HIV/AIDS

Main Text

Preamble

In this chapter, we explore the “many faces” of HIV/AIDS as it affects the CNS. We begin by discussing the manifestations of HIV itself in the brain, i.e., HIV encephalitis and the recently described HIV-associated CD8 encephalitis. We follow with a consideration of unusual but important associated findings, such as HIV vasculopathy, HIV-associated bone marrow changes, and benign salivary gland lymphoepithelial lesions.

We then consider the broad spectrum of opportunistic infections that complicate HIV/AIDS and what happens when an HIV-positive patient is also co-infected with tuberculosis (TB), another sexually transmitted disease, or malaria. Long-term survivors with treated AIDS and the phenomenon of immune reconstitution inflammatory syndrome (IRIS) are then presented. We conclude the chapter by discussing neoplasms that occur in the setting of HIV/AIDS (the so-called AIDS-defining malignancies).

HIV Infection

Preamble

HIV is a neurovirulent infection that has both direct and indirect effects on the CNS. Neurologic complications can arise from the HIV infection itself, from opportunistic infections or neoplasms, and from treatment-related metabolic derangements.

In this section, we consider the effects of the HIV virus itself on the brain. Extracranial manifestations of HIV/AIDS may also be identified on brain imaging studies, so we discuss these as well.

HIV Encephalitis

Between 75-90% of HIV/AIDS patients have demonstrable HIV-induced brain injury at autopsy (14-1). Although many patients remain asymptomatic for variable periods, brain infection is the initial presenting symptomatology in 5-10% of cases. Approximately 25% of treated HIV/AIDS patients develop moderate cognitive impairment despite good virologic response to therapy.

Terminology

HIV encephalitis (HIVE) and HIV leukoencephalopathy (HIVL) are the direct result of HIV infection of the brain. Opportunistic infections are absent early, although co-infections or multiple infections are common later in the disease course.

Etiology

HIV is a pathogenic neurotropic human RNA retrovirus. HIV-1is responsible for most cases of HIV/AIDS. HIV-2infection is found primarily in West Africa. Unless otherwise noted in this discussion, “HIV” or “HIV infection” refers to HIV-1 infection.

The two major targets of viral infection are lymphoid tissue—especially T cells—and the CNS. HIV crosses the blood-brain barrier (BBB) both as cell-free virus and infected monocytes and T cells, which migrate across the intact BBB, penetrating the brain within 24-48 hours after initial exposure.

While HIV does not directly infect neurons, it infects astrocytes and microglia. Recent studies have demonstrated that HIV persists in perivascular macrophages and microglia despite suppression with antiretroviral therapy (ART), thus remaining in a latent “hidden” state that can lead to sustained pathologic inflammatory responses.

Recent studies of cellular silencing mechanisms in microglia show that HIV-1 latency can be reversed by proinflammatory cytokines and signaling from damaged neurons, thus creating intermittent cycles of HIV-1 reactivation and silencing that can lead to sustained pathologic inflammatory responses.

Pathology

In early stages, the brain appears grossly normal. Advanced HIVE results in generalized brain volume loss (“atrophy”) with enlarged ventricles and subarachnoid spaces. Ill-defined, diffuse myelin pallor with poorly demarcated areas of myelin loss ensues. Lesions are most prominent in the deep periventricular white matter (WM) and corona radiata.

Microscopically, HIVE is characterized by gliosis, microglial activation, perivascular inflammation, and multinucleated giant cells containing viral antigens. Lymphocytic infiltrates, predominately T cells [often CD8(+)], are common.

Clinical Issues

Epidemiology

Almost 60% of all AIDS patients eventually develop overt neurologic manifestations. Despite potent suppression of HIV-1 viral replication in the CNS by ART, between 15-60% of patients exhibit ongoing neuroinflammation and symptoms of HIV-1-associated neurocognitive disorders (HANDs).

Presentation

Early brain infection with HIV is often asymptomatic, and cognitive and functional performances are both initially normal. HANDs develop as intermediate and long-term complications. A nadir CD4 cell count below 50/mL has the greatest risk of HIV-associated neurocognitive impairment.

