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Survival in people infected with HIV has improved because of an increasingly powerful array of antiretroviral Lancet Neurol 2012; 11: 605–17
treatments, but neurological symptoms due to comorbid conditions, including infection with hepatitis C virus, HIV Neuroscience Program,
malnutrition, and the effects of accelerated cardiovascular disease and ageing, are increasingly salient. A therapeutic Johns Hopkins University,
Baltimore, MD, USA
gap seems to exist between the salutary effects of antiretroviral regimens and the normalisation of neurological (I L Tan MBBS, B R Smith MD,
function in HIV-associated neurocognitive disorders. Despite the advances in antiretroviral therapy, CNS opportunistic G von Geldern MD,
infections remain a serious burden worldwide. Most opportunistic infections can be recognised by a combination of F J Mateen MD,
characteristic clinical and radiological features and are treatable, but some important challenges remain in the Prof J C McArthur MBBS)
host immune response against HIV. This robust immune processes (panel 1) and, therefore, unexpected
response leads to virus being trapped within dendritic worsening after treatment for an opportunistic infection
cells in lymphoid tissue and a marked reduction of is started should prompt consideration of a second
viraemia.17 The virus, however, is not completely process. Individuals who have had immunological
eliminated from the body and chronic, persistent viral recovery from cART might still be at risk of developing
replication leads to systemic immune activation. CNS opportunistic infections.
Additionally, quiescent CD4-positive memory T cells and Some infections, such as toxoplasmic encephalitis and
macrophages serve as long-term reservoirs for latent HIV cryptococcal meningitis, evolve over hours, whereas
infection.18 Persistent viral replication, chronic immune others, such as PML and CNS lymphoma, typically have
activation, and progressive deterioration of immune a more indolent course, with development often taking
function result in symptomatic disease with severe weeks to months. Many exceptions to these patterns may,
immune deficiency in advanced HIV infection.19 Typically, however, be seen. Although many CNS opportunistic
CNS opportunistic infections occur during this stage of infections are associated with non-specific symptoms,
the HIV infection; waning immunity and high HIV load, such as fever and lethargy, the combination of symptoms
both systemically and in the CNS, create a favourable such as a new pattern of headache or headache lasting
milieu. Apart from immune deficiency, other features of longer than 3 days, new-onset seizures, or altered mental
HIV-1 might directly facilitate CNS opportunistic function strongly suggest an acute focal brain lesion.20
infections, for example in PML. Most CNS opportunistic The incidence, temporal pattern, and typical CD4-cell
infections result from reactivation of latent pathogens, count for common CNS opportunistic infections are
including PML, toxoplasmic encephalitis, and primary presented in table 3. CSF and radiographic patterns are
CNS lymphoma. HIV infection produces substantial presented in tables 4 and 5, respectively. The neuro-
depletion of the CD4-cell count and preferentially destroys imaging features provide a guide, but diagnosis should
the cellular immune system, which is crucial for defence never be made on neuroimaging findings alone.
against viral, fungal, and parasitic infections. A diagnostic and management algorithm for the
assessment and management of intracranial mass
Clinical features of CNS opportunistic infections lesions in patients with AIDS was issued by the Quality
CNS opportunistic infections should be suspected in all Standard Subcommittee of the American Academy of
people with advanced HIV infection. Individuals who Neurology in 1998.38 We present an algorithm for the
are unaware of their HIV status can first present with management of patients presenting with headaches and
CNS opportunistic infections. Additionally, in patients symptoms suggestive of CNS infections (figure 1).
