hiv and the brain chris farnitano, md noon conference friday, october 31, 2008
TRANSCRIPT
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
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
Case Study #1: R.D.Case Study #1: R.D.
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?
Case Study #1: R.D.Case Study #1: R.D.
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
Diffuse low attenuation Diffuse low attenuation periventricularperiventricular white matter disease, no mass white matter disease, no mass effecteffect
Case Study #1: R.D.Case Study #1: R.D.
What is no longer in your What is no longer in your differential?differential?
Case Study #1: R.D.Case Study #1: R.D.
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
Case Study #1: R.D.Case Study #1: R.D.
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
AIDS Dementia ComplexAIDS Dementia Complex
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
AIDS Dementia ComplexAIDS Dementia Complex
process is slowly progressive over process is slowly progressive over monthsmonths
T cells usually <200 (median = 18)T cells usually <200 (median = 18)
AIDS Dementia ComplexAIDS Dementia Complex
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
AIDS Dementia ComplexAIDS Dementia Complex
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
AIDS Dementia ComplexAIDS Dementia Complex
Neuro exam: MotorNeuro exam: Motor– Early: Slowed movements, Early: Slowed movements,
clumsiness, ataxiaclumsiness, ataxia– Late: paraplegiaLate: paraplegia
AIDS Dementia ComplexAIDS Dementia Complex
Neuro exam: BehaviorNeuro exam: Behavior– Early: apathy, blunting of personality, Early: apathy, blunting of personality,
agitationagitation– Late: mutismLate: mutism
AIDS Dementia ComplexAIDS Dementia Complex
CSF findingsCSF findings– normal vs. mild pleocytosis, incr. normal vs. mild pleocytosis, incr.
Protein Protein – similar to asymptomatic HIV+ similar to asymptomatic HIV+
individualsindividuals
AIDS Dementia ComplexAIDS Dementia Complex
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
AIDS Dementia ComplexAIDS Dementia Complex
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
Headache in AIDSHeadache in AIDS
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
Headache in AIDSHeadache in AIDS
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.
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
Cryptococcal MeningitisCryptococcal Meningitis
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.
Cryptococcal MeningitisCryptococcal Meningitis
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%
Cryptococcal MeningitisCryptococcal Meningitis
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.
Cryptococcal MeningitisCryptococcal Meningitis
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.
Cryptococcal MeningitisCryptococcal Meningitis
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
Cryptococcal MeningitisCryptococcal Meningitis
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
Cryptococcal MeningitisCryptococcal Meningitis
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
Cryptococcal MeningitisCryptococcal Meningitis
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
Focal Brain Dysfunction in Focal Brain Dysfunction in AIDSAIDS
Differential Diagnosis - Abrupt Differential Diagnosis - Abrupt onset:onset:– CVACVA– TIATIA
Focal Brain Dysfunction in Focal Brain Dysfunction in AIDSAIDS
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
Focal Brain Dysfunction in Focal Brain Dysfunction in AIDSAIDS
Differential Diagnosis - insidious Differential Diagnosis - insidious onset (weeks):onset (weeks):– Progressive Multifocal Progressive Multifocal
Leucoencephalopathy (PML)Leucoencephalopathy (PML)
Focal Brain Dysfunction in Focal Brain Dysfunction in AIDSAIDS
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
Focal Brain Dysfunction in Focal Brain Dysfunction in AIDSAIDS
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
Cerebral ToxoplasmosisCerebral Toxoplasmosis
Note lesions on medial surface of both Note lesions on medial surface of both hemisphereshemispheres
Cerebral ToxoplasmosisCerebral Toxoplasmosis
Recurrent Sx 6 mo later: CT shows only Recurrent Sx 6 mo later: CT shows only old calcified lesionold calcified lesion
Cerebral ToxoplasmosisCerebral Toxoplasmosis
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
Progressive Multifocal Progressive Multifocal LeukoencephalopathyLeukoencephalopathy
T2-weighted MRIT2-weighted MRI
Progressive Multifocal Progressive Multifocal LeukoencephalopathyLeukoencephalopathy
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
Return to Case R.D.Return to Case R.D.
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”
Return to Case R.D.Return to Case R.D.
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
Return to Case R.D.Return to Case R.D.
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
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