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HIV Encephalopathy
HIV
ENCEPHALOPATHY
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Learning Objectives
Introduction
Neurocognitive
impairment in HIV
HIV
Meningoencephalitis
Pathophysiology
Clinical Features
HIV dementia scale
Examination
Differential Diagnosis
Investigation
HIV in the CSF
CNS penetration of
antiretrovirals
Key Points
Session Summary
References and
further reading
Self Assessment
Sam Nightingale and Alan Winston
Sam Nightingale is a neurology registrar and MRC clinical research
fellow. He runs the UK wide multi-centre PARTITION
study
looking at factors effecting the CNS penetration of antiretrovivals
and the role of the CNS as a sanctuary site for HIV.
Alan Winston is a Consultant Physician in HIV Medicine and Clinical
Senior Lecturer at St. Mary’s Hospital, London and Imperial College,
London. Dr Winston has an MD in antiretroviral pharmokinetics and
is the lead clinician for HIV clinical trials at St.Mary’s Hospital. He
runs research programs assessing the effects of antiretroviral
therapy on the CNS.
This session provides an overview of
neurocognitive disorders associated with
HIV infection.
Learning Objectives
HIV
ENCEPHALOPATHY
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Learning Objectives
Introduction
Neurocognitive
impairment in HIV
HIV
Meningoencephalitis
Pathophysiology
Clinical Features
HIV dementia scale
Examination
Differential Diagnosis
Investigation
HIV in the CSF
CNS penetration of
antiretrovirals
Key Points
Session Summary
References and
further reading
Self Assessment
By the end of this session you will be able to:
•Describe the changing spectrum of neurocognitive disease in the
post-antiretroviral era and define associated terms
•Define the symptoms and signs of HIV encephalopathy and the
features of a subcortical vs. cortical dementia
•Interpret the imaging and laboratory parameters used in the
investigation of HIV encephalopathy and use the international HIV
dementia scale to detect and quantify cognitive impairment in HIV
•List the differential diagnosis of cognitive impairment in HIV and
recognise the clinical features that suggest an alternative
diagnosis
•Demonstrate a familiarity with differing CNS exposure of different
antiretroviral medications and the relevance of HIV in the CNS
Introduction
HIV
ENCEPHALOPATHY
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Learning Objectives
Introduction
Neurocognitive
impairment in HIV
HIV
Meningoencephalitis
Pathophysiology
Clinical Features
HIV dementia scale
Examination
Differential Diagnosis
Investigation
HIV in the CSF
CNS penetration of
antiretrovirals
Key Points
Session Summary
References and
further reading
Self Assessment
This session explores cerebral impairment related to chronic
HIV infection. First it examines the changing spectrum of
neurocognitive disease in the post-antiretroviral era, then the
pathophysiology of CNS damage due to HIV infection is
explored.
The clinical features of HIV encephalopathy are explained and
assessment discussed, including the use of the HIV Dementia
Scale. The differential diagnosis of cognitive impairment in HIV
is provided, and relevant investigations discussed.
The differing CNS exposures of antiretroviral drugs and the
relevance of HIV in the CSF are discussed
Scanning electron micrograph of HIV-1
budding (in green) from
cultured
lymphocyte.
Neurocognitive Impairment in HIV I
HIV
ENCEPHALOPATHY
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Learning Objectives
Introduction
Neurocognitive
impairment in HIV
HIV
Meningoencephalitis
Pathophysiology
Clinical Features
HIV dementia scale
Examination
Differential Diagnosis
Investigation
HIV in the CSF
CNS penetration of
antiretrovirals
Key Points
Session Summary
References and
further reading
Self Assessment
Neurocognitive complications of HIV are frequently observed.
Prior to the advent of antiretroviral therapy (ART), dementia was
a common source of morbidity and mortality, usually observed in
the late stages of AIDS, and was seen in up to 50% of patients
prior to their death.
Since effective ART has been available, the incidence of HIV
encephalopathy has dramatically decreased, however, more
subtle neurocognitive impairment remains prevalent.
Cognitive impairment may become apparent in the early stages
of HIV infection, at high CD4+ cell counts, and may be seen in
patients with a well suppressed plasma viral load.
HIV encephalopathy. Diffuse sub cortical
white matter changes on T2-weighted MR
FLAIR scan. (Photo Tom Solomon).
