Transcript ABCs of HIV treatment

HIV and the Brain
Chris Farnitano, MD
Noon Conference
Friday, October 31, 2008
Learning Objectives
-Review the differential diagnosis, workup
and treatment of three common
presentations of central neurologic
disease in AIDS:
*Dementia
*Headache
*focal neuro signs
Forms
Case Study #1: R.D.
R.D. is a 44 y.o. male with AIDS
 Hx of non-adherence to meds and clinic
visits
 brought to clinic 2/03 by teenage
daughter who has been caring for him

Case Study #1: R.D.
c/o incontinence, increased confusion,
trouble walking
 requiring help with bathing, dressing,
feeding
 Sx developed over months
 T cells 15, Viral load 16,000
 What could his diagnosis be?

Case Study #1: R.D.
exam shows MMSE 14/30
 CSF: protein 324, glucose 8
 CSF WBC 24: 90% lymphs, 7% monos

CT scan Patient R. D.
Diffuse low attenuation periventricular
white matter disease, no mass effect
MRI Patient R.D.
Case Study #1: R.D.

What is no longer in your differential?
Case Study #1: R.D.
Toxo titer neg
 India ink prep negative
 CSF Smears bacteria, AFB neg
 CSF PCR HSV, MTB neg
 serum and CSF crypo antigen low titer
positive

Case Study #1: R.D.

Diagnosis?
Case Study #1: R.D.

Diagnosis?
– Cryptococcal meningitis (CRAG)
– Progressive Multifocal Leukencephalopathy
(clinical picture, imaging studies)
– AIDS dementia complex (clinical picture)
AIDS Dementia Complex
Also known as HIV associated cognitivemotor complex
 Occurs in 1/3 of adults with AIDS

AIDS Dementia Complex

Pathogenesis:
– Neurons not directly infected
– CNS macrophages overrespond to infection
with release of neurotoxic substances
AIDS Dementia Complex
process is slowly progressive over
months
 T cells usually <200 (median = 18)

AIDS Dementia Complex

Symptoms:
– 1) Declining mental acuity (difficulty in
memory, concentration, mathematical
calculations)
– 2) Preservation of alertness(even a patient
with advanced dementia can be aroused to
a level of alertness. This is an important
distinction between this and other CNS
etiologies
AIDS Dementia Complex

Neuro exam:
– non-focal
AIDS Dementia Complex

Neuro exam: Cognition
– Early: Inattention, decr. concentration,
forgetfulness, slowing of thought processes
– Late: Global Dementia
AIDS Dementia Complex

Neuro exam: Motor
– Early: Slowed movements, clumsiness,
ataxia
– Late: paraplegia
AIDS Dementia Complex

Neuro exam: Behavior
– Early: apathy, blunting of personality,
agitation
– Late: mutism
AIDS Dementia Complex

CSF findings
– normal vs. mild pleocytosis, incr. Protein
– similar to asymptomatic HIV+ individuals
AIDS Dementia Complex

CT/MRI
– usually normal in early disease
– atrophy can be seen in late disease
HIV Dementia

Note widened sulci and enlarged ventricles
AIDS Dementia Complex

Treatment
– Antiviral therapy useful in preventing as
well as reversing dementia
– importance of CSF penetration of various
antivirals not clear
– Case P.J. –complete reversal of severe
dementia with Combivir
Headache in AIDS

Differential Diagnosis - with any T cell
count
– medications (especially zidovudine)
– aseptic HIV meningitis
– bacterial meningitis (usuals plus increased
risk of Listeria)
– TB meningitis
– Syphilitic meningitis - may have focal neuro
findings, i.e. cranial nerve palsies
Headache in AIDS

Differential Diagnosis - with any T cell
count
– bacterial sinusitis - occurs in 1/3 to 2/3 of
adults with AIDS



xray: 79% have air fluid level
60% recur or fail to respond to ABT Rx
refer to ENT for antral puncture and Cx if fail to
respond
Headache in AIDS

Differential Diagnosis - with T cells
<100
– Above plus Fungal meningitis


most common is Cryptococcus (most have T
cells <50)
also consider Coccidiomycosis (Sonoran life
zone including all of California Central Valley)
and Histoplasmosis (Missisipi Valley and Central
America) in endemic areas.
Endemic Areas For
Histo and Cocci
Cryptococcal Meningitis

