www.thelancet.

com/neurology Vol 11 July 2012 605

Review
Lancet Neurol 2012; 11: 60517
HIV Neuroscience Program,
Johns Hopkins University,
Baltimore, MD, USA
(I L Tan MBBS, B R Smith MD,
G von Geldern MD,
F J Mateen MD,
Prof J C McArthur MBBS)
Correspondence to:
Prof Justin C McArthur,
Department of Neurology, Johns
Hopkins University, Meyer 6113,
600 North Wolfe Street,
Baltimore, MD 21287, USA
jm@jhmi.edu
HIV-associated opportunistic infections of the CNS
Ik Lin Tan, Bryan R Smith, Gloria von Geldern, Farrah J Mateen, Justin C McArthur
Survival in people infected with HIV has improved because of an increasingly powerful array of antiretroviral
treatments, but neurological symptoms due to comorbid conditions, including infection with hepatitis C virus,
malnutrition, and the eects of accelerated cardiovascular disease and ageing, are increasingly salient. A therapeutic
gap seems to exist between the salutary eects of antiretroviral regimens and the normalisation of neurological
function in HIV-associated neurocognitive disorders. Despite the advances in antiretroviral therapy, CNS opportunistic
infections remain a serious burden worldwide. Most opportunistic infections can be recognised by a combination of
characteristic clinical and radiological features and are treatable, but some important challenges remain in the
diagnosis and management of HIV-associated opportunistic infections.
Introduction
HIV infection leads to substantial morbidity and
mortality worldwide. In 2009, 333 million adults and
children were living with HIV, two-thirds of whom were
in sub-Saharan Africa.
Overall, the annual incidence of new infections has
declined by 19% since the peak of the worldwide HIV
epidemic in 1999, in line with the Millennium Development
Goal. Nevertheless, about 26 million individuals were
newly infected in 2009, and the incidence continues to
increase in some regions.
1
7000 new HIV infections occur
daily, 95% of which are in low-income and middle-income
countries, where only about a third of patients who require
antiretroviral drugs have access to them.
1

In high-income countries, the introduction of
combination antiretroviral therapy (cART) in 1996 greatly
changed the incidence of neurological opportunistic
infections, from 131 per 1000 patient-years in 199697 to
10 per 1000 in 200607 (tables 1, 2).
2,7
Many of the
opportunistic infections that aect the CNS are AIDS-
dening conditions, including progressive multifocal
leukoencephalopathy (PML), CNS cytomegalovirus, CNS
tuberculosis, cryptococcal meningitis, and cerebral
toxoplasmosis, including toxo plasmic encephalitis
(table 2), and all have high associated mortality.
8
Treatment
of CNS opportunistic infections in conjunction with
cART improves survival, but such infections continue to
be important, especially where access to cART is limited.
In this Review we focus on the most common CNS
opportunistic infections associated with HIV infection
worldwide, and provide a summary of each in terms of
epidemiology, clinical presentations, diagnosis, and
treatment.
Biology of HIV-1
HIV-1 infection accounts for most of the global HIV
pandemic. Only 12 million of the 33 million HIV
infections are caused by HIV-2. HIV-1 belongs to the
family Retroviridae and genus Lentivirus.
9
It is a single-
stranded, positive-sense RNA virus that contains a reverse
transcriptase, which transcribes viral RNA into DNA that is
integrated into the hosts genome as a provirus. HIV-1
primarily targets CD4 receptors and infects CD4-positive
T lymphocytes and cells of the monocyte or macrophage
lineages. HIV-1 also infects CD4-negative cells, including
astrocytes, but in a restrictive manner. HIV-1 subtypes are
dened by chemokine co-receptors: T-tropic viruses use
CXCR4 (receptor for SDF1, also termed CXCL12) to infect
lymphocytes, and M-tropic viruses use CCR5 (receptor for
RANTES, also termed CCL5, and MIP1 or CCL3/4) to
infect macrophages.
10,11

HIV infection is characterised by three stages: acute
primary infection, an asymptomatic (latent) stage, and
symptomatic chronic illness. Disease progression is
highly variable: from 6 months after seroconversion to
more than 2030 years, or minimal progression might be
seen in elite suppressors. In the absence of cART, the
mean time to the development of AIDS is 1011 years,
12

and median survival after AIDS develops is 1337 years,
depending on the CD4-cell count.
13

After primary infection, acute disseminated viraemia is
seen.
14
The initial massive depletion of gut-associated
memory T cells
15
leads to physical and immunological
breaches of the gut mucosa, as well as expansions of some
HIV-specic CD8-positive T-cell responses,
16
the crucial
Incidence per
1000 person-years
Overall 10*
Progressive multifocal leukoencephalopathy 07
Toxoplasmic encephalitis 04
Cryptococcal meningitis 02
Data are from 200607.
2
*The sum of the individual opportunistic infections is
more than 10 because some individuals have more than one infection.
Table 1: Incidence of HIV-associated CNS opportunistic infections
Common CNS opportunistic infections
Asian and Pacic regions
3
Cryptococcal meningitis, cerebral toxoplasmosis, tuberculous meningitis,
Japanese encephalitis B
Sub-Saharan Africa
4
Tuberculous meningitis, cryptococcal meningitis, cytomegalovirus, malaria
Europe and North America
2
PML, toxoplasmic encephalitis, cryptococcal meningitis
South America
5
Cerebral toxoplasmosis, tuberculous meningitis, cryptococcal meningitis;
Chagas disease is reported in southern US states and South America
6
PML=progressive multifocal leukoencephalopathy.
Table 2: Incidence of HIV-associated CNS opportunistic infections by geographical region
606 www.thelancet.com/neurology Vol 11 July 2012
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host immune response against HIV. This robust immune
response leads to virus being trapped within dendritic
cells in lymphoid tissue and a marked reduction of
viraemia.
17
The virus, however, is not completely
eliminated from the body and chronic, persistent viral
replication leads to systemic immune activation.
Additionally, quiescent CD4-positive memory T cells and
macrophages serve as long-term reservoirs for latent HIV
infection.
18
Persistent viral replication, chronic immune
activation, and progressive deterioration of immune
function result in symptomatic disease with severe
immune deciency in advanced HIV infection.
19
Typically,
CNS opportunistic infections occur during this stage of
the HIV infection; waning immunity and high HIV load,
both systemically and in the CNS, create a favourable
milieu. Apart from immune deciency, other features of
HIV-1 might directly facilitate CNS opportunistic
infections, for example in PML. Most CNS opportunistic
infections result from reactivation of latent pathogens,
including PML, toxoplasmic encephalitis, and primary
CNS lymphoma. HIV infection produces substantial
depletion of the CD4-cell count and preferentially destroys
the cellular immune system, which is crucial for defence
against viral, fungal, and parasitic infections.
Clinical features of CNS opportunistic infections
CNS opportunistic infections should be suspected in all
people with advanced HIV infection. Individuals who
are unaware of their HIV status can rst present with
CNS opportunistic infections. Additionally, in patients
in whom cART is started, immune reconstitution in-
ammatory syndrome (IRIS) might unmask previously
un suspected CNS opportunistic infections. The main
diagnostic features of CNS opportunistic infections are
clinical presentation, temporal evolution, and CSF and
radiographic features. These infections typically develop
when the CD4-cell count is lower than 200 cells per L.
One important principle is that up to 15% of CNS
opportunistic infections involve multiple concurrent
processes (panel 1) and, therefore, unexpected
worsening after treatment for an opportunistic infection
is started should prompt consideration of a second
process. Individuals who have had immunological
recovery from cART might still be at risk of developing
CNS opportunistic infections.
Some infections, such as toxoplasmic encephalitis and
cryptococcal meningitis, evolve over hours, whereas
others, such as PML and CNS lymphoma, typically have
a more indolent course, with development often taking
weeks to months. Many exceptions to these patterns may,
however, be seen. Although many CNS opportunistic
infections are associated with non-specic symptoms,
such as fever and lethargy, the combination of symptoms
such as a new pattern of headache or headache lasting
longer than 3 days, new-onset seizures, or altered mental
function strongly suggest an acute focal brain lesion.
20

