Chronic and subacute viral infections of the CNS

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Chronic and subacute viral infections of the CNS

Chronic/subacute viral infections of the central nervous system (CNS) tend to progress over months or years rather than days or weeks. The incubation period is usually considerably longer than that of acute viral infections. In the past, classifications of chronic (slow) virus infections have included Creutzfeldt–Jakob disease and other spongiform encephalopathies (prion diseases), but according to current understanding of the pathogenesis of these diseases this designation is inappropriate. Prion diseases are considered in Chapter 32.

CHRONIC ENTEROVIRAL ENCEPHALOMYELITIS

Patients with X-linked agammaglobulinemia or combined variable immunodeficiency rarely develop a chronic encephalopathy or myelopathy due to impaired clearance of enteroviruses from the CNS. Histology reveals a patchy, non-necrotizing, meningoencephalitis or myelitis, with lymphocytic infiltrates, microglial nodules, and varying degrees of neuronal loss and gliosis.

SUBACUTE MEASLES ENCEPHALITIDES

MEASLES INCLUSION BODY ENCEPHALITIS

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Macroscopically, the brain usually appears normal, although there may be foci of softening and discoloration. Histology reveals occasional or numerous foci of hypercellularity (Fig. 13.1), within which many neurons and some astrocytes and oligodendrocytes contain eosinophilic inclusion bodies (Fig. 13.1). Most of these are intranuclear, largely filling the nucleus, apart from a few pyknotic clumps of marginated chromatin. Less well-defined eosinophilic inclusions may be visible in the cytoplasm. The lesions also contain reactive astrocytes and microglia, and occasional multinucleated cells. The lesions occur in any part of the brain. The inclusions are readily seen in hematoxylin–eosin preparations and can also be demonstrated immunohistochemically or by electron microscopy (Fig. 13.1).

13.1 Measles inclusion body encephalitis.
(a) Focus of hypercellularity in the cerebral cortex. (b) Inclusion bodies are prominent. They fill the nuclei of neurons and glia. Eosinophilic inclusions are also visible in the cytoplasm of some of the cells. (c) Clusters of CD68-immunoreactive microglia within a focus of hypercellularity. (d) Multinucleated cell (arrow) with nuclear inclusion bodies. (e) Immunohistochemical demonstration of measles virus antigen. In contrast to the paucity of viral antigen in SSPE, in measles inclusion body encephalitis antigen is abundant. (f) Measles virus nucleocapsid particles in the nucleus of an infected neuron.

MEASLES

Measles virus is an enveloped virus of the Morbillivirus genus in the Paramyxovirus family. It contains single-stranded, negative-sense RNA and six proteins (NP, L, P, H, F, and M). M (matrix) protein, is required for virus particle assembly, and H, F, and M proteins for budding of virus from infected cells. The virus is highly contagious and is acquired by inhalation of infected fomites. It usually causes a short-lived febrile disease and a characteristic maculopapular rash.

CNS involvement commonly produces an aseptic meningitis (see Chapter 12) or acute disseminated encephalomyelitis, which is a postinfectious inflammatory disorder. Much less commonly, measles causes a subacute or chronic infective encephalitis, of which there are two forms:

Measles inclusion body encephalitis, which develops within months of the initial systemic infection in patients with impaired cell-mediated immunity.

Subacute sclerosing panencephalitis (SSPE), which is a more delayed manifestation of the initial infection and occurs in patients without any immunologic impairment. Its pathogenesis involves: (a) hypermutation of regions of the viral genome that encode the M, H, and F proteins; (b) failure of production of M protein; (c) loss of the ability of assembled viral particles to bud from infected cells; (d) continuing spread by cell fusion (evading the immune system), and (e) clonal expansion of the mutated virus under the selective pressure of high levels of circulating antibodies to most measles antigens apart from M protein. By providing a similar selective pressure that favors the expansion of mutant clones, circulating maternal antibodies to measles virus may increase the risk of subsequent SSPE in children infected during the first few months of life.

MEASLES INCLUSION BODY ENCEPHALITIS

Measles inclusion body encephalitis is a rare disorder, developing within several months of exposure to, or apparent recovery from, measles.