Imaging

CT Findings

NECT scans may be normal in the early stages. Mild to moderate atrophy with patchy or confluent WM hypodensity develops as the disease progresses (14-2). HIVE does not cause mass effect and does not enhance on CECT.

MR Findings

Generalized volume loss with enlarged ventricles and sulci is best appreciated on T1WI or thin-section inversion recovery sequences. WM signal intensity is generally normal or near normal on T1WI.

T2/FLAIR initially shows bilateral, patchy, relatively symmetric WM hyperintensities. With time, confluent “hazy,” ill-defined hyperintensity in the subcortical and deep cerebral WM develops, and volume loss ensues (14-4). HIVE usually does not enhance on T1 C+ and usually shows no restriction on DWI. In fulminant cases, perivenular enhancement may indicate acute demyelination.

Differential Diagnosis

Progressive multifocal leukoencephalopathy (PML) has strikingly asymmetric hyperintensities on T2/FLAIR. Both the hemispheric and posterior fossa WM (often both cerebral peduncles) are commonly affected. PML also often involves the subcortical U-fibers, which are usually spared in HIVE.

Co-infections with other infectious agents are common in HIVE and may complicate its classic imaging appearance. Cytomegalovirus (CMV) can also cause a similarly diffuse encephalitis but frequently exhibits ependymal enhancement. Toxoplasmosis causes multifocal punctate and “target” or ring-enhancing lesions that are most prominent in the basal ganglia.

Herpes encephalitis and human herpesvirus-6 (HHV-6) encephalitis both involve the temporal lobes, especially the cortex.

HIV-associated CD8 encephalitis (HIV-CD8E)is a distinct disorder characterized by acute brain inflammation and infiltration by CD8(+) T lymphocytes. Imaging shows brain swelling with diffuse T2/FLAIR WM hyperintensity. Enhancement along penetrating arteries, medullary veins, and edges of the WM abnormalities is typical (14-6).

Immune reconstitution inflammatory syndrome (IRIS)occurs with and is characterized by other associated infectious agents (e.g., JC virus, TB, fungal infections). HIV viral antigens are inconstant and minimally detected.

HIV-Associated CD8 Encephalitis

Terminology

HIV-associated CD8 encephalitis (HIV-CD8E) is a severe inflammatory disorder with perivascular and diffuse brain infiltration by CD8(+) T lymphocytes. HIV-CD8E is clinically and pathologically distinct from classic HIV encephalitis (HIVE).

Etiology

HIV viral escape in the CSF has been identified in nearly 70% of HIV-CD8E cases, but the exact pathogenesis of the disorder is unknown. Antiretroviral therapy (ART) and immune reconstitution inflammatory syndrome (IRIS) each occur in 27% of proven cases.

Pathology

Marked cerebral inflammation and swelling—both supra- and infratentorial—is the hallmark of HIV-CD8E. CD8(+) T cells flood into the brain, causing perivascular and diffuse cerebral infiltrates, almost always in WM. The cerebrum, brainstem, and cerebellum are predominately affected.

Other infectious causes of encephalitis must be excluded. CSF and brain tissue viral studies (HSV, HHV6, HHV8, VZV, EBV, CMV, JC, West Nile, parvovirus) are negative except for HIV-1 (“viral escape”).

Clinical Issues

HIV-CD8E typically occurs when the virus is apparently well controlled by ART and should be considered in an HIV patient whose brain function suddenly deteriorates. Signs and symptoms are related to marked cerebral inflammation and swelling. Coma and death may ensue unless the disease is treated promptly with corticosteroids, which reduces fatality from nearly 70% to 30%.

Black (especially African) ethnicity appears to be a key risk factor in the majority of published cases.

Imaging

Imaging shows diffuse WM changes and cerebral swelling/edema. The cerebral ventricles and sulci may appear compressed. Multifocal confluent areas of T2/FLAIR hyperintensity in the cerebral and cerebellar WM are typical (14-6A). Multiple enhancing foci are present on T1 C+ sequences (14-7A). Distended, enhancing medullary veins may be striking and are strongly suggestive of the diagnosis (14-6B) (14-6C).