The incidence, temporal pattern, and typical CD4-cell
count for common CNS opportunistic infections are
presented in table 3. CSF and radiographic patterns are
presented in tables 4 and 5, respectively. The neuro-
imaging features provide a guide, but diagnosis should
never be made on neuroimaging ndings alone.
A diagnostic and management algorithm for the
assess ment and management of intracranial mass
lesions in patients with AIDS was issued by the Quality
Standard Sub committee of the American Academy of
Neurology in 1998.
38
We present an algorithm for the
management of patients presenting with headaches and
symptoms suggestive of CNS infections (gure 1).
Although many advances have been made in the
diagnosis and treatment of CNS opportunistic infections,
the algorithm approach remains applicable, especially in
resource-poor settingsfor example, in patients with
multiple CNS lesions, empirical treatment with
antitoxoplasmosis therapy might be appropriate. Patients
with severe immune suppression (CD4-cell count lower
than 200 cells per L) are at risk of toxoplasmic
encephalitis, cryptococcal meningitis, cytomegalovirus
infection, primary CNS lymphoma, and PML, whereas
patients with moderate immune suppression (CD4-cell
counts of 200500 cells per L) are at risk of tuberculous
meningitis and PML.
In resource-rich settings, a battery of investigations is
used to diagnose CNS opportunistic infections
(panel 2). Assessment of CSF with antibody testing or
PCR detection can be especially helpful in the denitive
identication of the causative organism. However, the
availability and sensitivity of these tests vary, and in
some cases diagnosis remains a challenging task.
Stereotactic brain biopsy might lead to a denitive
diagnosis in such cases, or sometimes after failed
empirical therapy.
39,40
Image-guided stereotactic brain
biopsy, particularly with MRI-compatible stereotactic
systems that are associated with high diagnostic yields
(up to 8890%) for focal CNS lesions and low mortal-
ity (23%), facilitates early detection, diagnosis,
Panel 1: Principles of HIV-associated CNS opportunistic
infections
CNS opportunistic infections typically occur when the
CD4-cell count is less than 200 cells per L
Diagnosis should be based on clinical presentation, temporal
evolution, CSF, and radiographic features
Multiple infections are present in 15% of cases and some
infections might be revealed only after combination
antiretroviral therapy is started
Combination antiretroviral therapy should be started,
modied, or continued with appropriate antimicrobial
therapy
Antimicrobial treatment is generally required until immune
recovery (CD4-cell count more than 200 cells per L) is
achieved with antiretroviral therapy
www.thelancet.com/neurology Vol 11 July 2012 607
Review
appropriate treatment, and improved prognosis.
3941
The
opportunistic infections most frequently diagnosed
with stereotactic biopsy are PML (2930%), primary
CNS lymphoma (2325%), and toxoplasmosis (1516%).
MRI-guided stereotactic brain biopsy might be
indicated in patients with solitary lesions on neuro-
imaging, those who have multiple lesions that have not
responded to antitoxoplasmosis treatment, and those
with multiple lesions and neurological pro gression.
40

cART and management of CNS opportunistic
infections
In patients with CNS opportunistic infections, the timing
of cART initiation is pertinent to the management of
treatment-naive patients as well as those who have
previously received cART. The use of cART to achieve
immune restoration is especially eective in patients
with opportunistic infections for which no eective
antimicrobial therapy is available, including PML, but
several complications are of concern, including drug
interactions, toxic eects, and IRIS.
CNS opportunistic infections that develop in patients
who are already taking cART might be due to IRIS,
especially within the rst 12 weeks after cART is started
(table 6). Alternatively, infection could be due to cART
treatment failure, and the patients adherence should be
assessed and antiretroviral resistance should be tested.
In both scenarios, cART should be continued and
modied if virological failure (inability to achieve or
maintain viral replication to an HIV RNA level lower
than 200 copies per mL), immunological failure (inability
to achieve or maintain an adequate CD4 response despite
virological suppression), or adverse reactions develop, in
addition to antimicrobial therapy.
In resource-poor countries where cART is not available,
a prophylactic antimicrobial regimen might help to
prevent CNS opportunistic infections. Region-specic
policies on the timing and type of prophylaxis are
needed.
4
Guidelines from the Centers for Disease Control
and Prevention (CDC) on the prevention and treatment
of opportunistic infections in adults and adolescents
infected with HIV provide useful recommendations.
6

