Documente Academic
Documente Profesional
Documente Cultură
Course Faculty
IPS 2012
Course 06
COURSE 6
IMPACT OF PSYCHIATRIC DISORDERS ON HIV MANAGEMENT
EDUCATIONAL OBJECTIVES:
At the conclusion of this session, the participant should be able to: 1) Discuss the most
common psychiatric disorders observed in HIV-infected patients; 2) Understand the
increased risk of cognitive impairment among patients; 3) Describe the signs and
symptoms of cognitive decline and 4) Recognize state-of-the-art approaches to HIV
clinical management (including cognitive assessment).
Impact of Psychiatric Disorders on HIV Management
Friday, October 5, 2012 – 9:00 AM – 4:00 PM
Sheraton New York and Towers, New York, NY
Agenda
9:00-9:30 am
It’s Complicated: Emerging Issues FORSTEIN
9:30-10:15 am
Common Psychiatric Syndromes (overview of psychosis, anxiety, depression, et al…when to make
referrals…) COURNOS
10:30-11:15 am
HIV and Substance Use: WAINBERG
11:15 -12:00
HIV-Related Cognitive Impairment (with benefits and limitations of screening; include a differential for
aging) FERNANDEZ
Participants generally have plenty of difficult cases to discuss in the groups, but we usually ask faculty
to come with a case in mind in case the group needs a spark. Case does NOT need to be written up.
1:00 – 2:00 pm
Managing Difficult Patients (Multidisciplinary break out session) FORSTEIN
2:00 – 3:30 pm
Clinical Case Discussion: Differential Diagnosis (Multidisciplinary break out session) ALL
3:30-4:00 pm
Question and Answers
What Clinicians Need to Know:
Current and Emerging Issues in HIV
Marshall Forstein, MD
Associate Professor of Psychiatry
Harvard Medical School
Chair, Steering Committee on HIV Psychiatry
American Psychiatric Association
Where the epidemic is in 2012
• Transformation of the epidemic (
potentially) from an acute to a chronic
disease.
• Approx. 50,000 new infections each year
over past decade in U.S.
• Worldwide 2.7 million new infections
yearly
Race and ethnicity in US 2010
How do we account for this?
• Estimate: about 25% of people do not know
they are infected.
• Access to care is not equitable
– Health care disparities highest in those at risk
• Adherence problems
– Readiness
– Environment ( living situation)
Medical Issues
• Routine testing for HIV
substance use,
Medical Issues
• When to start ART?
– Rationale for starting as soon as diagnosed
• Inadequate adherence
– Increases risk for mutation against ART
– Increases the risk of transmitting HIV
Medical Co-Morbidity
• More prevalent as people with HIV age
and are at risk for complications from HIV
and other non-HIV related illness.
Endocrine dysfunction
and mental dysfunction
• Clinical and subclinical hypothyroidism
– 16% prevalence
• Beltran S, Lescure F-X, Desailloud R, et al.: Increased
prevalence of hypothyroidism among human immunodefi
ciency virus infected patients: a need for screening. Clin
Infect Dis 2003, 37:579–583.
• Hypogonadism
– Up to 50% in symptomatic HIV
• Mylonakis E, Koutkia P, Grinspoon S: Diagnosis and
treatment of androgen deficiency in human immunodefi
ciencyvirus-infected men and women. Clin Infect Dis 2001,
33:857–864.
Endocrine dysfunction
and mental dysfunction
• Adrenal insufficiency
– 50% in severely ill HIV
• Mayo J, Callazos J, Martinez E, Ibarra S: Adrenal function in
the human immunodeficiency virus-infected patient. Arch
Intern Med 2002, 162:1095–1098.
• Graves disease
• Chen F, Day SL, Metcalfe RA, et al.: Characteristics of
autoimmune thyroid disease occurring as a late complication
of immune reconstitution in patients with advanced human
immunodeficiency virus (HIV) disease. Medicine (Baltimore)
2005, 84:98–106.
HIV and HepC
• Interaction between HIV and HepC
– HIV increases risk for progression of HepC
– HepC does not increase progression of HIV
12
10
8 HIV Dementia
6
HIV sensory
HAART
4 neuropathy
0
94
96
98
00
01
02
03
04
19
19
19
20
20
20
20
20
Prevalence of
neurocognitive 51% 39% 23% 59%
deficit
N (% men) 1562 (74%) 1160 (87%) 158 (79%) 834 (73%)
Mean age, years 43 41 44 47
ARV 83% 100% 86% 100%
1. CHARTER: http://www.charterresource.ucsd.edu/images/M_images/x‐sect_cohort_rep.pdf
2. Robertson K: AIDS 2007, 21:1915–1921
3. Vasallo M, et al. 16th CROI, Montreal 2009, abstract # 464.
4. Carvalhal et al. 19th CROI, Seattle 2012, abstract # 484
Changing prevalence of HAND
Modified from Heaton R., et al: HIV‐associated neurocognitive disorders (HAND) persist in the era of
potent antiretroviral therapy: The CHARTER Study; and Heaton R., J Int Neuropsychol Soc. May
1995;1(3):231‐251)).
What Now?
• Difficult to convince colleagues of need to address CNS
1000
Low
CD4Moderate
< 500:
Constitutional
HIV RNA, on
800 Symptoms
HAART, Low CD4
Develop
level resistance VL (x1000)
600
CD4 < 200: AIDS
Diagnosis, Development of
400 Virologic
Low HIV Setpoint:
RNA, on HAART
Carries prognostic
OI’s including CNS
No Resistance
significance disorders
200
0
Months Years
Time Since Infection
Primary HIV Infection
Pathogenesis of HIV-associated dementia (HAD)
• Circulation and
ingress of activated
monocytes
• Productive CNS
infection established
• Reservoir in
macrophages and
astrocytes
• Release of
inflammatory
mediators and toxic
HIV proteins (tat,
gp120)
• Astrocytosis, BBB
and neuronal
Zink C
dysfunction
HAD Pathogenesis – DA
Summary
• Cognitive impairment in HIV/AIDS is still a
controversial topic
• There is little agreement on type and impact on
day-to-day life
• Cognitive impairment can occur early and
continues to worsen
• Inflammation in CNS compartment may be
responsible for the cognitive changes see.
Overview
• HIV-neurocognitive impairment continues to be an
important problem
– For all people living with HIV
• In both less and more resource limited settings
• HIV-neurocognitive impairment can be recognized
easily
– Neurodiagnostic tests can improve confidence in the
diagnosis and exclude N-OIs
• HIV-neurocognitive impairment can be treated
– Primary therapy ART in CNS leads to better outcomes
– Secondary anti-inflammatory therapies
– Palliative therapies
Clinical Presentation of HIV-CNS
HIV-associated Neurocognitive Disorders (HAND)
(HIV-1-Associated Dementia)
(HIV-associated Cognitive/Motor Complex)
(HIV-associated Mild Neurocognitive Disorder)
(Asymptomatic Neurocognitive Impairment)
(HIV-Associated Mild Cognitive/Motor Disorder)
(HIV-Related Encephalopathy)
(AIDS Dementia Complex)
Neuropsychological Deficit
Asymptomatic Neuropsychological
Impairment Clear
abnormality
Mild Neurocognitive Impairment Abnormality in in one
(Minor Cognitive /Motor Disorder) two or more cognitive
cognitive ability
Abilities
HIV Dementia Cognitive
impairment with
No functional
mild
Marked cognitive impairment
functional
impairment with impairment
marked functional
impairment
Diagnostic Criteria for HIV-Associated
Dementia (HAD)
(American Academy of Neurology, 1991)
(NINDS/NIMH Working Group, 2007)
• Severe acquired abnormality in at least two
cognitive abilities for at least a month:
– Attention, Speed of processing, Abstraction,
Executive functions, Learning skills
• Marked interference with day-to-day
functioning
Criteria for HAD
Acquired Interferes with No Pre- Delirium
Impairment in ≥ Daily existing Absent
2 Cognitive Functioning Cause
Abilities
Asymptomatic
Neurocognitive
Impairment (ANI)
Mild No ● ●
Mild Neurocognitive
Disorder (MND)
Mild Mild ● ●
HIV-Associated
Dementia (HAD)
Marked Marked ● ●
HIV INFECTION IN THE CNS
A General Medical-Psychiatric
Evaluation is Essential!
Clinical Work-up for CNS
Disorders in HIV Infection
• General medical work-up
• Psychiatric work-up and differential diagnosis
• Cognitive screening and neuropsychological
testing
• Functional status assessment
Cognitive Screening Work-Up
• Mini-Mental Status Exam
– Insensitive; higher cut-offs might be useful
(<26/30 to be suspected/monitored)
• Brief Neurocognitive Screen
– TMT-A & B and WAIS Digit Symbol Task
• Sensitive in detecting NPI in HIV-infection
• Following treatment effects
HIV Dementia Scale
• Antisaccadic Eye Movement
– Errors Can be eliminated from scale in
the “modified HDS”
• Timed Alphabet (if able to say
alphabet; otherwise, use numbers 1-
26)
• Verbal Memory (with cueing) - recall
should be at 5 min.
• Cube Copy time (“as precisely and
quickly as possible”)
Limitations of the HDS
• HDS has issues with validity across
cultures (inside and outside the USA)
• Few Hispanics; the cube copy issue
• Standardized on predominantly
young male sample with higher
educational level
• Most sensitive to more severe
impairment
• ARV regimens were pre-HAART
• HAND is now milder post-HAART –
with ANI > MND > HAD
International HIV Dementia Scale
(IHDS)
• HDS issues with validity across cultures
(inside and outside the USA)
• IHDS:
– Finger Tapping for Motor Speed
– Psychomotor Speed: Non-dominant hand
coordination/speed
• Clench hand in fist on flat surface
• Put hand flat palm down
• Put hand perpendicular on side of 5th digit)
– Verbal Memory
– Sacktor et al. (2005), Johns Hopkins
Modified HIV Dementia Scale
Max Pt. Task
Score Score • Developed for HAD
Memory-Registration Give four words to recall (dog,
hat, green, peach) - 1 second to say each. Then ask the
screening
patient all 4 after you have said them.) o Not proven for
6 Psychomotor Speed Ask patient to write the alphabet in
upper case letters horizontally across the page below
MND
and record time: ____ seconds. o Timed items –
less than or equal to 21 sec = 6; 21.1 - 24 sec = 5; 24.1 subcortical
- 27 sec = 4; 27.1 - 30 sec = 3; 30.1 - 33 sec = 2; 33.1 -
36 sec = 1; > 36 sec = 0) • Risk for HAD is
Memory - Recall Ask for 4 words from Registration
4 above. Give 1 point for each correct. For words not scored as < 7.5/12
recalled, prompt with a "semantic" clue, as follows:
animal (dog); piece of clothing (hat), color (green),
• Significant variation
fruit (peach). Give 1/2 point for each correct after in the quality of the
prompting.
Construction Copy the cube; record time: ____ cube copy item
2 seconds.
(< 25 sec = 2; 25 - 35 sec = 1; > 35 sec = 0)
observed by
ethnicity as well as
Total
score /12 educational level.
Max = • Sensitivity = 70%
12 Specificity = 71%
Modified from the Johns Hopkins University Department of Neurology HIV Dementia Scale- Powers, et al.
Montreal Assessment of
Cognitive Impairment (MOCA)
• Rapid screen of 11 items requiring
about 20 minutes; Normal: >26 of 30
• Includes TMT-B and DS (forward and
backward) as well as verbal memory
• Abstraction, object naming, clock
draw and language not frequently
related to HIV infection
• Less data specifically demonstrating
validation for HAND
EXIT Interview
• Long for screening test at 25 items
• Includes many neurobehavioral
examination items
• Requires more training
• Strong correlation with full battery
• Overlaps IHDS on Luria Hand
sequence II
• Has been tested in HAND
– Less sensitive than HDS but ↑ specificity
Screening for HAND by Self
Report
MOS HIV Cognitive Functional Status Scale
1. Difficulty reasoning and solving
problems?
2. Forget things that happened recently?
3. Trouble keeping your attention on any
activity for long?
4. Difficulty doing activities involving
concentration and thinking?
Validated against NP overall performance
Asymptomatic
Neurocognitive
Impairment (ANI)
Mild No ● ●
Mild Neurocognitive
Disorder (MND)
Mild Mild ● ●
HIV-Associated
Dementia (HAD)
Marked Marked ● ●
Diagnostic Criteria for
Mild Neurocognitive Disorder
(NINDS/NIMH Working Group, 2007)
Decreased
–
–
–
–
Driving ability
Work performance
Medication adherence
Less compliant with medical care
Survival
– Less compliant with drug cessation
– Less compliant with protective sex
measures
– Increased unemployment
– Decreased quality of life
– Subjective perception of diminished
work performance
HIV-
Associated Other
Neuro- medical
cognitive conditions
Disorder
HIV positive
Baseline cerebral blood flow
HIV negative
• Prophylaxis of CNS
• Primary Treatments
– Antiretroviral medications
• Secondary Treatments
– Immunostimulants and inflammatory mediators
• Palliative Treatments
– Psychotropic agents
– Nutritional
What to start with?
Entry Inhibitors
• Maraviroc
Primary Therapy
• Zidovudine – ATEU 005
– Relatively good brain penetrance
• CSF:blood concentration ratio - 0.6
– Only a group receiving a high dose (2,000
mg/day) showed neuropsychological
improvement over 16 and 32 weeks
– Shown to decrease quinolinic acid levels in the
CSF
Neuroimaging: Pre- and Post-Rx
HAD HAD-ZDV
ART trials for HIV-dementia
• Definition
–CSF level of ART exceeds the
level needed to inhibit replication
of HIV
Neuro-AIDS Can Be Treated
Higher CPE Scores and Lower Viral Loads
in CSF
• PIs
– Indinavir – stones
– Ritonavir – GI
– Nelfinavir – Diarrhea
– Amprenavir - GI
ART Effects on Abeta (1-40) Production
in Cultured Cells
50 AZT
Abeta1-40 production (% over control)
40 Lamivudine (3TC)
30 Indinavir
20 Abacavir
10
AZT/3TC
0
AZT/Indinavir
-10
AZT/Abacavir
-20
3TC/Indinavir
-30
-40 3TC/Abacavir
-50 Indinavir/Abacavir
Figure 1
Secondary Pharmacotherapy
Palliative or Adjunctive Therapy
80
Percent Change from Baseline
60
40
20
Placebo
0 MPD
1 2 3 4 5 6 7 8 9
-20
80
60
40
20
0
Condition:
gp120 gp120/ACh gp120/gal
Pre-treatment of microglia with ACh or Gal for 30 minutes and then challenge these cells
with gp120 for 38 hours
October 5, 2012
Neuropsychiatric Problems Are
Common among HIV+ People
Mood disorders
Anxiety disorders
Psychotic illnesses
Alcohol/Substance use disorders
Somatic problems:
insomnia, pain, fatigue, sexual dysfunction, body habitus
changes
Reference documents at www.psych.org/aids and www.hivguidelines.org
Rule Out Medical Problems Whenever HIV+ Patients
Present with Mental Status Changes
AFFECTIVE SOMATIC
Depressed mood Appetite/Weight loss
Loss of interest Sleep disturbance
Guilt, worthlessness Agitation/retardation
Hopelessness Fatigue
Suicidal ideation Loss of concentration
Some Easy to Use Screening Tools:
PHQ-2, PHQ-9 and GAD-7
Over the last two weeks how often have you been
bothered by any of the following problems:
Little interest or pleasure in doing things.
– 0=Not at all
– 1=Several days
– 2=More than half the days
– 3=Nearly every day
USE: WITHDRAWAL:
Amphetamines Alcohol
Ecstasy Benzodiazepines
Caffeine Opiates
Cocaine
Nicotine
Diagnostic Instrument for Generalized
Anxiety Disorder:
GAD-7 – Items Rated from 0-3
Psychopharmacology
– Antipsychotics for acute management
– Mood stabilizers ± antipsychotics for long-term
management:
» Lithium – do not use if HIV nephropathy
» Anticonvulsants, however,
Carbamazepine: potent CYP3A4 enzyme inducer, may decrease levels
of PIs and NNRTIs - AVOID
Valproic acid: inhibitor of glucuronidation; increases zidovidune, but
dosage adjustment not recommended
Consider side effects & toxicities; labs
– Benzodiazepines as adjunct
Electroconvulsive therapy (ECT)
Practice Guideline for the Treatment of Patients with Bipolar Disorder, 2nd Ed. Available
online at http://www.psychiatryonline.com/pracGuide/pracGuideHome.aspx
Use of Psychotropic Medications: Other
Key Points
HIVInSite
http://hivinsite.ucsf.edu
AETC National Programs
Warmline/PEPline (UCSF)
– Telephone consultation for HIV clinical
management and post-exposure prophylaxis
management
– Warmline: 800-933-3413
– PEPline: 888-448-4911
PRISSMA Project / NIMH R01-
65163/ 2002-2006 & 2006-2011
Background
Heavy drinking can compromise HIV survival,
especially among the HCV co-infected
Resource-limited HIV primary clinics interventions
must be effective requiring little staff time
In general primary care patients without alcohol
dependence, brief drinking-reduction interventions
are efficacious
Little information is available on brief interventions
among primary care patients with HIV
Unsafe Drinking in Primary HIV Care
The Study
We tested the efficacy of a technological enhancement
to brief motivational interviewing (MI) to reduce heavy
drinking among HIV primary care patients (NYC)
ACTION
MAINTENANCE
RELAPSE PREPARATION
&
RECYCLE
CONTEMPLATION
PRECONTEMPLATION
MOTIVATIONAL INTERVIEWING
Overview
A directive, client-centered counseling style
that enhances motivation for change by
helping the client clarify and resolve
ambivalence about behavior change.
The goal of Motivational Interviewing is to
create and amplify discrepancy between
present behavior and broader goals
Create cognitive
dissonance between and where one
where one is wants to be
MOTIVATIONAL INTERVIEWING
Assumptions
Motivation is a state of readiness to change,
which may fluctuate from one time or situation
to another. This state can be influenced.
Motivation for change does not reside solely
within the client.
The counselor’s style is a powerful
determinant of client resistance and change.
An empathic style is more likely to bring out
self-motivational responses and less
resistance from the client.
MOTIVATIONAL INTERVIEWING
Assumptions
• People struggling with behavioral problems
often have fluctuating and conflicting
motivations for change, also known as
ambivalence.
• Ambivalence is a normal part of considering
and making change, and is not pathological.
• Each person has powerful potential for change.
• The task of the counselor is to release that
potential and facilitate the natural change
process already inherent in the individual.
MOTIVATIONAL INTERVIEWING
General Principles
EXPRESS EMPATHY
DEVELOP DISCREPANCY
AVOID ARGUMENTATION
• Foundation of MI
“expensive”
“I love my
vodka cold…” “my children
OLD
are learning to
BEHAVIOR “It relaxes me”
drink”
“I feel better”
“my liver”
“spend more
NEW time with my “I will lose my
HEALTHIER children” friends”
BEHAVIOR “get further in “bored”
school/work”
MOTIVATIONAL INTERVIEWING
Strategies - OARS
SUMMARIZE
Design
Three-arm randomized trial comparing:
MI+HealthCall MI-only Advice/education control
Brief MI (30’) was administered at baseline in the
two MI arms
MI+HealthCall participants called HealthCall daily
for 1-3 min to report alcohol and health behaviors;
Call data were summarized in monthly feedback
graphs for patients
Main Outcome (Timeline Followback at baseline,
30 & 60 days)
Mean number of drinks per drinking days
(NumDD)
Percent days abstinent (PDA) measured
Unsafe Drinking in Primary HIV Care
6
Mean # Drinks
5
Advice / Education
4 MI-ONLY
3 MI+Healthcall
0
0 30 60
Time Point (Days)
Unsafe Drinking in Primary HIV Care
6
5
Advice / Education
4 MI-ONLY
3 MI+Healthcall
2 NumDD @ 60 days:
MI+Healthcall < advice/education
1 (t=3.53, df=93, p=0.0007) and
0 MI+Healthcall < MI-only
0 30 60 (t=2.17 df=93, p=0.03)
Time Point (Days) (large/moderate effect sizes)
Unsafe Drinking in Primary HIV Care
Possible mechanisms of
HealthCall’s action
IVR Feedback graph
Self-monitoring More accurate reporting on
Reminding patients of IVR than retrospective recall
the MI goals/plan More intervention time (i.e.,
Improved self-efficacy higher dose) without requiring
additional staff time – 4th IVR
calls alone treatment arm?
9
7
Mean # Drinks
Education/advice
a
(control)
6 b
MI-Only
5 c
MI+Healthcall
4
3
90 180 365
Time Point (Days)
Conclusions
Unsafe Drinking in Primary HIV Care
Among the non-dependent patients, all the brief
interventions were helpful, including brief advice to reduce
drinking and general health education, analogous to usual
clinic care.
Those with alcohol dependence need more: MI + HealthCall
Screen and increase level of treatment – Stepped-Care
HealthCall, an inexpensive technologically-based method to
enhance brief intervention that places little additional
demands on clinic staff, is feasible and potentially
efficacious among these patients.
Resources
Counselors where clinic providers with no prior experience
with specialized substance treatments
Task-shifting
Summary
1st RCT of brief intervention for drinking reduction in heavy-drinking
within HIV primary care clinics.
60-day results:
Non-dependent patients, NumDD decreased in all groups.
In the full sample and in alcohol dependent patients, end-of-
treatment NumDD was significantly lower for patients in
MI+HealthCall than in control, with large effects in the alcohol-
dependent patients, while MI-only differed from control weakly or not
at all.
Among alcohol dependent patients, the MI+HealthCall advantage
persisted throughout 12 months, although significance of group
differences did not persist.
Any brief intervention is helpful for HIV patients without alcohol
dependence, but among alcohol dependent HIV patients, MI-only is not
a sufficient drinking-reduction intervention.
MI+HealthCall is feasible and appears effective in helping HIV-infected
alcohol dependent patients make clinically meaningful reductions in
drinking quantity during active treatment yet brief, inexpensive and
clinic resource-protective.
Summary…
End of treatment for a chronic illness (SUD) in the presence
of at least one (or maybe more) chronic illnesses (HIV, HepC,
Mental Illness, metabolic) and chronic social stressors, is
unlikely to take place
The idea that a brief intervention within a short treatment of
60 days would suffice for a population with multiple
diagnoses, multiple medical and psychosocial stressors and
long SUD history is clearly a great hope but not a reality.
No one expects – although we all hope -- for end of treatment
in many chronic illnesses. Even today, HIV patients are
never discharge from treatment as cured.
Combined, these findings may suggest the public health
need to test implementation of brief intermittent interventions
+ technology for alcohol-dependent patients to decrease
burden yet address ‘chronically’ this participants’ realities.
Thank You!
The patients who try our patience
Marshall Forstein, MD
APA Minority Student HIV Elective Training
August, 2012
Difficult patient? Difficult provider?
Literature on the Difficult Patient
• Shocket BR , The difficult patient in the general hospital,
Am Fam Physician, 1973, March: 95‐9.
• Roukema RW. The Problem patient in your waiting room.
J Med Society New Jersey, 1976; 73: 985‐8
• Groves JE, Taking care of the the hateful patient. N Engl J
Med, 1978; 298:883‐7
• Klein D, Najman J, Kohrman A, Munro C. Patient
characteristics that elicit negative responses from family
physicians. J Fam Pract 1982; 14:881‐8
Common themes
• Difficult patients:
– Impede treatment
• Poor adherence
• Negative attitude
• Unrealistic expectations
– Undermine the physician’s authority, or prestige
• Devaluation, comparison
– Impede communication with provider/ staff
• Dishonesty, withholding information, passive aggressiveness
– Violate providers norms (professionally or personally)
• Hygiene
• Malingering
• Sexual orientation/race
The Hateful Patient‐ Groves 1978
• Describes 4 types of patients who
provoke reactions from providers
– Dependent clingers
– Entitled demanders
– Manipulative help rejecters
– Self destructive deniers
Dependent Clingers
• “Clingers escalate from mild and appropriate
requests for reassurance to repeated,
perfervid, incarcerating cries for explanation,
affection, analgesics, sedatives and all forms
of attention imaginable”
• “They are naive about their effect on the
physician, and they are overt in their
neediness”
Dependent Clingers
• May start with genuine appreciation, and
move rapidly towards unremitting demands
for more and more.
• Requires the provider to accept limitations of
what can be offered
– Not feel inadequate for being unable to meet the
unquenchable thirst for attention and attachment
Entitled Demanders
• “Demanders resemble clingers in the
profundity of their neediness, but they differ
in that — rather than flattery and unconscious
seduction — they use intimidation,
devaluation and guilt‐induction to place the
doctor in the role of the inexhaustible supply
depot. “
Entitled Demanders
• Expect the provider to be inexhaustible and to
prioritize needs over all else.
