Dennis Kolson, MD, PhDProfessor of Neurology
University of Pennsylvania
Philadelphia, Pennsylvania
Update on Neurologic Complications in
Persons With HIV Infection: 2017
FORMATTED: MM/DD/YY
Chicago, Illinois: May 10, 2017
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Learning Objectives
Recognize and list the early neurologic manifestations of acute HIV
infection
Describe the chronic neurologic manifestations and potential
management options for neurologic complications of HIV infection
in individuals on suppressive antiretroviral therapy
To describe the rationale for adjunctive neuroprotective strategies
for cognitive impairment in individuals on suppressive antiretroviral
therapy
After attending this presentation, learners will be able to:
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• HAND prevalence remains ~ 40%
BUT
• less severe HAND: encephalitis & dementia now ~2%
• neuropathy prevalence < 30% with newer ARTs
HAND
Post-ART era
neuropathy
Neurological complications of chronic HIV infection are less
severe with use of antiretroviral therapy/ARTPre-ART era
HIV-encephalitis (HIVE)
HIV-associated neurocognitive disorders (HAND)
• HIV-associated neurocognitive disorders (HAND) ~ 40%
• severe HAND: HIV encephalitis & dementia ~20%
• neuropathy prevalence ~ 30%
HIV encephalitisHAND
neuropathy
Slide 4a of 34
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• HAND prevalence remains ~ 40%
BUT
• less severe HAND: encephalitis & dementia now ~2%
• neuropathy prevalence < 30% with newer ARTs
HAND
Post-ART era
neuropathy
Neurological complications of chronic HIV infection are less
severe with use of antiretroviral therapy/ARTPre-ART era
HIV-encephalitis (HIVE)
HIV-associated neurocognitive disorders (HAND)
• HIV-associated neurocognitive disorders (HAND) ~ 40%
• severe HAND: HIV encephalitis & dementia ~20%
• neuropathy prevalence ~ 30%
HIV encephalitisHAND
neuropathy
Slide 4b of 34
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HIV infiltrates the CNS early (days-week) after systemic HIV
Infection meningitis symptoms
Adapted from Gill & Kolson, Crit. Rev. Immunol. (2013).
NEURON
ASTROCYTE
MACROPHAGE
proinflammatorycytokines/chemokines
ACTIVATEDMACROPHAGE/
MICROGLIA
viral replication
NMDA Receptor Excitotoxins
Glutamate
Regulation
Neuronal Injury(loss of synapses and dendrites and
cell death)
Endothelial Lumen
Blood Brain Barrier
HIVMONOCYTE
Glutamate
QUIN, ROS,Ntox, PAF, TNF- , &
gp120, Tat
CD4+ T lymphocyteHIVHIV
Slide 5 of 34
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Acute neurological complications of HIV infection:• meningitis
• Acute Inflammatory Demyelinating Neuropathy (AIDP)
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Early neurological complications of HIV infection prior to
initiation of antiretroviral therapy/ART
• IRIS
• meningitis• Acute IDP
• HAND (less severe) • Chronic IDP
• DSPN • PML
Slide 7 of 34
HIV-associated neurocognitive disorders (HAND)
Distal Symmetric Polyneuropathy (DSPN)
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Early HIV infection (days 10-20) is associated with
symptoms of meningitis in ~25% of individuals*
Meningitis (~25%)
McMichael AJ, Nat. Rev. Immunol. (2010)
*Typically HIV antibody ELISA negative at this time
Slide 8 of 34
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HIV meningitis (acute HIV-1 infection):
• 25-50% of patients with clinical/subclinical meningitis
• duration ~ 2 weeks/self-limited
• occasional cranial nerve sx: facial droop or diplopia
• CSF: lymphocytes (5-70/mm3) in ~ 30% of acute infections
Protein (<70 mg/dl)
IgG index
• PATIENT WILL BE SERONEGATIVE!!!
