HIV and the brain Flashcards
How does HIV penetrate through the BBB?
in mononuclear cells
What cells in the CNS does HIV infect?
perivascular macrophages and microglial cells
Which neurotransmitters are involved in the damage seen with HIV associated brain damage?
glutamate and NO
What is seen on imaging with HIV associated dementia?
subcortical white matter abnormalities; generalised atrophy/ventricular enlargement
What are the neuropathological features of HIV-associated dementia?
persistent astrocytosis and microglial activation
What are the symptoms of HAD?
memory deficits; attention and mental slowing; mood distubrances; social withdrawal and apathy; slowness and loss of balance
Where is there a prediliction for HIV-encephalitis?
subcortical regions esp. the basal ganglia
What are the pathological features of HIV encephalitis?
microglial activation, perivascular astrocytosis in the central white matter and leucoencephalopathy causing myelin/axonal damage
Waht does the clinical severity of HAD correlate with?
severity of HIV -encephalitis
What are the menifestations of primary HIV infection in the brain
aseptic meningitis; meningo-encephalitis and encephalitis
What are the possible outcomes of the brain menifestations of primary HIV in the brain?
self-limiting or persistent neurological sequelae
Why are the brain menifestations of primary HIV difficult to diagnose?
often presents to praimry care; recent negative HIV-Ab doesn’t exclude diagnosis
What are the conditions given by the BHIVA guidelines for starting ART ASAP due to risk of increased progression or morbidity?
neuro involvement; any AIDS-defining illness; CD4 <350; PHI diagnosed within 12 weeks of a pervious negative test
What has changed about neuropathology since the introduction of cART?
prevalence of CNS OI has reduced lots but HIV-encephalitis is still found in upto 25% of cases –persistent astrocytosis and microglial activation
What are the factors invovled in the pathogenesis of HIV-associated cognitive impairment in the cART era?
lifestyle and comorbidities; persistent immune activation; sub-optimal CNS penetration of ART; ART toxicity; accelerated brain aging?; neurodegeneration
What is a clinical marker of persistent immune activation?
nadir CD4 coutn
What is a clinical marker of sub-optimal CNS penetration?
CSF HIV-1 escape
What virus is responsible for progressive multifocal leucoencephalopathy
JC virus
What type of virus is JC virus?
human polymovarius
What are the causes of PML?
HIV and other immunocompromise; steroids; chemo; efalizumab; rituximab; inflixumab
What is the pupose of the CPE score?
it is a CNS penetration effectiveness score- measure of the CSF exposure to an ART
Is there any clinical significance to the CPE score?
it was at the beginning of hte ART era, but now with more powerful ART regimens, there is no clinical signficance of hte CPE score
What are the treatments of PML?
effective ART; steorids; adjunctive therapies- e.g mefloquine; mirtazapine
In whihc patients does cryptococcal meningitis remain common?
patients unaware of HIV serostatus
What are the symptoms of cryptococcal meningitis?
sub-acute: fever; HA; malaise; confusion; pneumonia; cryptococcaemia
What is the median number of days of symptoms of cryptococcal meningitis beore diagnosis?
30
What are the serological tests for cryptococcal meningitis?
antigen detection; cryptococcal latex agglutination
What are the CSF tests for cryptococcal meningitis?
cell count/protein; opening pressure; culture organism
How often is CSF cell coutn and protein abnormal with cryptococcal meningitis?
40%
Why is opening pressure often raised with cryptococcal meningitis?
organisms/ polysaccharide fungal antigen covers reabsorption of CSF in arachnoid villi increasing the ICP
What is seen on imaging with cryptococcal meningitis?
often normal
What is the recomended treatment for cryptococcal meningitis?
liposomal amphotericin B and 5-flucytosine then fluconazole
What are the 2 forms of IRIS?
unmasking and paradoxical
What is unmasking IRIS?
OI appears for the first time in a patietn who, prior to commencing HAART did not have symtpoms of that OI
What is the cause of unmasking IRIS?
sub-clinical or unrecognised infections surface because of the emergence of pathogen-specific immune response
What is paradoxical IRIS?
an individual with a previously diagnosed OI or malignancy experiences a clinical deterioration while on effective HAART
Which infections is paradoxical IRIS most common with?
mycobacterial and cryptococcal disease
Why is IRIS in the CNS such a big problem?
inflammation can be life-threatening
What are the infectious causes of CNS mass lesions?
toxoplasmosis; M. tb and PML
What are some of hte malignancy causes of mass lesions on CT?
