatus deteriorates

patient becomes nonverbal, patient becomes nonverbal, nonambulatory, more confusednonambulatory, more confused

significant nausea and vomiting significant nausea and vomiting appear to be due to antiviralsappear to be due to antivirals


What do you do now?What do you do now? After discussion with his children, After discussion with his children,

agree to d/c to SNF and hospiceagree to d/c to SNF and hospice antivirals are stopped, fluconazole antivirals are stopped, fluconazole

continued as “palliation”continued as “palliation”


1 Month later:1 Month later: patient much improved, ambulating, patient much improved, ambulating,

talking, more orientedtalking, more oriented discharged from SNF to home care discharged from SNF to home care

with children, hospicewith children, hospice patient offered to resume antivirals, patient offered to resume antivirals,

but declines, decides to go to Mexico but declines, decides to go to Mexico to stay with extended familyto stay with extended family


Lessons from this case:Lessons from this case:– Ockham’s Razor does not apply in Ockham’s Razor does not apply in

advanced AIDSadvanced AIDS– remissions of previously untreatable remissions of previously untreatable

diseases are seen with immune diseases are seen with immune reconstitutionreconstitution

– ““It ain’t over til its over” - Yogi BerraIt ain’t over til its over” - Yogi Berra

FormsForms

SummarySummary

– HIV related CNS disease is less HIV related CNS disease is less common in U.S. today but still occurs, common in U.S. today but still occurs, especially in non-adherent patientsespecially in non-adherent patients

– Three major categories of disease are Three major categories of disease are dementia, headache and focal brain dementia, headache and focal brain dysfunctiondysfunction

– The advent of CSF PCR tests has made The advent of CSF PCR tests has made it possible to avoid brain biopsy on it possible to avoid brain biopsy on some patients with focal mass lesionssome patients with focal mass lesions

HIV and the Brain Chris Farnitano, MD Noon Conference Friday, October 31, 2008.

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Transcript of HIV and the Brain Chris Farnitano, MD Noon Conference Friday, October 31, 2008.