Sx:
– Subacute meningitis w/ fever, HA, malaise

Clinical exam:
– Stiff neck in 1/4
– focal neuro exam in 1/5 (often cranial
nerve palsy), altered mental status (ie
encephalitis) in some
– skin lesions resembling molluscum in 310%
Cutaneous Cryptococcus

Note similar appearance to molluscum
Cryptococcal Meningitis

Diagnosis:
– Serum CRAG >99% positive. Excellent
screening test. Not useful for monitoring
response to therapy.
– CT scan: always do in AIDS patient before
LP to rule out mass lesion, given the
increased frequency of space occupying
lesions in AIDS pts with HA even without
focal neuro findings.
Cryptococcal Meningitis

Diagnosis:
– LP opening pressure >200 in 60%
– Cell counts low (mean 4 lymphs/mm3)
– india ink prep positive in 75%
– Blood Cx positive in 75%
– Serum CRAG positive in 95%
– CSF CRAG positive in >90%
Cryptococcal Meningitis

Increase intracranial pressure:
– associated with obtundation, cranial nerve palsies,
papilledema, blindness and incr. Mortality
– 13/14 deaths in one trial with opening pressure
(OP)>250
– In observational studies, aggressive management
of increased pressure often led to survival without
permanent neuro sequellae.
Cryptococcal Meningitis

Increase intracranial pressure:
– if opening pressure >300, urgently Rx with
drainage of enough CSF to decrease OP by 50%
(at least 10-20 ml)
– follow up with daily LP drainage until OP normal x
2 days
– Consider placement of lumbar drain if OP>400 or
daily LP fails to control Sx
– No proven benefit to dexamethasone , diamox or
mannitol.
Cryptococcal Meningitis

Treatment:
– Amphotericin B associated with less
mortality than initial treatment with
Fluconazone
– Adding Flucytosine to Ampho B gave
significantly higher rate of CSF sterilization
and lower relapse rate than Ampho alone
Cryptococcal Meningitis

Treatment:
– Amphotericin B IV and Flucytosine PO x 2
weeks (or until afebrile, HA, N/V resolved)
– then Fluconazole 400mg PO qd x 8 weeks
– then Fluconazole 200 mg PO qd until Tcells
>100 for six months
Cryptococcal Meningitis

Treatment:
– If normal mental status, >20 WBC in CSF,
and CSF CRAG <1:32, can use fluconazole
alone
Cryptococcal Meningitis

Treatment:
– High failure rate and high mortality (often
weeks after Tx started) in pre-combo
antiviral era
Focal Brain Dysfunction in
AIDS

Presenting Signs or symptoms:
– Focal neuro complaint or exam
– New onset seizure
Focal Brain Dysfunction in
AIDS

Differential Diagnosis - Abrupt onset:
– CVA
– TIA
Focal Brain Dysfunction in
AIDS

Differential Diagnosis - subacute onset
(days):
– Toxoplasmosis
– Primary CNS lymphoma
– Tubercular brain abcess
– Cryptococcoma
– Varicella encephalitis
– CMV
– Herpes Simplex Encephalitis
Focal Brain Dysfunction in
AIDS

Differential Diagnosis - insidious onset
(weeks):
– Progressive Multifocal
Leucoencephalopathy (PML)
Focal Brain Dysfunction in
AIDS

Workup:
– CT with and without contrast
– MRI
– LP if no midline shift or other signs of
herniation: send for fungal and AFP smears
and Cx, VDRL, cytology, CRAG
Focal Brain Dysfunction in
AIDS

Workup:
– Serum Toxo IgG
– Serum CRAG
– CSF for PCR
Toxoplasmosis:
– almost all have positive Toxo IgG (this is a
reactivation disease)
– Toxo acquired from undercooked meat or cysts in
cat feces
– 15% US adults Toxo IgG+, 50-75% in Europe
– In advanced AIDS, if Toxo IgG+ and not on
prophylaxis, 12 mo. incidence of Toxo encephalitis
is 33%
– rare if adherent to Septra prophylaxis
Toxo Encephalitis:
80% have T cells <100
– Clinical: altered MS (70%), focal signs
(60%), HA (50%), fever
– CT/MRI: multiple ring enhancing lesions
Cerebral Toxoplasmosis