primary cerebral lymphoma; CNS involvement with systemic lymphoma; glioma; breast ca
What are the common neurological presentations in HIV patietns on ART?
headaches; neuropsychiatric disorders and depression; cognitive complaints
What is seen on CT with toxoplasmosis?
ring-enhancing lesions particularly in the basal ganglia
What psychiatric disease is more prevalent in HIV?
depression
What may be a cause of increased depression in HIV?
social? - people more likely to get HIV are more lilkley to be depressed; or is it a symptom of HIV itself
What suggests that depression is more common in HIV patients because of social reasons?
there is reduced condom use in those with depression
What is the highest risk factor for suicide in those with HIV?
not being on ART
What is a common adverse effect iwth ART?
insomnia- common cause for ART discontinuation
What has changed in the causes of cognitive impairment after the introduction of ART?
reduced HIV-associated dementia but incrased minor neurocognitive disorders
What are the criteria for HIV associated dementia?
marked impairment (at least 2 SD below mean) involving at least 2 cognitive domains; impairs with day-to-day functioning
What is the criteria for HIV associated mild neurocongitive disorder?
cognitive impairment (1 SD below mean) in at least 2 domains which has mild interference with functioning
What is the criteria for HIV associated asymptomatic neurocognitive impairment
impairment >1 SD in 2 or more domains which doesn’t interfere with daily life
How does level of education affect the risk of HIV associated cognitive impairment?
increased in those with <13 years of education
What is one way of screening for HIV associated cognitive impairment?
with questions:
- frequent memory loss?
- slower when reasoning; planning activities or solving problems?
- difficulties paying attention?
Who should be screened for HIV-associated congitive impairment?
HIV patients or their relatives reporting cognitive problems without obvious confounding condition
What tests should be done when HIV associated cognitive impairment is suggested?
further Ix to exclude confounding condition- MRI brain; CSF examination
Where are the main areas of damage with HIV-dementia?
basal ganglia and thalamus
What are the differences between the symptoms of alzhemiers and FTD and HIV dementia?
don’t get language problems/ aphasia; memory problems with HIV-dementia whereas do get personality and attention problems in HIV-demenita
What type of dementia is HIV-dementia most similar to?
parkinsons and huntingtons
What is N-acetyl aspartate a measure of
the integrity of neurones
What comorbidities are associated with an increased risk of poorer cognitive performance?
CVD and hypertension
What does the increased CVD associated with HIV-dementia suggest about its pathogenesis?
may be a result of unerlying cerebral vascular disease or may be the result of increased inflammatory resposnes
What suggests taht ART toxicity may be a cause of HIV-dementia?
efavirenz use is associated with HIv-dementia in some studies
what class of ART are generally best at CNS penetration?
NRTIs
What are the advantages of the CNS penetration effectivness score?
cART with optimal CNS exposure associated with lower CSF HIV VL and better CNS penetrating drugs (NRTIs) shown to protect against HAD
What are the disadvantages of CNS penetration effectiveness score?
treatment intensification have failed to demonstrate HIV RNA reduction in the CSF; CNS targeted cART not superior for congitive improvement or virologic suppression
Why should ART to started when a diagnosis of HIV-associated ognitive impairment is diagnosed?
its symptomatic of HIV disease; in general improvements in cognitive function are seen when starting ART; avoids further CD4 coutn decline - RF for cognitive impairment
What are the virological definitions of CSF HIV RNA escape?
either CSF RNA detectable and plasma is undetectable OR both CSF and plasma RNA is detectable- at same or higher
What should happen if there is a diagnosis of HIV-associated cognitive impairment and there is viral escape?
optimise ART based on plasma and CSF resistance testing
What is the mx for HIV associated cognitive impairment with viral suppression?
reassess for other causes of cognitive impairment, condier ARt toxicity
What is the function of empirical treatment of toxoplasma?
allows the distinction of toxoplasma encephalitis from priamry CNS lymphoma- imaging is often nondiagnostic
Which OI should not be treated without prior confirmation?
cryptococcus
What is the commonest systemic fungal infection with HIV?
cryptococcus
How common was cryptococcosis pre-ARt?