Neurocognitive Impairment in HIV II
Milder Forms of Cognitive Impairment
HIV
ENCEPHALOPATHY
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Learning Objectives
Introduction
Neurocognitive
impairment in HIV
HIV
Meningoencephalitis
Pathophysiology
Clinical Features
HIV dementia scale
Examination
Differential Diagnosis
Investigation
HIV in the CSF
CNS penetration of
antiretrovirals
Key Points
Session Summary
References and
further reading
Self Assessment
These milder forms of cognitive impairment may be very
common. US and European cohort studies have suggested
neurocognitive impairment may be present in 25-50% of HIVinfected subjects, even those on stable antiretroviral therapy,
although this may relate to a number of factors including
hepatitis C co-infection, cardiovascular disease, drug use and
depression.
Although mild, these subtle impairments represent a significant
clinical problem as they have been shown to affect basic daily
activities such as driving, shopping, medication adherence and
financial management, as well as being associated with
unemployment and a poorer quality of life. As such, cognitive
impairment in HIV remains an area of concern in the HAART
era. In particular it is not clear how the brain will age in the
presence of chronic, treated HIV infection.
Neurocognitive Impairment in HIV III
HIV
ENCEPHALOPATHY
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Learning Objectives
Introduction
Neurocognitive
impairment in HIV
HIV
Meningoencephalitis
Pathophysiology
Clinical Features
HIV dementia scale
Examination
Differential Diagnosis
Investigation
HIV in the CSF
CNS penetration of
antiretrovirals
Key Points
Session Summary
References and
further reading
Self Assessment
Terms to Define Impairment
Prior to ART several terms were used to describe impairment in
cerebral function secondary to chronic HIV infection:
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HIV dementia
AIDS dementia complex
HIV associated cognitive motor complex
AIDS related dementia
All these terms are synonymous with HIV encephalopathy, or
HIVE. This describes a syndrome of marked cognitive
impairment that occurs in advanced disease, usually at CD4
counts less than 200 cells/ml and is an AIDS defining illness
HIV encephalopathy. Diffuse sub-cortical
white matter changes in T2-weighted MRI.
(Photo Ian Turnball)
Neurocognitive Impairment in HIV IV
HIV
ENCEPHALOPATHY
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Learning Objectives
Introduction
Neurocognitive
impairment in HIV
HIV
Meningoencephalitis
Pathophysiology
Clinical Features
HIV dementia scale
Examination
Differential Diagnosis
Investigation
HIV in the CSF
CNS penetration of
antiretrovirals
Key Points
Session Summary
References and
further reading
Self Assessment
Different terms are used to describe HIV associated cognitive
impairment in the post-ART era. These are divided into 'mild
neurocognitive disorder ' (MND) and 'HIV encephalopathy'
(HIVE) depending on the degree of symptoms patients
encounter.
MND: Impairment of least 1 standard deviation from matched controls
in at least 2 cognitive domains. The impairment produces at least mild
interference in daily functioning.
HIVE: Marked cognitive impairment, often with motor or behavioural
abnormalities, causing significant interference in daily functioning.
Usually occurs in advanced immunosupression at CD4 counts less
than 200 cells/ml. Is an AIDS defining illness.
In this country, MND is the more frequent presentation and HIVE
is rarely observed with effective ART. However, HIVE remains
prevalent in countries where effective ART is not generally
available. In this country HIVE may be the first presentation of
untreated HIV, or occur in poorly adherent patients or those with
ART resistance.
Neurocognitive Impairment in HIV V
HIV
ENCEPHALOPATHY
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Learning Objectives
Introduction
Neurocognitive
impairment in HIV
HIV
Meningoencephalitis
Pathophysiology
Clinical Features
HIV dementia scale
Examination
Differential Diagnosis
Investigation
HIV in the CSF
CNS penetration of
antiretrovirals
Key Points
Session Summary
References and
further reading
Self Assessment
Within research studies, investigators often also classify a group
of subjects to have 'asymptomatic neurocognitive impairment'
(ANI). Such subjects sub-perform on neurocognitive testing
however do not have any interference with daily life. The clinical
consequence of asymptomatic impairment remains to be
defined.
ANI: Cognitive impairment as defined in MND above, however the
impairment does not interfere with everyday functioning. Currently a
research definition as the clinical significance is uncertain.
Any significant impairment in neurocognitive function is
described under the umbrella term, 'HIV associated
neurocognitive disorders' or 'HAND‘.