CD4-cell count at
presentation (cells per L)
Time from symptom onset to
presentation
Change in mental
status
Seizures Headache Fever Focal
decits
Cranial
neuropathies
Toxoplasmic encephalitis
21,22
<200 Days + to +++ + to ++ +++ ++ to +++ ++ to +++ +
PML
23,24
<100, but occasionally higher Generally weeks to months;
sometimes acute, mimicking stroke
++ to +++ + + to ++ + +++ +
Primary CNS lymphoma
25,26
<100 Weeks +++ + to ++ ++ to +++ None ++ to +++ +
Cytomegalovirus encephalitis
27,28
<50 Days +++ ++ + to ++ ++ + ++
Cryptococcal meningitis
2931
<50 (rarely, up to 200) Days + to +++ + +++ + to +++ + +
Tuberculous meningitis
3234
Variable, but <200 Days to weeks ++ to +++ + +++ +++ + to ++ ++ to +++
Herpes simplex virus
35
Variable Weeks +++ ++ + + to ++ ++ + to ++
+=uncommon (0<30%). ++=sometimes (30<60%). +++=often (>60%). PML=progressive multifocal leukoencephalopathy.
Table 3: Clinical characteristics of HIV-associated CNS opportunistic infections
White-blood-cell count Glucose concentration Protein concentration Other
Toxoplasmic encephalitis
21,22,36
Normal or increased
lymphocytes
Decreased or normal Normal or increased Toxoplasma gondii PCR nearly 100% specic and 5080% sensitive
PML
23,24
Normal, rarely increased
lymphocytes
Normal Normal or increased JC-virus PCR sensitivity variable at 5090%, but specicity 90100%
Primary CNS lymphoma
25,26
Normal or increased
lymphocytes
Normal Normal Epstein-Barr virus PCR nearly 100% sensitive and about 50% specic
Cytomegalovirus encephalitis
27,28
Normal, rarely increased
neutrophils
Normal Normal or increased PCR >90% sensitive and specic and <25% culture positive
Cryptococcal meningitis
29,30,37
Normal, rarely increased
lymphocytes
Decreased or normal Normal or increased
36
Opening pressure frequently raised; India ink stain 75% sensitive; CSF
cryptococcal antigen sensitivity 92% and specicity 83%; high CSF antigen
titre associated with poor prognosis, but change of titre with treatment has
little correlation with prognosis
Tuberculous meningitis
3234
Increased lymphocytes Decreased Normal or increased Mycobacterium tuberculosis culture has variable sensitivity, but use of
microscopy for acid-fast bacilli and CSF NAAT can increase sensitivity to >80%
Herpes simplex virus
35
Usually increased
lymphocytes
Normal or increased Increased CSF PCR sensitivity 100%, specicity 996%
PML=progressive multifocal leukoencephalopathy. NAAT=nucleic-acid amplication test.
Table 4: CSF characteristics of HIV-associated CNS opportunistic infections
608 www.thelancet.com/neurology Vol 11 July 2012
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Tuberculous meningitis and brain abscesses
WHO estimates that a third of the worlds population is
infected with Mycobacterium tuberculosis and that
individuals with HIV co-infection are at increased risk of
disseminated, active forms of disease, including
tuberculous meningitis.
42
The exact incidence of HIV-
associated tuberculous meningitis is uncertain because
epidemiological data are limited, especially for areas where
co-infection rates are highest, such as sub-Saharan Africa.
42
Infection with M tuberculosis occurs after inhalation of
airborne bacilli that traverse the alveoli into the
bloodstream. Intact T-cell-mediated immunity helps to
control haematogenous spread. The disease disseminates
readily in patients infected with HIV who have reduced
CD4-cell counts. In the brain, granulomas or Rich foci
can form within the subpial and subependymal layers
43

and these can expand to create tuberculomas or
parenchymal brain abscesses (table 5), or, more
commonly, rupture to cause meningitis.
Rapid detection is crucial in patients with HIV-associated
tuberculous meningitis, but detection of acid-fast bacilli or
the causative organism by positive culture or PCR is often
di cult (table 4).
44
Sensitivities for these tests have
traditionally been poor at about 50%, although patients
infected with HIV have higher yield rates of up to 80%,
possibly owing to incomplete immune responses and
increased bacterial loads.
45
Neither tuberculin skin tests
(sensitivity 31%) nor the interferon--release assay
QuantiFERON-TB Gold (Cellestis, Valencia, CA, USA;
sensitivity 60%) can precisely exclude tuberculosis in
individuals with HIV, especially when CD4-cell counts are
lower than 200 cells per L.
46
Repeated, large-volume
lumbar punctures might improve the yield.
44
CSF tests that
include a nucleic-acid amplication test have substantially
short ened detection times and can improve test
sensitivities when used in combination with acid-fast-
bacillus microscopy and repeated sample testing (table 4).
45
Treatment for tuberculosis does not dier signicantly
between patients with and without HIV infection. The
standard regimen begins with isoniazid, pyrazinamide,
ethambutol, and rifampicin for 2 months. Rifampicin
notably lowers levels of protease inhibitors and nevirapine
in plasma, but rifabutin is an appropriate alternative.
47

After this initial phase, isoniazid and rifampicin or
rifabutin are continued for at least 912 months.
48
The role
of corticosteroids and the optimum timing of the initiation
of cART in conjunction with antituberculosis therapy
remain controversial issues. In a randomised, controlled
trial of 545 patients with tuberculous meningitis in
Vietnam, an adjuvant corticosteroid (dexamethasone) was
associated with a 30% reduction in the relative risk of
death, but not a signicant reduction in the proportion of
severely disabled patients.
49
A smaller study assessed
253 patients who were treated with standardised anti-
tuberculosis treatment, adjuvant dexamethasone, and
prophylactic co-trimoxazole and who were followed-up for
12 months. Immediate start of cART did not improve
outcomes compared with cART deferred for 2 months.
32

Thus, delayed initiation of cART is recommended for
patients with HIV-associated tuberculous meningitis.
Mortality from HIV-associated tuberculous meningitis
often exceeds 50%, which is roughly double the rate in
patients without HIV.
43
Even with the addition of cART,
mortality is not improved.
32
Multidrug-resistant tuberculosis (resistant to at least
isoniazid and rifampicin) is estimated to account for
36% of incident tuberculosis diagnoses worldwide, and
extensively drug-resistant disease (also resistant to
Mass eect Proportion of
solitary lesions (%)
Typical locations Enhancement Other
Toxoplasmic
encephalitis
21,22,36

