welcome to i-tech hiv/aids clinical seminar series hiv and the nervous system, part 3 christina m....
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Welcome to I-TECH HIV/AIDS Clinical Seminar Series
HIV and the Nervous System, Part 3Christina M. Marra, MD
June 18, 2009
JW
• 57 yo man brought in by friend to ED – “Not himself” X past 3 weeks
• Decline in self-care and increasingly forgetful– Apartment messy– Recently lost job, car repossessed– Got lost while driving– Needs to be cued to eat, drink, dress, undress
• Complains of difficulty concentrating, dizziness, weight loss, depression
JW Pre-morbid Function
• Four years of college
• Program assistant for public health system
• Traveled to China and Tibet for his 50th birthday
• Occasional tobacco, rare alcohol, no other recreational drugs
JW PMH
• B3 HIV– “Fearful of antiretrovirals”– Nadir CD4 74 (2 mo prior), VL 103,000 copies/ml
• Hx neurosyphilis treated with IV PCN, 1987• Peripheral neuropathy• Hx B12 deficiency
JW Medications
• Atripla – Poor adherence
• Vitamin B12
• Bactrim DS one table PO q day
JW Exam
• Afebrile, thin, normal general medical examination
• Neurological examination– MMSE score 22 – Variably oriented – Fluent speech– Brisk ankle reflexes, right Babinski
JW Laboratory Data
• Serum RPR non-reactive
• TSH normal
• Negative toxicology screen
• Normal electrolytes
• Plasma HIV RNA 33,900 copies/ml
JW Laboratory Data
• CSF– 10 WBC, all mononuclear– Protein 99 mg/dl – Cryptococcal Ag negative– CSF-VDRL nonreactive– CMV, HSV, VZV, JCV PCRs negative– Beta-2 microglobulin 4.5– CSF HIV RNA 55,000 copies/ml
JW T1 and FLAIR MR
JW FLAIR MR
JW Follow up
• Admitted to nursing facility• Restarted Atripla
– Plasma HIV RNA undetectable 1 month later– CD4 remains ~100 cells/ul 7 months later
• Living independently• Driving• Still having trouble with math
Approach to Diagnosis
Meningeal Sx/Signs Nonfocal Parenchymal Sx/Signs Focal Parenchymal Sx/Signs
Syndrome
Approach to Diagnosis
HIV dementiaCMV encephalitis
NeurosyphilisDrugs, metabolic
Most Common Etiologies
CD4+ T cell countToxicology screen, TSH, B12
ConsiderationsTests
Nonfocal Parenchymal Sx/Signs
Cognitive Motor Behavioral
Forgetfulness Poor balance Apathy, social withdrawal
Decreased concentration
Leg weakness Depression
Confusion Irritability
Slow thinking Psychosis, mania
Clinical Features of HIV Dementia
“HAND”: HIV Associated Neurocognitive Disorder
Disorder NP Tests No NP Tests
HIV Dementia
Moderate NP impairment
Major functional decline
Moderate MSE impairment
Major functional decline
Risk Factors for HIV Dementia
• CASCADE (Bhaskaran K et al. Ann Neurol 2008;63:213)
– 23 cohorts Europe, Canada, Australia– Pre-1997 to 2006– 15,380 subjects– 222 HIV Dementia– Total follow-up 83,388 person-yrs
Current CD4 and HIV Dementia
CD4 Stratum Relative Risk
> 350 1
200-349 3.47
100-199 10.19
0-99 39.03
Adjusted for calendar period
HIV Dementia Epidemiology
Dore GJ. AIDS 2003;17:1539
• Infectious– Serum CrAg, TPPA
– Imaging
– CSF CMV PCR, HIV RNA, B-2-microglobulin, VDRL
• Non-infectious– Medication history– Tox screen
• Metabolic encephalopathy– Electrolytes, B12, TSH
HIV Dementia Evaluation
JW T1 and FLAIR MR
PML T1 and FLAIR MR
ADC Treatment
• Potent ARV– Does good CNS penetration matter?