Early neurologic complications of HIV-1 infection:
meningitis
Slide 9 of 34
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• IRIS
• meningitis• Acute IDP
• HAND (less severe) • Chronic IDP
• DSPN • PML
Early neurologic complications of HIV-1 infection:
Acute Inflammatory Demyelinating Polyneuropathy (AIDP)
Slide 10 of 34
HIV-associated neurocognitive disorders (HAND)
Distal Symmetric Polyneuropathy (DSPN)
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Early neurologic complications of HIV-1 infection:
Acute inflammatory Demyelinating Polyneuropathy (AIDP)
http://emedicine.medscape
• CSF: < 50 cells/ul
• elevated protein
• indistinguishable from GBS
Symptoms &
signs TreatmentNatural history
• weakness
• mild sensory sx.
• pain
• respiratory
• autonomic
• ankle reflexes absent
• plasmapheresis
• IVIG
• corticosteroids
• response rates probably similar to HIV-negative patients
• AIDP: (rare)
• most often at seroconversion (20-30d)
• progresses rapidly over days to < 4 weeks
Robinson-Papp, Muscle & Nerve. (2009)
Kaku M, Curr Opin HIV AIDS. (2014)
Slide 11a of 34
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Early neurologic complications of HIV-1 infection:
Acute inflammatory Demyelinating Polyneuropathy (AIDP)
http://emedicine.medscape
• CSF: < 50 cells/ul
• elevated protein
• indistinguishable from GBS
Symptoms &
signs TreatmentNatural history
• weakness
• mild sensory sx.
• pain
• respiratory
• autonomic
• ankle reflexes absent
• plasmapheresis
• IVIG
• corticosteroids
• response rates probably similar to HIV-negative patients
• AIDP: (rare)
• most often at seroconversion (20-30d)
• progresses rapidly over days to < 4 weeks
Robinson-Papp, Muscle & Nerve. (2009)
Kaku M, Curr Opin HIV AIDS. (2014)
Slide 11b of 34
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Chronic neurological complications of HIV infection:
• Chronic Inflammatory Demyelinating Neuropathy (CIDP)
• Distal Symmetric Polyneuropathy (DSPN)
• HIV-associated neurocognitive disorders (HAND)
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• IRIS
Later neurological complications of HIV infection after
initiation of antiretroviral therapy/ART
• meningitis• Acute IDP
• HAND (less severe) • Chronic IDP
• DSPN • PML
Slide 13 of 34
HIV-associated neurocognitive disorders (HAND)
Distal Symmetric Polyneuropathy (DSPN)
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• CSF: < 50 cells/ul
• elevated protein
• indistinguishable from idiopathic CIDP
Symptoms &
signs TreatmentNatural history• weakness
• mild sensory sx.
• pain
• respiratory
• autonomic
• ankle reflexes absent
• plasmapheresis
• IVIG
• response rates probably similar to HIV-negative patients
• CIDP: >1 year- later stages of HIV infection
• up to 30%of CIDP patients are HIV+*
• progresses over > 8 weeks
• relapses and remissions
Robinson-Papp, Muscle & Nerve. (2009)
Kaku M, Curr Opin HIV AIDS. (2014)
Later neurological complications of HIV infection:
Chronic inflammatory demyelinating polyneuropathy (CIDP)
Peripheral nerve onion-bulb in CIDP
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*http://emedicine.medscape
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• CSF: < 50 cells/ul
• elevated protein
• indistinguishable from idiopathic CIDP
Symptoms &
signs TreatmentNatural history• weakness
• mild sensory
• pain
• respiratory
• autonomic
• ankle reflexes absent
• plasmapheresis
• IVIG
• response rates probably similar to HIV-negative patients
• CIDP: >1 year- later stages of HIV infection
• up to 30%of CIDP patients are HIV+*
• progresses over > 8 weeks
• relapses and remissions
Robinson-Papp, Muscle & Nerve. (2009)
Kaku M, Curr Opin HIV AIDS. (2014)
Later neurological complications of HIV infection:
Chronic inflammatory demyelinating polyneuropathy (CIDP)
Peripheral nerve onion-bulb in CIDP
Slide 14b of 34
*http://emedicine.medscape
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• IRIS
Later neurological complications of HIV infection:
Distal symmetric polyneuropathy (DSPN)
• meningitis• Acute IDP
• HAND (less severe) • Chronic IDP
• DSPN • PML
• meningitis • HAND (less severe) • Chronic IDP
Slide 15 of 34
HIV-associated neurocognitive disorders (HAND)
Distal Symmetric Polyneuropathy (DSPN)
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Robinson-Papp, Muscle & Nerve. (2009)
Kaku M, Curr Opin HIV AIDS. (2014)
• Capsaicin (8% top.)