Frequent <20% Frontal, basal ganglia, parietal Frequent, mainly ring enhancing Generally 12 cm
PML
23,24,36
Rare ~50% Subcortical white matter,
cerebellum, brainstem
~25% show enhancement,
(especially in patients with IRIS)
Hyperintense areas in white matter on
T2-weighted, FLAIR MRI and hypointense
lesions on T1-weighted MRI, with sparing of
cortical ribbon
Primary CNS
lymphoma
25,26,36
Frequent 3050% Periventricular, frontal,
cerebellum, temporal
Frequent, potentially with
heterogeneous enhancement
Generally >3 cm diameter
Cytomegalovirus
encephalitis
27,28
None NA Periventricular <50% show periventricular
enhancement
About 50% of cases show normal imaging
Cryptococcal
meningitis
29,30
Communicating
hydrocephalus with raised
intracranial pressure
Typically multiple Basal ganglia Potentially leptomeningeal
enhancement, especially in
patients with IRIS
Frequently punched-out cystic lesions
Tuberculous
meningitis
3234
Hydrocephalus possible Mainly ill-dened
exudates
Infratentorial with basal ganglia
or cortical infarcts
<50% show basilar enhancement
on CT
Haemorrhage, tuberculomas, or abscesses
possible
Herpes simplex
virus
35
Minimal NA Inferomedial temporal lobes Frequent enhancement May involve brainstem, cerebellum,
diencephalon, and periventricular regions;
associated intracranial haemorrhage
PML=progressive multifocal leukoencephalopathy. IRIS=immune reconstitution inammatory syndrome. FLAIR=uid-attenuated inversion recovery. NA=not applicable.
Table 5: Radiographic characteristics of HIV-associated CNS opportunistic infections
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Review
uoroquinolones and second-line injectable drugs) has
been documented in at least 58 countries since 2010.
1

Case series of multidrug-resistant HIV-associated
tuberculous meningitis suggest that mortality is
extremely high.
50,51
This disease is of notable concern in
resource-poor settings because the cost of treatment is
100 times greater than that for susceptible tuberculous
meningitis.
52
Further studies are needed to better
characterise HIV-associated multidrug-resistant and
extensively drug-resistant tuberculous meningitis.
Toxoplasmic encephalitis
Toxoplasmic encephalitis remains the most commonly
reported neurological opportunistic infection since cART
was introduced, although declines in incidence have
been seen: in 2007, the incidence in the UK was 04 per
1000 person-years, which was a notable decline from 32
only 10 years earlier.
7
Because toxoplasmic encephalitis is
caused by reactivation of encysted bradyzoites rather
than primary infection, rates vary according to the
seroprevalence of Toxoplasma gondii in the population.
Risk factors for toxoplasmic encephalitis include the
degree of immunosuppression and whether or not
prophylaxis for Pneumocystis jiroveci pneumonia is being
used, since trimethoprim is also an eective preventive
therapy for toxoplasmic encephalitis.
After human ingestion of oocysts containing oocytes,
usually from feline denitive hosts, the active tachyzoites
replicate and transform into latent bradyzoites that
persist in the brain and muscle.
53
In immuno decient
individuals, CD4-positive T cells are unable to suppress
this latent infection, and the tachyzoites re-emerge and
replicate.
53
The tachzyoites commonly produce focal
necrotising cerebritis surrounded by a thick wall of
histiocytes and inamed vessels, although a more diuse
encephalitis, known as microglial nodular encephalitis,
can occur in people with severe immuno suppression.
53
The diagnosis of toxoplasmic encephalitis is often
established by clinical and radiographic improvements
after empirical treatment and by a positive test for IgG
antibodies to T gondii in serum. Only about 3% of
patients have negative serology.
54
When clinically feasible,
PCR of CSF obtained by lumbar puncture can be helpful
to detect the parasite. The specicity of PCR is excellent,
although the sensitivity is only about 50% when tested at
or near the time of treatment initiation (table 4).
55
New
PCR techniques and testing for CSF excretory-secretory
antigens oer increased sensitivity, but the costs of these
tests remain prohibitively high in resource-poor areas.
5658