in whom cART is started, immune reconstitution in- Although many advances have been made in the
flammatory syndrome (IRIS) might unmask previously diagnosis and treatment of CNS opportunistic infections,
unsuspected CNS opportunistic infections. The main the algorithm approach remains applicable, especially in
diagnostic features of CNS opportunistic infections are resource-poor settings—for example, in patients with
clinical presentation, temporal evolution, and CSF and multiple CNS lesions, empirical treatment with
radiographic features. These infections typically develop antitoxoplasmosis therapy might be appropriate. Patients
when the CD4-cell count is lower than 200 cells per μL. with severe immune suppression (CD4-cell count lower
One important principle is that up to 15% of CNS than 200 cells per μL) are at risk of toxoplasmic
opportunistic infections involve multiple concurrent encephalitis, cryptococcal meningitis, cytomegalovirus
infection, primary CNS lymphoma, and PML, whereas
patients with moderate immune suppression (CD4-cell
Panel 1: Principles of HIV-associated CNS opportunistic counts of 200–500 cells per μL) are at risk of tuberculous
infections meningitis and PML.
• CNS opportunistic infections typically occur when the In resource-rich settings, a battery of investigations is
CD4-cell count is less than 200 cells per μL used to diagnose CNS opportunistic infections
• Diagnosis should be based on clinical presentation, temporal (panel 2). Assessment of CSF with antibody testing or
evolution, CSF, and radiographic features PCR detection can be especially helpful in the definitive
• Multiple infections are present in 15% of cases and some identification of the causative organism. However, the
infections might be revealed only after combination availability and sensitivity of these tests vary, and in
antiretroviral therapy is started some cases diagnosis remains a challenging task.
• Combination antiretroviral therapy should be started, Stereotactic brain biopsy might lead to a definitive
modified, or continued with appropriate antimicrobial diagnosis in such cases, or sometimes after failed
therapy empirical therapy.39,40 Image-guided stereotactic brain
• Antimicrobial treatment is generally required until immune biopsy, particularly with MRI-compatible stereotactic
recovery (CD4-cell count more than 200 cells per μL) is systems that are associated with high diagnostic yields
achieved with antiretroviral therapy (up to 88–90%) for focal CNS lesions and low mortal-
ity (2–3%), facilitates early detection, diagnosis,
appropriate treatment, and improved prognosis.39–41 The CNS opportunistic infections that develop in patients
opportunistic infections most frequently diagnosed who are already taking cART might be due to IRIS,
with stereotactic biopsy are PML (29–30%), primary especially within the first 12 weeks after cART is started
CNS lymphoma (23–25%), and toxoplasmosis (15–16%). (table 6). Alternatively, infection could be due to cART
MRI-guided stereotactic brain biopsy might be treatment failure, and the patient’s adherence should be
indicated in patients with solitary lesions on neuro- assessed and antiretroviral resistance should be tested.
imaging, those who have multiple lesions that have not In both scenarios, cART should be continued and
responded to antitoxoplasmosis treatment, and those modified if virological failure (inability to achieve or
with multiple lesions and neurological progression.40 maintain viral replication to an HIV RNA level lower
than 200 copies per mL), immunological failure (inability
cART and management of CNS opportunistic to achieve or maintain an adequate CD4 response despite
infections virological suppression), or adverse reactions develop, in
In patients with CNS opportunistic infections, the timing addition to antimicrobial therapy.