Differential Diagnosis

In HIVE, T2/FLAIR confluent hyperintensities are present in the periventricular WM with relative sparing of the subcortical tracts. Mass effect and enhancement are absent.

Progressive multifocal leukoencephalopathy (PML)is asymmetric and multifocal, often affecting the subcortical U-fibers, and CSF is positive for JC virus.

Rare cases of CD8E have been reported with progressive hemispheric atrophy, resembling Rasmussen encephalitis.

Primary CNS lymphoma (PCNSL)is seen as T1-hypointense periventricular/deep WM lesions often occurring with rim enhancement on T1 C+ sequences. Restricted diffusion in the center of the lesion is common.

Other differential diagnostic considerations include HIV vasculitis, posterior reversible encephalopathy syndrome, acute disseminated encephalitis, and classic virus-associated or autoimmune encephalitis.

Miscellaneous Manifestations of HIV/AIDS

HIV/AIDS Bone Marrow Changes

Bone marrow alterations are common in HIV/AIDS patients (14-8). Fatty, T1-hyperintense, yellow marrow is replaced with T1-hypointense, active hematopoietic tissue (14-9). The calvarium and clivus appear mottled or gray. The affected vertebral bodies appear hypointense relative to the intervertebral discs (the bright disc sign).

Lymphoid Hyperplasia

Lymphoid hyperplasia of Waldeyer ring is the most common finding observed on brain MR. Unusually prominent tonsils and adenoids in a patient over 25-30 years of age should raise suspicion of HIV infection (14-10).

Benign Lymphoepithelial Lesions

Benign lymphoepithelial lesions of HIV (BLL-HIV) are nonneoplastic cystic masses that enlarge salivary glands. Bilateral lesions are common. The parotid glands are most frequently affected (14-12).

NECT scans show multiple bilateral, well-circumscribed cysts within enlarged parotid glands. A thin, enhancing rim is present on CECT scans (14-13). The cysts are homogeneously hyperintense on T2WI and demonstrate rim enhancement on T1 C+(14-14).

Vasculopathy

Recurrent strokes are increasingly common in chronic HIV/AIDS. HIV-associated vasculopathy can cause striking fusiform dilatation of the circle of Willis and proximal middle cerebral arteries (14-15).

Opportunistic Infections

Preamble

With the advent of effective antiretroviral therapy (ART), the prevalence of CNS opportunistic infections has decreased five- to tenfold. Nevertheless, these infections and HIV co-infections, such as TB, continue to create substantial morbidity.

Toxoplasmosis

Toxoplasmosis (toxo) is the most common opportunistic infection and most frequent cause of a cerebral mass lesion in patients with HIV/AIDS. As 20-70% of the population is seropositive for Toxoplasma gondii, infection in HIV/AIDS patients generally represents activation of latent infection.

With widespread use of ART, the worldwide prevalence of toxo has decreased substantially. In high-income countries, the prevalence is approximately 25%. However, in resource-poor regions, such as Africa, 35-50% of all HIV/AIDS patients develop CNS toxo. Infection most often becomes symptomatic when CD4 counts fall below 200.

CNS toxo most commonly involves the basal ganglia, thalami, corticomedullary junctions, and cerebellum (14-16). Multifocal lesions are more common than solitary ones. In contrast to lymphoma, only 15-20% of toxo lesions present as solitary masses. Although large lesions do occur, most lesions are small and average between 2-3 cm in diameter. The most common finding on NECT scan is multiple ill-defined hypodense lesions in the basal ganglia or thalamus with moderate to marked peripheral edema (14-17A).

MR shows a T1-hypointense mass that occasionally demonstrates mild peripheral hyperintensity caused by coagulative necrosis or hemorrhage. T2WI and FLAIR may exhibit a pattern of concentric zones of hypointensity and hyperintensity (14-17B).

One or more nodular and ring-enhancing masses are typical on T1 C+(14-17B). A ring-shaped zone of peripheral enhancement with a small, eccentric mural nodule represents the so-called eccentric target sign (14-17C)and can be identified in approximately 1/3 of cases. The enhancing nodule is a collection of concentrically thickened vessels, whereas the rim enhancement is caused by an inflamed vascular zone that borders the necrotic abscess cavity.