HAND: Any significant impairment in neurocognitive function; defined
as at least 1 standard deviation from matched controls in at least 2
cognitive domains.
HAND is an umbrella term which describes the spectrum of
neurocognitive impairment HIVE, MND and ACI.
HIV Meningoencephalitis I
HIV
Neurological presentations occur in 17-24% of patients at HIV
seroconversion.
ENCEPHALOPATHY
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Learning Objectives
Introduction
Neurocognitive
impairment in HIV
HIV
Meningoencephalitis
Pathophysiology
Clinical Features
HIV dementia scale
Examination
Differential Diagnosis
Investigation
HIV in the CSF
CNS penetration of
antiretrovirals
Key Points
Session Summary
References and
further reading
Self Assessment
Most commonly, aseptic meningitis occurs alone, without
involvement of the brain parenchyma, causing headache, neck
stiffness and photophobia. HIV meningitis is self-limiting and
does not require treatment.
Rarely, the brain parenchyma may be involved resulting in
encephalitis. Drowsiness, confusion and/or seizures develop
over hours or days, with or without features of meningism.
Although sometimes self-limiting, this can progress to
uncontrolled
seizures,
coma
and
death.
HIV
meningoencephalitis may respond to antiretrovirals and most
make a good functional recovery.
Diffusion-weighted MRI of the brain. The cortex of
the brain is diffusely hyperintense, a reflection of
the severe disturbance of the diffusion of the
protons in the cells, due to the cytotoxic oedema.
Newton PJ et al. BMJ Nov 2002
HIV Meningoencephalitis II
HIV
ENCEPHALOPATHY
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Learning Objectives
Introduction
Neurocognitive
impairment in HIV
HIV
Meningoencephalitis
Pathophysiology
Clinical Features
HIV dementia scale
Examination
Differential Diagnosis
Investigation
HIV in the CSF
CNS penetration of
antiretrovirals
Key Points
Session Summary
References and
further reading
Self Assessment
HIV meningoencephalitis has a very different presentation,
pathophysiology and prognosis to HIVE. It occurs soon after
infection rather than being a consequence of longstanding HIV
infection and is not a feature of AIDS. As such it is a very
different entity from the HIV-associated neurocognitive disorders
described in this chapter. However both diseases are sometimes
described in the literature by the same terms; 'HIV-encephalitis'
or 'HIV-encephalopathy' which can cause confusion.
In this session the term 'HIV encephalopathy (HIVE)' is used to
describe the syndrome of neurocognitive impairment as a result
of longstanding HIV infection rather than the inflammatory
meningoencephalitis of seroconversion.
Pathophysiology
HIV
ENCEPHALOPATHY
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Learning Objectives
Introduction
Neurocognitive
impairment in HIV
HIV
Meningoencephalitis
Pathophysiology
Clinical Features
HIV dementia scale
Examination
Differential Diagnosis
Investigation
HIV in the CSF
CNS penetration of
antiretrovirals
Key Points
Session Summary
References and
further reading
Self Assessment
The pathogenesis of HIV-related CNS disease is incompletely
understood. HIV enters the brain early via infected macrophages
and monocytes.
Pathologically, activated macrophages and astrocytes,
sometimes with multinucleated giant cells, are seen in brain
parenchyma.
Infection persists within the CNS in perivascular macrophages
and microglia, although direct neuronal infection is rare. Proinflammatory cytokines and toxic viral products cause blood–
brain barrier breakdown, rarefaction of white matter, astrocyte
apoptosis, dendritic simplification, and neuronal loss
This is a high power microscopic
view of a section of brain from a
child with HIV encephalitis. A
multinucleate giant cell is arrowed.
Clinical Features I
HIV
ENCEPHALOPATHY
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Learning Objectives
Introduction
Neurocognitive
impairment in HIV
HIV
Meningoencephalitis
Pathophysiology
Clinical Features
HIV dementia scale
Examination
Differential Diagnosis
Investigation
HIV in the CSF
CNS penetration of
antiretrovirals
Key Points
Session Summary
References and
further reading
Self Assessment
These pathological processes tend to affect the deep white
matter and so HIVE is a mainly subcortical dementia (similar to
Lewy body or vascular dementia), resulting in a combination of
cognitive and motor impairment.