of cART initiation is pertinent to the management of In resource-poor countries where cART is not available,
treatment-naive patients as well as those who have a prophylactic antimicrobial regimen might help to
previously received cART. The use of cART to achieve prevent CNS opportunistic infections. Region-specific
immune restoration is especially effective in patients policies on the timing and type of prophylaxis are
with opportunistic infections for which no effective needed.4 Guidelines from the Centers for Disease Control
antimicrobial therapy is available, including PML, but and Prevention (CDC) on the prevention and treatment
several complications are of concern, including drug of opportunistic infections in adults and adolescents
interactions, toxic effects, and IRIS. infected with HIV provide useful recommendations.6
CD4-cell count at Time from symptom onset to Change in mental Seizures Headache Fever Focal Cranial
presentation (cells per μL) presentation status deficits neuropathies
Toxoplasmic encephalitis21,22 <200 Days + to +++ + to ++ +++ ++ to +++ ++ to +++ +
PML23,24 <100, but occasionally higher Generally weeks to months; ++ to +++ + + to ++ + +++ +
sometimes acute, mimicking stroke
Primary CNS lymphoma25,26 <100 Weeks +++ + to ++ ++ to +++ None ++ to +++ +
Cytomegalovirus encephalitis27,28 <50 Days +++ ++ + to ++ ++ + ++
Cryptococcal meningitis29–31 <50 (rarely, up to 200) Days + to +++ + +++ + to +++ + +
Tuberculous meningitis32–34 Variable, but <200 Days to weeks ++ to +++ + +++ +++ + to ++ ++ to +++
Herpes simplex virus35 Variable Weeks +++ ++ + + to ++ ++ + to ++
PML=progressive multifocal leukoencephalopathy. IRIS=immune reconstitution inflammatory syndrome. FLAIR=fluid-attenuated inversion recovery. NA=not applicable.
Tuberculous meningitis and brain abscesses shortened detection times and can improve test
WHO estimates that a third of the world’s population is sensitivities when used in combination with acid-fast-
infected with Mycobacterium tuberculosis and that bacillus microscopy and repeated sample testing (table 4).45
individuals with HIV co-infection are at increased risk of Treatment for tuberculosis does not differ significantly
disseminated, active forms of disease, including between patients with and without HIV infection. The
tuberculous meningitis.42 The exact incidence of HIV- standard regimen begins with isoniazid, pyrazinamide,
associated tuberculous meningitis is uncertain because ethambutol, and rifampicin for 2 months. Rifampicin
epidemiological data are limited, especially for areas where notably lowers levels of protease inhibitors and nevirapine
co-infection rates are highest, such as sub-Saharan Africa.42 in plasma, but rifabutin is an appropriate alternative.47
Infection with M tuberculosis occurs after inhalation of After this initial phase, isoniazid and rifampicin or
airborne bacilli that traverse the alveoli into the rifabutin are continued for at least 9–12 months.48 The role
bloodstream. Intact T-cell-mediated immunity helps to of corticosteroids and the optimum timing of the initiation
control haematogenous spread. The disease disseminates of cART in conjunction with antituberculosis therapy
readily in patients infected with HIV who have reduced remain controversial issues. In a randomised, controlled
CD4-cell counts. In the brain, granulomas or Rich foci trial of 545 patients with tuberculous meningitis in
can form within the subpial and subependymal layers43 Vietnam, an adjuvant corticosteroid (dexamethasone) was
and these can expand to create tuberculomas or associated with a 30% reduction in the relative risk of
parenchymal brain abscesses (table 5), or, more death, but not a significant reduction in the proportion of
commonly, rupture to cause meningitis. severely disabled patients.49 A smaller study assessed
Rapid detection is crucial in patients with HIV-associated 253 patients who were treated with standardised anti-
tuberculous meningitis, but detection of acid-fast bacilli or tuberculosis treatment, adjuvant dexamethasone, and
the causative organism by positive culture or PCR is often prophylactic co-trimoxazole and who were followed-up for
difficult (table 4).44 Sensitivities for these tests have 12 months. Immediate start of cART did not improve
traditionally been poor at about 50%, although patients outcomes compared with cART deferred for 2 months.32
infected with HIV have higher yield rates of up to 80%, Thus, delayed initiation of cART is recommended for
possibly owing to incomplete immune responses and patients with HIV-associated tuberculous meningitis.