The major differential diagnosis is primary CNS lymphoma (PCNSL). Solitary toxo lesions are uncommon; most cases present with multifocal lesions. In contrast, approximately 70% of isolated CNS masses in HIV/AIDS patients are PCNSL (14-38). Mean relative cerebral blood volume (rCBV) in CNS toxo is low (< 1.5) compared to lymphoma. AIDS-related CNS toxo also has positive findings on serology in 80% of cases, and CSF PCR is definitive.

Cryptococcosis

Fungal infections can be life threatening in immunocompromised patients, especially those with HIV/AIDS. Although many different fungi can cause CNS infection, the most common fungi to affect patients with HIV/AIDS are Candida albicans, Aspergillus species, and Cryptococcus neoformans (crypto). Crypto is the third most common CNS infectious agent in HIV/AIDS patients after HIV and T. gondii. Prior to highly active ART (HAART), crypto-CNS infections occurred in 10% of HIV patients, but it is now relatively rare in developed countries. Crypto usually occurs when CD4 counts drop below 50-100 cells/μL.

Gelatinous mucoid-like cryptococcal capsular polysaccharides and budding yeast may accumulate within dilated perivascular spaces (PVSs) (14-18), especially in the basal ganglia (14-19), midbrain, dentate nuclei, and subcortical WM (14-18). NECT scans show hypodensity in the basal ganglia. Cryptococcal gelatinous pseudocysts (14-20)are hypointense to brain on T1WI and very hyperintense on T2WI (14-21). The lesions generally follow CSF signal intensity and suppress on FLAIR. Perilesional edema is generally absent. Lack of enhancement on T1 C+ is typical, although mild pial enhancement is sometimes observed.

The differential diagnosis includes prominent PVSs. Enlarged PVSs do not enhance. In HIV/AIDS patients with CD4 counts under 20, symmetrically enlarged PVSs should be considered cryptococcal infection and treated as such. Toxoplasmosis usually has multifocal ring- or target-like enhancing lesions with significant surrounding edema. TB usually demonstrates strong enhancement in the basal meninges. Tuberculomas are generally hypointense on T2WI. PCNSL in HIV/AIDS patients often shows hemorrhage, necrosis, and ring enhancement. Solitary lesions are more common than multifocal involvement.

Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection caused by the JC virus (JCV), a member of the Papovaviridae family. JCV is a ubiquitous virus that circulates widely. More than 85% of the adult population worldwide has antibodies against JCV. Asymptomatic infection is probably acquired in childhood or adolescence and remains latent until the virus is reactivated.

Pathologically, early lesions appear as small, yellow-tan, round to ovoid foci at the GM-WM junction. The cortex remains normal. With lesion coalescence, large, spongy-appearing depressions in the cerebral and cerebellar WM appear (14-22).

Imaging plays a key role in the diagnosis and follow-up of JCV infections. Classic PML (cPML) can appear as solitary or multifocal widespread lesions. Any area of the brain can be affected, although the supratentorial lobar WM is the most commonly affected site. The posterior fossa WM—especially the middle cerebellar peduncles—is the second most common location. In occasional cases, a solitary lesion in the subcortical U-fibers is present.

More than 90% of cPML cases show hypodense areas in the subcortical and deep periventricular WM on NECT; 70% are multifocal. Extent varies from small, scattered subcortical foci to large, bilateral but asymmetric confluent WM lesions. In the early acute stage of infection, some mass effect with focal gyral expansion can be present. At later stages, encephaloclastic changes with atrophy and volume loss predominate. PML lesions generally do not enhance on CECT.

MR is the imaging procedure of choice in suspected PML. Multifocal, bilateral but asymmetric, irregularly shaped hypointensities on T1WI are typical. The lesions are heterogeneously hyperintense on T2WI (14-23)and typically extend into the subcortical U-fibers all the way to the undersurface of the cortex, which remains intact even in advanced disease. Smaller, almost microcyst-like, very hyperintense foci within and around the slightly less hyperintense confluent lesions represent the characteristic spongy lesions seen in more advanced PML.