‘proved’ effective
Neurontin
Lamictal
(weak evidence)
• modify ART regimen
‘
Later neurological complications of HIV infection:
Distal symmetric polyneuropathy (DSPN)
Symptoms &
signs TreatmentNatural history
• Symmetric, distal, sensory
(axonal +/- demyelinating)
Pain predominates
• burning
• hyperalgesia
• tightness
• numbness
• preserved proprioception
• prevalence ~ 30%
• occurs with or without
ART use
• ART associated
(d-drugs):
d4T (Stavudine)
ddI (didanosine)
ddC (zalcitabine)
‘
Slide 16a of 34
http://emedicine.medscapeSimpson, Neurol. (2008),
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Robinson-Papp, Muscle & Nerve. (2009)
Kaku M, Curr Opin HIV AIDS. (2014)
• Capsaicin (8% top.)
‘proved’ effective
Neurontin
Lamictal
(weak evidence)
• modify ART regimen
‘
Later neurological complications of HIV infection:
Distal symmetric polyneuropathy (DSPN)
Symptoms &
signs TreatmentNatural history
• Symmetric, distal, sensory
(axonal +/- demyelinating)
Pain predominates
• burning
• hyperalgesia
• tightness
• numbness
• preserved proprioception
• prevalence ~ 30%
• occurs with or without
ART use
• ART associated
(d-drugs):
d4T (Stavudine)
ddI (didanosine)
ddC (zalcitabine)
‘
Stocking/glove distribution of pain in DSPN
Slide 16b of 34
http://emedicine.medscapeSimpson, Neurol. (2008),
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Later neurological complications of HIV infection:
Immune Reconstitution Inflammatory Syndrome (IRIS)
• meningitis• Acute IDP
• HAND (less severe) • Chronic IDP
• DSPN • PML
• meningitis • HAND (less severe) • Chronic IDP
• IRIS
Slide 17 of 34
HIV-associated neurocognitive disorders (HAND)
Distal Symmetric Polyneuropathy (DSPN)
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Initiation of cART (1-6 months): CNS syndrome (mild or severe) resulting from
heightened immunologic and/or inflammatory response against opportunistic pathogen (or other antigen
associated with HIV suppression by cART)
• robust inflammatory CNS infiltration (MRI detection)
• CNS IRIS in ~1-30% of pts. initiating cART
• rapid decline of viral load
- greatest risk with CD4 <50 and VL >100K
• most commonly associated with crypto meningitis, TB, PML
Johnson, Ann NY Acad Sci (2010)
Johnson, Curr Opin HIV AIDS (2014)
Later neurological complications of HIV infection:
Immune Reconstitution Inflammatory Syndrome (IRIS)
Slide 18a of 34
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Initiation of cART (1-6 months): CNS syndrome (mild or severe) resulting from
heightened immunologic and/or inflammatory response against opportunistic pathogen (or other antigen
associated with HIV suppression by cART)
• robust inflammatory CNS infiltration (MRI detection)
• CNS IRIS in ~1-30% of pts. initiating cART
• rapid decline of viral load
- greatest risk with CD4 <50 and VL >100K
• most commonly associated with crypto meningitis, TB, PML
Johnson, Ann NY Acad Sci (2010)
Johnson, Curr Opin HIV AIDS (2014)
Later neurological complications of HIV infection:
Immune Reconstitution Inflammatory Syndrome (IRIS)
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Slide 19 of 34HIV-associated CNS IRIS
Zafiri et al. New Microbiologica. (2013)
57 yo HIV+ man,
off ART x 3 years,
then re-start:
3 weeks right
hemiparesis,
slurred speech
CD4 T cells
24 99/mm3
CSF:
56 cells/ul
64 mg/dl prot.