increased bacterial loads.45 Neither tuberculin skin tests Mortality from HIV-associated tuberculous meningitis
(sensitivity 31%) nor the interferon-γ-release assay often exceeds 50%, which is roughly double the rate in
QuantiFERON-TB Gold (Cellestis, Valencia, CA, USA; patients without HIV.43 Even with the addition of cART,
sensitivity 60%) can precisely exclude tuberculosis in mortality is not improved.32
individuals with HIV, especially when CD4-cell counts are Multidrug-resistant tuberculosis (resistant to at least
lower than 200 cells per μL.46 Repeated, large-volume isoniazid and rifampicin) is estimated to account for
lumbar punctures might improve the yield.44 CSF tests that 3·6% of incident tuberculosis diagnoses worldwide, and
include a nucleic-acid amplification test have substantially extensively drug-resistant disease (also resistant to
In resource-limited settings, only amphotericin B and retinal necrosis, but macular oedema, retinal detachment,
fluconazole are generally available.75 A large trial in Africa and papillitis might also reduce visual acuity.84
supports the use of fluconazole as primary prophylaxis, Radiculomyelitis typically affects the lumbosacral regions
irrespective of whether patients are receiving cART.76 and can present as a rapidly progressive cauda equina
IRIS affects 10–40% of patients with cryptococcal syndrome. The clinical presentation resembles Guillain-
meningitis, and the risk is increased in individuals who Barré syndrome, except that the CSF generally has a
are antiretroviral naive and who have high concentrations neutrophilic predominance and MRI imaging shows
of HIV RNA. Mortality for IRIS associated with contrast-enhancing and greatly thickened nerve roots.
cryptococcal meningitis is 33–66%.77 Appropriate Little evidence is available to definitively guide the
management of IRIS includes continuation of cART, treatment of cytomegalovirus encephalitis. A combination
antifungal therapy, and a course of corticosteroids.6 of ganciclovir and foscarnet was generally used before the
introduction of cART, but this regimen is associated with
Cytomegalovirus encephalitis substantial adverse effects. The use of cART plus one
Neurological diseases caused by cytomegalovirus are rare anticytomegalovirus treatment is favoured. Ganciclovir
but very serious. Infection can lead to encephalitis, was the first available agent and remains the first-line
retinitis, radiculomyelitis, or mononeuritis multiplex. treatment, although mutations in the viral genes UL97 or
Although cytomegalovirus encephalitis seems to occur at UL54 can lead to drug resistance. Ganciclovir is only
similar rates worldwide, retinitis has a distinct available intravenously, but its prodrug, valganciclovir, can
geographical distribution—it is the predominant HIV- be given orally. While a sustained-release intraocular
associated eye disease in Asia, where up to a third of implant treats cytomegalovirus retinitis in the affected eye,
HIV-infected patients are affected. 78 oral ganciclovir is recommended to prevent cytomegalo-
The ubiquitous herpes virus, cytomegalovirus is virus retinitis or extraocular disease.85 Foscarnet is used
endemic worldwide and usually causes asymptomatic or when patients develop dose-limiting leucopenia while
clinically benign infections. Most people have been taking ganciclovir or in ganciclovir-resistant cases,
infected by the time they reach adulthood. The high although some cross-resistance has been shown. Cidofovir
neurovirulence of some cytomegalovirus strains and is a competitive inhibitor of the viral DNA polymerase
host genetic risk factors might play a part in the after conversion to an active form. As the activation of
development of neurological disease.79 cidofovir does not rely on viral kinases, it retains its activity
In cases of suspected cytomegalovirus encephalitis, for cytomegalovirus with UL97 mutations, but mutations
brain imaging with contrast should be done. Meningeal in DNA polymerase genes, such as UL54, lead to
enhancement or periventricular inflammation can be resistance.86 Secondary prophylaxis with long-term oral
seen in infected patients, but these findings are not anticytomegalovirus therapy should be continued until
specific to cytomegalovirus encephalitis (table 5).80 PCR sustained immune recovery is achieved with cART.87 Drug
of CSF is highly sensitive and specific in the diagnosis of susceptibility testing based on screening for known
cytomegalovirus encephalitis (table 4) and might also be resistance-inducing mutations in the viral genome can
positive in patients with cytomegalovirus radiculomyelitis. help to guide antiviral therapy.88
Quantitative PCR results can also help in the assessment
of disease severity and in monitoring response to Progressive multifocal leukoencephalopathy
antiviral therapy, having a sensitivity of 250 copies per mL PML is a rare but severe CNS opportunistic infection that
and a diagnostic specificity of 90–99%.81 A neutrophil- is caused by the reactivation of latent JC virus, a
predominant CSF pleocytosis with negative bacterial polyomavirus, in immunosuppressed individuals.