Appearance on DWI varies according to disease stage. In newly active lesions, DWI restricts strongly. Slightly older lesions show a central core with low signal intensity and high mean diffusivity (MD) surrounded by a rim of higher signal intensity and lower MD (14-25). Chronic, “burned-out” lesions show increased diffusion due to disorganized cellular architecture.

cPML generally does not enhance on T1 C+ scans, although faint, peripheral rim-like enhancement occurs in 5% of all cases. The exception is hyperacute PML in the setting of IRIS and in multiple sclerosis (MS) patients on natalizumab. In these cases, striking foci with irregular rim enhancement are frequently—but not invariably—present. Peripheral enhancement &/or mass effect decrease with corticosteroids.

The major differential diagnosis of cPML is HIV encephalitis (HIVE). HIVE demonstrates more symmetric WM disease while sparing the subcortical U-fibers. IRIS is usually more acute and demonstrates strong but irregular, ring-like enhancement.

Cytomegalovirus

CNS cytomegalovirus (CMV) is a late-onset disease in immunocompromised patients. With increasing use of HAART, < 2% of HIV/AIDS patients develop overt symptoms of CMV infection.

Acquired CMV in the setting of HIV/AIDS most commonly manifests as meningoencephalitis (14-26)and ventriculitis/ependymitis. Typical imaging findings are those of underlying HIVE (atrophy, “hazy” WM disease) with ependymal enhancement around the lateral ventricles (14-27).

Tuberculosis

TB is one of the most devastating co-infections in immunocompromised patients and is the main cause of morbidity and mortality in HIV-infected patients worldwide.

HIV is the most powerful known risk factor for reactivation of latent TB to active disease. HIV patients who are co-infected with TB have 100x increased risk of developing active TB. In turn, TB co-infection exacerbates the severity and accelerates the progression of HIV.

Patients with prior TB who become HIV positive may also reactivate their disease with old calcified tuberculomas developing new surrounding edema and mass effect (14-28). In severely immunocompromised HIV patients with especially low CD4 counts, fulminant reactivated TB may develop multiple ring-enhancing pseudoabscesses (14-29).

Immune Reconstitution Inflammatory Syndrome

Terminology

CNS immune reconstitution inflammatory syndrome (IRIS) is a T-cell-mediated encephalitis that occurs in the setting of treated HIV or autoimmune disease (e.g., MS). CNS IRIS is also called neuro-IRIS. The diagnosis of IRIS is based on evidence of clinical worsening and immune reconstitution in the setting of antiretroviral therapy (ART) initiation.

Etiology

Most investigators consider neuro-IRIS a dysregulated immune response and pathogen-driven disease whose clinical expression depends on host susceptibility, the intensity and quality of the immune response, and the specific characteristics of the “provoking pathogen” itself.

IRIS occurs when forced immune reconstitution causes an exaggerated response to infectious (or sometimes noninfectious) antigens with massive destruction of virus-infected cells. IRIS develops in two distinct scenarios: “Unmasking” IRIS and “paradoxical” IRIS. Both differ in clinical expression, disease management, and prognosis, although their imaging manifestations are similar.

“Unmasking” IRIS occurs when ART reveals a subclinical, previously undiagnosed opportunistic infection. Immune restoration leads to an immune response against a living pathogen. Here, brain parenchyma is damaged by both the replicating pathogen and the incited immune response.

“Paradoxical” IRIS occurs when a patient who has been successfully treated for a recent opportunistic infection unexpectedly deteriorates after initiation of ART. Here, there is no newly acquired or reactivated infection. The recovering immune response targets persistent pathogen-derived antigens or self-antigens and causes tissue damage.

Several different underlying pathogens have been identified with IRIS. The most common are JCV (PML-IRIS), TB (TB-IRIS), and fungal infections, especially Cryptococcus (crypto-IRIS). Some parasitic infections—such as toxoplasmosis—are relatively common in HIV/AIDS patients but rarely associated with IRIS.

Not all neurotropic viruses cause IRIS. HIV itself rarely causes neuro-IRIS. Herpesviruses (e.g., herpes simplex virus, varicella-zoster virus, CMV) are all rarely reported causes of neuro-IRIS.