• May threaten retaliation
– Suit
– Withholding payment
– Being late and expecting to be seen
• Must be seen as attempt by the patient to
preserve the integrity of the self when the
underlying feeling is one of being unsafe, terrified
or at risk for harm.
• Entitlement is in lieu of hope and faith
Manipulative Help‐Rejecters
• Quenchless emotional needs
– Unlike clingers, they are not seductive and
grateful
– unlike demanders they are not overtly hostile.
• Their pessimism and tenacious nay‐saying
appear to increase in direct proportion to the
physician's efforts and enthusiasm.
• Pathological dependency
Manipulative Help‐Rejecters
• Intention is not relief of symptoms
• “What is sought is an undivorcible marriage
with an inexhaustible caregiver”
• Symptoms are an “admission ticket to a
relationship that cannot be sundered so long
as symptoms exist”
• Yet provider fears that the patient’s style will
hide a real problem for which the provider
feels responsible.
Self‐ destructive Deniers
• unconsciously self‐murderous behaviors
• Must be distinguished from other major
deniers (without self‐ destructive intent)
– Tend to be likeable, hard workers, independent
• Grossly self‐destructive denial, on the other
hand stirs up malice
– Not independent‐ have given up on their needs
ever being met
– “glory in their own destruction”
Self‐ destructive Deniers
• main pleasure in furiously defeating the
physician's attempts to preserve their lives.
• They may represent a chronic form of suicidal
behavior; often they let themselves die.
• May provoke unacceptable feelings in the
provider for the patient to “get it over with
and die”
Provider reactions‐ Groves
• Dependent clingers evoke aversion
• En‐titled demanders evoke fear and then
counterattack upon entitlement
• Manipulative help‐rejecters evoke guilt and
feelings of inadequacy.
• Self‐destructive deniers (unlike "major deniers," who
generally stir up affection mingled with anxiety) evoke all
these negative feelings, as well as malice and, at
times, the secret wish that the patient will "die
and get it over with”
Psychological issues
• Providers and patients have unequal, non‐
reciprocal relationships
– Potential for unconscious manifestations of ENVY
• The greater the intensity of the affect, often fed
by unconscious, unmet needs, the less lucid the
thinking and strategizing about how to get needs
met.
– “Is the way things are playing out working for you?”
Case Example
Psychiatry Consult service request
• You are on the psychiatry consult service
called to see a patient on the medical ward.
Consult request:
• “The patient is giving the nurses a very
difficult time around her pain medication.”
• As the psychiatry resident on consult service,
you talk to the medical resident and charge
nurse after reading the chart.
• The medical resident and charge nurse agree
that the patient is disruptive to the care of
other patients and is manipulating for pain
medication.
• What do you want to know?
• Patient is called “borderline” by medical
resident
– What does this mean?
– How does it inform what you will encounter?
• Pain medication is written for 1‐2 Percocets
every 6‐8 hours as needed
– What do you think about this set of orders for
pain medication?
You go see the patient
• The patient has been placed in a private room
and upon you entering the room, asks in a
very angry voice “who the f‐‐‐ are you?”
• How do you reply?
Patient
• Ms. T is a 35 year old female admitted to the
medical service for treatment of a right foot
cellulitis.
– What are the facts thus far?
– What assumptions have you already made?
– What further history do you want?
– What medical tests would you find useful?
• You tell the patient that you were called by
the medical staff to see if you could help, but
before you can continue she yells and says
– “I need more pain medication”
– “if you won’t do that get out..!!!!”
– “The nurses won’t answer my calls for
medication”
• How do you proceed?
• What are some ways to manage the
interaction with the patient?
Patient history
• More info:
– 10 year history of heroin abuse
– On methadone for opioid substitution
– Has abused benzo’s, ETOH
– Has had hx of endocarditis
– Previously hospitalized for cutting
What makes patients difficult?
What makes patients difficult?
• Experience of trauma/ retraumatization
• Substance use
• Toxic states ( delirium)
• Cognitive dysfunction
– Frontal lobe
– CNS lesions
• Personality disorders/ traits
Issues that may underlie Patient demands
• Pain
• Loneliness
• Fear
• Anxiety
• Loss of body integrity
• Loss of cognitive function
• Loss of sexual function
What makes providers difficult?
What makes providers difficult?
• Premature assumptions
– Based on diagnosis
– Bias
– Cultural insensitivity
• Power
• Lack of empathy and appreciation for the
suffering of a patient
• Inattention to the counter‐transference
towards the patient.
Difficult patients in HIV Care
• Pain management
• History of substance use and abuse
• Pre‐existing personality traits
– Over attachment that intensifies with changing
medical status ( often accompanied by unrealistic
expectations, displacement of disappointment in
health status onto blame for provider)
– Passive aggression
– Envy and hostility
• Demanding disability
• Demanding controlled substances
What to do
• Listen to patient
• Assume nothing
• Diagnose patient anew each time
• Agree on the “problem”
• Agree on the course of action
• Set appropriate boundaries and limits
– Be up front about what you can and cannot do
• Establish written treatment contracts in settings
where splitting staff is a defense intended to meet
demands
Provider Responsibilities
• To acknowledge hateful, fearsome, negative
feelings toward the patient.
• Create a dynamic formulation that allows a
more dispassionate understanding to bear the
negative affects with an empathic stance:
– “The tragedy is that this person must resort to
coping mechanisms that in fact makes getting the
expressed or unconscious needs met”
AIDS Care, August 2006; 18(6): 561 568
Abstract
Excess drinking poses multiple substantial health risks to HIV-infected individuals. However, no published intervention
studies have focused on drinking reduction as the main outcome in HIV primary care patients. An intervention in this
setting must place minimal demands on pressured staff and resources. This pilot study tested such an intervention, which
consisted of brief Motivational Interviewing (MI) and HealthCall, an automated daily telephone self-monitoring system
based on Interactive Voice Response (IVR), designed to extend and enhance the effects of brief MI. Thirty-one patients
entered the study, received a 30-minute MI and were instructed in daily use of the IVR system. They received
graphical feedback on their daily drinking from the HealthCall database after 30 days. A statistically significant decrease in
drinking was found over time, both as reported in daily IVR calls (b/ /0.01, se 0.01, p/.03) and in follow-up interviews
(b/ /0.04, se 0.12, p/.02) at 60 days. The proportion of daily calls made supported the feasibility of the intervention.
The results indicate that HealthCall is acceptable to a disadvantaged HIV patient population, and preliminary data support
the efficacy of this intervention in reducing harmful drinking among HIV primary care patients.
Correspondence: Deborah S. Hasin, Ph.D., Columbia University/New York State Psychiatric Institute, 1051 Riverside Drive, Box 123,
New York, NY 10032. E-mail: dsh2@columbia.edu
(1) Motivational Interviewing (MI) demanding, broadening the base of patients who
may benefit (Copenhaver et al., 2003). Second, for
MI is a brief evidence-based intervention for reduc-
those uninterested in psychological exploration or
tion of excessive drinking and other conditions
self-disclosure, IVR may be more neutral and less
(Miller & Rollnick, 2002) that assumes ambivalence
personal. Third, research has demonstrated that
about ostensibly desirable behaviour change. MI
when combined with another intervention, methods
includes techniques to develop awareness of the
like IVR that increase self-monitoring can reduce
discrepancy between desires to engage and not to
drinking behaviours (Mullen et al., 1997). Fourth,
engage in the target behaviour, resolving ambiva-
IVR avoids the inconvenience of written self-mon-
lence about the behaviours, eliciting talk about
itoring aids that are often given to patients in many
change, gaining a commitment to change by goal-
drinking-reduction interventions (e.g., Fleming et
setting, and feedback (Emmons & Rollnick, 2001).
al., 1997; NIAAA, 1995, 2002). Fifth, an important
After training, non-physician counsellors are often
element in behaviour change is feedback. HealthCall
the personnel who administer MI. Randomized trials
allows a unique form of personalized feedback
show that MI reduces drinking across many settings
through generating a printed bar-graph display of
and populations (Dunn et al., 2001; Burke et al.,
the daily information collected via the IVR. In the
2002, 2003). Working closely with HIV primary care
study described below, we presented this visual
clinic staff, we tailored a 30-minute single-session
feedback to patients at 30-day intervals in brief
MI to these patients and setting. The brief MI
meetings with their MI counsellors.
session was designed to focus mainly on patients’
The goals for this pilot study were two-fold: (1) to
drinking in relation to their HIV status, as well as to
determine if low SES, largely minority HIV primary
hepatitis and medication. At the end of the session,
care patients would make regular calls to the IVR;
counsellors worked with patients who were willing to
and (2) to obtain preliminary evidence on whether
establish a reduced-drinking goal for the next 30
participation appeared to reduce drinking.
days. More complex goals were not attempted in
such a brief intervention.
Methods
MI, especially in its briefest form, may not be Thirty-one patients entered the study. Of these,
enough to sustain behaviour change among difficult 80.7% were male; the mean age was 40.3 (range
populations (Stein et al., 2002; Baker et al, 2002). 27 55). Ethnically, 51.6% were Hispanic, 38.7%
The problem is how to extend the ‘dose’ among a African-American, 6.5% white and 3.2% other.
disadvantaged HIV patient population without ex- About a fifth (20.7%) lived in shelters or other
tending demands on HIV staff time. We designed temporary housing, and 29.0% did not have their
HealthCall to address this problem. In practical own phone. Concerning health, 41.4% had Hepatitis
terms, HealthCall is an automated daily telephone B and/or C, 44.8% reported feeling ill or very ill in
self-monitoring system for drinking based on Inter- the week prior to entering the study, 35.5% reported
active Voice Response (IVR). Generically, IVR is a that their mood was low or very low during the same
telephone-based procedure allowing individuals to period, and 54.8% were taking antiretroviral medi-
interact with recorded questions and statements. cation. Drug use was reported by 35.5%. All patients
When an IVR is called, the caller hears scripted had 4/ drinks at least once in the last 30 days;
questions and inputs brief answers using the tele- 54.9% reported 5/ drinks at least once in the past
phone touchpad or voice response. The sequence of week and 87.1% reported 5/ drinks at least once in
questions is determined by individual responses as the past month.
they fit the decision tree programmed into the IVR
system. Answers can be collected in a database.
Procedure
Based on previous studies using IVR as a long-
itudinal data-collection tool on drinking (Helzer et Subjects were recruited via staff referrals from a
al., 2002; Mundt et al., 1995a, 1995b; Searles et al., large, hospital-based outpatient HIV primary care
1995, 2000, 2002), we designed HealthCall to clinic in New York City. Eligibility to participate in
administer 1 3 minutes of questions on alcohol the study was determined by having 4 or more drinks
and related behaviours in a friendly, pre-recorded per occasion at least once in the prior 30 days.
voice in English or Spanish via a toll-free number. Exclusion criteria included: patient was currently
Patients responded through the telephone touchpad. psychotic, suicidal or homicidal; patient had definite
There were several reasons to choose IVR as an plans to leave the greater New York metropolitan
intervention aid. First, IVR is cognitively non- area within the study period; and patient did not
Drinking reduction in the HIV primary care setting 563
speak English or Spanish or had a hearing impair- when a final 30 days were offered; 18 patients began
ment that precluded use of the telephone. IRB the final 90 days, and 15 returned for the 90-day
approval was received both by the hospital clinic interview. Patients were paid $40 per interview with
and by New York State Psychiatric Institute. the MI counsellor. They were not paid for calling the
Two bilingual health counsellors (a research nurse IVR because we wished to know if the intervention
and a health educator) from the HIV clinic were showed promise of being sustainable, and HIV
trained in MI by a certified MI trainer. During the clinics are unlikely to pay patients for participating
study, a licensed clinical psychologist (EA) super- in treatment.
vised the counsellors in weekly meetings. These
covered how the study procedures were working,
Measures
MI techniques, and patient reactions to the study.
During the first meeting, the patient gave in- In the first meeting and at the end of each 30-day
formed consent and was assessed with a structured calling period, the MI counsellor conducted a brief
questionnaire. The MI counsellor administered the structured interview with the patient. The structured
brief MI and trained the patient to use the IVR. The interview included three sections: (1) frequency
patient then made his/her first call to the IVR with (days) and quantity (drinks) of alcohol consumed
the MI counsellor present. The patient received a in the past week and month; (2) drug use (days/
wallet-sized reminder card with IVR calling instruc- week), mood, physical health and medication ad-
tions and date of the return visit. herence in the past week; and (3) additional ques-
The IVR ‘script’ began with an initial greeting, tions covering qualitative patient reactions to
and then included three questions about alcohol different aspects of the intervention. Questions on
consumption covering the number of drinks of beer, alcohol consumption were derived from the AUDA-
wine and liquor consumed in the previous 24 hours. DIS (Grant & Hasin, 1992; Grant et al., 1995;
For those who drank, nine questions covered reasons Hasin et al., 1997; Grant et al., 2003), which covers
for drinking (e.g. ‘to relax’, or ‘to be sociable’); for standard drinks defined to respondents, including
those who did not drink, nine questions covered beer, wine and liquor. The AUDADIS has been
reasons for not drinking (e.g. ‘felt guilty’ or ‘I made a shown to be reliable and valid in substance abuse,
commitment to myself not to drink’). The number of psychiatric and medical patients, as well as general
questions was equal for drinkers and non-drinkers so population samples, both in the US and internation-
that the telephone participation time would be the ally (Grant et al., 1995; Hasin et al., 1996, 1997;
same. The IVR then asked 7 questions about other Cottler et al., 1997; Pull et al., 1997; Chatterji et al.,
experiences in the prior 24 hours, including medica- 1997; Ustun et al., 1997; Canino et al., 1999).
tion adherence, stress, mood (ranging from good to Questions on mood were derived from the Schedule
bad), feelings of health/illness, and current feeling of for Affective Disorders and Schizophrenia (Endicott
intoxication. The IVR ended by thanking the patient & Spitzer, 1978).
for participation.
At the end of the 30-day calling period, the MI
Analysis
counsellor met with the patient again and showed
the bar graph representing his/her IVR-reported We examined two main outcomes: calling levels and
drinking. The counsellor then evaluated the patient drinking levels. Calling was defined as a binary
for all outcome measures, including patient reactions variable, while drinking level was indicated by
to the intervention. The MI counsellor placed a number of drinks per day. We investigated drinking
reminder call to the patient after two consecutive level from two sources of data: the IVR data that
missed calls. Due to counsellor caseload, the need patients called in, and their reports on drinking in
for a second or third reminder call was determined the past 7 days in the baseline, 30- and 60-day
on a case-by-case basis. interviews. The IVR data requires only short-term
Originally, we planned to offer the intervention (24-hour) recall, is made privately and is likely to be
only for 30 days, with the more limited goal of most accurate. However, missed calls lead to missing
determining calling feasibility. However, many pa- data. Drinking over the prior 7 days reported in
tients wished to continue after their MI counsellor baseline, 30- and 60-day interviews requires longer
showed them their bar graph. Thus, we extended the recall, but is complete among interviewed patients
intervention to determine how long patients would and is the type of data that would be used in a
call and the duration that seemed most helpful in randomized trial comparing the efficacy of IVR as a
drinking reduction. Among the 31 patients entering drinking reduction to another intervention. In ana-
the study, 28 patients returned for a 30-day inter- lysing the IVR drinking data, we addressed missing
view and began an additional 30 days of participa- data by imputing the highest drinking value reported
tion. Of these, 24 returned for a 60-day interview in the previous three days. At the point that patients
564 E. Aharonovich et al.
stopped calling completely, the IVR data were no after 60 days did well in maintaining consistent
longer available and were handled as missing. calling, a 60-day intervention appeared to optimize
Each outcome was analysed for within-subject participation relative to improvement in drinking
change over time with repeated measures analysis (see below). We thus present remaining results
with generalized linear models (GLM). Generalized mainly for the 60-day time.
estimating equations (GEE) were applied using SAS Repeated measures analysis of within-subject
to estimate model parameters. GEE takes into change in call likelihood over time indicated that
account within-subject correlations of the repeated there was no significant change in call likelihood over
measures, uses all available data, and allows covari- the first 30 days. Consistent with the descriptive
ate analysis. A binary or linear model was used, results showing that some patients did not continue,
depending on the form of the outcome variable. the GEE analysis using a logistic regression model
Covariates included: gender, age, race/ethnicity, showed a decline in calls over 60 days (b / /0.03, se
hepatitis, MI counsellor (to examine counsellor 0.01, p B/.0001). Variables associated with increased
effect), language preference, living in shelter/tem- calling likelihood over time at 60 days were use of
porary housing, and baseline (last 7 days) drinking cocaine at baseline (b /1.91, se 0.33, p B/.00001),
level, cocaine use, feeling ill, and low mood. having a home and/or cell phone (b /1.02, se 0.40,
p /.01), speaking Spanish (b /0.86, se 0.40, p /
Results .03), and feeling ill at baseline (b /2.00, se 0.39,
p B/.0001). Importantly, higher drinking at baseline
Calling results (largest drinks in the past 7 days) was also associated
Of all calls made to the IVR, 23.1% were from pay with greater call likelihood at 60 days (b /0.07, se
phones. Thus, lack of phones was not a barrier to 0.02, p B/.01).
participation, and some patients made a surprising As noted, we had planned to place reminder calls
effort to participate. During the first 30 days, 715, or to patients after they missed two consecutive days,
76.9% of the 930 possible IVR calls (31 /30) were up to three times for any patient. The highest
made. The median number of calls per patient was number of such calls would have been 176 over the
25. During the second 30 days (days 31 60), the 28 full 90 days. In fact, fewer reminder calls were placed
patients who continued made 548 (65.2%) of the (the actual number was unavailable) due to coun-
possible calls. The median number of calls made sellor absence and workload.
during this time was 23. Twenty-four patients
returned for a 60-day interview (77.4% of the
Drinking results
original sample). During the final 30 days (days
61 90), the 18 patients who wished to continue Figure 1 shows the mean IVR-reported number of
made 382 (70.7%) of the possible calls, and 15 (48% drinks per day, per patient, over 60 days. With some
of the original sample) returned for a 90-day inter- day-to-day variation, the graph clearly shows a
view. Thus, while patients who wished to continue downward trend.
6 y = -0.0675x + 4.667
Mean Number of Drinks
0
0 10 20 30 40 50 60
Day in Study
Within-subject analysis of change in drinking level reported positive reactions to the calls (‘making the
over time was first conducted using IVR-reported calls makes me feel good about myself’; ‘the calls
drinking. Drinking reduction was not statistically helped my self-control; I get pride to keep up with
significant at 30 days (b/ /0.01, se 0.01, p /.31), my goal’). No patient who received a reminder call
but at 60 days, the decline in drinking had become to keep calling reported a negative reaction to the
significant (b / /0.01, se 0.005, p /.03). (Results reminders; a few said such calls showed that some-
were also significant, p/.005, among patients re- one cared how they were doing.
maining for 90 days). In terms of characteristics Many patients reacted with surprise to the graph,
associated with change in drinking level at 60 either because their drinking was greater than they
days, patients with a home/cell phone decreased realized (‘. . . It was hard to see how much I was really
their drinking more (b/ /1.08, se 0.45, p /.02), drinking’), or because they did not realize they were
while patients not feeling ill in the week prior to doing so well (‘I’m surprised I was able to make my
baseline showed a trend towards greater decrease goal. I’m happy’). Either way, the graph made a
(b / /1.08, se 0.57, p /.05). strong, useful impact (‘. . . helped me be honest with
To analyse within-subject change in drinking level myself’; ‘. . . inspirational to continue on my goal’,
over time using the interview data, we created three ‘. . . made me feel good I could cut down’). Of the 17
drinking variables based on the 7-day drinking data patients on antiretroviral medication at baseline (as
collected in the interviews. These included highest indicated by their charts), 6 (35.3%) stated they
number of drinks in a single day, mean drinks per improved medication adherence through the inter-
day across the seven days, and total number of drinks vention; improvement in medication adherence was
in the seven days. The mean highest drinks per day seen in both the IVR and interview reports but did
was 8.4 (se 1.5) at baseline, 4.1 (se 1.1) at 30 days not reach statistical significance. Of drug users at
and 3.8 (se 1.3) at 60 days. Mean drinks per day was baseline, 11 of the 13 felt their drug use decreased as
3.2 (se 0.5) at baseline, 1.7 (se 0.5) at 30 days and a result of the intervention. About 2/3 of the patients
1.2 (se 0.4) at 60 days. The mean total drinks in the found the calls interesting or neutral as long as they
last 7 days was 22.3 (se 3.7) at baseline, 12.0 (se 3.4) continued to call. Others found the calls interesting
at 30 days and 8.6 (se 3.1) at 60 days. These all initially but somewhat repetitious later, especially in
suggest decreased drinking over time. the final 30 days.
Using repeated measures GLM with a linear
regression model, results were very similar regardless
Discussion
of the drinking variable, so we present highest
number of drinks/day in the prior 7 days. Drinking In terms of our first goal for this pilot study, we
level decreased significantly over the three time determined that among this low-income HIV pri-
points of baseline, 30 and 60 days (b / /0.49, se mary care patient population, a high proportion of
0.17, p/.003). Patients feeling healthy at baseline patients drinking excessively who participated in a
decreased their drinking more (b / /0.62, se 0.19, brief MI interview and IVR instruction were willing
p /.001) as did those with better baseline mood to make near-daily calls to the IVR for extended
(b / /0.92, se 0.24, p B/.01). periods of time. There was no significant decline in
To address whether patients with milder drinking calling over the first 30 days. While some decline
problems were more likely to return for follow-up at occurred by the 60-and 90-day points, the patients
60 days, largest numbers of drinks in the 7 days prior who remained in the study continued to make most
to baseline was compared between patients who did of their calls. Importantly, higher drinking at base-
not return at 60 days (n /7, median number of line was actually associated with better (higher) call
drinks 6.0) were compared with those who did likelihood at 60 days, suggesting that self-selection
return (n /24, median number of drinks 6.5). A for drinking was not responsible for the results.
non-parametric exact test indicated that this was not Because patients were paid for the interview but not
a statistically significant difference (p /.51). for making their calls, it is unlikely that the remu-
We did not intervene directly on cocaine use in neration was responsible for the patients’ impressive
either the MI or the IVR. However, cocaine use calling record, supporting feasibility and sustainabil-
as assessed in the brief interviews declined signifi- ity of IVR as a component of drinking-reduction
cantly at 60 days using the same method of analysis intervention.