CNS Penetration-Effectiveness Rank
Better=1 Intermediate=0.5 Worse=0NRTIs Abacavir, ABC Emtricitabine, FTC Didanosine, ddI
Zidovudine, AZT Lamivudine, 3TC Tenofovir, TDFStavudine, d4T Zalcitabine, ddC
NNRTIs Delavirdine, DLV Efavirenz, EFVNevirapine, NVP
PIs Indinavir, IDV Amprenavir-r, APV-r Amprenavir, APVIndinavir-r, IDV-r Atazanavir, ATZ Nelfinavir, NLFLopinavir-r, LPV-r Atazanavir-r, ATZ-r Ritonavir, RTV
Saquinavir, SAQSaquinavir-r, SAQ-rTipranavir-r, TPV-r
FusionInhibitors
Enfuvirtide, T20
Letendre et al, Archives of Neurology, 2008
P = 0.03
34%
18% 18%
12% 11% 8%
23%
CPE and CSF HIV RNA
ACTG 736
• 101 patients starting or changing potent ARVs– 0, 12, 24 weeks
• Plasma HIV RNA• CSF HIV RNA• Neuropsychological performance
• Data analyzed for 79 patients
NP Performance in Cognitively Impaired
Characteristic Estimate P Value
Entry NPZ4 0.86 <0.001
Number of ARV Agents -0.38 0.001
CPE rank > 2 -1.08 <0.001
CNS Escape
Venkataramana A et al. Neurol 2006;67
EC
• 38 yo man brought in by friend to clinic – “Not himself” X past 11 months
• Began with change in personality– Less reserved
• Decline work performance– Fired from job
• Little insight
EC Pre-morbid Function
• BA degree in zoology
• Laboratory soil analyst
• No tobacco, occasional alcohol, no other recreational drugs
EC PMH
• A1 HIV– No ARVs– CD4 530, plasma HIV RNA 13,000
copies/ml
• No medications
EC Exam
• Afebrile, thin, normal general medical examination
• Neurological examination– MMSE score 30 – Trouble following examination instructions– Mild left sided weakness
EC Laboratory Data
• Serum RPR 1:128
• TSH normal
• Negative toxicology screen
• Normal electrolytes
• Plasma HIV RNA 12,247 copies/ml
EC Laboratory Data
• CSF– 78 WBCs, all mononuclear– Protein 120 mg/dl – Cryptococcal Ag negative– CSF-VDRL 1:128– CMV, HSV, VZV, JCV PCRs negative– Beta-2 microglobulin ND– CSF HIV RNA ND
EC FLAIR MR
Two HIV+ Patients
• EJ– 42 yo woman presented Sept 6, 2006– HIV diagnosed in 1999
• CD4 293 cells/ul• Plasma HIV RNA 29,600 copies/ml
– Hepatitis C– Burning pain and numbness in feet for 4 months
• Began with stopping potent ARVs
– Progressive weakness
Two HIV+ Patients
• RM– 53 yo man under my care since 1990– Biopsy proven PML– Undetectable plasma HIV RNA and CD4 > 500
cells/ul X years– Type II DM X 4 years– Burning pain and numbness in feet for 2 years
DSPN in HIV
• Most common neurological complication of HIV
• Increasing in prevalence
• ARV-related– D-drugs (didanosine, stavudine)– ? PIs– Clinically indistinguishable from HIV DSPN
HIV DSPN
• Subjective– Numbness– Pain– Burning– Cramping– Unsteadiness
• Objective– Symmetrical– Lower extremities
involved before upper– Loss of pinprick,
temperature, vibration– Absent or reduced ankle
reflexes– Mild intrinsic foot
weakness
Stavudine and Neuropathy
• Sacktor et al. (Neurology 2009;72)
– 102 HIV+ beginning stavudine-lamivudine-nevirapine in Uganda
– Baseline • Pain in feet in 37% • Neuropathy signs in 43%
– Loss or diminished ankle reflexes– Diminished pin sensitivity in feet– Decreased vibration sensation at great toes
Stavudine and Neuropathy
• Sacktor et al. (Neurology 2009;72)
– Six months, previously asymptomatic• Pain in feet in 38%• Neuropathy signs in 31%
– Six months, previously symptomatic• No pain in feet in 22%• No neuropathy signs in 23%
PIs and DSPN
• Ellis et al. (Ann Neurol 2008;64)
– 1159 patients in CHARTER– 58% neuropathy
• Loss or diminished ankle reflexes• Diminished pin sensitivity in feet• Decreased vibration sensation at great toes• Symmetrical in all instances
– 58% with neuropathy were symptomatic
PIs and DSPN
Odds Ratio P-value
Age per 10 yr 2.40 <0.001
CD4 nadir per 100 cells 0.75 <0.001
D-drug exposure 2.57 <0.001
Log plasma HIV RNA 0.81 <0.001
Duration HIV per 5 yr 1.50 <0.001
Ellis et al. Ann Neurol 2008;64
PIs and DSPN
Ellis et al. Ann Neurol 2008;64
HOPSImmunodeficiency
+ Toxic DrugsBetter immunity + ?Fewer Toxic Drugs
Lichtenstein et al. Clin Infect Dis 2005;40
HIV DSPN
• Some other causes of neuropathy in HIV– Dapsone– INH– Vincristine, other chemotherapy– Ethambutol– Thalidomide– Megadose B6 – B12 deficiency– Alcohol– Diabetes
Neuropathy Work-up
• EMG, NCV– Large fiber
• QST– Small fiber
• ENFD– Small fiber
• Labs– SPEP, immunofixation– B12, B6, folate– TSH– TPPA– HbA1c– Cryoglobulins– ESR, CRP
DSPN Treatments
• Gabapentin +/- SR morphine
• Pregabalin
• Lidocaine patches
• Duloxetine
• Amitriptyline
• High dose capsaicin patch
• Cannabis
Capsaicin Patch
• Simpson et al. (Neurology 2008;70)
– Three doses high concentration capsaicin vs. low dose control
– 12 weeks– 203 treated, 73 controls– > 30% pain reduction in 34% vs. 18%– No dose response
Capsaicin Patch
Cannabis
• Abrams et al. (Neurology 2007;68)
– Smoked marijuana• 32 mg delta-9-THC/cigarette 3 times per day X
5 days
– Matched control cigarettes– 25 patients per group– > 30% pain reduction in 52% vs. 24%
Pain Intensity
Abrams et al. Neurology 2007:68
Welcome to I-TECH HIV/AIDS Clinical Seminar Series
Next session: July 9, 2009Dr. Nina Kim
HIV and Hepatitis
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