Primary CNS lymphoma is often the principal dierential
diagnosis. MRI, F-uorodeoxyglucose PET, and SPECT
might help to distinguish specic features,
59,60
but a brain
biopsy could be necessary if equivocal or worsened
response to empirical treatment is seen.
Combined pyrimethamine, folinic acid, and
sulfadiazine has traditionally been used, although
trimethoprim-sulfamethoxazole was equally eective in a
Figure 1: Algorithm of diagnostic principles for HIV-associated CNS opportunistic infections
Headache, seizure, altered mental state
+/ fever, focal decits
Neuroimaging (MRI/CT brain)
Lesions on MRI or CT
No sign of herniation
Single lesion Multiple lesions
Lumbar puncture
or brain biopsy
Toxoplasma serology
positive
Toxoplasma serology
negative
Trial of empirical
antitoxoplasmosis
treatment
If patient responds,
continue
If no response,
consider brain biopsy
Brain biopsy
Signs of herniation
Neurosurgical referral
for decompression
and brain biopsy
No mass lesion
Lumbar puncture for
microscopy and culture
Empirical antimicrobial therapy
Panel 2: Diagnostic work-up for patients with HIV
infection and presumed CNS opportunistic infections
Imaging
Neuroimaging with contrast-enhanced MRI or CT
Chest radiography or CT for tuberculosis
CSF
Bacterial, fungal, and mycobacterial culture
White-blood-cell count and dierential protein and
glucose concentrations
Cytology and ow cytometry
PCR for JC virus, Epstein-Barr virus, cytomegalovirus,
Toxoplasma gondii, herpes simplex virus types 1 and 2, and
varicella zoster virus
Cryptococcal antigen
Microscopy for India ink stain (Cryptococcus) and acid-fast
bacilli (Mycobacterium tuberculosis)
Other laboratory tests
CD4-positive T-cell count
IgG antibodies to Toxoplasma gondii in CSF, blood, and urine
Serum QuantiFERON-TB Gold test*
*Cellestis, Valencia, CA, USA.
610 www.thelancet.com/neurology Vol 11 July 2012
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small randomised trial, and is perhaps more economical
for resource-poor regions.
61
In a large clinical study of
patients treated presumptively for toxoplasmic
encephalitis, the median time to treatment response was
5 days; 74% improved within 7 days and 91% responded
within 14 days. Failure to improve within 1014 days of
starting treatment should, therefore, prompt reassess-
ment of the diagnosis, with either thallium SPECT or
brain biopsy.
38
Corticosteroids are indicated only when a
substantial mass eect is seen, and should be
discontinued as soon as possible. Induction treatment
should be continued for at least 6 weeks, until substantial
radiographic improvement is recorded, including the loss
of contrast enhancement,
6
although in a few patients
contrast enhancement might persist for months or even
years. Maintenance therapy should be continued in all
patients until immune reconstitution is achieved
(persistent CD4-cell count of more than 200 cells per L).
Anticonvulsants are indicated only in patients with a
history of seizures related to toxoplasmic encephalitis.
Despite the introduction of cART, mortality for
toxoplasmic encephalitis remains high at 2060% within
1 year of diagnosis.
21,62
Low CD4-cell counts at the time of
diagnosis, a history of other AIDS-dening illnesses, age
older than 45 years, and the presence of encephalopathy
portend a poor prognosis.
21
Cryptococcal meningitis
Before the introduction of cART, 510% of patients with
AIDS developed cryptococcal meningitis. Although the
incidence has fallen, this disease remains a major concern
in sub-Saharan Africa and south and southeast Asia.
63
Cryptococcus neoformans is an encapsulated yeast
commonly found in soil and in excrement from pigeons.
Cryptococcus gattii is generally found in tropical and
subtropical regions, and causes disease in immuno-
competent individuals.
64
Exposure to Cryptococcus spp
probably occurs via inhalation of spores, which leads to
primary pulmonary infection, latent infection, or
disseminated disease. Cryptococcal meningitis is thought
to be the result of reactivation of latent infection in
immunocompromised patients.
65
Although described as
meningitis, the yeast typically forms cystic accumulations
in Virchow-Robin spaces, around the deep-penetrating
blood vessels in the brain and cranial nerves, termed
soap-bubble cysts.
Lumbar puncture with manometry is especially helpful
for the diagnosis of cryptococcal meningitis, as the CSF
opening pressure is typically raised (table 4).
66
The CSF
prole at presentation is normal in about 30% of
patients.
67
Microscopic detection with India ink staining
and fungal culture of the CSF are diagnostic.
Immunoassays of cryptococcal antigens are rapid,
sensitive, and specic, and confer prognostic value.
68

Urinary antigen detection has high sensitivity, and can
be useful, especially in resource-poor settings, in the
appropriate clinical context.
69

Clinically, cryptococcal meningitis is most notable for
its propensity to cause communicating hydrocephalus
with increased intracranial pressure, which develops in
more than 15% of patients.
70
Aggressive management of
raised intracranial pressure is crucial to lessen the risk of
early death. Impaired reabsorption of CSF by the
arachnoid villi is thought to be due to sticky polysaccharide
capsules. Patients with increased intracranial pressure
typically present with headache, vomiting, visual
changes, hearing loss, palsy of the abducens nerve, and
impaired consciousness; however, this complication can
be silent and is potentially fatal. Dysfunction in multiple
cranial nerves might occur owing to associated basal
meningitis. Repeated high-volume lumbar puncture
frequently leads to immediate symptomatic relief, and
can reverse neurological morbidity, such as blindness or
deafness.
71
Data on the management of raised intra-
cranial pressure in cryptococcal meningitis are limited.
Guidelines recommend serial daily lumbar punctures if
the opening pressure is persistently greater than 25 cm
H
2
O.
72
Drainage of CSF to reduce the pressure by 50% or
to a pressure in the normal range (less than 20 cm H
2
O)
is recommended. Lumbar drains or even ventriculo-
peritoneal shunts have been used if increased intracranial
pressure remains di cult to control.
73
The recommended treatment for cryptococcal
meningitis is intravenous amphotericin B in combination
with oral ucytosine for a minimum of 2 weeks, followed
by oral uconazole for at least 8 weeks.
72
Liposomal
amphotericin B is associated with lower risks of renal
toxic eects and other side-eects than conventional
amphotericin B and has similar e cacy, but it is more
expensive.
74
Combined ucytosine with amphotericin B
leads to faster and greater sterilisation of CSF than does
amphotericin B alone.
75
Prophylaxis with uconazole is
required until a durable immune reconstitution with a
CD4-cell count higher than 200 cells per L is achieved.
IRIS Worsening or recurrent
opportunistic infection
Context Onset early (average 2 months)
after start of cART, generally in
patients with good adherence
to treatment
Generally not closely related to start of
cART, often seen in patients with a
history of non-adherence to treatment
Plasma HIV RNA concentration Decreased Increased
CD4-positive T-cell count Increased Decreased
CSF prole Lymphocytosis, raised protein
concentrations, and, frequently,
sterile culture
Lymphocytosis less intense than with
IRIS, raised protein concentrations,
possibly low glucose, and generally
positive culture
Neuroradiology Worsening lesion with cerebral
oedema and contrast
enhancement
May have worsening lesions, but
surrounding cerebral oedema might be
less intense than with IRIS; contrast
enhancement
Treatment Corticosteroid (anecdotal) Antimicrobial
IRIS=immune reconstitution inammatory syndrome. cART=combination antiretroviral therapy.
Table 6: Distinguishing features of IRIS and worsening or recurrent opportunistic infections
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Review
In resource-limited settings, only amphotericin B and
uconazole are generally available.
75
A large trial in Africa
supports the use of uconazole as primary prophylaxis,
irrespective of whether patients are receiving cART.
76
IRIS aects 1040% of patients with cryptococcal
meningitis, and the risk is increased in individuals who
are antiretroviral naive and who have high concentrations
of HIV RNA. Mortality for IRIS associated with
cryptococcal meningitis is 3366%.
77
Appropriate
management of IRIS includes continuation of cART,
antifungal therapy, and a course of corticosteroids.
6