(b / /0.70, se 0.36, p B/.05). We initially intended to offer the intervention for
only 30 days. However, we extended the trial when
some patients said they wished to continue, utilizing
Patient feedback on the intervention
the pilot phase to indicate an optimal duration to
All patients reported that the IVR calls increased achieve drinking improvement relative to continued
awareness of their drinking levels. Patients also participation. From this, a 60-day period appeared
566 E. Aharonovich et al.
best, suggesting that this period be used in a follow-up will provide more information about the
randomized trial of the intervention compared to a overall response to the intervention at the 30-day
control condition. Qualitative feedback from the and 60 day point as well as subsequently.
patients as well as input from the MI counsellors The two clinic counsellors who administered the
suggested that after the first 30 days, continued intervention were interested and enthusiastic about
calling would be enhanced by some variation in the what they did. Having non-physician clinic staff
outgoing greeting (e.g. acknowledgment of entering rather than physicians or specialized researchers
the 2nd 30 days, a comment that the day of the call administer the intervention is promising for later
falls on a holiday), an element that can be easily dissemination of the results.
incorporated. Antiretroviral medications reduce mortality from
In terms of our second goal based on a within- HIV/AIDS, but bring serious, chronic health issues
subjects change analysis, a significant and substantial to the fore. Thus, the development of sustainable,
drop in drinking levels occurred at the 60- and 90- effective drinking-reduction interventions among
day points. Qualitative comments from the debrief- HIV primary care patients is important. To our
ing interviews re-affirmed that a number of the knowledge, no published interventions focused on
patients found the intervention helpful, including drinking reduction as the primary outcome among
the initial interview, the daily calling, and viewing patients in HIV clinics have been developed or
their drinking in the bar graph presentation. We also tested. Extensive evidence supports brief motiva-
saw increases in medication adherence that did not tional interviewing (MI) as an effective drinking-
reach significance in this small group, and less use of reduction intervention in many treatment settings,
drugs that reached statistical significance (p B/.05) including primary care. However, risk reduction
by 60 days. This suggests that drinking reduction interventions often produce initial or short-term
was not achieved via replacement of alcohol by other behavioural changes that erode over time, and very
substances. These results are encouraging, and brief MI may require enhancement to be effective.
support the need for more rigorous scrutiny of a This preliminary study shows that rather than an
randomized controlled trial to understand their erosion of the effects of brief MI over time, the
efficacy better. In particular, the design of such a opposite occurred, with drinking continuing to
trial should allow determination of whether Health- diminish over 60 days. Thus, IVR plus periodic
Call offers significant improvement over a control graphical feedback may be a way to enhance brief MI
condition, or participation in the initial MI interview without extensive demands on clinic staff. The next
only. step is a rigorous controlled trial that will provide
Limitations to the study are noted. (1) This was a more information on efficacy and mechanisms of
preliminary ‘test-of-concept’ trial, so the target N effect. If efficacy is supported in a larger trial, then
was initially 30 patients, and no controlled compar- the efficacy of this intervention can also be tested in
ison group was included. A future controlled trial other types of patient groups where drinking reduc-
with a larger N is clearly warranted. (2) Refusals tion is important.
were not recorded systematically enough to report an
accurate response rate. Anecdotal reports from the Acknowledgements
counsellors indicated few refusals, but this is clearly
important to track in a future study. (3) While we Support is acknowledged from NIAAA grants K05
used alcohol measures whose psychometric proper- AA014223, and from the New York State Psychiatric
ties have been extensively demonstrated in English Institute. The authors wish to thank Valerie Rich-
and Spanish-speaking substance abuse, psychiatric mond, M.A., for editorial assistance and manuscript
and medical patients, blood alcohol content (BAC) preparation, and also Jesus Aquais and Daisy Sotto-
indicators of recent alcohol consumption were not Copola, R.N., for their excellent work with the
obtained at follow-up. BAC cannot substitute for patients. We also thank the two anonymous re-
number of drinks, and thus could not be used for the viewers for helpful comments.
analyses in this or a larger study. Further, sufficient
alcohol consumption was reported at follow-up that References
we have no reason to suspect wide-scale denial of Babor, T.F. (1990). Brief intervention strategies for harmful
drinking. However, BAC data would be helpful as a drinkers: new directions for medical education. Canadian
validity check to include in a future trial. (4) Medical Association Journal , 143 , 1070 76.
Although drinking was reduced at 30 days as shown Baker, A., Lewin, T., Reichler, H., Clancy, R., Carr, V., Garrett,
R., et al. (2002). Evaluation of a motivational interview for
on Figure 1, the results at this point were not yet
substance use within psychiatric in-patient services. Addiction ,
significant given the small N. Response to the 97 , 1329 37.
intervention was stronger and significant by 60 Burke, B.L., Vassilev, G., Kantchelov, A., & Zweben, A. (2002).
days. A larger trial that includes a post-intervention Motivational interviewing with couples. In W.R. Miller, & S.
Drinking reduction in the HIV primary care setting 567
Rollnick (Eds.), Motivational Interviewing, Preparing People for HIV Consensus Panel. Management of chronic viral hepatitis
Change (pp. 347 61). 2nd ed. New York: The Guilford Press. in HIV-infected patients: Spanish Consensus Conference. HIV
Burke, B.L., Arkowitz, H., & Menchola, M. (2003). The efficacy Clinical Trials , 3 , 99 114.
of motivational interviewing: a meta-analysis of controlled Grant, B.F., & Hasin, D.S. (1992). The Alcohol Use Disorder and
clinical trials. Journal of Consulting and Clinical Psychology, 71 , Associated Disabilities Interview Schedule (AUDADIS) . Rock-
843 61. ville, MD: National Institute on Alcohol Abuse and Alcohol-
Canino, G., Bravo, M., Ramirez, R., Febo, V.E., Rubio-Stipec, ism.
M., Fernandez, R.L., et al. (1999). The Spanish Alcohol Use Grant, B.F., Harford, T.C., Dawson, D.A., Chou, P.S., &
Disorder and Associated Disabilities Interview Schedule (AU- Pickering, R.P. (1995). The Alcohol Use Disorder and Asso-
DADIS): reliability and concordance with clinical diagnoses in ciated Disabilities Interview schedule (AUDADIS): reliability
a Hispanic population. Journal of Studies on Alcohol , 60 , 790 of alcohol and drug modules in a general population sample.
99. Drug and Alcohol Dependence , 39 , 37 44.
Chatterji, S., Saunders, J., Vrasti, R., Grant, B., Hasin, D., & Grant, B.F., Dawson, D.A., Stinson, F.S., Chou, P.S., Kay, W., &
Mager, D. (1997). Reliability of the alcohol and drug modules Pickering, R. (2003). The Alcohol Use Disorder and Asso-
of the Alcohol Use Disorders and Associated Disabilities ciated Disabilities Interview Schedule-IV (AUDADIS-IV):
Interview Schedule Alcohol/Drug Revised (AUDADIS- reliability of alcohol consumption, tobacco use, family history
ADR): an international comparison. Drug and Alcohol Depen- of depression and psychiatric diagnostic modules in a general
dence , 47 , 171 85. population sample. Drug and Alcohol Dependence , 20 , 7 16.
Chesney, M.A., Ickovics, J.R., Chambers, D.B., Gifford, A.L., Hasin, D., McCloud, S., Li, Q., & Endicott, J. (1996). Cross-
Neidig, J., Zwickl, B., et al. (2000). Self-reported adherence to system agreement among demographic subgroups: DSM-III,
antiretroviral medications among participants in HIV clinical DSM-III-R, DSM-IV and ICD-10 diagnoses of alcohol use
trials: the AACTG Adherence Instruments. AIDS Care , 12 , disorders. Drug and Alcohol Dependence , 41 , 127 35.
255 66. Hasin, D., Carpenter, K.M., McCloud, S., Smith, M., & Grant,
Cohen, M.H., French, A.L., Benning, L., Kovacs, A., Anastos, B.F. (1997). The Alcohol Use Disorder and Associated
K., Young, M., et al. (2002). Causes of death among women Disabilities Interview Schedule (AUDADIS): reliability of
with human immunodeficiency virus infection in the era of alcohol and drug modules in a clinical sample. Drug and
combination antiretroviral therapy. American Journal of Medi- Alcohol Dependence , 44 , 133 41.
cine , 113 , 91 98. Helzer, J.E., Badger, G.J., Rose, G.L., Mongeon, J.A., & Searles,
Conigliaro, J., Gordon, A.J., McGinnis, K.A., Rabeneck, L., & J.S. (2002). Decline in alcohol consumption during two years of
Justice, A.C. (2003). How harmful is hazardous alcohol use daily reporting. Journal of Studies on Alcohol , 63 , 551 58.
and abuse in HIV infection: do providers know who is at risk? Kresina, T.F., Flexner, C.W., Sinclair, J., Correia, M., Stapleton,
Journal of Acquired Immune Deficiency Syndrome , 33 , 521 25. J.T., Adeniyi-Jones, S., et al. (2002). Alcohol use and HIV
Conigliaro, J., Madenwald, T., Bryant, K., Braithwaite, S., pharmacotherapy. AIDS Research and Human Retroviruses , 18 ,
Gordon, A.J., Fultz, S.L., et al. (2004). The veterans aging 757 70.
cohort study: observational studies of alcohol use, abuse, and Lauchli, S., Heusser, R., Tschopp, A., & Gutzwiller, F. (1996).
outcomes among human immunodeficiency virus-infected Safer sex behavior and alcohol consumption. Research Group
veterans. Alcoholism: Clinical and Experimental Research , 28 , of the Swiss HIV Prevention Study. Annals of Epidemiology, 6 ,
313 21. 357 64.
Copenhaver, M., Avants, S.K., Warburton, L.A., & Margolin, A. Mariné-Barjoan, E., Saint-Paul, M.C., Pradier, C., Chaillou, S.,
(2003). Intervening effectively with drug abusers infected with Anty, R., Michiels, J.F., et al. (2004). Impact of antiretroviral
HIV: taking into account the potential for cognitive impair- treatment on progression of hepatic fibrosis in HIV/hepatitis C
ment. Journal of Psychoactive Drugs , 35 , 209 18. virus co-infected patients. AIDS , 18 , 2163 70.
Cottler, L.B., Grant, B.F., Blaine, J., Mavreas, V., Pull, C., Hasin, Marks, G., Cantero, P.J., & Simoni, J.M. (1998). Is acculturation
D., et al. (1997). Concordance of DSM-IV alcohol and drug associated with sexual risk behaviours? An investigation of HIV-
use disorder criteria and diagnoses as measured by AUDADIS- positive Latino men and women. AIDS Care , 10 , 283 95.
ADR, CIDI and SCAN. Drug and Alcohol Dependence , 47 , McKirnan, D.J., Vanable, P.A., Ostrow, D.G., & Hope, B. (2001).
195 205. Expectancies of sexual ‘escape’ and sexual risk among drug and
Dunn, C., Deroo, L., & Rivara, F.P. (2001). The use of brief alcohol-involved gay and bisexual men. Journal of Substance
interventions adapted from motivational interviewing across Abuse , 13 , 137 154.
behavioral domains: a systematic review. Addiction , 96 , 1725 Miguez, M.J., Shor-Posner, G., Morales, G., Rodriguez, A., &
42. Burbano, X. (2003). HIV treatment in drug users: impact of
Emmons, K.M., & Rollnick, S. (2001). Motivational interviewing alcohol use. Addiction Biology, 8 , 33 37.
in health care settings: opportunities and limitations. American Miller, W.R., & Rollnick, S. (2002). Motivational Interviewing:
Journal of Preventive Medicine , 20 , 68 74. Preparing People for Change , 2nd ed. New York: The Guilford
Endicott, J., & Spitzer, R.L. (1978). A diagnostic interview: the Press.
schedule for affective disorders and schizophrenia. Archives of Mullen, P.D., Simons-Morton, D.G., Ramı́rez, G., Frankowski,
General Psychiatry, 35 , 837 44. F., Green, L.W., & Mains, D.A. (1997). A meta-analysis of
Fleming, M.F., Barry, K.L., Manwell, L.B., Johnson, K., & trials evaluating patient education and counseling for three
London, R. (1997). Brief physician advice for problem alcohol groups of preventative health behaviors. Patient Education and
drinkers: A randomized controlled trial in community-based Counseling , 32 , 157 73.
primary care practices. Journal of the American Medical Associa- Mundt, J.C., Perrine, M.W., Searles, J.S., & Walter, D. (1995a).
tion , 277 , 1039 45. An application of interactive voice response (IVR) technology
Friedmann, P.D., McCullough, D., Chin, M.H., & Saitz, R. to longitudinal studies of daily behavior. Behavior Research
(2000). Screening and intervention for alcohol problems: a Methods, Instruments, Computers , 27 , 351 57.
national survey of primary care physicians and psychiatrists. Mundt, J.C., Searles, J.S., Perrine, M.W., & Helzer, J.E. (1995b).
Journal of General Internal Medicine , 15 , 84 91. Cycles of alcohol dependence: frequency-domain analyses of
Garcı́a-Samaniego, J., Soriano, V., Miró, J.M., del Romero, J., daily drinking logs for matched alcohol dependent and non-
Brugera, M., Castilla, J., et al. (2002). The Spanish Hepatitis- dependent subjects. Journal of Studies on Alcohol , 56 , 491 99.
568 E. Aharonovich et al.
National Institute on Alcohol Abuse and Alcoholism (1995; trauma surgeons’ use of alcohol screening and brief interven-
2002). How to cut down on your drinking No. 96-3770 1996, tion. Journal of Trauma , 55 , 849 56.
NIAAA. Searles, J.S., Perrine, M.W., Mundt, J.C., & Helzer, J.E. (1995).
Núñez, M., Lana, R., Mendoza, J.L., Martı́n-Carbonero, L., & Self-report of drinking using touch-tone telephone: extending
Soriano, V. (2001). Risk factors for severe hepatic injury after the limits of reliable daily contact. Journal of Studies on Alcohol ,
introduction of highly active antiretroviral therapy. Journal of 56 , 375 82.
Acquired Immune Deficiency Syndrome , 27 , 426 31. Searles, J.S., Helzer, J.E., & Walter, D.E. (2000). Comparison of
Orleans, C.T., George, L.K., Houpt, J.L., & Brodie, H.K.H. drinking patterns measured by daily reports and timeline follow
(1985). How primary care physicians treat psychiatric dis- back. Psychology of Addictive Behaviors , 14 , 277 86.
orders: a national survey of family practitioners. American Searles, J.S., Helzer, J.E., Rose, G.L., & Badger, G.J. (2002).
Journal of Psychiatry, 142 , 52 57. Concurrent and retrospective reports of alcohol consumption
Palepu, A., Horton, N.J., Tibbets, N., Meli, S., & Samet, J.H. across 30, 90 and 366 days: interactive voice response
(2004). Uptake and adherence to highly active antiretroviral compared with the timeline follow back. Journal of Studies on
therapy among HIV-infected people with alcohol and other Alcohol , 63 , 352 62.
substance abuse problems: the impact of substance abuse Selik, R.M., Byers, R.H., & Dworkin, M.S. (2002). Trends in
treatment. Addiction , 99 , 361 68. diseases reported on US death certificates that mentioned HIV
Pol, S., Lebray, P., & Vallet-Prichard, A. (2004). HIV infection
infection, 1987 1999. Journal of Acquired Immune Deficiency
and hepatic enzyme abnormalities: intricacies of the pathogenic
Syndromes , 29 , 378 87.
mechanisms. Clinical Infectious Diseases , 38 (Suppl 2), S65 72.
Spandorfer, J.M., Israel, Y., & Turner, B.J. (1999). Primary care
Powderly, W. G. (2004). Antiretroviral therapy in patients with
physicians’ views on screening and management of alcohol
hepatitis and HIV: weighing risks and benefits. Clinical In-
abuse: inconsistencies with national guidelines. Journal of
fectious Diseases , 1;38 (Suppl 2), S109 13.
Family Practice , 48 , 899 902.
Prakash, O., Tang, Z.Y., & Peng, X. (2001). Alcohol inhibits
Stein, M.D., Charuvastra, A., Maksad, J., & Anderson, B.J.
thymidine kinase activity essential for activation of Zidovudine
(2002). A randomized trial of a brief alcohol intervention for
(AZT) to its anti-HIV form. Abstract #123. Alcoholism: Clinical
and Experimental Research . needle exchangers (BRAINE). Addiction , 97 , 691 700.
Robins, A.G., Dew, M.A., Kingsley, L., & Becker, J.T. (1997). Do Sulkowski, M.S., Thomas, D.L., Chaisson, R.E., & Moore, R.D.
homosexual and bisexual men who place others at potential risk (2000). Hepatotoxicity associated with antiretroviral therapy in
for HIV have unique psychological problems? AIDS Education adults infected with human immunodeficiency virus and the
and Prevention , 9 , 239 51. role of hepatitis C or B virus infection. Journal of the American
Samet, J.H., Horton, N.J., Traphagen, E.T., Lyon, S.M., & Medical Association , 283 , 74 80.
Freedberg, K.A. (2003). Alcohol consumption and HIV Ustun, B., Compton, W., Mager, D., Babor, T., Baiyewu, O.,
disease progression: are they related? Alcoholism: Clinical and Chatterji, S., et al. (1997). WHO Study on the reliability and
Experimental Research , 27 , 862 67. validity of the alcohol and drug use disorder instruments:
Samet, J.H., Horton, N.J., Meli, S., Freedberg, K.A., & Palepu, overview of methods and results. Drug and Alcohol Dependence ,
A. (2004). Alcohol consumption and antiretroviral adherence 47 , 161 69.
among HIV-infected persons with alcohol problems. Alcoholism: Weller, D.P., Litt, J.C., Pols, R.G., Ali, R. ., Southgate, D.O., &
Clinical and Experimental Research , 28 , 572 77. Harris, R.D. (1992). Drug and alcohol related health problems
Schermer, C.R., Gentilello, L. M., Hoyt, D.B., Moore, E.E., in primary care what do GPs think? Medical Journal of
Moore, J.B., Rozycki, G.S., et al. (2003). National survey of Australia , 156 , 43 48.
Giunta et al. Molecular Brain 2011, 4:23
http://www.molecularbrain.com/content/4/1/23
Abstract
Up to 50% of long-term HIV infected patients, including those with systemically well-controlled infection, commonly
experience memory problems and slowness, difficulties in concentration, planning, and multitasking. Deposition of
Ab plaques is also a common pathological feature of HIV infection. However, it is not clear whether this
accumulation is due to AD-like processes, HIV-associated immunosuppression, Tat protein-induced Ab elevations,
and/or the effects of single highly active antiretroviral therapy (ART). Here we evaluated the effects of several ART
medications (Zidovudine, Lamivudine, Indinavir, and Abacavir) alone and in combination on: 1) Ab1-40, 42 generation
in murine N2a cells transfected with the human “Swedish” mutant form of APP; 2) microglial phagocytosis of FITC-
Ab1-42 peptides in cultured murine N9 microglia. We report for the first time that these antiretroviral compounds (10
μM) generally increase Ab generation (~50-200%) in SweAPP N2a cells and markedly inhibit microglial phagocytosis
of FITC-Ab1-42 peptides in murine microglia. The most significant amyloidogenic effects were observed with
combined ART (p < 0.05); suggesting certain ART medications may have additive amyloidogenic effects when
combined. As these antiretroviral compounds are capable of penetrating the blood brain barrier and reaching the
concentrations employed in the in vitro studies, these findings raise the possibility that ART may play a casual role in
the elevated Ab found in the brains of those infected with HIV. Therefore these compounds may consequently
contribute to cognitive decline observed in HIV associated neurocognitive disorders (HAND).
Keywords: antiretrovirals, microglial cells, HIV, cognitive disorders
© 2011 Giunta et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
Giunta et al. Molecular Brain 2011, 4:23 Page 2 of 6
http://www.molecularbrain.com/content/4/1/23
Interestingly, with such increased survival times Division of AIDS, NIAID, NIH: Zidovudine (AZT; Cat.#
imparted by ART, the prevalence of HAND is on the 3485), Abacavir (Cat.# 4680), Indinavir (Cat.# 8145), and
rise. At present, it is not clear whether this increased Lamivudine (3TC; Cat# 8146).
prevalence is due to the intrinsic risk of developing
dementia with age or due to other direct or indirect fac- Neuronal Ab Production Assay
tors of ART. In a recent clinical study, it was found that SweAPP N2a cells were seeded at 1 × 105 cells/well (n =
neurocognitive functioning significantly improved after 2 for each condition) in 24-well tissue-culture plates
immune competent, HIV-infected patients discontinued containing 0.5 mL of complete medium (MEM medium
ART treatment. Moreover, this improvement continued supplemented with 10% fetal calf serum). Cells were dif-
in the patients remaining off ART over the nearly two ferentiated prior to treatment with cAMP in 0.5 mL
year period of follow-up. Additionally, there was a lack Neurobasal media for 4 hours. Following differentiation,
of substantial neurocognitive improvement with resump- these cells were untreated (control vehicle; PBS) or trea-
tion of ART [8]. ted with ART medications both alone (10 μM) and in
There are several potential explanations underlying combination (10 μM) for 18 hours. Ab1-40, 42 peptides
this clinically meaningful finding. One of these is that were detected directly from the conditioned media and
ART may lead to neurotoxicity [9] which is manifested quantified in these samples using Ab1-40, 42 ELISA kits
in part by dysregulated neuronal amyloid precursor pro- in accordance with the manufacturer’s instructions.
tein (APP) processing and concurrent deposition of
amyloid beta (Ab) plaques in the brain. Microglial Phagocytosis Assay
While extracellular amyloid plaques are the primary N9 microglia were seeded at 1 × 105 cells/well (n = 4
amyloid pathology in Alzheimer’s disease (AD), intra- for each condition) in 24-well tissue-culture plates con-
neuronal amyloid accumulation or perivascular diffuse taining 0.5 mL of complete medium (RPMI 1640 med-
amyloid depositions are more of a feature of HAND [3]. ium supplemented with 5% fetal calf serum). In the
Strong evidence indicates this increased amyloid deposi- presence “aged” Ab1-42 peptide conjugated with FITC
tion in the brain of HIV-1-infected patients [10] as (supplied by BioSource, used at 300 nM dissolved in
opposed to true full blown AD-like pathology. A correla- dH 2 0 and pre-incubated for 24 h at 37°C) microglia
tion between the years of infection and amyloid deposi- were co-treated with retroviral drugs both alone (10
tion has also been shown [11]. Further, this amyloid μM) and in combination (10 μM) for 0, 30, 60, 120, and
deposition is most prevalent in the hippocampus and 180 minutes. For fluorometric analysis, in parallel treat-
frontal lobe regions [12], and also observed in pyramidal ments, the microglia were rinsed 3 times with complete
neurons and along axonal tracks in HIV infected patients. medium after collection of cell supernatants and sub-
Importantly, patients with HIV-associated encephalitis jected to cell lysate preparation [14,15]. The total cellu-
(HIVE) had higher levels of intraneuronal Ab immunor- lar protein of all groups was quantified and adjusted
eactivity compared to HIV-1 patients without HIVE. In using the Bio-Rad protein assay. Extracellular and cell
addition, intracellular deposition of Ab correlated with associated FITC-tagged Ab was quantified using an
age in the group of patients with HIVE [13]. Finally, SPECTRAmax GEMINI microplate fluorometer (Mole-
HAND in older populations is at least partially linked to cular Devices Corp.) with an emission wavelength of
early signs of b-amyloidosis observed in AD, further 538 nm and an excitation wavelength of 485 nm. In
demonstrating the importance of Ab deposition for the addition, in parallel 24-well tissue-culture plates, micro-
clinical outcome of HIV-1 infection. These studies raise glial cells were incubated at 4°C with FITC-conjugated
questions regarding possible iatrogenic mechanisms Ab with or without the various antiretroviral treatments
involved in the pathogenesis of both HAND and/or AD as controls for non-specifically incorporated Ab. Micro-
as a co-morbid neurodegenerative [3,13]. glial cells were rinsed 3 times in Ab-free complete med-
In the present pilot study, we investigate the potential ium, and the media was exchanged with fresh Ab-free
effects of various ART medications on neuronal Ab pro- complete medium for 10 min both to allow for removal
duction and clearance by microglial phagocytosis in of non-incorporated Ab and to promote concentration
murine N2a cells transfected with the human “Swedish” of the Ab into phagosomes. The relative mean fluores-
mutant form of APP (SweAPP N2a cells) and N9 micro- cence values for each sample at 37°C and 4°C at the
glia cultures, respectively. indicated time points were determined by fluorometric
analysis. Relative mean values were calculated as: (mean
Methods fluorescence value for each sample at 37°C - mean fluor-
Antiretrovirals escence value for each sample at 4°C). In this manner,
The following reagents were obtained through the NIH both extracellular and cell associated FITC-labeled Ab
AIDS Research and Reference Reagent Program, were quantified.