5-10%
Which stain can be used to detect cryptococcus in the CSF?
india ink
What are the poor prognostic factors in cryptococcal meningitis?
blood culture positivity; low WBC count; high CSF cryptoccal antigen; confused state and raised ICP
What is the benefit of 5-flucytosine added to amphotericin B when treating cryptococcal meningitis?
speeds the rate of sterilisation of CSF and reduces incidence of relapse in patients not on HAARt
What is the problem with adding 5-flucytosine to amphotericin B?
increased toxicity in some studies and has not had an impact on early or late mortality– benefits are mostly in patients not on HAART
Why should liposomal amphotericin B be used rather than standard amphotericin B?
to reduce renal toxicity
What should be considered in any patient with cryptococcal meningitis who deteriorates or develops new neuro signs?
repeat LP- to reduce ICP
What is the maintenance therapy for cryptococcal meningitis?
fluconazole
What can treat isolated pulmonary cryptococcus?
fluconazole
why is there no prophylaxis given or cryptoccoal meningitis?
although there is a reudction in incidence with prophylaxis, there is no effect on survival and there is a risk of resistance and is high cost
When should HAART be started with cryptococcal disease?
after 2 weeks, when induction therapy has been completed- increased mortality in patients started on HAART within 72 hours of starting treatment for cryptococcal disease
what is the commonest cause of mass lesions in the immunocompromised HIV postiive individual?
toxoplasma abscesses
What is toxoplasma gondii?
obligate intracellular protozoan
where does toxoplasma gondii complete its sexual cycle?
in feline intestinal tract
How do humans acquire toxoplasma?
eating animals with disseminated infection or by ingestion of ooxytes shed in cat faces that have contaminated soil, crops and water
What may be seen with primary toxoplasma infection in immunocompetent individuals?
mononucleosis-like syndrome
What causes toxoplasmosis in immunodeficient patients?
reactivation of chronic infection acquired earlier in life
what are manifestations of toxoplasma outside the brain?
chorioretinitis and pneumonia
What type of imaging is preferred for toxoplasma?
MRI
What is the differential for toxoplasma abscesses?
PCNSL; tuberculous disease and PML
What would suggest taht a lesion is primary cerebral lymphoma rather than toxoplasma?
if lesion is single; have a periventricular location or show sub-ependymal spread
What is the difference betweeen the lsions seen in toxoplasma and PML?
in PML tend to mainly involve white matter; are rarely contrast enhancing and don’t exhibit mass effect
What is the use of serology with toxoplasma?
only indicates previous infeciton, rising IgG titres would be indicative of reactivation however this doesn’t happen in immunocompromised patietns so only useful as a risk marker
What is the first line therapy for toxoplasma?
pyrimethamine; sulphadiazine and folinic acid
When should anti-toxoplasma therapy be started empirically?
in any HIV patient with CD4 <200 and a brain mass lesion
When should prophylaxis for toxoplasma be started?
in patients with CD4 <200
When should primary and secondary prophylaxis for toxoplasma be discontinued?
when CD4 counts are repeatedly aboe 200
Where does JC virus set up latent infection?
spleen; bone marrow; kidneys; B-cells
How is JC virus transported to the brain ?
via B- cells
What cells in the brain does JC virus infect?
oligodendrocytes
What receptor does JC vrius use to infect oligodendrocytes?
serotonin receptor
What causes the symptoms with PML?
demyelination of white matter
What are the symptoms of PML?
progressive focal neurology- mainly motor; altered mental.mood; ataxia or cortical visual symptoms
What symptom helps differentiate PML from HIV encephalopathy?
presence of focal features
How is PML diagnosed?
MRI appearances and JC virus detection by PCR in CSF– avoids biopsy which was gold standard
What is the only treatment which has improved clinical outcomes with PML?
HAART
How many patients developed CMV disease pre-ART?
20-40%, with many more having evidence of disease at post-mortem
Which site accounts for 3/4 of CMV disease?
retina
What are the neurological presentations of CMV?
encephalitis and polyradiculitis
What are the preferred diagnostic tests for CMV?
MRI scanning and CSF PCR
what is the treatment for CMV disease?
ganciclovir with/without foscarnet
What is seen with polyradiculitis?
rapidly progressive, painful bilateral ascending flaccid paralysis with saddle anaesthesia; arefelxia; sphincter dysfunctio nand urinary retention
Should prophylaxis for CMV encephalitis/polyradiculitis?
no, only trials for retinitis - but HAART reduces the incidence of these conditions
When does CMV end-organ disease typically occur?
CD4 <50
Why should ART starting be delayed after opportunistic infections?
IRIS
What is thought to be the important mediator of neurocognitive impairment in HIV?
synaptodendritic neuronal injury
When does HIV enter the CNS?
in the earliest stages of infection
How many patients develop neurocognitive impairment with HIV?