Admission: stroke 24 days post-ART:
IRIS
31 days post-ART:
IRIS
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HIV-associated CNS IRIS in PML patientSlide 20 of 34
Vendrely A, Acta Neuropathol. (2005)
52 yo HIV+ man,
ART naïve x 16
years, admitted
for sub-acute
cognitive decline
cART started:
CD4 T cells
117 284/mm3
JC virus
confirmed at
autopsy
Before ART
1 mo. post-ART
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Later neurological complications of HIV infection:
Progressive Multifocal Leukoencephalopathy (PML)
• meningitis• Acute IDP
• HAND (less severe) • Chronic IDP
• DSPN • PML
• meningitis • HAND (less severe) • Chronic IDP
• IRIS
Slide 22 of 34
HIV-associated neurocognitive disorders (HAND)
Distal Symmetric Polyneuropathy (DSPN)
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Later neurological complications of HIV infection:
Progressive Multifocal Leukoencephalopathy (PML)
Symptoms & signs TreatmentNatural history
• papovavirus (JC virus) activation in the brain
• white matter (myelin) damage, early in occipital areas
• ~4% of all untreated patients
• ~1% in ART-treated patients
• Death within ~1 year in 90%
• hemiparesis
• memory loss
• slurred speech
• seizures
• visual sxs., blind spots
• sensory disturbances
up to 60%
~30-60%
~20-40%
~15-30%
~25%
~20%
• None effective
• ?inhibit JC virus
• ?reconstitute immune system
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Later neurological complications of HIV infection:
Progressive Multifocal Leukoencephalopathy (PML)
Symptoms & signs TreatmentNatural history
• papovavirus (JC virus) activation in the brain
• white matter (myelin) damage, early in occipital areas
• ~4% of all untreated patients
• ~1% in ART-treated patients
• Death within ~1 year in 90%
• hemiparesis
• memory loss
• slurred speech
• seizures
• visual sxs., blind spots
• sensory disturbances
up to 60%
~30-60%
~20-40%
~15-30%
~25%
~20%
• None effective
• ?inhibit JC virus
• ?reconstitute immune system
Slide 23b of 34
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Later neurological complications of HIV infection:
Progressive Multifocal Leukoencephalopathy (PML)
Note lesions restricted to white matter
Slide 24 of 34
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Later neurological complications of HIV infection:
Progressive Multifocal Leukoencephalopathy (PML)
atypical PML: patchy enhancement in HIV+, 30 y.o. man
atypical PML: ring enhancementHIV+, 25 y.o. man
typical PML: no enhancement
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• IRIS
• meningitis • HAND
• DSPN • PML
Later neurological complications of HIV infection:
HIV-associated neurocognitive disorders (HAND)
Slide 26 of 34
HIV-associated neurocognitive disorders (HAND)
Distal Symmetric Polyneuropathy (DSPN)
• Acute IDP
• Chronic IDP
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HIV associated neurocognitive disorders (HAND) have
similar prevalence but decreased severity post-ART
Saylor, Nature Reviews Neurology (2016)
HAND sub-groups
ANI: Asymptomatic neurocognitive impairment
MND: Mild neurocognitive disorder
HAD: HIV-associated dementia
• functional impairment in certain ADLs
• affects ~20% of virally suppressed patients
Slide 27 of 34
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HIV-associated neurocognitive disorders (HAND)
Later neurological complications of HIV infection:
HIV-associated neurocognitive disorders (HAND)
• 1/3 have MRI evidence of white matter abnormality, with or without brain atrophy
46 year old man, HIV+ for ~20 years, CD4 nadir 50+ cells/ul
began ART after severe immunosuppresion;
white matter lesions + brain atrophy
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• Using ART regimens with higher CNS penetration?
multiple (conflicting) reports suggest no benefit
ART drugs may directly induce oxidative stress and neuronal damage
• Intensification of ART regimens with additional classes of antivirals?
recent studies of Maraviroc (CCR5 blocker) suggest possible benefit
additional studies underway
• Adjunctive therapies in addition to ART?
focus on controlling neuroinflammation & oxidative stress
How to reduce residual HAND impairment in
ART- treated individuals?