Giunta et al. Molecular Brain 2011, 4:23 Page 3 of 6
http://www.molecularbrain.com/content/4/1/23
La
Ab
AZ
AZ
3T
In
In
AZ
3T
di
di
m
C/
C/
T
ac
T/
T/
T/
na
na
Discussion
iv
In
3T
In
Ab
Ab
av
ud
vi
vi
di
di
C
ir
ac
ac
r/A
r
na
na
in
vi
ba
vi
ir
(3
ir
r
r
ca
TC
Figure 1 ART medications increase Ab generation in cultured approximately 1995 [16]. Indeed combination ART has
neuronal cells. Total Ab 1-40,42 peptides were analyzed in dramatically reduced medical morbidity and mortality
conditioned media from SweAPP N2a cells by ELISA (n = 2 for each with HIV infection, but high rates of HAND continue to
condition). Data are represented as a mean ± SEM percentage of
Ab 1-40,42 peptides secreted 18 hours after antiretroviral treatment
be reported [17]. Heaton and colleagues sought to deter-
relative to control (untreated). One-way ANOVA followed by post mine neurocognitive impairment in large groups of HIV
hoc comparison revealed significant increases in Ab 1-40,42 + and HIV - participants from the pre-combination
production following 3TC/Indinavir, 3TC/Abacavir, and Indinavir/ ART era (1988-1995; N = 857) and combination ART
Abacavir treatements (concentration of 10 μM for each individual era (2000-2007; N = 937). The rates of impairment
compound; p < 0.05).
increased with successive disease stages in both eras:
Giunta et al. Molecular Brain 2011, 4:23 Page 4 of 6
http://www.molecularbrain.com/content/4/1/23
membrane potential both promote the deposition of Ab also help prevent HAND. Clinical trials targeting HAND
plaques and increased amyloidogenic processing of APP prevention should specifically examine timing of ART
(for review see [21]). Furthermore, neurons treated with initiation [2].
antiretroviral medications exhibited dendritic beading Future studies are also warranted to investigate the
and pruning correlated over a range of doses, which has dose-response effects of newer BBB permeable antiretro-
been linked to cognitive dysfunction [22]. viral drugs including fusion inhibitors, alone and in
In our experiments, the median toxic doses for several combination, on microglial CNS Ab levels in an in vivo
ARVs were well within the therapeutic concentration murine model. Moreover, future studies will be required
range in plasma of HIV-infected patients, and a few to determine the effect of antiretrovirals on APP proteo-
showed some signs of damage in the range of CSF con- lysis and microglial Ab proteases including neprilysin,
centrations. These initial observations highlight potential insulin-degrading enzyme, and endothelin-converting
adverse effects of high concentrations of antiretroviral enzymes 1 and 2, as ART modulated proteolytic activity
medications in the CNS and indicate that there may be could affect the development of HAND and amyloidosis.
some negative tradeoffs to traditionally delivering “thera- This study was also limited to the effect of ART of
peutic concentrations” of these compounds to the CNS. microglia and neurons separately without other mitigat-
As previous pharmacokinetic studies have confirmed ing factors. In the future this work will need to be repli-
the moderate to high oral bioavailabilities and low to cated in vivo in mouse models to not only account for
moderate plasma protein binding properties of 3TC, astrocytes, but the entire brain milieu. Nevertheless, it is
Indinavir, and Abacavir, it is feasible that all of these clear from the most recent update by the World Health
antiretroviral compounds can reach systemic peak con- Organization in 2010 that the cost of rapid ART scale-
centrations >100 uM following normal dosing regimens. up is significant in terms of side-effects [16]. There is a
Needless to say, only a fraction of these concentrations need from patients and health-care providers to phase
needs to be distributed in the brain to mediate the amy- in less toxic ART regiments while maintaining simplified
loidogenic effects we observed in our in vitro studies, fixed-dose combinations.
which employed 10uM concentrations. Furthermore,
ART effects in vivo are likely to occur over long-term
Acknowledgements
exposures. Chronic, low dose, in vivo effects of any This work was in part supported by Johnnie B. Byrd, Sr. Alzheimer’s Center &
reagent are often very appropriately modeled in vitro, by Research Institute (DS and JT) and the NIH/NIA/NIMH (JT and BG).
proportionately higher doses of that same reagent, over Antiretroviral medications were provided by AIDS Research and Reference
Reagent Program.
more acute time frames [23]. For these reasons we used
10uM ART dose for these experiments. Author details
1
This brings us to a potential dilemma in ART con- Neuroimmunology Laboratory, Department of Psychiatry and
Neurosciences, College of Medicine, University of South Florida, Tampa, FL,
cerning an important parameter, blood brain barrier 33612, USA. 2Department of Molecular Medicine, Department of Psychiatry
(BBB) permeability. On one hand 3TC, Abacavir, and and Neurosciences, College of Medicine, University of South Florida, Tampa,
Indinavir have been reported to be moderately BBB FL, 33612, USA. 3Silver Child Development Center, Department of Psychiatry
and Neurosciences, College of Medicine, University of South Florida, Tampa,
permeable and consequently may be free to promote FL, 33612, USA. 4Center Excellence in Aging and Brain Repair, Department of
amyloidosis. On the other hand, these antiretroviral Neurosurgery, College of Medicine, University of South Florida, Tampa, FL,
compounds may also be more capable of reducing HIV 33612, USA. 5Department of Pharmacology and Physiology, College of
Medicine, University of South Florida, Tampa, FL 33612, USA.
load in the brain, which may be essential to avoid gen-
eral HIV encephalopathy. Furthermore, Liu and collea- Authors’ contributions
gues [24] demonstrated that the HIV-1 Tat protein BG and RS drafted the manuscript. JE and DO carried out the
immunoassays. JJ, LL, and LL performed statistical analysis. FF conceived of
competitively inhibits the LRP receptor, resulting in an the study. JT participated in its design and coordination. All authors read
inhibition of Ab clearance. Therefore, by minimizing and approved the final manuscript.
HIV replication and associated Tat protein expression in
Competing interests
the brain, BBB permeable antiretroviral compounds may The authors declare that they have no competing interests.
also prevent amyloidosis. In light of this complex situa-
tion, switching from an ART regimen that is associated Received: 8 March 2011 Accepted: 7 June 2011 Published: 7 June 2011
with both amyloidosis and the potentially related lipody-
References
strophy to one without these adverse effects may be the 1. Goodkin K, Fletcher MA, Cohen N: Clinical aspects of
best course of clinical action to reduce the risk of neu- psychoneuroimmunology. Lancet 1995, 345(8943):183-4.
rological complications. On the other hand, consistent 2. Schouten J, et al: HIV-1 infection and cognitive impairment in the cART
era: a review. AIDS 2011, 25(5):561-75.
association of neurocognitive impairment with nadir 3. Xu J, Ikezu T: The comorbidity of HIV-associated neurocognitive disorders
CD4 across pre-and post-ART eras suggests that earlier and Alzheimer’s disease: a foreseeable medical challenge in post-HAART
treatment to prevent severe immunosuppression may era. J Neuroimmune Pharmacol 2009, 4(2):200-12.
Giunta et al. Molecular Brain 2011, 4:23 Page 6 of 6
http://www.molecularbrain.com/content/4/1/23
doi:10.1186/1756-6606-4-23
Cite this article as: Giunta et al.: Antiretroviral medications disrupt
microglial phagocytosis of b-amyloid and increase its production by
neurons: Implications for HIV-associated neurocognitive disorders.
Molecular Brain 2011 4:23.
Practice points
Use HIV-specific diagnostic terminology to complement those of the Diagnostic and Statistical Manual of
Mental Disorders (DSM) for the diagnosis of HIV-associated neurocognitive disorders (HAND).
Rely upon formal neuropsychological testing, whenever possible, for documentation of the presence of
neurocognitive impairment as a criterion for the diagnoses of HAND.
Use a quantified cut-off based on neuropsychological testing to generate a standardized designation for the
documentation of the presence of HIV-associated neurocognitive impairment.
Use a minimum of two impaired domains to qualify for the documentation of the presence of HIV-associated
neurocognitive impairment.
Include information processing speed and motor function but exclude social cognition as separate domains to
be assessed for the documentation of the presence of HIV-associated neurocognitive impairment.
Use documentation of any type of changes in activities of daily living (not solely changes involving
independence) that are related to HIV-associated neurocognitive impairment as documentation for the
functional status decline required for HAND diagnoses.
Always rule out general medical illnesses, neurological diseases and psychiatric disorders that might confound
the diagnoses of HAND prior to making the diagnoses definitive.
1
Department of Psychiatry & Neurosciences, Institute for Research in Psychiatry, University of South Florida, Tampa, FL, USA
2
Department of Psychiatry, Harvard University, Boston, MA, USA
3
UCLA Semel Institute for Neuroscience, Department of Psychology, University of California at Los Angeles, Los Angeles, CA, USA
4
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
5
Department of Microbiology & Immunology, Research & Graduate Studies, School of Medicine, Universidad Central del Caribe,
Bayamón, Puerto Rico, USA
6
Laboratory of Neuropsychology, Department of Experimental Psychology, University of the State of São Paulo, Brazil
7
Department of Clinical Psychology, University of the State of São Paulo, Brazil
8
Infectious Diseases & HIV/AIDS Unit, Hospital Juan A Fernandez, Buenos Aires, Argentina
9
Department of Psychiatry, University of Kwa-Zulu Natal, South African Research Council, Durban, South Africa
†
Author for correspondence: AIDS Healthcare Foundation, 6255 W Sunset Blvd, 21st Floor, Los Angeles, CA 90028, USA;
Tel.: +1 323 860 5250; Fax: +1 323 962 8513; karl.goodkin@aidshealth.org
10.2217/NPY.11.57 © 2011 Karl Goodkin Neuropsychiatry (2011) 1(5), 431–440 ISSN 1758-2008 431
Management Perspective Goodkin, Fernandez, Forstein et al.
The current proposal for the criteria to be used process with a predilection for the basal ganglia,
for neurocognitive disorders in the Diagnostic periventricular white matter and the hippocam-
and Statistical Manual of Mental Disorders pus. HAND may occur at a much younger age
(DSM)-5 has been published in a draft form [1] . and is more likely to be reversible. At least ini-
This proposal is intended to include the area tially, HAND is best represented as a ‘subcortical
of HIV-associated neurocognitive disorders dementia’ as opposed to AD, which is best char-
(HAND). However, the proposal is based upon acterized as a ‘cortical dementia’. While it can be
an update of the more general criteria proposed argued that this differentiation is not definitive,
for “Delirium, Dementia, and Amnestic, and it aids heuristically in depicting how these dif-
Other Cognitive Disorders” published in the ferent types of neurocognitive disorder present.
DSM-IV [2,3] . The DSM-IV contained no spe- Moreover, the lack of inclusion of any explicitly
cific criteria for HAND, and the current pro- defined criteria for HAND was not justified in
posal for these disorders in the DSM-5 would the DSM-IV, just as it remains unjustified today
have the same result. Yet such an outcome for the DSM-5. When the DSM-IV was pub-
could lead to a continued lack of utilization by lished in 1994, specific criteria for HAND had
psychiatrists of diagnostic criteria with widely already been published by the AAN for 3 years [4] .
acknowledged specificity for HAND and a Those criteria had explicitly defined the disor-
lack of integration with the current research on ders of ‘HIV-associated dementia’ (HAD) and
HAND. HAND is not well represented by the ‘HIV-associated minor cognitive-motor disorder’
criteria developed for Alzheimer’s disease (AD), (MCMD). Yet, the DSM-IV criteria ultimately
which largely constitute the basis upon which made no reference to any specific criteria for
the DSM-IV criteria were defined in the afore- HAND. While a relevant diagnosis was nomi-
mentioned cognitive disorders subsection. This nally included in the DSM-IV (as a subtype of
remains the case when adding the consideration “dementia due to a general medical condition”
of the impact of ‘minor cognitive impairment’, as [294.1]), there were no specific criteria assigned
defined for the general population. This article to it. Furthermore, there was no analog for the
will systematically present the evidence address- less severe disorder of HIV-associated MCMD in
ing how the lack of integration of the DSM cri- the final, approved version of the DSM-IV [2,3] .
teria with the Frascati conference-based revision Although a ‘research diagnosis’ analogous to
of the American Academy of Neurology (AAN) MCMD was designated and listed in research
criteria for HAND over time detracts from the appendix B as ‘mild neurocognitive disorder’
future utility of the diagnoses of the neurocogni- (MND) in the DSM-IV [2,3] , the only approved
tive disorders associated with HIV infection in diagnostic term for this disorder was ‘cognitive
the DSM-5. disorder – not otherwise specified’ (294.9).
If the currently proposed draft criteria for The current proposal for neurocognitive dis-
neurocognitive disorders in the DSM-5 are suc- orders in the DSM-5 makes no reference to the
cessfully promulgated, not only will the criteria criteria that have been designated for HAND
that will be applied to HAND be improperly in neurology. However, 4 years ago, the AAN
depicted in an overly generalized fashion, but it criteria were revised and published by an expert,
will also remain the case that there will be no spe- international consensus panel. This revision was
cific criteria for HAND at all. First, it should be based upon the need to redefine the criteria for
stated that HAND is significantly different from HAND that were originally promulgated in 1991
AD, as HAND is based upon a neuroinfectious due to changes in the manifestations of HAND
over the subsequent 16 years, particularly follow- It is preferred that the domains selected for
ing the introduction of effective antiretroviral screening do not include the language domain,
therapy (ART). It has been reported that: the which is typically preserved in HAND until the
spectrum of severity of clinical symptoms has late stage of disease. However, a timed test of
been dampened in the era of effective ART [5] ; language performance may be employed
there are neuropathological correlates for this with validity.
reduced level of clinical severity (although the
prevalence remains high) [6] ; and patients with The neurocognitive impairment observed must
HAD have a longer survival time in the cur- be associated with marked interference in func-
rent era [7] . Thus, the DSM-IV criteria identify- tional status of activities of daily living. It
����������
is pre-
ing HAND only at the level of a dementia had ferred but not required that functional status be
become progressively less sensitive over time. confirmed by standardized measures with estab-
However, the diagnostic criteria currently pro- lished norms. However, standardized measures
posed for the neurocognitive disorders in DSM-5 are required for documentation of impaired
still make no reference to the revised criteria for neurocognitive performance. Ideally, both self-
HAND adopted in neurology. Thus, the same report and objective functional status measures
lack of cross-referencing of these disorders across should be employed, as patients frequently min-
related fields is likely to occur again. imize the report of the deficits consistent with a
Currently, the DSM-5 work group is recom- frontostriatal process like HAND. Of note,
mending that HAD be subsumed under a new examples of useful self-report functional status
disorder to be termed ‘major neurocognitive dis- measures are the Sickness Impact Profile [12], the
order’ (Table 1) [1] . For the purposes of discussion, Cognitive Difficulties Scale [13] and the Medical
please refer to the revised, HIV-specific AAN Outcomes Study (MOS)-HIV Cognitive Func-
criteria for HAD that follow: tional Status Subscale [14,15] . Examples of objec-
tive functional status measures are the Direct
There must be a marked, acquired impairment Assessment of Functional Status [16] and the
in neurocognitive performance, involving at University of California at San Diego (UCSD)
least two domains (or areas). In addition, the Performance-Based Skills Assessment [17] .
presence of neurocognitive impairment must be The neurocognitive impairment should not
ascertained by neuropsychological (NP) testing support the diagnosis of delirium. That is, dis-
with at least two domains demonstrating scores turbance of consciousness and a short period of
at 2 standard deviations (SDs) or greater below evolution of the observed impairment should
the demographically corrected means. Typi- not be prominent features [2,3] . If delirium is
cally, impairment is observed over multiple present, then the criteria for dementia must
domains, especially in the areas of information have been met previously.
processing speed, learning of new information,
verbal memory and attention/concentration. It There should be no evidence of another, pre-
is noted that for resource-limited settings where existing cause for the dementia. There are
NP testing is not available, a standard neuro- many potentially confounding conditions to be
psychiatric evaluation and simple bedside men- considered that are associated with or are spe-
tal status examination testing may be substi- cific to the immunodeficiency associated with
tuted for standardized NP testing. Nevertheless, HIV that would not be part of a standard work-
this should be done with standardized assess- up for dementia in an immunocompetent
ments of mental status. While the Mini-Mental patient. These confounding illnesses include
State Examination with an index for the pres- neurological conditions dating back to the
ence of neurocognitive impairment taken as a beginning of the epidemic (e.g., CNS toxoplas-
score of less than 26 [8] was referenced in the mosis, cryptococcal meningitis, cytomegalo
revised AAN criteria [9] , this screening device virus encephalopathy, primary CNS lym-
should not be used due to its lack of sensitivity phoma, neurosyphilis and tuberculous
for the predominantly subcortical neurocogni- meningitis). In addition, several conditions of
tive processes comprising HAND. Other stan- recently increasing neurological awareness and
dardized mental status examinations that might concern in the HIV infected should be assessed
be used include the HIV Dementia Scale [10] (e.g., cerebrovascular disease, CNS hepatitis C
and the International HIV Dementia Scale [11] . virus infection and immune reconstitution
Table 1. Criteria for neurocognitive disorders proposed for the Diagnostic and Statistical Manual of Mental Disorders 5 and the
Frascati conference-based revision of American Academy of Neurology criteria.
DSM-5 Frascati conference-based revision of AAN criteria
Major neurocognitive disorder HIV-associated dementia
A. Evidence of significant cognitive decline from a previous level of A. Marked acquired impairment in cognitive functioning,
performance in one or more of the domains outlined in the text based on: involving at least two ability domains; typically the impairment
1. Reports by the patient or a knowledgeable informant, or observation is in multiple domains, especially in the learning of new
by the clinician, of clear decline in specific abilities as outlined for specific information, slowed information processing and defective
domains in the text; and: attention/concentration. The cognitive impairment must be
2. Clear deficits in objective assessment of the relevant domain (typically ascertained by neuropsychological testing with at least two
>2 SD below the mean [or below the 2.5th percentile] of an appropriate domains being 2 SD or greater below that of demographically
reference population [i.e., age, gender, education, premorbid intellect and corrected means
culturally adjusted]) B. The cognitive impairment produces marked interference with
B. The cognitive deficits are sufficient to interfere with independence day-to-day functioning (work, home life and social activities)
(e.g., at a minimum requiring assistance with instrumental activities of daily C. The pattern of cognitive impairment does not meet criteria
living [i.e., more complex tasks such as finances or managing medications]) for delirium
C. The cognitive deficits do not occur exclusively in the context of D. There is no evidence of another, pre-existing cause for
a delirium the dementia (e.g., other CNS infection, CNS neoplasm,
D. The cognitive deficits are not wholly or primarily attributable to another cerebrovascular disease, pre-existing neurologic disease or
axis I disorder (e.g., major depressive disorder or schizophrenia) severe substance abuse compatible with CNS disorder)
Minor neurocognitive disorder HIV-associated mild neurocognitive disorder
A. Evidence of minor cognitive decline from a previous level of 1. Acquired impairment in cognitive functioning, involving
performance in one or more of the domains outlined in the text based on: at least two ability domains, documented by performance of
1. Reports by the patient or a knowledgeable informant, or observation at least 1 SD below the mean for age/education-appropriate
by the clinician, of minor levels of decline in specific abilities as outlined norms on standardized neuropsychological tests. The
for the specific domains in the text. Typically, these will involve greater neuropsychological assessment must survey at least the
difficulty performing these tasks or the use of compensatory strategies; following abilities: verbal/language, attention/working memory,
2. Mild deficits on objective cognitive assessment (typically 1–2 SD below abstraction/executive, memory (learning and recall), speed of
the mean [or in the 2.5–16th percentile] of an appropriate reference information processing, sensory–perceptual and motor skills
population [i.e., age, gender, education, premorbid intellect and culturally 2. The cognitive impairment produces at least mild interference
adjusted]). When serial measurements are available, a significant (e.g., 0.5 in daily functioning (at least one of the following):
SD) decline from the patient’s own baseline would serve as more definitive a) Self-report of reduced mental acuity, inefficiency in work,
evidence of decline homemaking or social functioning;
B. The cognitive deficits are not sufficient to interfere with independence b) Observation by knowledgeable others that the individual has
(Instrumental Activities of Daily Living are preserved), but greater effort undergone at least mild decline in mental acuity with resultant
and compensatory strategies may be required to maintain independence inefficiency in work, homemaking, or social functioning
C. The cognitive deficits do not occur exclusively in the context of 3. The cognitive impairment does not meet criteria for delirium
a delirium or dementia
D. The cognitive deficits are not wholly or primarily attributable to another 4. There is no evidence of another pre-existing cause for the
axis I disorder (e.g., major depressive disorder or schizophrenia) mild neurocognitive disorder. If the individual with suspected
mild neurocognitive disorder also satisfies criteria for a severe
episode of major depression with significant functional
limitations or psychotic features, or substance dependence, the
diagnosis of mild neurocognitive disorder should be deferred to
a subsequent examination conducted at a time when the major
depression has remitted or at least 1 month after cessation of
substance use
In DSM-IV criteria [2,3], there are currently no criteria for a diagnosis analogous to ‘mild neurocognitive disorder’ of the Frascati conference-based revision of the AAN criteria (with
the exception of the research appendix).
AAN: American Academy of Neurology; DSM: Diagnostic and Statistical Manual of Mental Disorders; SD: Standard deviation.
Table 1. Criteria for neurocognitive disorders proposed for the Diagnostic and Statistical Manual of Mental Disorders 5 and the
Frascati conference-based revision of American Academy of Neurology criteria (cont.).
DSM-5 (cont.) Frascati conference-based revision of AAN criteria (cont.)
No equivalent criteria HIV-associated asymptomatic neurocognitive impairment
– 1. Acquired impairment in cognitive functioning, involving
at least two ability domains, documented by performance of
at least 1 SD below the mean for age/education-appropriate
norms on standardized neuropsychological tests. The
neuropsychological assessment must survey at least the
following abilities: verbal/language, attention/working memory,
abstraction/executive, memory (learning and recall); speed of
information processing, sensory–perceptual and motor skills
2. The cognitive impairment does not interfere with
everyday functioning
3. The cognitive impairment does not meet criteria for delirium
or dementia
4. There is no evidence of another pre-existing cause for the
asymptomatic neurocognitive impairment
In DSM-IV criteria [2,3], there are currently no criteria for a diagnosis analogous to ‘mild neurocognitive disorder’ of the Frascati conference-based revision of the AAN criteria (with
the exception of the research appendix).
AAN: American Academy of Neurology; DSM: Diagnostic and Statistical Manual of Mental Disorders; SD: Standard deviation.
revised AAN criteria, while the revised AAN the DSM-5 Work Group criteria do not impose
criteria denote information processing speed a quantified impairment definition and only
and motor skills as separate domains not specify that ‘typically’ the deficits will be
included by the DSM-5 criteria. Little to no >2 SDs below the mean (or below the 2.5th
data exist on the importance of social and emo- percentile) of an appropriate reference popula-
tional cognition in the diagnosis of HAND, tion. In order to generally standardize diagno-
and it is likely that the inclusion of this domain ses of HAND, the use of a quantified NP
would bias against the likelihood of reaching impairment definition would improve reliabil-
a HAND diagnosis. The revised AAN criteria ity and validity, and the revised AAN criteria
are based upon the research on HAND dem- present a yet more differentiated approach to
onstrating that information processing speed the level of HAND with respect to MND ver-
is considered to be the hallmark of deficits sus HAD by the application of its differential,
observed in early HAND [18] . In addition, the quantitative NP cutoffs for these diagnoses.
motor domain is well known to be affected by
Sixth, the DSM-5 Neurocognitive Disorder
HIV infection of the brain, manifesting as sec-
Work Group criteria require that the neuro-
ondary Parkinsonism [19] related to basal gan-
cognitive deficits be associated specifically
glia infection occurring as an early-recognized
with deficits in functional status in activities
event [20] and associated with neurocognitive
of daily living involving independence. How-
changes [21] . It is unclear how the inclusion of
ever, the revised AAN criteria simply require
the virtually unstudied domain of social cogni-
that the neurocognitive impairment produces
tion by the DSM-5 could be expected to offset
marked interference with any activities of
its omissions of the frequently impaired
daily living (e.g., work, home life or social
domains of information processing speed and
activities – regardless of whether they interfere
motor function in HAND.
with independence). The requirement of def-
Fourth, another important difference icits in independence would likely skew the
between these two criteria sets is that the frequency of these diagnoses toward a more
revised AAN criteria set requires that at least severe level than would otherwise be the case
two NP domains be impaired, whereas the when general activities of daily living are
DSM-5 Neurocognitive Disorder Work assessed. The rationale for prioritizing inde-
Group criteria require only one NP domain pendence in HAND diagnoses or for neuro-
to be impaired. The issue with the use of a cognitive disorder diagnoses more generally is
single domain-based impairment definition is unclear. Another advantage of the revised
that it is not sufficient to denote the global AAN criteria is that they recommend (but not
deterioration of neurocognitive performance require) that standardized functional status
required by definition with the use of the term instruments be used. Of note, the instruments
‘dementia’ and – analogously – by ‘major neu- chosen should have norms that are appropriate
rocognitive disorder’ as well. In fact, it is not to the patient population being examined (i.e.,
uncommon to find that isolated impairment for that patient’s culture and a comparable
in the memory domain may particularly sociodemographic group).
occur without any impairment in other
A seventh and final issue with the criteria pro-
domains, and such a condition is better
moting ‘major neurocognitive disorder’ (as
defined as a different syndrome.
defined by the DSM-5) versus those promoting
Fifth, the quantified level of deficit required in ‘HAD’ (as defined by the revised AAN criteria)
NP performance differs between the two crite- are the exclusionary criteria that must be met.