> 50%
How has cART altered the character of the predominant neuro manifestation of hiv infection?
changed from a devastating, severe dementia to a chronic, milder degree of neurocognitive impairment
What is the function of tight junctions between brain endothleial cells?
prevents the diffusion of polar molecules- lipophilicity is therefore a major determinant of CNS penetration
Which parts of hte brain does HIV particularly affect?
those that govern executive functions - esp. striatum and hippocampus
Give examples of the neural dysfunction caused by HIV?
axonal disruption; pruning or aberrant sprouting of synaptodendritic connections
Which strain of HIV is predominant in the CNS?
R5
what is the relationship between HIV encephalitis; neuronal apoptosis and synaptodendritic degenerative changes and cognitive impairment?
HIV encephalitis and neuronal apoptosis do not correlate with the degree of cognitive impairment whereas synaptodendritic changes correlate closely to the presence and severity of cognitive impairment
What is the reuslt of synaptodendritic changes?
loss of normal neuronal communication and axoplasmic flow
How can synaptodendritic injury be demonstated in preserved tissue?
immunostaining with antibodies to SYP and MAP2 is reduced in correlation with neurocognitive impairment
What is SYP?
presynaptic synaptophysin
What is MAP2?
expressed in neuronal cell bodies and dendrites- post synaptic microtubule-associated protein 2
How can synaptodendritic injury be assessed during life?
meausre synaptodendritic proteins released from damaged neurons into the extracellular space- CSF and blood e.g neurofilament protein; neuroimaging
What have studies with SIV shown about early and mid stage HIV disease?
cognitive, behavioural and electrophysiological abnormalities- infiltration of CD8 cells and upregulation of immune repsonse genes e.g CCL5
What is thought to be the mechanism in HIV encephalitis?
infected/activated microglia and macropahges release toxic factors e.g viral products; excitotoxins and cytokines that damage neurons
What is the result of homozygosity for the TNF2 allele (TNFa gene rpomoter region) in cerebral malaria?
marked increased risk of death and severe neurological sequelae
How is gp120 invovled in neuronal injury?
interacts with cellular receptors to alter glutamate pathway siganlling –increases caspases and induce cytokine production that can injure neurons and affect the activation state of microglia and astrocytes
What is the effect of gp41 on neuronal function?
disrupts glutamate signalling; increases iNOS generation
What are the 3 calsses of genes that encode proteins in HIV?
structural; regulatory and accessory
What are the strucutral HIV genes?
Gag, pol and env
What are the regulatory HIV genes?
Tat; Rev
What are the accessory HIV genes?
Vpu; Vpr; Vif; Nef
What cements that role that gp120 plays in neurocognitive degeneration?
dendritic alterations seen in the brains of cognitively ipaired HIV patients that come to autopsy can be replicatedi n cultures of human nervous tissue exposed to gp120
What do astrocytes infected with HIV release?
not whole virions, generate Tat
What is the effect of Tat?
mitochondrial dysfunction; dendritic loss; neurotoxicity; glial cell activation; cell death
What does abnormal activation of cytokine and chemokine receptors in the context of HIV result in?
dendritic beading and loss of dendritic spines
What is the effect of HCV infection on HIV neurocognitive disorders?
increases the likelihood
What is the effect of HIV on neurregeneration?
viral proteins or virally induced immune changes can intersect with the pathways invovled in trophic factor gene expression; protein production or signalling cascades
Give examples of neurotrophic factors?
brain derived neurotrophic factor; insulin-like growth factor
What is the effect of significant reductions in neurotrophic factors?
increases neurons vulnerability to injury and limits ability to undergo repair
What was the prevalence of HIV-associated dementia in pts with advanced HIV?
arund 20%
What can be used to identify HIV associated cognitive impairment before it becomes symptomatic?
before a breakdown in accuracy or speed of performance, functioanl imaging studies have shown that the HIV-infected brain recruits or activates more widespread regions to accomplish the same level of performance
What are the treatment options for HIV-associated cognitive impairment?
optimising cART, however as not all patients get benefit from this- trophic factors supplied by gene therapy or drugs may reverse or arrest damage
Give an example of a drug which may be useful in neurocognition in HIV?
lithium- prevents induction of dendritic spine loss by gp120– resulted in improved performance in patients with HAND
What is the effect of minocycline?
reduces activation of macrophages and microglia; reduces influx of cytotoxic cells into brain- reudcing encephalitis severity; suppressing viral load and dampening expression of CNS inflam markers in SIV macaques
Why are there fluctuations of cognitive impairment?
reflect disturbances in the dynamic balance between synaptodendritic injury and repair