Features may include bradykinesia, pyramidal signs and
emotional blunting. Motor features may not be present in those
with more subtle impairment (MND).
Early symptoms are sometimes noted by friends and relatives
rather than the patient themselves so it is important to obtain a
collateral history.
HIV encephalopathy. Diffuse subcortical white matter changes on
T2-weighted MRI. (Photo Ian
Turnball)
Clinical Features II
HIV
ENCEPHALOPATHY
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Learning Objectives
Introduction
Neurocognitive
impairment in HIV
HIV
Meningoencephalitis
Pathophysiology
Clinical Features
HIV dementia scale
Examination
Differential Diagnosis
Investigation
HIV in the CSF
CNS penetration of
antiretrovirals
Key Points
Session Summary
References and
further reading
Self Assessment
The subclinical phase can be shown on neuropsychological
testing. Early symptoms include forgetfulness and inability to
concentrate, as well as personality changes such as apathy,
diminished libido, emotional lability and depression. Individuals
may withdraw from social activities or have difficulty managing
the financial and administrative aspects of their life.
In moderate disease motor abnormalities become more
prominent, particularly slowing and impairment of fine
movements (e.g. typing, buttoning up). Disturbance of gait, leg
weakness, tremor and ataxia may occur.
Late features include psychiatric disturbances, mutism,
paraplegia, seizures, incontinence, myoclonus and frontal
release signs.
Clinical Features III
HIV
ENCEPHALOPATHY
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Learning Objectives
Introduction
Neurocognitive
impairment in HIV
HIV
Meningoencephalitis
Pathophysiology
Clinical Features
HIV dementia scale
Examination
Differential Diagnosis
Investigation
HIV in the CSF
CNS penetration of
antiretrovirals
Key Points
Session Summary
References and
further reading
Self Assessment
Clinical Features Suggesting Alternative Pathology
Rapid onset: Symptoms develop slowly over the course of weeks and
months. Rapidly developing symptoms should warrant investigation for
another aetiology.
Psychotic symptoms: Psychotic symptoms are very rare, even in
advanced disease.
Impairment of consciousness: Impairment of consciousness is not a
feature of HAND.
Headache/neck stiffness: Meningism is not a feature
of HAND.
Focal of lateralising neurological signs: Focal or
lateralising neurological signs such as hemiplegia
or aphasia suggest an alternative focal pathology
(eg toxoplasmosis, image on right).
(Image courtesy Dr Ian Turnball)
Seizures: Focal and generalized epileptic seizures are rare in isolated
HAND.
HIV Dementia Scale I
HIV
ENCEPHALOPATHY
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Learning Objectives
Introduction
Neurocognitive
impairment in HIV
HIV
Meningoencephalitis
Pathophysiology
Clinical Features
HIV dementia scale
Examination
Differential Diagnosis
Investigation
HIV in the CSF
CNS penetration of
antiretrovirals
Key Points
Session Summary
References and
further reading
Self Assessment
The international HIV dementia scale is an easy-to-use bedside
instrument for the detection and quantification of cognitive
impairment in HIV and has the advantage of being validated in
both Caucasian and African populations.
4 neurocognitive domains are assessed:
1. Registration
2. Recall
3. Motor speed
4. Psychomotor speed
A score of 10 or less out of a possible 12 is suggestive of HAND
and would warrant further assessment.
HIV Dementia Scale II
HIV
ENCEPHALOPATHY
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Learning Objectives
Introduction
Neurocognitive
impairment in HIV
HIV
Meningoencephalitis
Pathophysiology
Clinical Features
HIV dementia scale
Examination
Differential Diagnosis
Investigation
HIV in the CSF
CNS penetration of
antiretrovirals
Key Points
Session Summary
References and
further reading
Self Assessment
Examination
HIV
ENCEPHALOPATHY
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Learning Objectives
Introduction
Neurocognitive
impairment in HIV
HIV
Meningoencephalitis
Pathophysiology
Clinical Features
HIV dementia scale
Examination
Differential Diagnosis
Investigation
HIV in the CSF
CNS penetration of
antiretrovirals
Key Points
Session Summary
References and
further reading
Self Assessment
In HIVE, neurological examination can reveal impaired gait,
slowing of rapidly alternating movements, hypomimia and
occasionally tremor and short stepped gait.
There may be slowing of saccadic eye movements and frontal
release signs. Pyramidal signs may be present however
coexisting peripheral neuropathy is common in HIV which may
confuse the clinical picture.