ria sets as well. The revised AAN criteria for The DSM-5 Work Group states that the neu-
HAD indicate that impairment must be ascer- rocognitive deficits not be wholly or primarily
tained by NP testing with at least two domains attributable to another axis I psychiatric disor-
being 2 SDs or greater below demographically der (e.g., major depressive disorder or schizo-
corrected means. Alternatively, the patient phrenia). By contrast, the revised AAN criteria
could score greater than 2.5 SDs below norms state that there should be no evidence of
(an operational definition for moderate to another, pre-existing cause for the dementia
severe impairment) on one domain and greater (e.g., other CNS infection, CNS neoplasm,
than 1 SD below norms on another. However, cerebrovascular disease or pre-existing
neurologic disease). Of note, the revised AAN Work Group’s statement about the term ‘demen-
criteria for HAD include ruling out relevant tia’ having acquired pejorative and stigmatiz-
psychiatric disorders as a pre-existing cause as ing connotations, it would seem that the work
well (e.g., substance dependence compatible group might be similarly concerned about the
with CNS disorder and major depressive dis- connotations for the public of the term ‘minor
order), whereas the DSM-5 Neurocognitive neurocognitive disorder’. This term could be
Disorder Work Group criteria do not analo- anticipated to be perceived as diminishing the
gously specify exclusion of neurological or gen- importance of the functional consequences
eral medical conditions of any kind. It would of this disorder. In fact, the patients so diag-
seem that the latter approach should be modi- nosed may perceive this disorder as anything
fied at this time in the development of research but ‘minor’ in terms of its impact in their own
on CNS diseases when specific etiologies are lives. Hence, it is unclear why the switch from
generally becoming much more commonly ‘mild neurocognitive disorder’ to ‘minor neuro-
focused upon and are of manifest relevance to cognitive disorder’ would have been made, and
the definition of HAD. the change seems to be inconsistent with that
made by deleting the term ‘dementia’ in favor
Considering the less severe neurocognitive dis- of ‘major neurocognitive disorder’.
order subsumed by the term ‘HAND’, there are Beyond diagnostic labels, the comparison of
also currently no HIV-specific criteria denoted the less severe neurocognitive disorder criteria
in the DSM-IV [2,3] for either ‘HIV-associated sets themselves are similar to those between
MND’ as defined by Antinori et al. [9] , or for ‘major neurocognitive disorder’ and ‘HAD’ –
the previously defined AAN diagnosis of HIV- with two exceptions. One is that the NP defi-
associated minor cognitive-motor disorder [4] . cits are now defined as mild on NP testing by
This diagnosis – as alluded to previously – falls the DSM-5 Neurocognitive Disorders Work
under the DSM-IV generic diagnosis of ‘cogni- Group (i.e., ‘typically’ 1–2 SDs below the mean
tive disorder not otherwise specified’ (294.9). [or in the 2.5–16th percentile] of an appropri-
However, we have previously noted that the ate reference population). The other is that the
MND diagnosis could be mapped to the non- deficits must not be sufficient to interfere with
HIV-specific research diagnosis of the same functional status related to the maintenance of
name contained in appendix B of DSM-IV. In independence, although greater effort and com-
that research appendix, the term ‘MND’ is not pensatory strategies might be required to main-
related to etiology and is defined as requiring tain independence. In terms of the comparison
two or more of the following: memory impair- between the mild and more severe disorders as
ment, executive function deficits, attention and defined by the revised AAN criteria, the crite-
information processing speed deficits, percep- ria for MND are similar to those defined for
tual–motor impairment and language impair- HAD, with the exceptions that the acquired
ment. Of note, the functional status criterion impairment in neurocognitive performance
of MND in DSM-IV appendix B was that the involves performance on standardized NP tests
neurocognitive deficits should cause “marked of at least 1 SD below the mean for appropri-
distress or impairment in social, occupational ate norms (with the same domains defined as
and other important areas…”, which would seem those for HAD), and that the neurocognitive
to be inappropriate for this ‘mild’ disorder. impairment is associated with at least mild
The current criteria proposed for this neuro- interference in functional status of activities of
cognitive disorder in the DSM-5 have changed daily functioning. It is also suggested that per-
the DSM-IV research diagnosis nomenclature formance-based, standardized functional status
of ‘mild neurocognitive disorder’ to ‘minor tests should also be administered, with patient
neurocognitive disorder’. As such, this is the scores >1 SD below an appropriate normative
opposite of the analogous change in nomencla- mean required for the diagnosis. In addition and
ture between the prior [4] and current [9] sets of of specific relevance to MND, language func-
AAN neurocognitive disorder criteria. In this tion is typically preserved until late-stage HIV
case, the prior term was ‘HIV-associated minor CNS disease. Hence, the proposed DSM-5 Work
cognitive-motor disorder’ and the current term Group criteria including language as a domain
is ‘HIV-associated mild neurocognitive disor- for MND are not as well supported as those
der’. Given the DSM-5 Neurocognitive Disorder proposed for the revised AAN criteria, in which
Bibliography 2 American Psychiatric Association. Diagnostic 5 Brew BJ. Evidence for a change in AIDS
Papers of special note have been highlighted as: and Statistical Manual of Mental Disorders dementia complex in the era of highly active
n
of interest (4th Edition). American Psychiatric antiretroviral therapy and the possibility of
of considerable interest
n n
Association, VA, USA (1994). new forms of AIDS dementia complex. AIDS
3 American Psychiatric Association. 18(Suppl. 1), S75–S78 (2004).
1 Jeste D, Blacker D, Blazer D et al.
Neurocognitive Disorders. A Proposal from the Diagnostic and Statistical Manual of Mental 6 Neuenburg JK, Brodt HR, Herndier BG
DSM-5 Neurocognitive Disorders Work Group. Disorders (4th Edition). Text Revision. et al. HIV-related neuropathology, 1985
American Psychiatric Association, VA, USA, American Psychiatric Association, VA, USA to 1999: rising prevalence of HIV
1–17 (2010). (2000). encephalopathy in the era of highly active
4 American Academy of Neurology. antiretroviral therapy. J. Acquir. Immune
n n
Sets forth the proposed neurocognitive Defic. Syndr. Hum. Retrovirol. 31, 171–177
Nomenclature and research case definitions
disorder criteria (subsuming HIV- (2002).
for neurological manifestations of human
associated neurocognitive disorders
immunodeficiency virus type-1 (HIV-1) n
Demonstrates that neuropathological data
[HAND]) to be incorporated into the
infection. Neurology 41, 778–785 (1991). confirmed the reduced level of clinical
Diagnostic and Statistical Manual of Mental
Historical paper that first set forth severity of HAND noted in the era of
Disorders (DSM)-5. n
7 Dore GJ, McDonald A, Li Y, Kaldor JM, 13 McNair DM, Kahn RJ. The Cognitive n
Demonstrates that the domain of motor
Brew BJ. Marked improvement in survival Difficulties Scale. In: Assessment in Geriatric function is explicitly relevant to the
following AIDS dementia complex in the era Psychopharmacology. Crook T, Ferris S, presentation of HAND and is specific for
of highly active antiretroviral therapy. AIDS Bartus R (Eds). Mark Powley Associates, CN, the predilection of HIV for the basal
17(10), 1539–1545 (2003). USA, 137–143 (1983). ganglia, which supports the need for
n
Epidemiological paper that indicates a 14 Wu AW, Rubin HR, Mathews WC et al. HIV-specific diagnostic criteria for
marked improvement in survival time for A health status questionnaire using 30 items neurocognitive disorders.
patients with HIV-associated dementia in from the medical outcomes study. Med. Care 20 Rottenberg D, Moeller J, Strother SC et al.
the era of effective ART, suggesting that the 29, 786–798 (1991). The metabolic pathway of the AIDS
prevalence of HIV-associated dementia had 15 Knippels HMA, Goodkin K, Weiss JJ, dementia complex. Ann. Neurol. 22, 700–706
actually increased. Wilkie FL, Antoni MH. The importance of (1987).
8 Crum RM, Anthony JC, Bassett SS, cognitive self-report in early HIV-1 infection: 21 Arendt G, Hefter H, Hilperath F,
Folstein MF. Population-based norms for the validation of a cognitive functional status von Giesen HJ, Strohmeyer G, Freund HJ.
mini-mental state examination by age and subscale. AIDS 16, 259–267 (2002). Motor analysis predicts progression in
educational level. JAMA 269, 2386–2391 n
Demonstrates that a brief self-report HIV-associated brain disease. J. Neurol. Sci.
(1993). measure of neurocognitive functioning 123, 180–185 (1994).
9 Antinori A, Arendt G, Becker JT et al. could provide valid data similar to those 22 Jack CR, Albert MS, Knopman DS et al.
Updated research nosology for HIV- provided by formal neuropsychological Introduction to the recommendations from
associated neurocognitive disorders testing, suggesting that the use of such the National Institute on Aging and the
(HAND). Neurology 69, 1789–1799 self-report screening measures could be Alzheimer’s Association Workgroup on
(2007). effectively applied in resource-limited Diagnostic Guidelines for Alzheimer’s disease.
n n
Set forth the revision of the historical settings both nationally and internationally. Alzheimers Dement. 7(3), 257–262 (2011).
HAND criteria [4] for the era of effective 16 Lowenstein DA, Bates BC. Manual for 23 McKhann GM, Knopman DS, Chertkow H
ART and added the new condition of Administration and Scoring of the Direct et al. The diagnosis of dementia due to
‘asymptomatic neurocognitive impairment’. Assessment of Functional Status Scale in Older Alzheimer’s disease: recommendations from
Adults (DAFS). Mt Sinai Medical Center, FL, the National Institute on Aging and the
10 Power C, Selnes OA, Grim JA,
USA (1992). Alzheimer’s Association Workgroup.
McArthur JC. The HIV dementia scale:
Alzheimers Dement. 7(3), 263–269 (2011).
a rapid screening test. J. Acquir. Immune 17 Patterson TL, Goldman S, McKibbin CL,
Defic. Syndr. Hum. Retrovirol. 8, 273–278 Hughs T, Jeste DV. UCSD performance- 24 Sperling RA, Aisen PA, Beckett LA et al.
(1995). based skills assessment: development of a new Toward defining the preclinical stages of
measure of everyday functioning for severely Alzheimer’s disease: recommendations from
11 Sacktor N, Wong M, Nakasujja N et al.
mentally ill adults. Schizophr. Bull. 27, the National Institute on Aging and the
The International HIV Dementia Scale:
235–245 (2001). Alzheimer’s Association Workgroup.
a new rapid screening test for HIV dementia.
Alzheimers Dement. 7(3), 280–292 (2011).
AIDS 19, 1367–1374 (2005). 18 Law WA, Mapou RL, Roller TL, Martin A,
Nannis ED, Temoshok LR. Reaction time 25 Albert MS, DeKosky ST, Dickson D et al.
12 Bergner M, Bobbitt RA, Carter WB,
slowing in HIV-1-infected individuals: role of The diagnosis of mild cognitive impairment
Gilson BS. The sickness impact profile
preparatory interval. J. Clin. Exp. due to Alzheimer’s disease: recommendations
development and final revision of a health
Neuropsychol. 17, 122–133 (1995). from the National Institute on Aging –
status measure. Med. Care 19, 787–805
Alzheimer’s Association Workgroups on
(1981). 19 Mirsattari SM, Power C, Nath A.
Diagnostic Guidelines for Alzheimer’s disease.
Parkinsonism with HIV infection.
Alzheimers Dement. 7(3), 270–279 (2011).
Mov. Disord. 13, 684–689 (1998).
Recent publications estimate the prevalence of human immunodeficiency virus (HIV)–associated neurocognitive
Downloaded from http://cid.oxfordjournals.org/ at Long Island College Hospital on October 26, 2011
disorders (HAND) exceeds 50%, and this rate is likely higher among older patients. Cognitive impairment may
impact medication adherence, and symptomatic impairment has been linked to all-cause mortality providing
some impetus for early detection. There are currently insufficient data to inform solid recommendations on
screening methods. Most HIV-specific tools have poor performance characteristics for all but the most severe
form of impairment, which accounts for <5% of cases. Reliance on symptoms is likely to miss a substantial
proportion of individuals with HAND due to poor insight, confounding mood disturbances, and lack of
well-informed proxies. In the aging HIV-positive population, broader screening tools may be required to allow
sensitivity for both HIV and neurodegenerative disorders. We describe the clinical presentation of HAND,
review existing data related to screening tools, and provide preliminary and practical recommendations in
the absence of more definitive studies.
THE SCOPE OF COGNITIVE DISORDERS The current diagnostic categories of HAND are
IN THE ERA OF COMBINATION designed for research settings and emphasize perfor-
ANTIRETROVIRAL THERAPY mance on comprehensive neuropsychological testing
batteries [4]. The most severe form of impairment is
Human immunodeficiency virus (HIV) is neurovirulent. HIV-associated dementia (HAD), requiring test per-
Prior to widespread availability of combination an- formance .2 standard deviations below average in 2
tiretroviral therapy (cART), the prevalence of HIV- cognitive domains (eg, memory and executive func-
associated dementia was estimated to be between 6 and tion) and marked evidence of impaired daily function.
30% among patients with AIDS. With treatment, the Mild neurocognitive disorder (MND) similarly requires
frequency of dementia is attenuated, but milder forms of confirmation of impact on daily activities, but to a lesser
impairment remain highly prevalent and increase with degree, and involves less-severe neuropsychological
age [1]. Less severe impairment correlates to measurable impairment. A third diagnostic category, asymptomatic
abnormalities on tasks associated with daily functioning, neurocognitive impairment (ANI), is used for partic-
thus deeming them important clinical syndromes [2]. ipants with impaired neuropsychological performance
The presence of symptomatic cognitive impairment pre- in the absence of identifiable functional deficits. Such
dicts non–central nervous system (non-CNS) morbidity cases are frequent in research settings. A recent survey
and overall HIV mortality [3]. of 1555 community-dwelling HIV-positive participants
in the United States reported HAD frequency at about
Received 6 April 2011; accepted 6 July 2011.
Correspondence: Victor Valcour, MD, Department of Neurology, Memory and
2%, but identified non-HAD impairment in 45% of
Aging Center, University of California–San Francisco, 350 Parnassus Ave, Ste 905, participants who lacked major confounding factors
San Francisco, CA 94143-1207 (vvalcour@memory.ucsf.edu).
(12% MND and 33% ANI) [1]. Thus, among impaired
Clinical Infectious Diseases 2011;53(8):836–842
Ó The Author 2011. Published by Oxford University Press on behalf of the Infectious
participants, most were asymptomatic. Using impairment
Diseases Society of America. All rights reserved. For Permissions, please e-mail: ratings rather than diagnostic categories, 1 group [5]
journals.permissions@oup.com.
1058-4838/2011/538-0013$14.00
noted no change in the frequency of impairment
DOI: 10.1093/cid/cir524 when comparing pre- and post-cART eras. In short,
Downloaded from http://cid.oxfordjournals.org/ at Long Island College Hospital on October 26, 2011
not represent disease-free baseline performance for many in- deterioration that is the cornerstone of neurodegenerative
dividuals. The designation of ‘‘asymptomatic’’ may more ac- disorders [4].
curately reflect our inability to document impaired function,
possibly related to lack of insight, frontal lobe processing defi- CLINICAL CHARACTERISTICS OF
cits, limited daily activity (floor effect), or poor objective proxy HIV-ASSOCIATED DEMENTIA—IMPACT ON
information. Undetected cognitive impairment may increase the SCREENING TOOLS
risk of poor adherence, lead to financial errors, or result in other
adverse outcomes [2, 6]. Because functional impairment is the HIV enters the central nervous system (CNS) during acute in-
cornerstone of diagnosing dementia, optimal assessments may fection; however, neurons remain largely uninfected and the
require objective evaluation of everyday function. primary mechanism of brain injury relates to extensive in-
flammation leading to neuronal dysfunction and synapto-
AGING AND COGNITIVE DISORDERS IN HIV dendritic injury [8]. Early studies identified HIV staining
concentrated in subcortical and deep grey matter structures, an
Nearly all studies investigating the effects of age on the frequency anatomy that informs the clinical presentation of HAND, with
of HAND identify increased risk, although data are mixed when motor, behavioral, and predominantly subcortical cognitive
considering only neuropsychological testing performance [7]. features [11]. Early neuropsychological screening batteries were
Few studies include sufficient numbers of cases over age 60 and designed with a focus on these subcortical features, targeting
none have systematically addressed potential non-HIV etiologies psychomotor speed and information processing as well as ex-
such as Alzheimer’s disease (AD). In older participants, co- ecutive functioning and memory. The clinical–anatomic corre-
morbidities such as cumulative cerebrovascular disease may lations are further bolstered by findings associating cognitive
have significant contributions. impairment and apathy to deep grey matter structures, princi-
The risk for acceleration of neurodegeneration in HIV has pally the caudate nucleus and the nucleus accumbens, re-
been raised, though the issue currently remains largely theoretical. spectively. Extrapyramidal motor features are often observed
Proteins associated with age-related neurodegenerative disorders, and increase with age [12]. Although memory deficits occur, the
Figure 1. Brain magnetic resonance imaging (MRI) of an asymptomatic 79-year-old human immunodeficiency virus (HIV)–positive patient with
extensive neuropsychological testing abnormalities. Images demonstrate global brain atrophy and diffuse white matter injury.
Downloaded from http://cid.oxfordjournals.org/ at Long Island College Hospital on October 26, 2011
Most agencies provide mixed or limited support for routine memory impairments and performance on objective neuro-
screening for dementia in HIV-negative populations, despite psychological tests, and tighter association with depressive
knowledge that dementia remains frequently underdiagnosed symptoms. The Patient Assessment of Own Functioning
[14]. Citing limited outcome data for clinical intervention, ef- (PAOF), for example, identified depressive symptoms and psy-
fects related to stigma associated with cognitive disease, and lack chomotor inefficiency rather than neuropsychological testing
of specificity for existing screening instruments, the most recent performance, and when applied to HIV-negative substance
(2003) United States Preventative Service Task Force (USPSTF) abusers, there was no correlation to neuropsychological testing
guidelines concluded that there is insufficient evidence to performance [26, 27]. Importantly, screening for symptoms
recommend for or against routine screening in the absence of would not identify ANI, the largest subset of impaired partici-
known impairments [15]. The recommendations suggest pants. It is possible that, combined with a clinical risk identifi-
screening for patients who exhibit functional changes. The cation schema that includes risk factors such as CD4 nadir
American Academy of Neurology recommends increased count, plasma viral load, and age, these metrics could be im-
screening for patients with mild cognitive impairment (MCI) proved, given reports that such clinical variables may have some
due to heightened risk for progression to dementia; however, for utility [28].
asymptomatic elders, it concurs with the USPSTF [16]. Past Computer-delivered cognitive assessments have a theoretical
recommendations from the American Geriatric Society, the benefit in that they alleviate the time burden on clinical staff. In
American Medical Association, and the American Academy of the pre-cART era, the Sequential and Choice Reaction Time
Family Physicians similarly focus on symptomatic disease rather Program (CALCAP), a measure of reaction time, attention,
than screening asymptomatic participants [17]. psychomotor speed, and memory, identified advanced disease
but not milder disease [29, 30]. More recently, the CogState was
HIV DEMENTIA SCREENING TOOLS evaluated and similarly performed well in identifying advanced
dementia [31]. A pilot study revealed some promise in using the
The most commonly referenced HIV screening tool is the HIV Computer-based Assessment of Mild Cognitive Impairment
Dementia Scale (HDS) [18]. This tool provides a rapid assess- (CAMCI); however, the study design and size limited in-
ment of eye movements, motor skills, simple learning, and at- terpretation for the clinical setting [32]. In general, computer
tention. The HDS performance characteristics are modest with approaches have several important limitations including an in-
acceptable sensitivity only for the most severe disease. For ex- ability to test verbal learning efficiency, complicated outputs
ample, among hospitalized patients, 12% of whom met clinical requiring interpretation, cost burdens, limitations in the face of
criteria for HAD, the sensitivity at a cut-point of 10 (out of 16) literacy and non-English speakers, and a need to train staff.
was 0.92 and the specificity was 0.71, resulting in a positive Understanding which subtests within comprehensive batter-
predictive value (PPV) of 0.3 and a negative predictive value ies best correlate to cognitive impairment could provide pivotal
(NPV) of 0.98 [19]. The performance characteristics are much information for screening tool development. A domestic study
worse for detecting milder impairment [20, 21]. A study of noted that a combination of tests tapping verbal memory
HIV-positive individuals interested in returning to work noted (Hopkins Verbal Learning Test—revised total recall) and psy-
sensitivity and specificity for all impairment to be only 39% and chomotor speed (Grooved Pegboard or digit symbol modalities)
85%, respectively [22]. emerged as best predictors of rater-determined impairment [33].
Downloaded from http://cid.oxfordjournals.org/ at Long Island College Hospital on October 26, 2011
older age. The most widely used screening tool for AD, the Mini ated with HIV appear less than would be anticipated in com-
Mental State Exam (MMSE), does not test executive function or parison with studies that utilize published normative data. This
motor skill, rendering it less sensitive to subcortical neuropa- suggests that some of the impairment noted in HIV-positive
thology, and limited investigations confirm poor sensitivity to populations is influenced by other coexisting factors that are
HAND [36, 37]. Among the first 75 cases enrolled into the UCSF absent in published control data sets. In the current era, the
Memory and Aging HIV Cohort (all with age .60 years), the prevalence of cognitive impairment in HIV infection appears to
MMSE did not appear to provide sufficient variability by be high, estimated at 46% in cases without severe confounding
cognitive group to help diagnostically [mean score out of factors when published controls are used for comparison [1].
30 possible points (sample size, standard deviation) were as Among these impaired participants, most are asymptomatic
follows: normal cognition: 29.3 (37, 0.75); ANI: 28.7 (13, 1.49); (meet ANI criteria). Neuropsychological impairment has been
MND: 28.3 (20, 1.26) and HAD: 23 (4, 11.37) (unpublished linked to medication adherence; however, there are no studies
data). Notably, the HAD group included 1 patient thought to demonstrating that early identification will impact adherence.
have comorbid advanced AD and an MMSE score of 6]. Overall, Based on our knowledge from HIV-negative populations, other
the narrow distribution of these scores demonstrates poor potential benefits of early recognition may ensue, including
likelihood of utility even in aged HIV-positive participants. protection from unsafe situations and financial abuse, and in-
In summary, studies related to screening have broad limi- creased quality of life through information sharing and im-
tations, are often underpowered, and attempt to identify only proved life planning [38]. Generally, providing information to
the most severe form of impairment (Table 1). Nearly all have patients is an important aspect of clinical care and serves as
been completed in younger populations; it is anticipated that the a mechanism to develop or implement compensatory strategies
performance characteristics would be even less favorable in older to maintain independence.
participants. There are insufficient data to make firm recom- Medication treatment strategies for impairment have been
mendation on optimal screening tools, but it appears clear that disappointing. The potential benefits of CNS-penetrant anti-
the MMSE is not a good choice. retroviral drugs in the setting of long-term plasma suppression
of virus are unclear despite published case series where in-
SHOULD WE SCREEN FOR COGNITIVE tervention to change antiretroviral choice is required [39].
IMPAIRMENT AND IF SO, HOW? Should clear data emerge recommending specific treatment
strategies, or should adjuvant treatments prove to be efficacious,
We could find no published dementia screening guidelines in the need for early identification would be greater. Identification
the setting of HIV. The American Academy of HIV Medicine of cognitive impairment could provide a stimulus for starting
recently convened a panel to address clinical recommendations cART in ART-naive patients, or signal the need for intensified
for aged HIV-positive participants. These recommendations, adherence counseling in those patients already receiving treat-
still unpublished, will likely focus on symptomatic cases (per- ment. Among impaired participants with comorbid conditions
sonal communication as a panel member). It is critical that that may lead to cognitive impairment (eg, obstructive sleep
practical recommendations consider competing priorities in apnea, coexisting neurovirulent infections such as syphilis, vi-
complex HIV care settings. The use of comprehensive neuro- tamin deficiencies, and metabolic derangements), it is reasonable
psychological batteries is not feasible for screening. The USPSTF to believe that treatment may improve cognition. Counseling to
Modified HIV dementia HDS with eye movement Validated in HIV, quick to Less sensitive for non–HIV Reasonable to consider in 5 minutes
HIV/AIDS
scale (mHDS) portion removed perform related impairment/ younger age (,65 years)
[Davis AIDS Reader, neurodegenerative disorders recognizing limitations in all
2002] and all but the most severe but severe disease
form of HAND
International HIV dementia 4-item set of tests completed Validated in HIV Requires less training than Reasonable to consider in 5 minutes
scale (iHDS) by clinician include memory (internationally), saccadic eye movements, younger age (,65 years)
[Sacktor AIDS, 2005] task, finger tapping, a quick to perform may not be sensitive to recognizing limitations in all
sequential motor task (Luria non–HIV related impairment/ but severe disease, may have
Sequence) and recall neurodegenerative disorders less cultural influence than
mHDS in US setting
Mini mental state exam 30-item test heavily weighted Familiar to many Copyright protected, not Not recommended as not 10 minutes
(MMSE) on orientation (10 items) clinicians sensitive to HIV-related injury likely to identify HIV-related
[Folstein J Psychiatr rather than psychomotor impairment
Res, 1975] speed
Assessment of symptoms Subjective reporting of cognitive Easy to perform, can be done Only identifies symptomatic May be useful in concert with Variable
using standardized symptoms by patients in waiting room disease (likely to miss most objective screening
questions such as the participants with impaired instruments or considered
Medical Outcomes testing performance); not as an initial screen with
Survey sensitive for neuropsychological follow-up testing (will not
testing impairment identify ANI)
Neuropsychological testing Tailored set of tests that can Comprehensive Impractical for primary care Best reserved for referral of 1–4 hours
test a broad area of assessment of function, setting due to time needed concerned cases and
cognitive domains likely most sensitive to perform testing and research
to cognitive impairment specialized training to interpret
Montreal cognitive 30-item test that taps multiple May have broader Not validated in HIV; initial Reasonable choice but more 10 minutes
assessment (MoCA) domains subserved by applicability to milder pilot study with less than work is needed
[Nasreddine JAGS, cortical and subcortical impairment in the era of optimal performance
2005] regions cART and to heterogeneity characteristics
of disease potentially seen
in elder HIV patients; free,
available online and
translated into multiple
languages
Computerized Several available and test Can be done in doctor’s Often costly, limitations in More work is needed before Variable
assessments multiple domains including office with little supervision, assessing learning efficiency; recommendations can be
attention, reaction time, time-saving comprehensive sometimes require trained made
memory and psychomotor evaluation than simple interpretation
speed screening instruments
Summary of neuropsychological screening tools and their sensitivity to detection of cognitive impairment in HIV.