CT with contrast: Note ring enhancement
and surrounding edema
Cerebral Toxoplasmosis

Note lesions on medial surface of both
hemispheres
Cerebral Toxoplasmosis

Recurrent Sx 6 mo later: CT shows only old
calcified lesion
Cerebral Toxoplasmosis

Recurrent Sx 6 mo later: MRI shows multiple
new lesions
Primary CNS lymphoma:
– Used to occur in up to 10% of AIDS pts.
– T cells almost always <50
– CSF cytology pos in <15%, CSF PCR for EBV high
specificity and sensitivity
– median survival 10-18 months (used to be <3 mo)
– whole brain radiation improves survival by 5
months
– cases of remission with antiviral induced immune
reconstitution
Primary CNS lymphoma

Note edema and mass effect, similar
radiographic appearance to Toxo
Progressive Multifocal
Leucoencephalopathy (PML):








caused by JC virus
Most humans infected early in life; 70% of
adults are Ab+
MRI: multiple non-enhancing fluffy lesions in
sub-cortical white matter
no mass effect
CSF PCR for JC 58% sens, 92-100% specific
No specific treatment
death usual within 6 months
prolonged survival and remission with
antivirals reported
Progressive Multifocal
Leukoencephalopathy

Note vague hypodense region suggestive of
stroke
Progressive Multifocal
Leukoencephalopathy

T2-weighted MRI
Progressive Multifocal
Leukoencephalopathy

Note extensive white matter degeneration in
parietal lobe
Focal Brain Lesion Rx
Algorithm

If Toxo IgG pos and not on prophylaxis:
– Treat for Toxo, Bx if no response in 10-14
d or worsens
Focal Brain Lesion Rx
Algorithm

If Toxo IgG neg or Toxo IgG pos but on
prophylaxis:
– Consider sending CSF for PCR for EBV, JC
virus, CMV; also CSF Toxo IgG
Focal Brain Lesion in AIDS
– PCR EBV pos = lymphoma, Bx to confirm
– PCR JCV pos = PML Bx to confirm only if
there is mass effect as this is atypical of
PML, likely have more than one diagnosis
– PCR CMV pos =Treat for CMV encephalitis
– If CSF Toxo IgG pos then treat for Toxo,
Bx if no response in 7-10 d or worsens
– If all tests negative proceed with brain bx
Role of Brain Biopsy
– Definitive diagnosis reached in 9396% of AIDS patients with focal CNS
lesions
– 0 to 3.1 percent mortality
– 0.5 to 9 percent major morbidity
– 2 to 4 percent minor morbidity
Return to Case R.D.
Treated with Ampho B/Flucytocine
followed by high dose Fluconazone
 Triple drug anti-HIV therapy initiated

Case R.D.: 6 weeks later:
T cells improve 15 -> 25, viral load
16,000 -> 600
 Despite this lab response, clinical status
deteriorates
 patient becomes nonverbal,
nonambulatory, more confused
 significant nausea and vomiting appear
to be due to antivirals

Return to Case R.D.
What do you do now?
 After discussion with his children, agree
to d/c to SNF and hospice
 antivirals are stopped, fluconazole
continued as “palliation”

Return to Case R.D.
1 Month later:
 patient much improved, ambulating,
talking, more oriented
 discharged from SNF to home care with
children, hospice
 patient offered to resume antivirals, but
declines, decides to go to Mexico to
stay with extended family

Return to Case R.D.

Lessons from this case:
– Ockham’s Razor does not apply in
advanced AIDS
– remissions of previously untreatable
diseases are seen with immune
reconstitution
– “It ain’t over til its over” - Yogi Berra
Forms
Summary
– HIV related CNS disease is less common in
U.S. today but still occurs, especially in
non-adherent patients
– Three major categories of disease are
dementia, headache and focal brain
dysfunction
– The advent of CSF PCR tests has made it
possible to avoid brain biopsy on some
patients with focal mass lesions