Cytomegalovirus encephalitis
Neurological diseases caused by cytomegalovirus are rare
but very serious. Infection can lead to encephalitis,
retinitis, radiculomyelitis, or mononeuritis multiplex.
Although cytomegalovirus encephalitis seems to occur at
similar rates worldwide, retinitis has a distinct
geographical distributionit is the predominant HIV-
associated eye disease in Asia, where up to a third of
HIV-infected patients are aected.
78
The ubiquitous herpes virus, cytomegalovirus is
endemic worldwide and usually causes asymptomatic or
clinically benign infections. Most people have been
infected by the time they reach adulthood. The high
neurovirulence of some cytomegalovirus strains and
host genetic risk factors might play a part in the
development of neurological disease.
79
In cases of suspected cytomegalovirus encephalitis,
brain imaging with contrast should be done. Meningeal
enhancement or periventricular inammation can be
seen in infected patients, but these ndings are not
specic to cytomegalovirus encephalitis (table 5).
80
PCR
of CSF is highly sensitive and specic in the diagnosis of
cytomegalovirus encephalitis (table 4) and might also be
positive in patients with cytomegalovirus radiculomyelitis.
Quantitative PCR results can also help in the assessment
of disease severity and in monitoring response to
antiviral therapy, having a sensitivity of 250 copies per mL
and a diagnostic specicity of 9099%.
81
A neutrophil-
predominant CSF pleocytosis with negative bacterial
culture is highly suggestive of cytomegalovirus
infection.
82
Retinitis associated with cytomegalovirus
infection is typically diagnosed by areas of haemorrhagic
infarction, perivascular sheathing, and retinal
opacication on fundoscopy.
Patients with cytomegalovirus encephalitis commonly
present with rapidly progressive encephalopathy, often
with hyponatraemia due to adrenal involvement.
83

Brainstem symptoms and seizures can also occur.
Patients with extraocular complications frequently have
previous or concurrent cytomegalovirus retinitis and
should undergo fundoscopy, as blindness can develop if
retinal disease remains untreated. Visual symptoms can
include oaters, loss of peripheral vision, or central
scotoma, but not all patients are symptomatic. The visual
loss in cytomegalovirus retinitis is usually the result of
retinal necrosis, but macular oedema, retinal detachment,
and papillitis might also reduce visual acuity.
84

Radiculomyelitis typically aects the lumbosacral regions
and can present as a rapidly progressive cauda equina
syndrome. The clinical presentation resembles Guillain-
Barr syndrome, except that the CSF generally has a
neutrophilic predominance and MRI imaging shows
contrast-enhancing and greatly thickened nerve roots.
Little evidence is available to denitively guide the
treatment of cytomegalovirus encephalitis. A com bination
of ganciclovir and foscarnet was generally used before the
introduction of cART, but this regimen is associated with
substantial adverse eects. The use of cART plus one
anticytomegalovirus treatment is favoured. Ganciclovir
was the rst available agent and remains the rst-line
treatment, although mutations in the viral genes UL97 or
UL54 can lead to drug resistance. Ganciclovir is only
available intravenously, but its prodrug, valganciclovir, can
be given orally. While a sustained-release intraocular
implant treats cyto megalovirus retinitis in the aected eye,
oral ganciclovir is recommended to prevent cytomegalo-
virus retinitis or extraocular disease.
85
Foscarnet is used
when patients develop dose-limiting leucopenia while
taking ganciclovir or in ganciclovir-resistant cases,
although some cross-resistance has been shown. Cidofovir
is a competitive inhibitor of the viral DNA polymerase
after conversion to an active form. As the activation of
cidofovir does not rely on viral kinases, it retains its activity
for cytomegalovirus with UL97 mutations, but mutations
in DNA polymerase genes, such as UL54, lead to
resistance.
86
Secondary prophylaxis with long-term oral
anticytomegalovirus therapy should be continued until
sustained immune recovery is achieved with cART.
87
Drug
susceptibility testing based on screening for known
resistance-inducing mutations in the viral genome can
help to guide antiviral therapy.
88
Progressive multifocal leukoencephalopathy
PML is a rare but severe CNS opportunistic infection that
is caused by the reactivation of latent JC virus, a
polyomavirus, in immunosuppressed individuals.
Unlike most of the other HIV-associated CNS
opportunistic infections, which are very rare when the
CD4-cell count is higher than 100200 cells per L, PML
occasionally occurs in patients with much higher CD4-
cell counts (table 3).
89,90
The seroprevalence of JC virus in
the general population is 5090%,
9193
and about 30% of
people shed the virus in urine.
94
The incidence of PML
has declined from seven cases per 1000 patient-years
before the introduction of cART to 07 per 1000 (table 1).
7

The mechanisms underlying the pathogenesis of PML,
especially the mode of acquisition, latency, and
dissemination of JC virus, site of reactivation, and the
escape of CNS immunosurveillance, remain unclear.
95

Primary JC-virus infection is typically asymptomatic
93
and
the virus remains in the kidneys, bone marrow, and
lymphoid tissue.
96
JC-virus DNA is detectable in brain
612 www.thelancet.com/neurology Vol 11 July 2012
Review
tissue from individuals without PML, but with variable
frequency (1168%).
97,98
The pathogenic sequence of events
in the development of PML is uncertain. The archetypal
virus is non-pathogenic, and for neuro virulence and PML
to occur, mutational changes are required in the non-
coding control region and in the capsid viral protein VP1,
which modulates ganglioside binding.
99
Whether PML
develops from a primary brain ingress of neurovirulent JC
virus from circulating lymphocytes after reactivation in
the bone marrow
96,100,101
or whether the latent virus
undergoes secondary reactivation within the brain is
unclear. In the brain, JC virus infects mainly oligo-
dendrocytes
102
and astrocytes,
103
and, occasionally,
cerebellar granular cells
104
and cortical pyramidal
neurons.
105,106
HIV-1 may act directly as a cofactor for JC-
virus replication via the HIV-1 TAT protein, through
transactivation of the JC-virus late promoter in glial cells,
which provides an additional pathogenic mechanism.
107
PML typically causes multifocal demyelinating lesions
in white matter, and patients often present with focal
neurological decit that has developed over several
weeks. Rarely, the decit will develop acutely and could
be mistaken for stroke.
108
Other, less common diseases
associated with JC-virus infection have been reported,
including JC-virus granule cell neuronopathy
101
with
cerebellar ataxia, JC-virus encephalopathy, and JC-virus
meningitis.
105.106
Unifocal or multifocal areas of hyperintensity in
subcortical white matter on T2-weighted, uid-attenuated
inversion recovery MRI associated with well-demarcated
hypointense lesions on T1-weighted MRI are highly
suggestive of PML. The cortical ribbon is classically
spared (table 5, gure 2). Minimal tissue oedema or no
contrast enhancement is usual unless PML is
complicated by IRIS.
109,110
Rarely, the only radiological
nding is severe cerebellar atrophy.
111