culture is highly suggestive of cytomegalovirus Unlike most of the other HIV-associated CNS
infection.82 Retinitis associated with cytomegalovirus opportunistic infections, which are very rare when the
infection is typically diagnosed by areas of haemorrhagic CD4-cell count is higher than 100–200 cells per μL, PML
infarction, perivascular sheathing, and retinal occasionally occurs in patients with much higher CD4-
opacification on fundoscopy. cell counts (table 3).89,90 The seroprevalence of JC virus in
Patients with cytomegalovirus encephalitis commonly the general population is 50–90%,91–93 and about 30% of
present with rapidly progressive encephalopathy, often people shed the virus in urine.94 The incidence of PML
with hyponatraemia due to adrenal involvement.83 has declined from seven cases per 1000 patient-years
Brainstem symptoms and seizures can also occur. before the introduction of cART to 0·7 per 1000 (table 1).7
Patients with extraocular complications frequently have The mechanisms underlying the pathogenesis of PML,
previous or concurrent cytomegalovirus retinitis and especially the mode of acquisition, latency, and
should undergo fundoscopy, as blindness can develop if dissemination of JC virus, site of reactivation, and the
retinal disease remains untreated. Visual symptoms can escape of CNS immunosurveillance, remain unclear.95
include floaters, loss of peripheral vision, or central Primary JC-virus infection is typically asymptomatic93 and
scotoma, but not all patients are symptomatic. The visual the virus remains in the kidneys, bone marrow, and
loss in cytomegalovirus retinitis is usually the result of lymphoid tissue.96 JC-virus DNA is detectable in brain
tissue from individuals without PML, but with variable paradoxically worsen PML, with variable outcomes.109
frequency (11–68%).97,98 The pathogenic sequence of events Corticosteroids administered at various doses and for
in the development of PML is uncertain. The archetypal different treatment durations have had some positive
virus is non-pathogenic, and for neurovirulence and PML effects on brain inflammation. The CDC guidelines
to occur, mutational changes are required in the non- suggest the use of corticosteroids for PML-associated
coding control region and in the capsid viral protein VP1, IRIS, but not in individuals without any evidence of
which modulates ganglioside binding.99 Whether PML inflammation.6
develops from a primary brain ingress of neurovirulent JC
virus from circulating lymphocytes after reactivation in Primary CNS lymphoma
the bone marrow96,100,101 or whether the latent virus HIV infection is a well-established risk factor for primary
undergoes secondary reactivation within the brain is CNS lymphoma.123 Since cART was introduced, the
unclear. In the brain, JC virus infects mainly oligo- incidence among people with HIV infection has
dendrocytes102 and astrocytes,103 and, occasionally, substantially declined,124 and it is now a rare disease.