Spastic tetraplegia and double incontinence may occur in the
terminal stages, however, marked generalised weakness and
spasticity occurring before cognitive impairment is advanced is
unusual and should prompt investigation for other causes such
as myelopathy.
Differential Diagnosis I
HIV
ENCEPHALOPATHY
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Learning Objectives
Introduction
Neurocognitive
impairment in HIV
HIV
Meningoencephalitis
Pathophysiology
Clinical Features
HIV dementia scale
Examination
Differential Diagnosis
Investigation
HIV in the CSF
CNS penetration of
antiretrovirals
Key Points
Session Summary
References and
further reading
Self Assessment
Important differentials include opportunistic CNS infections.
HAND is a diagnosis of exclusion. No laboratory test result on its
own establishes the diagnosis and tests are mainly employed to
exclude other diagnoses.
Space occupying lesion
Focal neurological signs may suggest a space occupying lesion such as
toxoplasmosis or CNS lymphoma
Localised white matter lesions
White matter lesions without mass effect suggests progressive multifocal
leucoencephalopathy (PML).
Cryptococcal meningitis
Headache with or without meningism may suggest cryptococcal
meningitis and should prompt lumbar puncture.
TB meningitis
HAND typically develops over months to years. Infective differentials are
acute or subacute. Tuberculous meningitis usually presents over days to
weeks and is accompanied by fever and meningism.
Differential Diagnosis II
HIV
ENCEPHALOPATHY
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Learning Objectives
Introduction
Neurocognitive
impairment in HIV
HIV
Meningoencephalitis
Pathophysiology
Clinical Features
HIV dementia scale
Examination
Differential Diagnosis
Investigation
HIV in the CSF
CNS penetration of
antiretrovirals
Key Points
Session Summary
References and
further reading
Self Assessment
Tuberculous meningitis. MRI with gadolinium enhancement
showing (a) basal meningeal enhancement (arrow) (b) two
small ring enhancing lesions in the right parietal cortex,
diffuse meningeal enhancement, and hydrocephalus.
(Image courtesy of Tom Solomon).
Differential Diagnosis III
HIV
ENCEPHALOPATHY
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Learning Objectives
Introduction
Neurocognitive
impairment in HIV
HIV
Meningoencephalitis
Pathophysiology
Clinical Features
HIV dementia scale
Examination
Differential Diagnosis
Investigation
HIV in the CSF
CNS penetration of
antiretrovirals
Key Points
Session Summary
References and
further reading
Self Assessment
Antibody testing and CSF analysis should be performed for
neurosyphilis, noting that serological findings may be atypical in
active neurosyphilis.
Acute and chronic hepatitis C virus (HCV) infection can also
cause a cerebral impairment, even in subjects with normal
hepatic synthetic function. HCV status should be assessed
when assessing subjects with HIV related brain disease.
Cutaneous secondary syphilis. Rash may involve palms.
Differential Diagnosis IV
HIV
ENCEPHALOPATHY
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Learning Objectives
Introduction
Neurocognitive
impairment in HIV
HIV
Meningoencephalitis
Pathophysiology
Clinical Features
HIV dementia scale
Examination
Differential Diagnosis
Investigation
HIV in the CSF
CNS penetration of
antiretrovirals
Key Points
Session Summary
References and
further reading
Self Assessment
Encephalitis
CMV encephalitis is uncommon and usually occurs alongside
involvement of other organs, e.g. retinitis, colitis, pneumonitis
and esophagitis. It can be tested by PCR for CMV in CSF and
blood/CSF IgG antibody.
VZV encephalitis generally causes marked inflammatory and
haemorrhagic changes on imaging and in the CSF. There are
often antecedent or accompanying cutaneous zoster lesions. It
can be tested by VZV PCR in CSF and VZV IgG in blood and
CSF (IgM may be absent).
Hepatitis C virus can infect the CNS and contribute to cognitive
impairment although it does not cause an acute encephalitic
illness.