Abbreviations: HAND, human immunodeficiency virus–associated neurocognitive disorders; HIV, human immunodeficiency virus.
Downloaded from http://cid.oxfordjournals.org/ at Long Island College Hospital on October 26, 2011
Table 2. Questions That May Inform Dementia Screening in difficulty of some items for application in typical HIV clinics
Aged Human Immunodeficiency Virus (HIV) Participants (Adapted [41]. Other tests that combine list-learning tasks with tasks of
From United States Preventative Service Task Force [USPSTF] cognitive flexibility and psychomotor speed may be superior.
Evidence Review for Dementia Screening in HIV-Negative Adults)
Individuals with symptoms may require more in-depth neuro-
1) Does screening for cognitive impairment in primary care settings psychological testing if screening is negative, because false-
affect clinical outcomes? negative cases occur with all screening tests. This should be
2) What is the prevalence of undiagnosed cognitive impairment in combined with a screen for depression (eg, Back Depression
primary care patients?
Scale-II). These can be completed in about 10 minutes. Use of
3) Does a reliable and valid screening test exist to detect cognitive
impairment in older HIV patients? only symptom-based screening tools is likely to miss .50% of
4) Do pharmacological or non-pharmacological interventions, impaired cases. The addition of a neurological examination
including care-giver interventions improve outcomes? focused on motor speed, tone, and reflexes and integration with
5) What are the adverse effects of screening for cognitive
impairment?
clinical variables (eg, CD4 nadir, viral load) may add specificity.
6) What are the costs and cost-effectiveness of screening for Overall, there are important considerations for early detection
cognitive impairment? of cognitive impairment, particularly among older HIV-positive
7) What are the side effects of treatment? patients. Unlike the general healthy population, older HIV-
Downloaded from http://cid.oxfordjournals.org/ at Long Island College Hospital on October 26, 2011
Abbreviations: HAND, HIV-associated neurocognitive disorders; ANI, positive patients are managing a complex medical condition that
asymptomatic neurocognitive impairment.
disrupts CNS integrity and cognitive function and may be life
avoid psychoactive medications and illicit drugs may also be threatening if not adequately controlled through medical in-
advantageous. In summary, it is likely that identifying impair- tervention. With HIV, treatment failure and broad antiretroviral
ment may impact treatments aimed at improving quality of life, medication resistance are potential outcomes of cognitive im-
but intervention trials are lacking and this effort must be con- pairment. As such, unlike in the healthy older population, failure
sidered within the context of competing priorities for primary to identify cognitive deficits in the HIV-positive population may
care settings. Given the frequency of cognitive impairment in the directly influence successful management of the disease. In
HIV-positive population, screening is likely to identify far more balance, there are important clinical needs that can be addressed
truly impaired cases than false-positive cases. by research aimed at demonstrating whether improved de-
tection results in improved outcomes.
GENERAL RECOMMENDATIONS AND
CONCLUSIONS Notes
Acknowledgments. We thank Zhaoyan Diao for assistance with sta-
At this point, only general recommendations can be made tistical analyses.
regarding appropriate screening tools for HAND. Both HIV and Financial support. This work supported by the National Institutes of
cerebrovascular disease–specific pathology would be expected Health (grant numbers K23-AG032872 to V. V., P50-AG023501 to B. M.,
R01-MH085604 to R. P.).
to demonstrate preferential subcortical involvement, thereby Potential conflicts of interest. V. V. serves as a consultant for the-
negating the utility of screening measures that do not adequately American Academy of HIV Medicine and a faculty member for the In-
tap cognitive domains and effectively excluding use of the MMSE ternational Antiviral Society-USA. B. M. has received grant support from
Novartis, is a consultant for TauRx and Allon Therapeutics and is a board
as a screening tool. Currently available HIV-targeted screening member on the John Douglas French Alzheimer’s Foundation and the Larry
instruments, such as the HDS, have marked limitations in that L. Hillblom Foundation. All other authors: No reported conflicts.
they are sensitive only for the most severe forms of impairment. All authors have submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the
Screening tools that tap both cortical and subcortical pro-
content of the manuscript have been disclosed.
cesses exist, but have not been broadly used in HIV. Among such
tools is the Montreal Cognitive Assessment (MoCA), which is References
free (http://www.mocatest.org/) and translated (but not neces-
1. Heaton RK, Clifford DB, Franklin DR Jr, et al. CHARTER Group. HIV-
sarily validated) in many languages. The MoCA provides some
associated neurocognitive disorders persist in the era of potent anti-
coverage of executive function, motor skill, language fluency, retroviral therapy: CHARTER Study. Neurology 2010; 75:2087–96.
and verbal learning. To date, the MoCA has been tested in a pilot 2. Heaton RK, Marcotte TD, Mindt MR, et al. HNRC Group. The impact
of HIV-associated neuropsychological impairment on everyday func-
study of 119 relatively young (mean age 43 years) participants
tioning. J Int Neuropsychol Soc 2004; 10:317–31.
identifying 45 of 78 impaired participants (59%) at a cut-point 3. Vivithanaporn P, Heo G, Gamble J, et al. Neurologic disease burden in
of #25 (PPV: 85%, NPV: 53%). Shifting the cut point to 27 treated HIV/AIDS predicts survival: A population-based study. Neu-
increased sensitivity but overall performance characteristics were rology 2010; 75:1150–8.
4. Antinori A, Arendt G, Becker JT, et al. Updated research nosology
not reported [40]. A recent publication identified that the for HIV-associated neurocognitive disorders. Neurology 2007; 69:
MoCA may benefit from modifications designed to increase 1789–99.
Downloaded from http://cid.oxfordjournals.org/ at Long Island College Hospital on October 26, 2011
Force G, Keohane C. Neuropathology and neurodegeneration in human HIV-related impairments. J Int Neuropsychol Soc 2003; 9:64–71.
immunodeficiency virus infection. Pathogenesis of HIV-induced lesions 30. Worth JL, Savage CR, Baer L, Esty EK, Navia BA. Computer-based
of the brain, correlations with HIV-associated disorders and modifications neuropsychological screening for AIDS dementia complex. AIDS 1993;
according to treatments. Clin Neuropathol 2001; 20:146–55. 7:677–81.
12. Valcour V, Watters MR, Williams AE, Sacktor N, McMurtray A, 31. Cysique LA, Maruff P, Darby D, Brew BJ. The assessment of cognitive
Shikuma C. Aging exacerbates extrapyramidal motor signs in the era function in advanced HIV-1 infection and AIDS dementia complex
of highly active antiretroviral therapy. J Neurovirol 2008; 5:362–7. using a new computerised cognitive test battery. Arch Clin Neuro-
13. Woods SP, Scott JC, Dawson MS, et al. Construct validity of Hopkins psychol 2006; 21:185–94.
Verbal Learning Test—Revised component process measures in an 32. Becker JT, Dew MA, Aizenstein HJ, Lopez OL, Morrow L, Saxton J.
HIV-1 sample. Arch Clin Neuropsychol 2005; 20:1061–71. Concurrent validity of a computer-based cognitive screening tool for use
14. Borson S, Scanlan JM, Watanabe J, Tu SP, Lessig M. Improving in adults with HIV disease. AIDS Patient Care STDS 2011; 25:351–7.
identification of cognitive impairment in primary care. Int J Geriatr 33. Carey CL, Woods SP, Rippeth JD, et al. Initial validation of a screening
Psychiatry 2006; 21:349–55. battery for the detection of HIV-associated cognitive impairment. Clin
15. U.S. Preventive Services Task Force. Screening for dementia: recom- Neuropsychol 2004; 18:234–48.
mendation and rationale. Ann Intern Med 2003; 138:925–6. 34. Valcour VG, Shiramizu BT, Sithinamsuwan P, et al. HIV DNA and
16. Petersen RC, Stevens JC, Ganguli M, Tangalos EG, Cummings JL, cognition in a Thai longitudinal HAART initiation cohort: The
DeKosky ST. Practice parameter: Early detection of dementia: Mild SEARCH 001 Cohort Study. Neurology 2009; 72:992–8.
cognitive impairment (an evidence-based review). Report of the 35. Ellis RJ, Evans SR, Clifford DB, et al. Clinical validation of the Neu-
Quality Standards Subcommittee of the American Academy of Neu- roScreen. J Neurovirol 2005; 11:503–11.
rology. Neurology 2001; 56:1133–42. 36. Ganasen KA, Fincham D, Smit J, Seedat S, Stein D. Utility of the HIV
17. American Medical Association. Practical guide for the primary care Dementia Scale (HDS) in identifying HIV dementia in a South African
physician on the diagnosis, management and treatment of dementia. sample. J Neurol Sci 2008; 269:62–4.
Chicago, IL: Program on Aging and Community Health, 2001. 37. Skinner S, Adewale AJ, DeBlock L, Gill MJ, Power C. Neurocognitive
18. Power C, Selnes OA, Grim JA, McArthur JC. HIV Dementia Scale: screening tools in HIV/AIDS: Comparative performance among pa-
A rapid screening test. J Acquir Immune Defic Syndr Hum Retrovirol tients exposed to antiretroviral therapy. HIV Med 2009; 10:246–52.
1995; 8:273–8. 38. Milne A. Dementia screening and early diagnosis: The case for and
19. Berghuis JP, Uldall KK, Lalonde B. Validity of two scales in identifying against. Health Risk Soc 2010; 12:65–76.
HIV-associated dementia. J Acquir Immune Defic Syndr 1999; 21:134–40. 39. Marra CM, Zhao Y, Clifford DB, et al. AIDS Clinical Trials Group 7736
20. Bottiggi KA, Chang JJ, Schmitt FA, et al. The HIV Dementia Scale: Study Team. Impact of combination antiretroviral therapy on cere-
Predictive power in mild dementia and HAART. J Neurol Sci 2007; brospinal fluid HIV RNA and neurocognitive performance. AIDS 2009;
260:11–5. 23:1359–66.
21. Richardson MA, Morgan EE, Vielhauer MJ, Cuevas CA, Buondonno 40. Overton E, Ances B, Grubb J, et al. Novel screening tools for HIV-
LM, Keane TM. Utility of the HIV dementia scale in assessing risk for associated neurocognitive disorders. Paper presented at: 18th Conference
significant HIV-related cognitive-motor deficits in a high-risk urban on Retroviruses and Opportunistic Infections; 27 February–8 March
adult sample. AIDS Care 2005; 17:1013–21. 2011; Boston, MA. Paper 401.
22. Smith CA, van Gorp WG, Ryan ER, Ferrando SJ, Rabkin J. Screening 41. Koski L, Brouillette MJ, Lalonde R, et al. Computerized testing aug-
subtle HIV-related cognitive dysfunction: the clinical utility of the HIV ments pencil-and-paper tasks in measuring HIV-associated mild cog-
dementia scale. J Acquir Immune Defic Syndr 2003; 33:116–8. nitive impairment. HIV Med 2011; 12:472–80.
Elyse J. Singer, M.D. [Director; Professor of Neurology]a,b, Miguel Valdes Sueiras, M.D.
[Assistant Professor of Neurology]c, Deborah Commins, M.D., Ph.D. [Associate Professor of
Pathology (Neuropathology)]d, and Andrew Levine, Ph.D. [Assistant Researcher in
Neurology]e
a)David Geffen School of Medicine at University of California, Los Angeles, CA
Keywords
AIDS; HIV; brain; opportunistic infection; encephalitis
The human immunodeficiency virus (HIV), the cause of acquired immunodeficiency syndrome
(AIDS) has infected an estimated 33 million individuals worldwide{1}. HIV is a member of
the lentivirus genus, part of the Retroviridae (retrovirus) family{2}. HIV is associated with
immunodeficiency, neoplasia and neurological disease.
HIV is neuroinvasive (can enter the central nervous system ((CNS)), neurotrophic (can live in
neural tissues), and neurovirulent (causes disease of the nervous system){2}. Presumed
mechanisms of CNS invasion include the “Trojan horse” mechanism in which HIV-infected
monocytes are admitted by the blood-brain barrier and mature into long-lived, persistently
infected perivascular macrophages; infection of the choroid plexus; and direct infection of
capillary endothelial cells, among others. HIV-infected cells include capillary endothelium,
microglia, monocytes, macrophages, astrocytes, and choroid plexus {3}. Neurons and
NIH-PA Author Manuscript
oligodendrocytes are rarely, if ever, infected (although this is still under discussion), and
“indirect” mechanisms are postulated to account for most damage {4}. There is a burst of viral
replication in primary infection, followed by an aggressive immune response that declines over
time, and by a long period of subclinical infection, followed by recrudescence of disease, and
death {2}. Persistent infection and inflammation results in blood-brain barrier breakdown,
neuronal and axonal injury, neurotoxicity, and clinical symptoms; damage to the immune
system, particularly cell-mediated immunity, results in vulnerability to OI.
In addition to its importance as a cause of neurological problems, HIV infection of the CNS
constitutes a serious barrier to management and eradication of the virus. The CNS is
incompletely permeable to antiretroviral drugs, resulting in subtherapeutic levels of many
antiretrovirals {5}; it is part of a protected reservoir {6} (along with the gut and several other
organs), where HIV can evade the immune system; and it provides an environment where HIV
can replicate, mutate, and re-infect the circulation. HIV stimulates a persistent inflammatory
response that may activate pathways leading to other neurodegenerative diseases {7}.
Acute HIV infection is the period from initial infection to complete seroconversion. During this
time 40-90% of individuals describe physical symptoms, similar to influenza, or
mononucleosis. The most common features include a short period of fever, lymphadenopathy,
night sweats, headache, and/or rash {8,9}. Early CNS infection is usually asymptomatic, but
cerebrospinal fluid (CSF) {10} and imaging studies {11} can detect abnormalities even during
the “asymptomatic” period that presage later neurological events.
A minority of seroconverters will experience a neurologic event that brings them to medical
attention, such as aseptic meningitis, Bell’s palsy {12,13}, or inflammatory neuropathy.
Individuals with symptomatic neurological disease tend to have higher CSF HIV levels than
those without. Neurological symptoms may occur before an HIV diagnosis is suspected, e.g.,
before there are sufficient HIV antibodies to produce a positive HIV enzyme-linked
immunosorbent antibody (ELISA, also called an HIV enzyme immunoassay). In such cases,
a Western Blot or a polymerase chain reaction (PCR) test for HIV may lead to the diagnosis.
Early diagnosis of acute HIV infection is important, as these individuals are at high risk to
transmit the virus.
The most common neurologic syndrome associated with primary HIV infection is an acute
aseptic (viral) meningitis or meningoencephalitis. The symptoms are similar to other viral
NIH-PA Author Manuscript
meningitides, with fever, headache, stiff neck, and photophobia. Cerebrospinal fluid (CSF)
shows a mild lymphocytic pleocytosis, normal or slightly elevated total protein, and normal
glucose {14}. HIV may be detectable by antigen or PCR testing {15}. Most individuals will
recover with supportive care. A few will have recurrent bouts.
Information on the management of HIV aseptic meningitis is limited to case reports. Initiating
treatment with cART, or changing and intensifying the regimen to include more CNS-
penetrating drugs, may suppress the symptoms {16}. Others have recurrent meningitis when
they stop combined antiretroviral therapy (cART), e.g. during structured treatment
interruptions {17}.
Although HAND can affect any neuropsychological domain, the most commonly reported
deficits are in attention/concentration, psychomotor speed, memory and learning, information
processing, and executive function, while language and visuospatial abilities are relatively
NIH-PA Author Manuscript
HIV can have profound effects on the pyramidal and extrapyramidal motor systems. Milder
manifestations of CNS motor impairment include ataxia, motor slowing, incoordination, and
tremor. This may progress to disabling weakness, spasticity, extrapyramidal movement
disorders, and paraparesis {24,25}. Behavioral effects of HAND include apathy, irritability,
and psychomotor retardation {26-28}, which can be mistaken for depression. This is difficult
to disentangle because of the high rate of major depression and dysthymia in the HIV
population, {29}, and because many symptoms queried in depression screening instruments,
such as loss of appetite, can be due to HIV. Some AIDS patients develop “manic” symptoms
NIH-PA Author Manuscript
{30}. Again, this must be disentangled from a pre-existing bipolar disorder, or a reaction to
drugs. So-called “secondary” or AIDS mania tends to occur in patients with poorly controlled
disease, concurrent cognitive deficits, irritability, aggression, and talkativeness, and have
hallucinations and paranoia {31}.
Historically, the onset of HAND was associated with low CD4+ counts{32}, other AIDS
symptoms{33}, elevated CSF viral load {34}, and elevated CSF markers of immune activation
(e.g. beta 2 microglobulin and neopterin) {35}. Much of this dates back to the 1980s when no
effective treatment was available and only the most demented patients came to medical
attention {36,37}. At that time, a diagnosis of HAD was considered to be a precursor of death
{32}. These aggressive forms of HAND remain prevalent in Third World countries and among
individuals with late diagnosis, or who have refused or failed cART. However, such
presentations are uncommon in cART-treated individuals, who manifest a milder, more slowly
progressing and less lethal “attenuated” form of HAND {38,39}.These mild presentations
typically occur in persons with partial immune reconstitution, higher CD4 + counts, and
suppressed viral loads, and are less strongly associated with markers of immune activation
{40,41} {42} {43}. Due to increased awareness of HAND it is also possible that it is identified
NIH-PA Author Manuscript
at an earlier stage.
The traditional neuroimaging approach (in which a diagnosis is made through qualitative image
examination) is useful in excluding structural or inflammatory processes, such as abscess, or
tumor, that may mimic HAND, but is limited as a diagnostic marker. The HAND brain may
appear grossly normal until advanced disease, when atrophy may be noted. White matter
changes may appear, typically in the periventricular region. These must be differentiated from
other diseases that affect myelin such as progressive multifocal leukoencephalopathy (PML),
and unrelated processes such as leukoariosis. Currently, there are few ways to distinguish
among these white matter abnormalities except for the pattern and distribution of the lesions,
which are not definitive. Advanced, investigative neuroimaging techniques show promise as
biomarkers of HAND {44}. Brain mapping indicates that there may be a unique pattern of
atrophy in HAND that distinguishes it from other dementias. There are reports of ventricular
enlargement, atrophy of the caudate, putamen, nucleus accumbens, and other subcortical
regions that may characterize HAND {45,46} {47}. Another technique that may identify
HAND and measure its progression or improvement, is magnetic resonance spectroscopy
(MRS){44,45}. MRS is sensitive to the earliest signs of CNS infection. Lentz et al {48},
reported on subjects followed from early seroconversion and reported initial decline in n-
NIH-PA Author Manuscript
acetylaspartate (NAA), a marker of neuronal viability, in the frontocortical gray matter. NAA
levels were found to be decreased in the centrum semiovale white matter of chronically HIV-
infected subjects, but not in early infection. This study is still ongoing so further follow up will
be needed to map changes over time. Paul et al, {49} reported that impaired neuropsychological
performance in HIV is associated with reduced NAA and increased myoinositol (MI, a marker
of gliosis) in the basal ganglia and frontal white matter, but not with markers in the parietal
region (Figure 1). Flurodeoxyglucose (FDG) positron emission tomography (PET) studies in
HIV are few, but show early hypermetabolism in the basal ganglia {50}, followed by
hypometabolism in late HAND {51}. This pattern is unlike Alzheimer’s disease and other
dementias.
“boosted” protease inhibitor (PI). Ritonavir (in small doses) is a PI most commonly used as a
booster; it enhances other PI so they can be given in lower doses. No placebo–controlled trials
of cART for HAND have been performed, because it would be unethical to refuse treatment
to a symptomatic patient. Based on well-conducted (albeit, not randomized, double blinded,
controlled) studies {54}, it appears that cART improves neuropsychological performance
{55}. It also appears that cART has reduced the incidence of new cases of severe HAND
(HAD), while apparently increasing the number and lifespan of individuals living with milder
forms of HAND {38,56}.
The CNS penetration of the various components of a cART regimen may vary widely, and
there is ongoing discussion regarding the importance of the CNS-penetrability of a cART
regimen. Letendre et al., have proposed a CNS-Penetration Effectiveness (CPE) Rank {5} in
which cART regimens are ranked by summing up various criteria associated with CNS
effectiveness. In a large study, subjects whose regimens scored low on the CPE ranking had
higher CSF viral loads{5} In a related study, Marra et al.{57}, confirmed the association of
low CPE scores with higher probability of detectable CSF viral load, and poorer
neuropsychological performance. An independent group {58} confirmed that higher CPE
NIH-PA Author Manuscript
from other causes of myelopathy such as infection with Human T-cell lymphotropic virus
(HTLV) I or II; herpes simplex 1 or 2, varicella zoster, cytomegalovirus, enteroviruses, syphilis
and tuberculosis, tumors, and nutritional deficiencies such as B12 {64}. In the past, HIV VM
was more common in patients with opportunistic conditions{63}, but this association has not
be reviewed in the cART era.
The clinical presentation of HIV VM is slowly progressive leg weakness, which may be
asymmetric at first, spasticity, dorsal column (vibration, position) sensory loss, ataxic gait, and
urinary frequency and urgency{65}. Erectile dysfunction is an early sign in men. Paresthesias
in the legs are common but neuropathic pain rarely rises to the level seen with peripheral
neuropathy. There is prominent hyperreflexia, and extensor plantar responses. In advanced
cases, patients may become wheelchair-bound and doubly incontinent {65}.The diagnosis
should be questioned if symptoms present in an acute fashion, the arms are affected, there is a
sensory level, or if there is back pain.
The most important test is a spinal MRI, to rule out abscess or tumor. In many HIV VM cases,
the MRI is normal. Some will have high signal hyperintense areas on T2 weighted imaging,
primarily in the thoracic region and affecting the posterior columns, that do not enhance with
NIH-PA Author Manuscript
contrast; these areas correlate to vacuolation on histopathology{66}. Cord atrophy has also
been reported{67}. A lumbar puncture is important to exclude treatable infections or
carcinomatous meningitis. Somatosensory evoked potentials are useful to disentangle cases in
which both HIV VM and sensory neuropathy are present {68}.
There is no specific treatment for HIV VM. A pilot, open label study of L-methionine to address
the suspected abnormality of transmethylation mechanisms in HIV VM did not show benefit
{77}. There are case reports of improvement with cART{78-80}. However, axonal
degeneration is a late feature of HIV VM {81}, and would not be expected to resolve. Patients
with HIV VM benefit from physical and occupational therapy, baclofen, tizanidine, dantrolene,
NIH-PA Author Manuscript
and intramuscular botulinum toxin to manage spasticity, pain management, and anticholinergic
drugs to improve bladder function{65}.
HIV associated distal peripheral sensory neuropathy (DSPN) (also called predominantly
sensory neuropathy, or distal symmetrical peripheral neuropathy), is the most common
neurological problem in AIDS {82}, with incidences ranging from 19-66%, depending upon
the age, disease stage, and treatment history of the cohort {83}. The risk factors for HIV DSPN
are older age, history of alcohol abuse, and advanced HIV disease (e.g., a low nadir CD4+
count and high plasma HIV viral load){84,85}, prior use of a neurotoxic antiretroviral drug
(e.g., didanosine, stavudine, zalcitabine), and diabetes.