cerebellar granular cells104 and cortical pyramidal Between 2001 and 2007 in the USA, around 26 new cases
neurons.105,106 HIV-1 may act directly as a cofactor for JC- of primary CNS lymphoma per 100 000 person-years
virus replication via the HIV-1 TAT protein, through were reported among people with AIDS compared with
transactivation of the JC-virus late promoter in glial cells, 0·38 cases among people without AIDS.125
which provides an additional pathogenic mechanism.107 Primary CNS lyphoma must be distinguished from
PML typically causes multifocal demyelinating lesions secondary involvement of the CNS in systemic
in white matter, and patients often present with focal lymphoma. The pathogenesis of primary CNS
neurological deficit that has developed over several lymphoma in HIV/AIDS is variably associated with
weeks. Rarely, the deficit will develop acutely and could multiple genetic alterations, including proto-oncogene
be mistaken for stroke.108 Other, less common diseases activation (MYC, PIM1, RHOH, also known as TTF, and
associated with JC-virus infection have been reported, PAX5),126 and monoclonal Epstein-Barr virus infection.127
including JC-virus granule cell neuronopathy101 with Most primary CNS lymphomas are high-grade B-cell
cerebellar ataxia, JC-virus encephalopathy, and JC-virus tumours that are multicentric and express markers of
meningitis.105.106 the germinal centre, including BCL-6 and IRF-4 (also
Unifocal or multifocal areas of hyperintensity in known as MUM1) and pan-B-cell markers, including
subcortical white matter on T2-weighted, fluid-attenuated CD19, CD20, CD22, and CD79a.128
inversion recovery MRI associated with well-demarcated Clinical features of primary CNS lymphoma are non-
hypointense lesions on T1-weighted MRI are highly specific, and may include lethargy, cognitive changes,
suggestive of PML. The cortical ribbon is classically headache, and focal neurological symptoms from an
spared (table 5, figure 2). Minimal tissue oedema or no intracranial mass lesion. Presentations may also be
contrast enhancement is usual unless PML is limited to the leptomeninges and, exceptionally, to the
complicated by IRIS.109,110 Rarely, the only radiological spinal cord. Lymphoma cells are seen in the anterior
finding is severe cerebellar atrophy.111 chamber of the eye in 20% of patients.128 Typical
A definitive diagnosis of PML is established by the B systemic symptoms are not usually present.
detection of JC virus in CSF by PCR. The diagnostic Contrast-enhanced CT or MRI usually reveals
sensitivity varies across laboratories, but specificity is multifocal lesions, predominantly supratentorial, that
high (table 4).112,113 Brain biopsy might occasionally be spread along the white-matter tracts, which show
required to confirm the diagnosis. heterogeneous contrast enhancement with gadolinium
The mainstay of treatment for PML in patients infected (table 5). Use of contrast-enhanced body imaging, such as
with HIV is immune reconstitution with cART. This CT of the chest, abdomen, and pelvis, or whole-body PET
approach has improved survival from 10% before the scanning, is imperative to exclude systemic lymphoma.
introduction of cART to 50–75% since.23,114–116 The presence The gold standard for diagnosis of primary CNS
of JC-virus-specific CD8-positive cytotoxic T lymphocytes in lymphoma is brain biopsy. PCR is highly sensitive
plasma is associated with improved survival.117 No antiviral (table 4) and should be used to test for Epstein-Barr virus
therapy with proven efficacy is available. Various agents, DNA in CSF unless lumbar puncture is contraindicated.
including interferon alfa,118 cytarabine,119 mefloquine, The positive predictive value of Epstein-Barr virus DNA
mirtazapine (a 5-HT2A-receptor blocker that can prevent JC- might be as low as 29%, and specificity is also low.129
virus entry into glial cells),120 and cidofovir,121 have shown Quantification of Epstein-Barr virus DNA present in the
little or no efficacy. The low efficacy of cidofovir might be CSF can improve the specificity for primary CNS
due to poor CNS penetration and dose-limiting side-effects, lymphoma compared with qualitative detection (96% vs
but a lipid derivative, CMX001 (Chimerix, Durham, NC, 66% when a cut-off DNA load of 10 000 copies per mL is
USA), has shown promising results in vitro.122 A common used).130 CSF cytopathology is almost never informative.
complication, the exaggerated inflammatory response, ²⁰¹Thallium SPECT can help to distinguish primary CNS
IRIS, that is associated with cART, might unmask or lymphoma from other infections, such as toxoplasmic
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