CMV retinitis in a HIV positive
individual
Differential Diagnosis V
HIV
ENCEPHALOPATHY
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Learning Objectives
Introduction
Neurocognitive
impairment in HIV
HIV
Meningoencephalitis
Pathophysiology
Clinical Features
HIV dementia scale
Examination
Differential Diagnosis
Investigation
HIV in the CSF
CNS penetration of
antiretrovirals
Key Points
Session Summary
References and
further reading
Self Assessment
Metabolic and Endocrine Problems
Metabolic and endocrine problems are common in HIV. The
following should be routinely checked:
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Electrolytes
Renal function
Hepatic function
Blood count
B12/folate levels
Thyroid function
Both antiretroviral medications and HIV infection itself can cause
endothelial dysfunction and accelerated atherosclerosis. As
such, stroke and vascular dementia are more common in HIV.
Subcortical arteriosclerotic encephalopathy can mimic HAND.
Depression is very common in HIV and must be distinguished
from cognitive impairment. Mood should always be assessed in
any HIV positive individual presenting with cognitive symptoms
to exclude pseudo-dementia. Substance misuse should also be
excluded.
Investigations I
HIV
ENCEPHALOPATHY
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Learning Objectives
Introduction
Neurocognitive
impairment in HIV
HIV
Meningoencephalitis
Pathophysiology
Clinical Features
HIV dementia scale
Examination
Differential Diagnosis
Investigation
HIV in the CSF
CNS penetration of
antiretrovirals
Key Points
Session Summary
References and
further reading
Self Assessment
Neuroimaging
In HIVE (and to a lesser degree in MND) MRI may show large
confluent periventricular lesions, hyperintense and relatively
symmetrical in the white matter with atrophy representing
leukoencephalopathy. However, none of these findings are
specific for HIVE and the disease may be present with a normal
MRI.
Although there may be some faint symmetrical contrast
enhancement in the basal ganglia, oedema, space occupying
lesions and frank asymmetry of the white matter are not typical
for HIVE and should raise suspicion of other conditions.
More advanced imaging techniques like MR spectroscopy,
diffusion tensor imaging and magentization transfer imaging are
promising, but so far have no place in routine clinical practice.
Investigations II
HIV
ENCEPHALOPATHY
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Learning Objectives
Introduction
Neurocognitive
impairment in HIV
HIV
Meningoencephalitis
Pathophysiology
Clinical Features
HIV dementia scale
Examination
Differential Diagnosis
Investigation
HIV in the CSF
CNS penetration of
antiretrovirals
Key Points
Session Summary
References and
further reading
Self Assessment
HIV encephalopathy. Diffuse sub-cortical white matter
changes on T2-weighted MR FLAIR scan. (Photo Tom
Soloman).
Investigations III
HIV
ENCEPHALOPATHY
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Learning Objectives
Introduction
Neurocognitive
impairment in HIV
HIV
Meningoencephalitis
Pathophysiology
Clinical Features
HIV dementia scale
Examination
Differential Diagnosis
Investigation
HIV in the CSF
CNS penetration of
antiretrovirals
Key Points
Session Summary
References and
further reading
Self Assessment
Lumbar Puncture and EEG
CSF analysis is normal or shows a mild pleocytosis, not usually
exceeding 50 x106/l. Total protein and albumin concentrations
may be slightly elevated due to blood-brain-barrier disruption.
Oligoclonal bands are often present, matched or unmatched in
the serum; however, this is nonspecific and frequently found in
the asymptomatic stages of HIV infection unrelated to cognitive
impairment.
Although the EEG may show severe slowing or focal arrhythmic
delta activity in HIVE, the EEG is often normal or just shows mild
generalised slowing in the lesser forms of cognitive impairment.
HIV in the CSF
HIV
ENCEPHALOPATHY
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Learning Objectives
Introduction
Neurocognitive
impairment in HIV
HIV
Meningoencephalitis
Pathophysiology
Clinical Features
HIV dementia scale
Examination
Differential Diagnosis
Investigation
HIV in the CSF
CNS penetration of
antiretrovirals
Key Points
Session Summary
References and
further reading
Self Assessment
HIV can sometimes be demonstrated in the CSF of individuals
despite antiretroviral therapy. In some cases, HIV is present in
the CSF despite undetectable levels in the plasma. A statistically
significant association between higher CSF viral load with HAND
has been reported.
In subjects with symptoms of HIV associated brain disease, this
may be of importance. However, cognitive impairment can
develop in the absence of detectable levels of HIV in the CSF. In
addition, HIV may be present in the CSF in the absence of
cognitive impairment.
Individuals may have different HIV quasispecies within the CNS
and the plasma, suggesting that the CNS virus is partially
independent from the hematolymphatic compartment and can
evolve separately.