The most universally reported symptoms are paresthesias {86}, that virtually always begin in
the feet, as this is a length-dependent neuropathy. Patients complain of burning, of numbness,
NIH-PA Author Manuscript
of hot or cold sensations, and of episodic electric-shock like sensations. Some complain of a
sensation that they are walking on sand, or glass. Many cannot bear to wear shoes. The
symptoms ascend over time, as far as the thighs, and will also involve the hands in a glove-
like fashion. Cramps and fasiculations may develop in the extremities. Most patients do not
develop any motor weakness or muscle wasting until late in their course, and this is limited to
the distal extremities {87}. The most common physical findings are decreased or absent ankle
jerks, diminished vibratory sensation in the legs, and increased threshold to temperature and
pinprick (alternatively, some patients develop hyperesthesia) {87}. Some patients will have
all the physical findings of neuropathy but do not report pain. They usually have an
asymptomatic neuropathy. Others will have hyper-reflexia proximally and hypo-reflexia
distally, in which case a mixed myelopathy and neuropathy should be suspected.
The pathogenesis of HIV DSPN is unknown. Related viruses such as feline immunodeficiency
virus (FIV) also cause neuropathy in cats {88}. FIV (and HIV-1) infects and activates
macrophages{88} and CD8+lymphocytes {89} in the dorsal root ganglion, and these cells can
release substances, such as tumor necrosis factor {88}, that are toxic to neurons and
oligodendrocytes. The HIV protein gp120 is also neurotoxic, causing hyperesthesia, allodynia,
and spinal gliosis{90}. The major neuropathologic features in HIV DSPN include a loss of
NIH-PA Author Manuscript
unmyelinated axons in the distal regions of sensory nerves, followed by Wallerian degeneration
of the distal myelinated fibers. Some degree of demyelination and remyelination and has also
been reported{91}.
In most cases, an electromyogram (EMG) and nerve conduction studies (NCS) are not
necessary to diagnose HIV DSPN {92}. If an electrodiagnostic study is performed, it will
demonstrate findings similar to other degenerative, predominantly axonal neuropathies, such
as reduced or absent action potentials. A few patients have apparently normal studies. They
most likely have a small-fiber neuropathy, and quantitative sensory testing may be helpful if
there is a reason to document the clinical diagnosis. It is important to search for processes that
can mimic or exacerbate HIV DSPN, including syphilis, diabetes, B12 or folate deficiency,
thyroid disease, hepatitis C virus, and any neurotoxic medication.
Treatment of DSPN itself is generally frustrating. Studies of nerve growth factor {93} and the
experimental drug prosaptide {94} were unproductive. Randomized, controlled clinical trials
of drugs to control neuropathic pain showed positive results for lamotrigine {95}, for an
NIH-PA Author Manuscript
improvement{111}; reduction in symptoms usually occurs by six weeks, but some may take
up to six months.
A chronic IDP (CIDP) may occur in late infection and is often associated with a CD4+ count
of under 50 cells/mm3 {120}. Unlike acute HIV IDP, this syndrome progresses slowly and
NIH-PA Author Manuscript
may have a relapsing and remitting nature. It must be differentiated from neuropathies caused
by CMV and related viruses. Treatment of HIV CIDP is similar to that of non-HIV related
CIDP, with the exception for the need to control HIV infection, and is based on case reports
on HIV patients and the non-HIV literature.
Most cases of AIDS PML occur during severe immunosuppression (under 100 CD4+cells/
mm3) although exceptions occur in about 11% of cases {124}. Most present with the subacute
onset of altered mental status, accompanied by focal symptoms referable to the location of the
NIH-PA Author Manuscript
one or more PML lesions, such as hemiparesis, hemianopsia, ataxia, vertigo, speech disorders,
and seizures {125}. Patients usually do not have headaches, fevers, nausea, vomiting, or
papilledema.
larger lesions may be necrotizing at the center with loss of both myelin and axons and
replacement by confluent lipid-laden macrophages. At the periphery there are scattered virally
infected oligodendroglial cells with enlarged nuclei that contain deep amphophilic (purple)
viral inclusions. PML lesions also contain grossly enlarged, pleomorphic “pseudoneoplastic”
astrocytes. If necessary the diagnosis can be confirmed with immunohistochemistry or in
situ hybridization for JCV.
There is no specific treatment for PML with or without AIDS. Multiple agents have been tried
without success including topotecan {131}, cytarabine {132,133}, and cidofovir {134}.
However, cART has improved the course of AIDS PML, decreasing the mortality rate,
improving the neuroimaging features, improving survival, and decreasing CSF JCV viral load
{135,136} {125}. Patients who survive AIDS PML are likely to have serious residual
neurocognitive deficits. Levine et al (2008) reported that eight patients with past PML differed
as a group from AIDS patients without history of CNS-OI with regards to information
processing and motor functioning{137}. Further, while the PML group was less severely
impaired overall than those with history of AIDS and toxoplasmosis, their deficits in
information processing and motor functioning were the most severe of all groups examined.
NIH-PA Author Manuscript
Cytomegalovirus (CMV)
Cytomegalovirus (CMV), a member of the Herpesvirus family, can infect the brain, spinal
cord, meninges, retina, the dorsal root ganglion of peripheral nerves, and many visceral organs
{138}. Approximately 60% of the population show evidence of exposure to CMV {139} but
the prevalence is higher in homosexual men {140}. Cytomegalovirus (CMV) establishes a life-
long, latent infection without clinical disease in immunocompetent individuals after initial
infection, and may remain latent for years, or reactivate under conditions such as HIV or other
immunodeficient states. CMV and HIV are known to transactivate each other in vitro {141}.
Typically, CMV of the nervous system presents in individuals with CD4+ counts under 50
CD4+ cells/mm3, CMV viremia, and one or more systemic site(s) of infection {138}.
Neurological CMV disease can present as encephalitis, ventriculitis, myelitis,
radiculoganglionitis and peripheral polyneuropathy, or various combinations thereof {138,
142}. Presenting signs and symptoms are extremely variable depending upon the area affected;
CMV encephalitis and ventriculitis may present with fever, lethargy, confusion, or coma,
seizures, and cranial nerve palsies, ataxia and hemiparesis, or even coma; some patients present
NIH-PA Author Manuscript
with dementia, which may or may not be due to a concurrent HIV encephalitis {143,144}.
CMV infection of the spinal cord may cause either a transverse myelitis or a myeloradiculitis
characterized by flaccid paraparesis associated with back pain, incontinence, areflexia,
paresthesias and sensory loss, and ascending weakness{145,146}.
The CSF CMV PCR is considered the gold standard for identifying and quantifying CNS CMV
and for following the response to therapy {147}. The literature also refers to a CSF profile that
consists of a polymorphonuclear pleocytosis, {148}, but this is not a consistent finding{145}.
Unlike HIV, CMV can directly infect astrocytes, neurons, oligodendroglia, endothelial,
ependyma, and meningeal cells {149,150}, and can directly kill, neural cells, e.g., by inducing
apoptosis {151,152}. The most common pathological finding is a microglial nodule
encephalitis, but other findings include ventriculoencephalitis (a focal or diffuse destruction
of the ependymal lining and necrosis of periventricular tissue); focal necrosis; and isolated
cytomegalic cells{153}.(Figure.3)
Randomized, placebo-controlled trial data regarding treatment of CNS CMV is lacking. Based
on data extrapolated from case reports and clinical trials of other organ systems, it is
NIH-PA Author Manuscript
Common presenting symptoms of CM include malaise, headache, and fever. As the disease
progresses, patients may develop seizures and signs of increased intracranial pressure (nausea,
vomiting, visual loss, diplopia, coma){156}. A diagnosis of CM can be made by visualizing
the yeast in CSF, using India ink; or by detecting cryptococcal antigen in the CSF using the
latex agglutination test {54}. If lumbar puncture is contraindicated, a presumptive diagnosis
can be made with a serum antigen test. AIDS patients may not have a CSF cellular pleocytosis,
abnormal protein, or low CSF glucose{158}. Neuroimaging may be normal, but abnormalities
such as masses (cryptococcomas), dilated perivascular spaces, or pseudocysts, are associated
with higher blood and CSF antigen titers {159}.
Immediate treatment is essential to prevent loss of brain and loss of life, as this is a lethal
disease and even with optimal treatment, the mortality rate is still 15% {160}. The
recommended initial standard treatment is amphotericin B, at a dose of 0.7 mg/kg daily,
combined with flucytosine, at a dose of 100 mg/kg daily in four divided doses, for at least 2
weeks for those with normal renal function {155}. Primary treatment with fluconazole has
failed {161}. In addition to antifungal therapy and cART, it is important to manage increased
intracranial pressure, as this may lead to permanent neurologic deficits, blindness, and death
NIH-PA Author Manuscript
{162}. The CSF can be removed by repeated lumbar puncture, or a lumbar drain or shunt may
be necessary{54}. After at least a 2-week period of successful induction therapy, defined as
significant clinical improvement and a negative repeat CSF culture, amphotericin B and
flucytosine may be discontinued and follow-up therapy initiated with fluconazole 400 mg daily
{155}. This should continue for at least eight weeks. Discontinuation of secondary prophylaxis
can be considered in patients with sterile CSF, clinical improvement, and an increase in CD4
+ cell count to at least 200 cells/mm3.
With treatment, most HIV+ individuals will survive CM. Long-term outcomes in
neurocognitive functioning have only recently been examined. In an exploratory study, Levine
et. al., examined neurocognitive functioning in a cohort of fifteen individuals with history of
AIDS and CM, compared to 61 individuals with AIDS, but without history of CNS disease.
Those with a history of CM continued to demonstrate deficits in verbal fluency and motor
functioning relative to HIV infected controls without CM.
definitive host is the cat, but the parasite can be carried by all mammals. Infection can be
acquired transplacentally, or by ingesting contaminated water, undercooked meat, soil, or cat
feces. Once in the gut, the parasite disseminates to the brain, muscles, and eyes, and invades
cells, where it forms intracellular cysts. Most primary infections are asymptomatic or there
may be flu-like symptoms. The parasite may remain latent for years; cases of AIDS-associated
Toxoplasmosis encephalitis (TE) almost always result from reactivation, usually when the CD4
+ count has declined below 200 cells/mm3; higher risk is present when the CD4+ is under 50
cells/mm3 {155,163}.
Fever, headache, focal neurological deficit, cognitive dysfunction, seizures, and altered mental
status are the most common presenting symptoms of TE {164,165}. Because these are highly
inflammatory and necrotic lesions with mass effect, elevated intracranial pressure is often a
serious problem. The typical neuroimaging presentation includes multiple (in seventy percent
of cases), contrast-enhancing lesions, frequently surrounded by edema {166}. Most lesions are
supratentorial, and located at the gray-white matter junction or in the basal ganglia. MRI
typically shows several T2 weighted hyperintense lesions with enhancement on postcontrast
T1 images{166}. Some lesions are hemmorhagic.{167}. The most important differential
diagnosis in AIDS patients is primary central nervous system lymphoma (PCNSL). Some
NIH-PA Author Manuscript
mouth, four times a day (to treat the parasite) and leucovorin (folinic acid) 10 mg by mouth
per day, to reduce toxicity caused by pyrimethamine {54,155}. An alternative regimen is
pyrimethamine 200 mg by mouth loading dose followed by 50 mg by mouth per day, plus
NIH-PA Author Manuscript
clindamycin 600 mg by mouth four times a day plus leucovorin 10 mg per day. Acute therapy
should be continued for at least six weeks, provided that the patient is improving, and longer
in cases with extensive disease. Secondary prophylaxis should be continued until the lesions
are resolved, symptoms have improved, cART has raised the CD4+ cell count to at least 200
cells/mm3, and viral load is suppressed{170}.
Persistent neuropsychological deficits are evident in many survivors of TE. Examining the
long term neurocognitive outcomes of individuals who survived AIDS CNS-OIs, Levine et al
(2008) found that those with past TE performed worse on all but one neuropsychological
domain than those with history of other AIDS CNS OI, including PML and CM {137}.
The presenting symptoms of PCNSL include lethargy, confusion, impaired memory, headache,
seizures, or focal weakness. Many patients develop cranial neuropathies and/or ocular
involvement. Increased intracranial pressure and herniation can result in papilledema, and
coma if untreated.
The usual neuroimaging findings on CT or MRI are one or sometimes multiple, contrast-
enhancing lesions surrounded by edema, with mass effect. On MRI, they are hyperintense on
T1 imaging and often show a periventricular distribution These lesions typically have a high
uptake of radioactive tracers on thallium 201 SPECT {168} or fluorodeoxyglucose PET
{169}, as opposed to TE. If it is safe to perform a lumbar puncture, the CSF may be helpful.
EBV can be detected and quantified by PCR in the CSF{177} and plasma {178} of these
patients, and may be a biomarker of PCNSL. However, diagnosis ultimately depends on a
NIH-PA Author Manuscript
tissue diagnosis.
AIDS PCNSL are almost always high-grade, diffuse B-cell lymphomas, often of
immunoblastic subtype. Compared with similar tumors seen in immunocompetent individuals,
they are more likely to be multifocal and necrotic. Biopsy can be problematic{179}, especially
a needle biopsy, because of the small sample, the possibility of extensive necrosis of the tumor,
and the angiocentric nature. Administration of corticosteroids to reduce cerebral edema prior
to biopsy can result in lysis of most neoplastic lymphocytes, resulting in a non-diagnostic
biopsy{179}.
The tumor is treated with cranial irradiation (usual adult dose is fractionated 4000-5000 cGy),
and by instituting or optimizing cART. Chemotherapy, if used, typically includes methotrexate,
and there are also some positive results using antiviral therapies (e.g., ganciclovir) that decrease
EBV viral load {180}, but there are no large controlled trials that establish optimal therapy.
Unfortunately, many treatments for AIDS PCNSL can result in residual cognitive impairment,
particularly when both whole brain radiation and methotrexate-based chemotherapy are used
{181}. The literature on this topic almost exclusively involves non-HIV cases. Harder et al.
NIH-PA Author Manuscript
{182} reported on the neurocognitive status and quality of life among 19 non-HIV patients
treated for PCNSL. All patients were in remission after combined whole-brain radiation and
methotrexate-based chemotherapy. Neurocognitive and quality of life scores were compared
to demographically-matched controls who had systemic malignancies and had undergone
chemotherapy or non-brain radiotherapy. The authors found neurocognitive impairment in
twelve patients with PCNSL, with four showing severe cognitive deficits. Only two control
subjects were cognitively impaired according to their criteria. Only 42% of the PCNSL patients
returned to work, as compared to 81% of controls.
pressure may rise {185}, requiring the use of corticosteroids. Among the most common CNS
infections reported to be involved in IRIS are HIV encephalitis {186-188}, TE {187,189}, CM
{185}, and PML {184} {155}. Risk factors for IRIS include taking cART for the first time,
active or subclinical OI, CD4+ counts under 50 cells/mm3, high CD8+ cells, anemia, and a
rapid decline in HIV viral load {190,191}. There are relatively few biopsy or autopsy studies
of IRIS, in part because most patients survive the syndrome. Some studies have reported both
active lesions containing the pathogen (HIV-associated multinucleated giant cells, JCV,
Toxoplasma parasites, etc.), and “sterile” lesions with inflammatory infiltrates. The treatment
of CNS IRIS with corticosteroids has been advocated and remains controversial, as there are
no formal studies, but should be considered if increased intracranial pressure is present.
The continuing evolution of the HIV epidemic has spurred an intense interest into a hitherto
neglected area of medicine, neuroinfectious diseases and their consequences. This work has
broad applications for the study of CNS tumors, dementias, neuropathies, and CNS disease in
other immunosuppressed individuals.
Acknowledgments
NIH-PA Author Manuscript
This work was supported by Grants No. NS38841, U01MH083500, and R03DA026099, from the National Institutes
of Health
References
1. UNAIDS. Report on the global AIDS epidemic 2008. UNAIDS; Geneva: 2007.
2. Patrick MK, Johnston JB, Power C. Lentiviral neuropathogenesis: comparative neuroinvasion,
neurotropism, neurovirulence, and host neurosusceptibility. J Virol 2002;76:7923–7931. [PubMed:
12133996]
3. Wiley CA, Schrier RD, Nelson JA, et al. Cellular localization of human immunodeficiency virus
infection within the brains of acquired immune deficiency syndrome patients. Proceedings of the
National Academy of Sciences of the United States of America 1986;83:7089–7093. [PubMed:
3018755]
4. Kaul M, Lipton SA. Mechanisms of neuronal injury and death in HIV-1 associated dementia. Curr
HIV Res 2006;4:307–318. [PubMed: 16842083]
5. Letendre S, Marquie-Beck J, Capparelli E, et al. Validation of the CNS Penetration-Effectiveness rank
NIH-PA Author Manuscript
for quantifying antiretroviral penetration into the central nervous system. Arch Neurol 2008;65:65–
70. [PubMed: 18195140]
6. Clements JE, Li M, Gama L, et al. The central nervous system is a viral reservoir in simian
immunodeficiency virus--infected macaques on combined antiretroviral therapy: a model for human
immunodeficiency virus patients on highly active antiretroviral therapy. Journal of neurovirology
2005;11:180–189. [PubMed: 16036796]
7. Brew BJ, Crowe SM, Landay A, et al. Neurodegeneration and ageing in the HAART era. J
Neuroimmune Pharmacol 2009;4:163–174. [PubMed: 19067177]
8. Huang ST, Lee HC, Liu KH, et al. Acute human immunodeficiency virus infection. Journal of
microbiology, immunology, and infection = Wei mian yu gan ran za zhi 2005;38:65–68.
9. Fox R, Eldred LJ, Fuchs EJ, et al. Clinical manifestations of acute infection with human
immunodeficiency virus in a cohort of gay men. AIDS (London, England) 1987;1:35–38.
10. Resnick L, Berger JR, Shapshak P, et al. Early penetration of the blood-brain-barrier by HIV.
Neurology 1988;38:9–14. [PubMed: 3422110]
11. Tarasow E, Wiercinska-Drapalo A, Kubas B, et al. Cerebral MR spectroscopy in neurologically
asymptomatic HIV-infected patients. Acta Radiol 2003;44:206–212. [PubMed: 12694109]
12. Krasner CG, Cohen SH. Bilateral Bell’s palsy and aseptic meningitis in a patient with acute human
immunodeficiency virus seroconversion. West J Med 1993;159:604–605. [PubMed: 8279169]
NIH-PA Author Manuscript
13. Serrano P, Hernandez N, Arroyo JA, et al. Bilateral Bell palsy and acute HIV type 1 infection: report
of 2 cases and review. Clin Infect Dis 2007;44:e57–61. [PubMed: 17304442]
14. Hollander H, Stringari S. Human immunodeficiency virus-associated meningitis. Clinical course and
correlations. Am J Med 1987;83:813–816. [PubMed: 3674088]
15. Hollander H, Levy JA. Neurologic abnormalities and recovery of human immunodeficiency virus
from cerebrospinal fluid. Ann Intern Med 1987;106:692–695. [PubMed: 3646001]
16. Wendel KA, McArthur JC. Acute meningoencephalitis in chronic human immunodeficiency virus
(HIV) infection: putative central nervous system escape of HIV replication. Clin Infect Dis
2003;37:1107–1111. [PubMed: 14523776]
17. Worthington MG, Ross JJ. Aseptic meningitis and acute HIV syndrome after interruption of
antiretroviral therapy: implications for structured treatment interruptions. AIDS (London, England)
2003;17:2145–2146.
18. Antinori A, Arendt G, Becker JT, et al. Updated research nosology for HIV-associated neurocognitive
disorders. Neurology 2007;69:1789–1799. [PubMed: 17914061]
19. Woods SP, Moore DJ, Weber E, et al. Cognitive neuropsychology of HIV-associated neurocognitive
disorders. Neuropsychology review 2009;19:152–168. [PubMed: 19462243]
20. Reger M, Welsh R, Razani J, et al. A meta-analysis of the neuropsychological sequelae of HIV
infection. J Int Neuropsychol Soc 2002;8:410–424. [PubMed: 11939699]
NIH-PA Author Manuscript
21. Tross S, Price RW, Navia B, et al. Neuropsychological characterization of the AIDS dementia
complex: a preliminary report. AIDS (London, England) 1988;2:81–88.
22. Delis DC, Peavy G, Heaton R, et al. Do patients with HIV-associated minor cognitive/ motor disorder
exhibit a ‘subcortical’ memory profile? Evidence using the California verbal learning test.
Assessment 1995;2:151–165.
23. Pillon B, Deweer B, Michon A, et al. Are explicit memory disorders of progressive supranuclear
palsy related to damage to striatofrontal circuits? Comparison with Alzheimer’s, Parkinson’s, and
Huntington’s diseases. Neurology 1994;44:1264–1270. [PubMed: 8035927]
24. Navia BA, Cho ES, Petito CK, et al. The AIDS dementia complex: II. Neuropathology. Ann Neurol
1986;19:525–535. [PubMed: 3014994]
25. Tisch S, Brew B. Parkinsonism in hiv-infected patients on highly active antiretroviral therapy.
Neurology 2009;73:401–403. [PubMed: 19652146]
26. Castellon SA, Hinkin CH, Myers HF. Neuropsychiatric disturbance is associated with executive
dysfunction in HIV-1 infection. J Int Neuropsychol Soc 2000;6:336–347. [PubMed: 10824505]
27. Cole MA, Castellon SA, Perkins AC, et al. Relationship between psychiatric status and frontal-
subcortical systems in HIV-infected individuals. J Int Neuropsychol Soc 2007;13:549–554.
[PubMed: 17445305]
NIH-PA Author Manuscript
28. Mateos, JL Ayuso; Singh, AN.; Catalan, J. Drug treatment of HIV associated neuropsychiatric
syndromes. Neurologia (Barcelona, Spain) 2000;15:164–171.
29. Bing EG, Burnam MA, Longshore D, et al. Psychiatric disorders and drug use among human
immunodeficiency virus-infected adults in the United States. Archives of general psychiatry
2001;58:721–728. [PubMed: 11483137]
30. Lyketsos CG, Schwartz J, Fishman M, et al. AIDS mania. The Journal of neuropsychiatry and clinical
neurosciences 1997;9:277–279. [PubMed: 9144109]
31. Nakimuli-Mpungu E, Musisi S, Mpungu SK, et al. Primary mania versus HIV-related secondary
mania in Uganda. The American journal of psychiatry 2006;163:1349–1354. quiz 1480. [PubMed:
16877646]
32. Portegies P, Enting RH, de Gans J, et al. Presentation and course of AIDS dementia complex: 10
years of follow-up in Amsterdam, The Netherlands. AIDS (London, England) 1993;7:669–675.
33. McArthur JC, Hoover DR, Bacellar H, et al. Dementia in AIDS patients: incidence and risk factors.
Multicenter AIDS Cohort Study. Neurology 1993;43:2245–2252. [PubMed: 8232937]
34. Ellis RJ, Moore DJ, Childers ME, et al. Progression to neuropsychological impairment in human
immunodeficiency virus infection predicted by elevated cerebrospinal fluid levels of human
immunodeficiency virus RNA. Arch Neurol 2002;59:923–928. [PubMed: 12056927]
35. Stern Y, McDermott MP, Albert S, et al. Factors associated with incident human immunodeficiency
NIH-PA Author Manuscript
43. Cysique LA, Brew BJ, Halman M, et al. Undetectable cerebrospinal fluid HIV RNA and beta-2
microglobulin do not indicate inactive AIDS dementia complex in highly active antiretroviral
therapy-treated patients. Journal of acquired immune deficiency syndromes (1999) 2005;39:426–
429. [PubMed: 16010165]
44. Descamps M, Hyare H, Stebbing J, et al. Magnetic resonance imaging and spectroscopy of the brain
in HIV disease. Journal of HIV therapy 2008;13:55–58. [PubMed: 19039299]
45. Paul RH, Ernst T, Brickman AM, et al. Relative sensitivity of magnetic resonance spectroscopy and
quantitative magnetic resonance imaging to cognitive function among nondemented individuals
infected with HIV. J Int Neuropsychol Soc 2008;14:725–733. [PubMed: 18764968]
46. Paul RH, Brickman AM, Navia B, et al. Apathy is associated with volume of the nucleus accumbens
in patients infected with HIV. J Neuropsychiatry Clin Neurosci 2005;17:167–171. [PubMed:
15939969]
47. Chiang MC, Dutton RA, Hayashi KM, et al. 3D pattern of brain atrophy in HIV/AIDS visualized
using tensor-based morphometry. NeuroImage 2007;34:44–60. [PubMed: 17035049]
48. Lentz MR, Kim WK, Lee V, et al. Changes in MRS neuronal markers and T cell phenotypes observed
during early HIV infection. Neurology 2009;72:1465–1472. [PubMed: 19398702]
49. Paul RH, Yiannoutsos CT, Miller EN, et al. Proton MRS and neuropsychological correlates in AIDS
NIH-PA Author Manuscript
56. Brodt HR, Kamps BS, Gute P, et al. Changing incidence of AIDS-defining illnesses in the era of
antiretroviral combination therapy. AIDS (London, England) 1997;11:1731–1738.