Slide 29a of 34
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• Using ART regimens with higher CNS penetration?
multiple (conflicting) reports suggest no benefit
ART drugs may directly induce oxidative stress and neuronal damage
• Intensification of ART regimens with additional classes of antivirals?
recent studies of Maraviroc (CCR5 blocker) suggest possible benefit
additional studies underway
• Adjunctive therapies in addition to ART?
focus on controlling neuroinflammation & oxidative stress
How to reduce residual HAND impairment in
ART- treated individuals?
Slide 29b of 34
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HIV-associated neurocognitive disorders (HAND)
Distal Symmetric Polyneuropathy (DSPN)
• IRIS
• meningitis• Acute IDP
• HAND (less severe) • Chronic IDP
• DSPN • PML
• meningitis • Chronic IDP
Neuropathy (less severe)
HAND
Neurological complications of HIV can persist in ART-treated
individuals and require adjunctive therapies to limit morbidity
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Thank you!
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Kolson Lab: Univ. of Pennsylvania
• Alexander Gill, MD, PhD student
• Colleen Kovacsics, PhD student
• Yoelvis Garcia-Mesa, PhD
• Rolando Garza, BS
• Patricia Vance, BS
Penn Center for AIDS Research
• Ron Collman, MD (Director)
University of Texas Medical Branch
• Ben Gelman, MD, PhD
University of North Carolina, Chapel Hill
• Kevin Robertson, PhD
AcknowledgementsSlide 32 of 34
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Dr Kolson Suggested Readings
Activity #: HIV 17 CHI (F)
05-04-17
Page: 1
SUGGESTED READINGS
1. Hellmuth J, Fletcher JL, Valcour V, et al. Neurologic signs and
symptoms frequently manifest in acute HIV infection. Neurology.
2016;87(2):148-154.
Ref ID: 15078
2. Johnson T, Nath A. Neurological complications of immune
reconstitution in HIV-infected populations. Ann N Y Acad Sci.
2010;1184:106-120.
Ref ID: 15079
3. Johnson TP, Nath A. New insights into immune reconstitution
inflammatory syndrome of the central nervous system. Curr Opin HIV
AIDS. 2014;9(6):572-578.
Ref ID: 15080
4. Kaku M, Simpson DM. HIV neuropathy. Curr Opin HIV AIDS.
2014;9(6):521-526.
Ref ID: 15081
5. Pavlovic D, Patera AC, Nyberg F, Gerber M, Liu M. Progressive
multifocal leukoencephalopathy: current treatment options and
future perspectives. Ther Adv Neurol Disord. 2015;8(6):255-273.
Ref ID: 15082
6. Robinson-Papp J, Simpson DM. Neuromuscular diseases associated
with HIV-1 infection. Muscle Nerve. 2009;40(6):1043-1053.
Ref ID: 15083
7. Saylor D, Dickens AM, Sacktor N, et al. HIV-associated
neurocognitive disorder - pathogenesis and prospects for
treatment. Nat Rev Neurol. 2016;12(5):309.
Ref ID: 15084
8. Schutz SG, Robinson-Papp J. HIV-related neuropathy: current
perspectives. HIV AIDS (Auckl ). 2013;5:243-251.
Ref ID: 15085
9. Simpson DM, Brown S, Tobias J. Controlled trial of high-
concentration capsaicin patch for treatment of painful HIV
neuropathy. Neurology. 2008;70(24):2305-2313.
Ref ID: 10401