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HIV-associated opportunistic infections of the CNS remain a serious burden worldwide. A therapeutic gap seems to exist between the salutary effects of antiretroviral regimens and the normalisation of neurological function in HIV-associated neurocognitive disorders. In 2009, 33 3 million adults and children were living with HIV, two-thirds of whom were in sub-saharan africa.
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2. HIV-Associated Opportunistic Infections of the CNS
HIV-associated opportunistic infections of the CNS remain a serious burden worldwide. A therapeutic gap seems to exist between the salutary effects of antiretroviral regimens and the normalisation of neurological function in HIV-associated neurocognitive disorders. In 2009, 33 3 million adults and children were living with HIV, two-thirds of whom were in sub-saharan africa.
HIV-associated opportunistic infections of the CNS remain a serious burden worldwide. A therapeutic gap seems to exist between the salutary effects of antiretroviral regimens and the normalisation of neurological function in HIV-associated neurocognitive disorders. In 2009, 33 3 million adults and children were living with HIV, two-thirds of whom were in sub-saharan africa.
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 Review 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 Review 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 www.thelancet.com/neurology Vol 11 July 2012 609 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 Review 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 www.thelancet.com/neurology Vol 11 July 2012 611 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. References 1 UNAIDS. Global report: UNAIDS report on the global AIDS epidemic, 2010. Geneva: Joint United Nations Programme on HIV/AIDS, 2010. 2 Garvey L, Winston A, Walsh J, et al. HIV-associated central nervous system diseases in the recent combination antiretroviral therapy era. Eur J Neurol 2011; 18: 52734. 3 Wright EJ, Nunn M, Joseph J, et al. 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