An unusual type of IRIS occurs in MS patients treated with natalizumab who subsequently develop PML. Natalizumab-related PML is managed by discontinuation of the drug and instituting plasmapheresis/immunoadsorption (PLEX/IA). Neurologic deficits and imaging studies in some patients worsen during subsequent immune reconstitution, causing natalizumab–associated PML-IRIS. Two types are recognized: Patients with early PML-IRIS (IRIS develops before institution of PLEX/IA) and patients with late PML-IRIS (IRIS develops after treatment with PLEX/IA). Neurologic outcome is generally worse in early PML-IRIS with a mortality rate approaching 25%.

Pathology

There are no specific histologic features or biomarkers for neuro-IRIS; rather, the diagnosis is established on the basis of clinical manifestations, exclusion of other disorders, and imaging or histopathologic evidence of inflammatory reaction.

Clinical Issues

Epidemiology

Between 15-35% of AIDS patients beginning ART develop IRIS. Of these, ~ 1% develop neuro-IRIS. The two most important risk factors are a low CD4 count and a short time interval between treatment of the underlying infection and the commencement of ART. The highest risk is in patients with a count < 50 cells/μL.

While CNS IRIS is thought to be prevalent in resource-limited settings, its identification is constrained by limited data on pretreatment HIV disease and diagnostic testing.

Epidemiology varies according to the specific “provoking pathogen.” The most common cause of neuro-IRIS is JCV. Latent virus is reactivated when patients become immunodeficient. The reactivated virus infects oligodendrocytes, causing the lytic demyelination characteristic of PML. Nearly 1/3 of patients with preexisting PML worsen after beginning HAART and are considered to have “unmasking”PML-IRIS.

TB-IRIS occurs in 15-18% of patients who are co-infected with TB-HIV if ART is initiated before the TB is adequately treated. Significant increase in CD4 count between ART initiation and IRIS onset supports the diagnosis of IRIS. Almost 20% of TB-IRIS patients develop neurologic involvement characterized by meningitis, tuberculomas, and radiculomyelopathies. TB-IRIS is associated with a mortality rate of up to 30%. Corticosteroids remain the only trial-supported therapy for prevention and management of TB-IRIS.

“Paradoxical”crypto-IRIS affects 20% of HIV-infected patients in whom ART was initiated after treatment of neuromeningeal cryptococcosis. The major manifestation of crypto neuro-IRIS is aseptic recurrent meningitis. Parenchymal cryptococcomas are rare.

Despite the high prevalence of parasitic infestations in resource-poor countries, only a few cases of parasite-associated neuro-IRIS have been reported. All have been caused by T. gondii.

Natalizumab-associated IRIS is rare. To date, ~ 50 cases have been reported. Most are PML-IRIS.

Presentation

Neuro-IRIS is a polymorphic condition with heterogeneous clinical manifestations. The most common presentation is clinical deterioration of a newly treated HIV-positive patient despite rising CD4 counts and diminishing viral loads.

Natural History and Treatment Options

Given that a low CD4 T-cell count is a major risk factor for developing IRIS, starting HAART at a count of > 350 cells/μL will prevent most cases.

Systemic IRIS is usually mild and self-limited. Prognosis in neuro-IRIS is variable. Corticosteroids and cytokine neutralization therapy have been used for treatment of neuro-IRIS with mixed results and are controversial.

Patients with neuro-IRIS may die within days to weeks. Mortality from PML-IRIS exceeds 40%, whereas that of crypto-IRIS is ~ 20%. TB-IRIS mortality is slightly lower (13%).

Imaging

A widespread pattern of confluent and linear or “punctate” perivascular hyperintensities on T2/FLAIR is virtually pathognomonic of PML-IRIS. A punctate pattern of enhancement is typical in the acute stage (14-31).

Bizarre-looking parenchymal masses and progressively enlarging lesions can also occur in PML-IRIS. A rind of restricted diffusion and incomplete enhancement likely represent fulminant virus-induced demyelination (14-32).

IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME

Terminology and Etiology

• Neuro-IRIS

 “Unmasking” IRIS (HAART “unmasks” existing subclinical opportunistic infection)

 “Paradoxical” IRIS (treated infection worsens after HAART)

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