CNS Penetration of Antiretrovirals I
HIV
ENCEPHALOPATHY
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Learning Objectives
Introduction
Neurocognitive
impairment in HIV
HIV
Meningoencephalitis
Pathophysiology
Clinical Features
HIV dementia scale
Examination
Differential Diagnosis
Investigation
HIV in the CSF
CNS penetration of
antiretrovirals
Key Points
Session Summary
References and
further reading
Self Assessment
CSF drug levels are often several orders of magnitude lower
than plasma and more than half have mean CSF levels below
the estimated minimum inhibitory concentration (MIC) even
allowing for protein binding.
Studies have attempted to determine a hierarchy of CNS
penetration between different antiretrovirals agents. The CNS
Penetration Effectiveness (CPE) scale is based on drug
chemical properties, CSF concentration, and effectiveness in
clinical studies. However to date, no conclusive evidence have
suggested that antiretroviral drug combinations with higher
composite CPE scores have any benefit on neurocognitive
function.
There is also concern that highly penetrating antiretrovirals may
be neurotoxic in some cases. In particular, neuropsychological
side effects are common with efavirenz (Sustiva) including bad
dreams, dizziness, depression and anxiety. These are rarely
severe and usually resolve within 4 weeks if the medication is
continued.
Prognosis
HIV
ENCEPHALOPATHY
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•
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Learning Objectives
Introduction
Neurocognitive
impairment in HIV
HIV
Meningoencephalitis
Pathophysiology
Clinical Features
HIV dementia scale
Examination
Differential Diagnosis
Investigation
HIV in the CSF
CNS penetration of
antiretrovirals
Key Points
Session Summary
References and
further reading
Self Assessment
Many individuals with HIVE or lesser neurocognitive
impairments, improve when commenced on antiretroviral
medications. In some cases, this can be quite marked with many
returning to independence.
However around 40% do not improve and persistent impairment
is not uncommon. Despite initial improvement or stabilisation of
symptoms on ART, most cases eventually progress.
In one large cohort study of prognosis, mean survival in pre-ART
era after diagnosis of HIV dementia was 11.9 months, and in
post-ART era was 48.2 months.
Key Points
HIV
ENCEPHALOPATHY
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•
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Learning Objectives
Introduction
Neurocognitive
impairment in HIV
HIV
Meningoencephalitis
Pathophysiology
Clinical Features
HIV dementia scale
Examination
Differential Diagnosis
Investigation
HIV in the CSF
CNS penetration of
antiretrovirals
Key Points
Session Summary
References and
further reading
Self Assessment
• Although the incidence of HIVE has decreased since
antiretrovirals, milder forms of impairment remain common.
• HIV is a subcortical dementia syndrome and can be assessed
with the HIV Dementia Scale.
• There are a number of opportunistic infections and other HIVrelated complications that can mimic HIVE.
• HIV can be found in the CSF although the exact significance
of this is currently uncertain.
• Antiretrovirals have differing CNS exposures.
Session Summary
HIV
ENCEPHALOPATHY
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•
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Learning Objectives
Introduction
Neurocognitive
impairment in HIV
HIV
Meningoencephalitis
Pathophysiology
Clinical Features
HIV dementia scale
Examination
Differential Diagnosis
Investigation
HIV in the CSF
CNS penetration of
antiretrovirals
Key Points
Session Summary
References and
further reading
Self Assessment
Having completed this session you will now be able to:
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Describe the changing spectrum of neurocognitive disease in the
post-antiretroviral era and define associated terms
Recall the symptoms and signs of HIV encephalopathy and the
features of a subcortical vs. cortical dementia
Interpret the imaging and laboratory parameters used in the in
investigation of HIV encephalopathy and use the international HIV
dementia scale to detect and quantify cognitive impairment in HIV
List the differential diagnosis of cognitive impairment in HIV and
recognise the clinical features that suggest an alternative diagnosis
Demonstrate a familiarity with differing CNS exposure of different
antiretroviral medication and the relevance of HIV in the CSF
References and further reading
1.
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HIV
2.
ENCEPHALOPATHY
3.