A denitive diagnosis of PML is established by the
detection of JC virus in CSF by PCR. The diagnostic
sensitivity varies across laboratories, but specicity is
high (table 4).
112,113
Brain biopsy might occasionally be
required to conrm the diagnosis.
The mainstay of treatment for PML in patients infected
with HIV is immune reconstitution with cART. This
approach has improved survival from 10% before the
introduction of cART to 5075% since.
23,114116
The presence
of JC-virus-specic CD8-positive cytotoxic T lymphocytes in
plasma is associated with improved survival.
117
No antiviral
therapy with proven e cacy is available. Various agents,
including interferon alfa,
118
cytarabine,
119
meoquine,
mirtazapine (a 5-HT
2A
-receptor blocker that can prevent JC-
virus entry into glial cells),
120
and cidofovir,
121
have shown
little or no e cacy. The low e cacy of cidofovir might be
due to poor CNS penetration and dose-limiting side-eects,
but a lipid derivative, CMX001 (Chimerix, Durham, NC,
USA), has shown promising results in vitro.
122
A common
complication, the exaggerated inammatory response,
IRIS, that is associated with cART, might unmask or
paradoxically worsen PML, with variable outcomes.
109

Corticosteroids administered at various doses and for
dierent treatment durations have had some positive
eects on brain inammation. The CDC guidelines
suggest the use of corticosteroids for PML-associated
IRIS, but not in individuals without any evidence of
inammation.
6

Primary CNS lymphoma
HIV infection is a well-established risk factor for primary
CNS lymphoma.
123
Since cART was introduced, the
incidence among people with HIV infection has
substantially declined,
124
and it is now a rare disease.
Between 2001 and 2007 in the USA, around 26 new cases
of primary CNS lymphoma per 100 000 person-years
were reported among people with AIDS compared with
038 cases among people without AIDS.
125

Primary CNS lyphoma must be distinguished from
secondary involvement of the CNS in systemic
lymphoma. The pathogenesis of primary CNS
lymphoma in HIV/AIDS is variably associated with
multiple genetic alterations, including proto-oncogene
activation (MYC, PIM1, RHOH, also known as TTF, and
PAX5),
126
and monoclonal Epstein-Barr virus infection.
127

Most primary CNS lymphomas are high-grade B-cell
tumours that are multicentric and express markers of
the germinal centre, including BCL-6 and IRF-4 (also
known as MUM1) and pan-B-cell markers, including
CD19, CD20, CD22, and CD79a.
128

Clinical features of primary CNS lymphoma are non-
specic, and may include lethargy, cognitive changes,
headache, and focal neurological symptoms from an
intracranial mass lesion. Presentations may also be
limited to the leptomeninges and, exceptionally, to the
spinal cord. Lymphoma cells are seen in the anterior
chamber of the eye in 20% of patients.
128
Typical
B systemic symptoms are not usually present.
Contrast-enhanced CT or MRI usually reveals
multifocal lesions, predominantly supratentorial, that
spread along the white-matter tracts, which show
heterogeneous contrast enhancement with gadolinium
(table 5). Use of contrast-enhanced body imaging, such as
CT of the chest, abdomen, and pelvis, or whole-body PET
scanning, is imperative to exclude systemic lymphoma.
The gold standard for diagnosis of primary CNS
lymphoma is brain biopsy. PCR is highly sensitive
(table 4) and should be used to test for Epstein-Barr virus
DNA in CSF unless lumbar puncture is contraindicated.
The positive predictive value of Epstein-Barr virus DNA
might be as low as 29%, and specicity is also low.
129

Quantication of Epstein-Barr virus DNA present in the
CSF can improve the specicity for primary CNS
lymphoma compared with qualitative detection (96% vs
66% when a cut-o DNA load of 10 000 copies per mL is
used).
130
CSF cytopathology is almost never informative.
Thallium SPECT can help to distinguish primary CNS
lymphoma from other infections, such as toxoplasmic
www.thelancet.com/neurology Vol 11 July 2012 613
Review
encephalitis, with sensitivity and specicity of about
90%.
131
We recommend thallium SPECT imaging when
empirical treatment for toxoplasmic encephalitis seems
to be failing, as tracer uptake generally indicates neoplasm
rather than infection.
Corticosteroids can obscure biopsy results and,
therefore, they should be avoided unless required to
prevent imminent herniation. Patients with HIV
infection and primary CNS lymphoma generally have
poor outlook despite treatment,
132
with a median survival
of 2 months.
133
The level of evidence for the treatment of
primary CNS lymphoma is low; people with HIV
infection have been excluded from two phase 3 trials and
one randomised phase 2 chemotherapy trial for primary
CNS lymphoma.
128
cART is the denitive treatment for
HIV-related primary CNS lymphoma, and radiotherapy
might improve survival.
134

Herpes simplex virus encephalitis
Herpes simplex virus is an infrequent cause of CNS
opportunistic infections. In studies from before and after
the widespread use of cART, PCR detection in CSF of
DNA for herpes simplex virus type 1 or 2 was only 2%,
135,136

whereas detection of cytomegalo virus was 74% in adults
with HIV infection and neurological symptoms.
35
Co-
infection of herpes simplex virus 2 and Epstein-Barr
virus has been reported.
136