57. Marra CM, Zhao Y, Clifford DB, et al. Impact of combination antiretroviral therapy on cerebrospinal
fluid HIV RNA and neurocognitive performance. AIDS (London, England) 2009;23:1359–1366.
58. Tozzi V, Balestra P, Salvatori MF, et al. Changes in cognition during antiretroviral therapy:
comparison of 2 different ranking systems to measure antiretroviral drug efficacy on HIV-associated
neurocognitive disorders. Journal of acquired immune deficiency syndromes (1999) 2009;52:56–63.
[PubMed: 19731418]
59. Uthman OA, Abdulmalik JO. Adjunctive therapies for AIDS dementia complex. Cochrane Database
Syst Rev 2008:CD006496. [PubMed: 18646159]
60. Breitbart W, Rosenfeld B, Kaim M, et al. A randomized, double-blind, placebo-controlled trial of
psychostimulants for the treatment of fatigue in ambulatory patients with human immunodeficiency
virus disease. Arch Intern Med 2001;161:411–420. [PubMed: 11176767]
61. Hinkin CH, Castellon SA, Hardy DJ, et al. Methylphenidate improves HIV-1-associated cognitive
slowing. J Neuropsychiatry Clin Neurosci 2001;13:248–254. [PubMed: 11449032]
62. Petito CK. Review of central nervous system pathology in human immunodeficiency virus infection.
Annals of neurology 1988;23(Suppl):S54–57. [PubMed: 3279904]
63. Dal Pan GJ, Glass JD, McArthur JC. Clinicopathologic correlations of HIV-1-associated vacuolar
NIH-PA Author Manuscript
70. Petito CK, Vecchio D, Chen YT. HIV antigen and DNA in AIDS spinal cords correlate with
macrophage infiltration but not with vacuolar myelopathy. J Neuropathol Exp Neurol 1994;53:86–
94. [PubMed: 8301324]
NIH-PA Author Manuscript
71. Rosenblum M, Scheck AC, Cronin K, et al. Dissociation of AIDS-related vacuolar myelopathy and
productive HIV-1 infection of the spinal cord. Neurology 1989;39:892–896. [PubMed: 2739916]
72. Eilbott DJ, Peress N, Burger H, et al. Human immunodeficiency virus type 1 in spinal cords of acquired
immunodeficiency syndrome patients with myelopathy: expression and replication in macrophages.
Proc Natl Acad Sci U S A 1989;86:3337–3341. [PubMed: 2717618]
73. Geraci A, Di Rocco A, Liu M, et al. AIDS myelopathy is not associated with elevated HIV viral load
in cerebrospinal fluid. Neurology 2000;55:440–442. [PubMed: 10932285]
74. Di Rocco A, Bottiglieri T, Werner P, et al. Abnormal cobalamin-dependent transmethylation in AIDS-
associated myelopathy. Neurology 2002;58:730–735. [PubMed: 11889235]
75. Tan SV, Guiloff RJ. Hypothesis on the pathogenesis of vacuolar myelopathy, dementia, and peripheral
neuropathy in AIDS. Journal of neurology, neurosurgery, and psychiatry 1998;65:23–28.
76. Tan SV, Guiloff RJ, Henderson DC, et al. AIDS-associated vacuolar myelopathy and tumor necrosis
factor-alpha (TNF alpha). Journal of the neurological sciences 1996;138:134–144. [PubMed:
8791251]
77. Di Rocco A, Werner P, Bottiglieri T, et al. Treatment of AIDS-associated myelopathy with L-
methionine: a placebo-controlled study. Neurology 2004;63:1270–1275. [PubMed: 15477550]
78. Bizaare M, Dawood H, Moodley A. Vacuolar myelopathy: a case report of functional, clinical, and
radiological improvement after highly active antiretroviral therapy. Int J Infect Dis 2008;12:442–
NIH-PA Author Manuscript
12491149]
87. Cornblath DR, McArthur JC. Predominantly sensory neuropathy in patients with AIDS and AIDS-
related complex. Neurology 1988;38:794–796. [PubMed: 2834669]
88. Kennedy JM, Hoke A, Zhu Y, et al. Peripheral neuropathy in lentivirus infection: evidence of
inflammation and axonal injury. AIDS (London, England) 2004;18:1241–1250.
89. Zhu Y, Antony J, Liu S, et al. CD8+ lymphocyte-mediated injury of dorsal root ganglion neurons
during lentivirus infection: CD154-dependent cell contact neurotoxicity. J Neurosci 2006;26:3396–
3403. [PubMed: 16571746]
90. Herzberg U, Sagen J. Peripheral nerve exposure to HIV viral envelope protein gp120 induces
neuropathic pain and spinal gliosis. Journal of neuroimmunology 2001;116:29–39. [PubMed:
11311327]
91. de la Monte SM, Gabuzda DH, Ho DD, et al. Peripheral neuropathy in the acquired immunodeficiency
syndrome. Annals of neurology 1988;23:485–492. [PubMed: 2839106]
92. Evans SR, Clifford DB, Kitch DW, et al. Simplification of the research diagnosis of HIV-associated
sensory neuropathy. HIV clinical trials 2008;9:434–439. [PubMed: 19203909]
93. McArthur JC, Yiannoutsos C, Simpson DM, et al. A phase II trial of nerve growth factor for sensory
NIH-PA Author Manuscript
neuropathy associated with HIV infection. AIDS Clinical Trials Group Team 291. Neurology
2000;54:1080–1088. [PubMed: 10720278]
94. Evans SR, Simpson DM, Kitch DW, et al. A randomized trial evaluating Prosaptide for HIV-
associated sensory neuropathies: use of an electronic diary to record neuropathic pain. PLoS One
2007;2:e551. [PubMed: 17653259]
95. Simpson DM, McArthur JC, Olney R, et al. Lamotrigine for HIV-associated painful sensory
neuropathies: a placebo-controlled trial. Neurology 2003;60:1508–1514. [PubMed: 12743240]
96. Simpson DM, Brown S, Tobias J. Controlled trial of high-concentration capsaicin patch for treatment
of painful HIV neuropathy. Neurology 2008;70:2305–2313. [PubMed: 18541884]
97. Abrams DI, Jay CA, Shade SB, et al. Cannabis in painful HIV-associated sensory neuropathy: a
randomized placebo-controlled trial. Neurology 2007;68:515–521. [PubMed: 17296917]
98. Ellis RJ, Toperoff W, Vaida F, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a
randomized, crossover clinical trial. Neuropsychopharmacology 2009;34:672–680. [PubMed:
18688212]
99. Hahn K, Arendt G, Braun JS, et al. A placebo-controlled trial of gabapentin for painful HIV-associated
sensory neuropathies. Journal of neurology 2004;251:1260–1266. [PubMed: 15503108]
100. Kieburtz K, Simpson D, Yiannoutsos C, et al. A randomized trial of amitriptyline and mexiletine
for painful neuropathy in HIV infection. AIDS Clinical Trial Group 242 Protocol Team. Neurology
NIH-PA Author Manuscript
107. Lee H, Hanes J, Johnson KA. Toxicity of nucleoside analogues used to treat AIDS and the selectivity
of the mitochondrial DNA polymerase. Biochemistry 2003;42:14711–14719. [PubMed: 14674745]
108. Peltier AC, Russell JW. Recent advances in drug-induced neuropathies. Current opinion in neurology
2002;15:633–638. [PubMed: 12352008]
109. Zhu Y, Antony JM, Martinez JA, et al. Didanosine causes sensory neuropathy in an HIV/AIDS
animal model: impaired mitochondrial and neurotrophic factor gene expression. Brain
2007;130:2011–2023. [PubMed: 17616550]
110. Canter JA, Haas DW, Kallianpur AR, et al. The mitochondrial pharmacogenomics of haplogroup
T: MTND2*LHON4917G and antiretroviral therapy-associated peripheral neuropathy. The
pharmacogenomics journal 2008;8:71–77. [PubMed: 17684475]
111. Berger AR, Arezzo JC, Schaumburg HH, et al. 2′,3′-dideoxycytidine (ddC) toxic neuropathy: a study
of 52 patients. Neurology 1993;43:358–362. [PubMed: 8382349]
112. Hagberg L, Malmvall BE, Svennerholm L, et al. Guillain-Barre syndrome as an early manifestation
of HIV central nervous system infection. Scandinavian journal of infectious diseases 1986;18:591–
592. [PubMed: 3468607]
113. de Castro G, Bastos PG, Martinez R, et al. Episodes of Guillain-Barre syndrome associated with the
acute phase of HIV-1 infection and with recurrence of viremia. Arquivos de neuro-psiquiatria
2006;64:606–608. [PubMed: 17119803]
NIH-PA Author Manuscript
114. Teo EC, Azwra A, Jones RL, et al. Guillain--Barre syndrome following immune reconstitution after
antiretroviral therapy for primary HIV infection. Journal of HIV therapy 2007;12:62–63. [PubMed:
17962793]
115. McLeod JG. Electrophysiological studies in the Guillain-Barre syndrome. Annals of neurology
1981;9(Suppl):20–27. [PubMed: 6261678]
116. Cornblath DR. Treatment of the neuromuscular complications of human immunodeficiency virus
infection. Annals of neurology 1988;23(Suppl):S88–91. [PubMed: 2831807]
117. Bani-Sadr F, Neuville S, Crassard I, et al. Acute Guillain-Barre syndrome during the chronic phase
of HIV infection and dramatic improvement under highly active antiretroviral therapy. AIDS
(London, England) 2002;16:1562.
118. Sloan DJ, Nicolson A, Miller AR, et al. Human immunodeficiency virus seroconversion presenting
with acute inflammatory demyelinating polyneuropathy: a case report. J Med Case Reports
2008;2:370. [PubMed: 19055816]
119. Gorshtein A, Levy Y. Intravenous immunoglobulin in therapy of peripheral neuropathy. Clinical
reviews in allergy & immunology 2005;29:271–279. [PubMed: 16391402]
120. Wulff EA, Wang AK, Simpson DM. HIV-associated peripheral neuropathy: epidemiology,
pathophysiology and treatment. Drugs 2000;59:1251–1260. [PubMed: 10882161]
121. Astrom KE, Mancall EL, Richardson EP Jr. Progressive multifocal leuko-encephalopathy; a hitherto
NIH-PA Author Manuscript
133. Hall CD, Dafni U, Simpson D, et al. Failure of cytarabine in progressive multifocal
leukoencephalopathy associated with human immunodeficiency virus infection. AIDS Clinical
Trials Group 243 Team. The New England journal of medicine 1998;338:1345–1351. [PubMed:
NIH-PA Author Manuscript
9571254]
134. Marra CM, Rajicic N, Barker DE, et al. A pilot study of cidofovir for progressive multifocal
leukoencephalopathy in AIDS. AIDS (London, England) 2002;16:1791–1797.
135. Clifford DB, Yiannoutsos C, Glicksman M, et al. HAART improves prognosis in HIV-associated
progressive multifocal leukoencephalopathy. Neurology 1999;52:623–625. [PubMed: 10025799]
136. Giudici B, Vaz B, Bossolasco S, et al. Highly active antiretroviral therapy and progressive multifocal
leukoencephalopathy: effects on cerebrospinal fluid markers of JC virus replication and immune
response. Clin Infect Dis 2000;30:95–99. [PubMed: 10619739]
137. Levine AJ, Hinkin CH, Ando K, et al. An exploratory study of long-term neurocognitive outcomes
following recovery from opportunistic brain infections in HIV+ adults. J Clin Exp Neuropsychol
2008:1–8.
138. Griffiths P. Cytomegalovirus infection of the central nervous system. Herpes 2004;11(Suppl 2):
95A–104A.
139. Staras SA, Dollard SC, Radford KW, et al. Seroprevalence of cytomegalovirus infection in the
United States, 1988-1994. Clin Infect Dis 2006;43:1143–1151. [PubMed: 17029132]
140. Embil JA, Pereira LH, MacNeil JP, et al. Levels of cytomegalovirus seropositivity in homosexual
and heterosexual men. Sex Transm Dis 1988;15:85–87. [PubMed: 2840745]
141. Skolnik PR, Kosloff BR, Hirsch MS. Bidirectional interactions between human immunodeficiency
NIH-PA Author Manuscript
149. van Den Pol AN, Mocarski E, Saederup N, et al. Cytomegalovirus cell tropism, replication, and
gene transfer in brain. J Neurosci 1999;19:10948–10965. [PubMed: 10594076]
150. Wiley CA, Schrier RD, Denaro FJ, et al. Localization of cytomegalovirus proteins and genome
during fulminant central nervous system infection in an AIDS patient. J Neuropathol Exp Neurol
1986;45:127–139. [PubMed: 3005516]
151. Chiou SH, Liu JH, Chen SS, et al. Apoptosis of human retina and retinal pigment cells induced by
human cytomegalovirus infection. Ophthalmic research 2002;34:77–82. [PubMed: 11914609]
152. Odeberg J, Wolmer N, Falci S, et al. Human cytomegalovirus inhibits neuronal differentiation and
induces apoptosis in human neural precursor cells. J Virol 2006;80:8929–8939. [PubMed:
16940505]
153. Morgello S, Cho ES, Nielsen S, et al. Cytomegalovirus encephalitis in patients with acquired
immunodeficiency syndrome: an autopsy study of 30 cases and a review of the literature. Hum
Pathol 1987;18:289–297. [PubMed: 3028930]
154. Jabs DA, Bolton SG, Dunn JP, et al. Discontinuing anticytomegalovirus therapy in patients with
immune reconstitution after combination antiretroviral therapy. Am J Ophthalmol 1998;126:817–
822. [PubMed: 9860006]
NIH-PA Author Manuscript
155. Kaplan JE, Benson C, Holmes KH, et al. Guidelines for prevention and treatment of opportunistic
infections in HIV-infected adults and adolescents: recommendations from CDC, the National
Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of
America. MMWR Recomm Rep 2009;58:1–207. quiz CE201-204.
156. Jarvis JN, Harrison TS. HIV-associated cryptococcal meningitis. Aids 2007;21:2119–2129.
[PubMed: 18090038]
157. Polacheck I, Platt Y, Aronovitch J. Catecholamines and virulence of Cryptococcus neoformans.
Infect Immun 1990;58:2919–2922. [PubMed: 2117574]
158. Moosa MY, Coovadia YM. Cryptococcal meningitis in Durban, South Africa: a comparison of
clinical features, laboratory findings, and outcome for human immunodeficiency virus (HIV)-
positive and HIV-negative patients. Clin Infect Dis 1997;24:131–134. [PubMed: 9114135]
159. Charlier C, Dromer F, Leveque C, et al. Cryptococcal neuroradiological lesions correlate with
severity during cryptococcal meningoencephalitis in HIV-positive patients in the HAART era.
PLoS One 2008;3:e1950. [PubMed: 18414656]
160. Lortholary O, Poizat G, Zeller V, et al. Long-term outcome of AIDS-associated cryptococcosis in
the era of combination antiretroviral therapy. Aids 2006;20:2183–2191. [PubMed: 17086058]
161. Larsen RA, Leal MA, Chan LS. Fluconazole compared with amphotericin B plus flucytosine for
cryptococcal meningitis in AIDS. A randomized trial. Ann Intern Med 1990;113:183–187.
NIH-PA Author Manuscript
[PubMed: 2197908]
162. Graybill JR, Sobel J, Saag M, et al. Diagnosis and management of increased intracranial pressure
in patients with AIDS and cryptococcal meningitis. The NIAID Mycoses Study Group and AIDS
Cooperative Treatment Groups. Clin Infect Dis 2000;30:47–54. [PubMed: 10619732]
163. Nascimento LV, Stollar F, Tavares LB, et al. Risk factors for toxoplasmic encephalitis in HIV-
infected patients: a case-control study in Brazil. Ann Trop Med Parasitol 2001;95:587–593.
[PubMed: 11672464]
164. Ho YC, Sun HY, Chen MY, et al. Clinical presentation and outcome of toxoplasmic encephalitis in
patients with human immunodeficiency virus type 1 infection. J Microbiol Immunol Infect
2008;41:386–392. [PubMed: 19122919]
165. Luft BJ, Remington JS. Toxoplasmic encephalitis in AIDS. Clin Infect Dis 1992;15:211–222.
[PubMed: 1520757]
166. Bousson V, Brunereau L, Meyohas M, et al. Brain imaging in AIDS. J Radiol 1999;80:99–107.
[PubMed: 10209706]
167. Bhagavati S, Choi J. Frequent hemorrhagic lesions in cerebral toxoplasmosis in AIDS patients. J
Neuroimaging 2009;19:169–173. [PubMed: 19705517]
168. Ruiz A, Ganz WI, Post MJ, et al. Use of thallium-201 brain SPECT to differentiate cerebral
lymphoma from toxoplasma encephalitis in AIDS patients. AJNR Am J Neuroradiol 1994;15:1885–
1894. [PubMed: 7863938]
NIH-PA Author Manuscript
169. Pierce MA, Johnson MD, Maciunas RJ, et al. Evaluating contrast-enhancing brain lesions in patients
with AIDS by using positron emission tomography. Ann Intern Med 1995;123:594–598. [PubMed:
7677300]
170. Miro JM, Lopez JC, Podzamczer D, et al. Discontinuation of primary and secondary Toxoplasma
gondii prophylaxis is safe in HIV-infected patients after immunological restoration with highly
active antiretroviral therapy: results of an open, randomized, multicenter clinical trial. Clin Infect
Dis 2006;43:79–89. [PubMed: 16758422]
171. MacMahon EM, Glass JD, Hayward SD, et al. Epstein-Barr virus in AIDS-related primary central
nervous system lymphoma. Lancet 1991;338:969–973. [PubMed: 1681341]
172. Birx DL, Redfield RR, Tosato G. Defective regulation of Epstein-Barr virus infection in patients
with acquired immunodeficiency syndrome (AIDS) or AIDS-related disorders. N Engl J Med
1986;314:874–879. [PubMed: 3005862]
173. Petito CK, Cho ES, Lemann W, et al. Neuropathology of acquired immunodeficiency syndrome
(AIDS): an autopsy review. J Neuropathol Exp Neurol 1986;45:635–646. [PubMed: 3021914]
174. Levy RM, Bredesen DE, Rosenblum ML. Neurological manifestations of the acquired
immunodeficiency syndrome (AIDS): experience at UCSF and review of the literature. J Neurosurg
1985;62:475–495. [PubMed: 2983051]
NIH-PA Author Manuscript
175. Wolf T, Brodt HR, Fichtlscherer S, et al. Changing incidence and prognostic factors of survival in
AIDS-related non-Hodgkin’s lymphoma in the era of highly active antiretroviral therapy (HAART).
Leuk Lymphoma 2005;46:207–215. [PubMed: 15621803]
176. Skiest DJ, Crosby C. Survival is prolonged by highly active antiretroviral therapy in AIDS patients
with primary central nervous system lymphoma. Aids 2003;17:1787–1793. [PubMed: 12891064]
177. Bossolasco S, Cinque P, Ponzoni M, et al. Epstein-Barr virus DNA load in cerebrospinal fluid and
plasma of patients with AIDS-related lymphoma. J Neurovirol 2002;8:432–438. [PubMed:
12402169]
178. Fan H, Kim SC, Chima CO, et al. Epstein-Barr viral load as a marker of lymphoma in AIDS patients.
J Med Virol 2005;75:59–69. [PubMed: 15543571]
179. Gerstner E, Batchelor T. Primary CNS lymphoma. Expert Rev Anticancer Ther 2007;7:689–700.
[PubMed: 17492932]
180. Bossolasco S, Falk KI, Ponzoni M, et al. Ganciclovir is associated with low or undetectable Epstein-
Barr virus DNA load in cerebrospinal fluid of patients with HIV-related primary central nervous
system lymphoma. Clin Infect Dis 2006;42:e21–25. [PubMed: 16421782]
181. Correa DD, DeAngelis LM, Shi W, et al. Cognitive functions in survivors of primary central nervous
system lymphoma. Neurology 2004;62:548–555. [PubMed: 14981169]
182. Harder H, Holtel H, Bromberg JE, et al. Cognitive status and quality of life after treatment for primary
NIH-PA Author Manuscript
Figure 1.
Marked gliosis of the white matter is a common finding in HIV+ patients at autopsy and may
underlie changes seen premortem by magnetic resonance spectroscopy (MRS).
Immunoperoxidase stain (brown) for the astrocytic marker, glial fibrillary acidic protein
(GFAP).
NIH-PA Author Manuscript
Figure 2.
This coronal section through the formalin-fixed brain of an HIV+ person who succumbed to
progressive multifocal leukoencephalopathy (PML) shows the characteristic multifocal areas
of white matter discoloration.
NIH-PA Author Manuscript
Figure 3.
Cytomegalovirus (CMV) infection of cells may result in the morphological changes shown
here ie, cytomegaly and both intranuclear and intracytoplasmic viral inclusions.
Immunohistochemistry for CMV (not shown) may detect additional infected cells that appear
normal. Hematoxylin and Eosin stain.
NIH-PA Author Manuscript
Sikkema KJ, Watt MH, Drabkin AS, et. al. (2010) Mental health treatment to reduce HIV transmission risk
behavior: A positive prevention model, AIDS Behav. 14, 252–262.
Background article: Cournos F, McKinnon K, Wainberg M. (2011) Global Initiatives for HIV/AIDS and
Programs Promoting Global Access to Mental Health Care: Putting Mental Health into Public Health, in
Mental Health in Public Health, Cottler LB, (ed), Oxford University Press, pp57-76.
1. Which of the following HIV medication regiment is FDA approved for prevention?
a. PrEP
b. PEP
c. AMFAR
d. ZDV
3. Among HIV infected people, chronic depression has been associated with
4. When an HIV positive patient presents with a sudden change in mental status, the first
step is to
5. There is higher mortality risk for HIV-infected patients who were diagnosed with
Substance Use (SU) dependence or abuse in comparison with HIV-infected patients
without an SU diagnosis. Which of the following statements best describe the found
elevated risk:
1) In all subcategories of SU dependence/abuse diagnosis, i.e., alcohol use only, illicit
drug use only, and combined alcohol and illicit drug use
2) Hepatitis B and C are the sole reason for the increased mortality
3) The effect remains even after adjustment for confounders such as age, race, immune
status, HIV viral load, history of ARV therapy use, hepatitis B or hepatitis C viral
infection.
4) SU treatment completely reverts the effect
6. Manualized and brief interventions have been developed to treat SU disorders. About
these:
1) Multiple randomized clinical trials have demonstrated their efficacy in HIV treatment
clinics
2) Few randomized clinical trials have demonstrated their efficacy in HIV treatment
clinics.
3) The burden of these interventions makes it unfeasible to incorporate them within HIV
treatment clinics and thus should only be referred to specialized SU clinics.
4) Abstinence only programs are the only treatment that have shown efficacy to treat
alcohol abuse.
8. A 46-year-old gay male was diagnosed as HIV positive in 1997 receiving HAART. Current
CD4+ cell count is 120 cells/mm3 (nadir: 35 cells/mm3) and his HIV-1 RNA level is 40,000
copies/mL (highest value: 385,000 copies/mL). After being recently diagnosed with
virologic failure, he decides to go on a drug holiday. Progressively worse, the patient
agrees to resume antiretroviral therapy. After re-staging, a combination of fixed-dose
tenofovir/emtricitabine, abacavir, and efavirenz is initiated. Within 1 hour of taking his
first dose of these medications, the patient noted a sensation of “rushing in the ears”
and on the same night experienced unusual vivid dreams. By Day 3, he noted tremors
involving his head and hands, generalized anxiety, feelings of depression, and dizziness
worsening with exertion. He also develops difficulty falling and staying asleep. What is
the most likely cause of the CNS symptoms described by the patient?
a. HIV-Associated Dementia
b. Immune Reconstitution Syndrome
c. Efavirenz related side-effects
d. HIV-related delirium
10. Which of the following is/ are troubling for providers in caring for patients with HIV?
01. A
02. B
03. E
04. C
05. C
06. B
07. E
08. C
09. C
10. D