Learning Objectives
Introduction
Neurocognitive
impairment in HIV
HIV
Meningoencephalitis
Pathophysiology
Clinical Features
HIV dementia scale
Examination
Differential Diagnosis
Investigation
HIV in the CSF
CNS penetration of
antiretrovirals
Key Points
Session Summary
References and
further reading
Self Assessment
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
d'Arminio MA, Cinque P, Mocroft A, Goebel FD, Antunes F, et al. Changing incidence of central
nervous system diseases in the EuroSIDA cohort. Ann. Neurol. 2004;55, 320–328.
LetendreSL, Ellis RJ, Everall I, Ances B, Bharti A, McCutchanJA. Neurologic complications of HIV
disease and their treatment. Top HIV Med. 2009 Apr-May;17(2):46-56.
Gorman AA, Foley JM, Ettenhofer ML, et al.: Functional consequences of HIV-associated
neuropsychological impairment. Neuropsychol Rev 2009, 19:186–203.
Brew BJ. Benefit or toxicity from neurologically targeted antiretroviral therapy?ClinInfect Dis. 2010
Mar 15;50(6):930-2.
Letendre S: Revised CNS penetration-effectiveness ranks. 17th CROI. February 16-19th, 2010; San
Francisco, MA
LetendreS, Marquie-Beck J, CapparelliE, Best B, et al. CHARTER Group. Validation of the CNS
Penetration-Effectiveness rank for quantifying antiretroviral penetration into the central nervous
system. Arch Neurol. 2008 Jan;65(1):65-70.
Winston A, DuncombeC, Li PC, Gill JM, et al; Altair Study Group. Does choice of combination
antiretroviral therapy (cART) alter changes in cerebral function testing after 48 weeks in treatmentnaive, HIV-1-infected individuals commencing cART? A randomized, controlled study. ClinInfect
Dis. 2010 Mar 15;50(6):920-9.
Marra CM, Zhao Y, Clifford DB, LetendreS, Evans S, Henry K, Ellis RJ, Rodriguez B, Coombs
RW, SchifittoG, McArthur JC, Robertson K; AIDS Clinical Trials Group 736 Study
Team.AIDS. Impact of combination antiretroviral therapy on cerebrospinal fluid HIV RNA and
neurocognitive performance. 2009 Jul 17;23(11):1359-66.
LetendreSL, Ellis RJ, Ances BM, McCutchanJA. Neurologic complications of HIV disease and their
treatment. Top HIV Med 2010 Apr-May;18(2):45-55.
Robertson KR, Su Z, Margolis DM, KrambrinkA, HavlirDV, Evans S, SkiestDJ; A5170 Study Team.
Neurocognitive effects of treatment interruption in stable HIV-positive patients in an observational
cohort. Neurology. 2010 Apr 20;74(16):1260-6.
Letendre S, FitzSimons C, Ellis R, Clifford D, Collier A, et al. and the CHARTER Group. Correlates
of CSF Viral Loads in 1,221 Volunteers of the CHARTER Cohort [Abstract 172] 17th CROI.
February 16-19th, 2010; San Francisco, MA. View
Acute meningoencephalitis and meningitis due to primary HIV infection. Newton PJ, Newsholme W,
Brink NS, Manji H, Williams IG, Miller RF. BMJ. 2002 Nov 23;325(7374):1225-7.
Del Saz, SV; Sued, O; Falcó, V; Agüero, F; Crespo, M; Pumarola, T; Curran, A; Gatell, JM et al.
(2008). Acute meningoencephalitis due to human immunodeficiency virus type 1 infection in 13
patients: clinical description and follow-up. Journal of neurovirology 14 (6): 474–9.
Self Assessment
Question 1
HIV
ENCEPHALOPATHY
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•
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Learning Objectives
Introduction
Neurocognitive
impairment in HIV
HIV
Meningoencephalitis
Pathophysiology
Clinical Features
HIV dementia scale
Examination
Differential Diagnosis
Investigation
HIV in the CSF
CNS penetration of
antiretrovirals
Key Points
Session Summary
References and
further reading
Self Assessment
Which one of the following antiretroviral medications is
often associated with neuropsychiatric side effects?
A.
B.
C.
D.
E.
Nevirapine
Emtricitibine
Abacavir
Efavirenz
Zidovudine
To learn more about neurological infectious diseases…
NeuroID 2013: Liverpool Neurological Infectious Diseases Course
Liverpool Medical Institution, UK
Provisional date: May 2013
Ever struggled with a patient with meningitis or encephalitis, and not known quite what to do?
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