Herpes simplex virus is a neurotropic virus. Type 1 is
commonly acquired in early life and may remain latent
in specic CNS sensory ganglia. Type 2 is acquired
through contact with infected mucosal surfaces, and
seroprevalence increases with age and number of sexual
partners.
35
Necrotising encephalitis, which frequently
aects the temporal and inferior frontal lobes, occurs in
patients with HIV infection, although fatal encephalitis
can occur even in the absence of a vigorous inammatory
response. Cutaneous herpetic lesions are not predictive
of CNS infection by herpes simplex virus.
Clinical presentation of CNS herpes simplex virus
infection in the setting of HIV/AIDS varies widely, and
includes fever, headache, neck stiness, vomiting,
disorientation, memory loss, dysphasia, depression, con-
fusion, personality change, seizures, visual hallucinations,
and photophobia.
35
Herpes simplex virus type 1 typically
causes encephalopathy that might develop subacutely
over several weeks. Herpes simplex virus type 2 typically
causes a diuse meningoencephalitis that can recur. PCR
of the CSF is highly sensitive (100%) and specic (996%)
for herpes simplex virus DNA, as conrmed by autopsy,
135

and can help to identify cases of mild encephalitis,
although false-negative results are possible when testing
is done less than 72 h after the onset of symptoms.
137

Electroencephalography most commonly shows periodic
lateralised epileptiform discharges in frontotemporal
regions.
35
T2-weighted brain imaging shows hyper-
intensities in most cases and sometimes gadolinium-
enhancing lesions involving the inferomedial temporal
lobes,
35
but lesions can also involve the brainstem,
cerebellum, diencephalon, and periventricular zones.
The treatment of choice is 30 mg/kg aciclovir daily,
given intravenously for 1421 days. The drug is converted
to aciclovir triphosphate, a potent inhibitor of herpes
simplex virus DNA polymerase, which is required for viral
replication. Progression can occur despite treatment,
especially if CD4-cell counts are low.
135
Ganciclovir and
foscarnet have also been used with some success,
135,136
and
aciclovir resistance has been described.
138
Relapses within
3 months of treatment have been reported, and a trial of
90 days of valaciclovir after induction treatment has been
Figure 2: Axial MRI of the brain in patients with HIV and CNS opportunistic infections
(A) Cryptococcal meningitis in a man aged 58 years who presented with headache, weight loss, anorexia, and a
generalised seizure, with a CD4-cell count of 10 cells per L. The arrow shows gadolinium enhancement of the
posterior meninges on T1-weighted MRI. A cryptococcoma is present in the right basal ganglion. (B) Cerebral
toxoplasmosis in a man aged 39 years who presented with generalised seizure and nadir in CD4-cell count of
2 cells per L. Diagnosis was conrmed by brain biopsy. Multiple hyperintense lesions with surrounding oedema
(arrow), appearing as a hypointense rim, with mass eect can be seen on T2-weighted, uid-attenuated inversion
recovery MRI. (C) Primary CNS lymphoma in a man aged 21 years who presented with acute-onset left-sided
weakness and a CD4-cell count of 0 cells per L. Diagnosis was conrmed by brain biopsy. A rim-enhancing lesion
(arrow) is visible in the right temporoparietal lobe on gadolinium-enhanced MRI. (D) Progressive multifocal
leukoencephalopathy in a man aged 42 years who presented with lethargy, left hemiparesis, dysphagia, seizures,
and visual hallucinations. T2-weighted, uid-attenuated inversion recovery MRI shows asymmetric, conuent
hyperintensities involving the cerebral white matter (arrow) without mass eect. All patients were started on
combination antiretroviral therapy and appropriate antimicrobials and supportive treatment, and all survive.
A B
C D
614 www.thelancet.com/neurology Vol 11 July 2012
Review
completed, but the results are awaited (ClinicalTrials.gov,
NCT00031486).
Conclusions
Although CNS opportunistic infections are decreasing in
frequency, they continue to have a devastating eect on
HIV-positive individuals, especially those in whom
diagnosis is delayed or HIV treatment is inadequate.
Mortality is often high even with appropriate treatment,
and recurrences and residual neurological decits are
common. For some disorders, such as PML, primary
CNS lymphoma, and multidrug-resistant tuberculosis,
curative treatments are not yet available, which
underscores the urgent need for prevention and early
detection of HIV and associated CNS opportunistic
infections. Access to cART can be lifesaving, and global
programmes to roll out this treatment in resource-poor
countries are clearly major factors in reducing the
incidence of CNS opportunistic infections.
Concurrent infection with more than one CNS
opportunistic infection is an important consideration in
the care of patients infected with HIV, which adds to the
challenge of managing the neurological complications of
HIV infection. The relations between HIV and infectious
diseases such as neurosyphilis, varicella zoster, and some
that are uncommon in high-income settings (eg, cerebral
malaria, Chagas disease, and neurocysticercosis) are not
discussed here, but they deserve further research and
attention. Vigilance is required in patients with HIV
infection receiving cART because CNS-associated IRIS
must always be considered when a patient clinically
worsens after treatment is started (table 6). Owing to the
dearth of data from clinical trials, the treatment of nearly
all CNS opportunistic infections requires a therapeutic
choice based on data from patients without HIV infection
or indirect evidence from cohort studies or case series.
Overall, the burden of CNS opportunistic infections in
people with HIV/AIDS has declined substantially, which
is a measure of widespread, successful treatment with
cART. Knowledge acquired as the HIV epidemic unfolds
has led to improved understanding of multiple infections
that were previously rare. This knowledge can now be
used to treat patients in other settings, such as in the
context of immunosuppression for transplanted
allografts and in the testing of new immunomodulatory
drugs for autoimmune diseases. Nevertheless, patients
with unrecognised, and thus untreated, HIV infections
will continue to present with CNS opportunistic
infections. Whether due to stigma associated with a
diagnosis of HIV, poor access to medical care,
unavailability of cART, non-adherence, or other factors,
the persistence of this vulnerable group of individuals
must prompt eorts to improve the outcomes for patients
with CNS opportunistic infections in the context of HIV.
Contributors
All authors contributed to the literature search, the writing, and the
review of the paper.
Conicts of interest
We declare that we have no conicts of interest.
Acknowledgments
This work is supported by a grant from the Johns Hopkins National
Institute for Mental Health Research Center (P30MH075673). ILT is
supported by a Whitehurst foundation gift. BRS is supported by the
Johns Hopkins University T32 Training Program in Hematology. GvG is
supported by John Hopkins University Project RESTORE and Multiple
Sclerosis Center. FJM is supported by an American Academy of
Neurology Practice Research Fellowship grant.
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