Most patients have depressed cell-mediated immunity.

Presenting symptoms and signs include seizures, confusion, and a variety of focal neurologic deficits, and later coma.

It is usually fatal within a few weeks of onset.

SUBACUTE SCLEROSING PANENCEPHALITIS (SSPE)

MACROSCOPIC APPEARANCES

Often the brain is macroscopically normal. However, in cases of longer duration, there is usually moderate to marked brain atrophy and the white matter may have an abnormally firm texture and a mottled gray appearance that can simulate a leukodystrophy (Fig. 13.2).

13.2 Macroscopic appearance of brain in SSPE.
This coronal slice through the frontal lobes shows obvious atrophy, with ventricular dilatation and sulcal widening, and loss of volume as well as ill-defined gray discoloration of the white matter.

SUBACUTE SCLEROSING PANENCEPHALITIS

SSPE is a chronic progressive encephalitis that follows exposure to the measles virus by several years

Age of onset is usually 5–15 years.

SSPE is more likely if the initial exposure to measles occurs at less than 18 months of age.

The risk of SSPE is reduced 10- to 20-fold by measles vaccination.

The course of disease is variable. It can result in death within months or progress only intermittently. Survival in excess of 10 years is well documented.

Clinical staging of SSPE

I Intellectual impairment and behavioral changes.

II Repetitive, symmetric myoclonic jerks every 5–10 seconds.

III Increasing mental deterioration, development of various combinations of ataxia, spasticity, choreoathetosis and dystonias, and gradual disappearance of myoclonus.

IV Stupor, autonomic disturbances, coma, and eventually death.

MICROSCOPIC APPEARANCES

There is a chronic encephalitis, with leptomeningeal, perivascular, and parenchymal infiltration by lymphocytes (predominantly T cells) and microglia (Fig. 13.3).

13.3 SSPE.
Leptomeningeal, perivascular, and parenchymal infiltration of the cerebral cortex (a) and white matter (b) by mononuclear inflammatory cells in SSPE. Note the marked reactive gliosis. (c) Dense gliosis of the white matter and deep cerebral cortex in SSPE. Immunostained for glial fibrillary acidic protein. (d) Intranuclear inclusions. These are sparse in SSPE and may be absent, particularly if the disease has run a protracted course. (e) Scattered neurofibrillary tangles (arrows) in the cerebral cortex. These are most numerous in cases with illness of long duration. (f) In a patient with longstanding SSPE, the cerebral cortex includes many neurons and neuritic processes that are immunopositive for phospho-tau.

The distribution and severity of lesions are variable, but the cerebral cortex, white matter, basal ganglia, and thalamus are usually involved. The affected gray matter shows inflammation, gliosis, loss of neurons, occasional neuronophagia, and sparse intranuclear inclusions, which are sharply defined eosinophilic bodies with a surrounding clear space (‘halo’) (Fig. 13.3). In most cases these sparse inclusion bodies can be detected immunohistochemically. Another finding, in some cases of several years’ duration, is the presence of Alzheimer-type neurofibrillary tangles (Fig. 13.3). These are most often found in the cerebral cortex and hippocampus, and may be numerous.

The affected white matter is severely gliotic and is characterized by a predominantly perivascular inflammation and a patchy, in some cases extensive, loss of myelinated fibers (Fig. 13.3).

CHRONIC GRANULOMATOUS HERPES SIMPLEX ENCEPHALITIS

Very rarely, children who have experienced an otherwise typical attack of acute herpes encephalitis (see Chapter 12) develop focal or multifocal chronic granulomatous encephalitis, sometimes after an intervening symptom-free period of months or years. Histology reveals a patchy cortical and leptomeningeal infiltrate of chronic inflammatory cells and scattered, well-circumscribed granulomas that contain epithelioid macrophages and giant cells, with surrounding lymphocytes, macrophages, and plasma cells. Foci of necrosis and mineralization may be prominent. In some patients, HSV DNA or antigen are demonstrable by PCR or immunohistochemistry (Fig. 13.4).

13.4 (a) Chronic granulomatous herpes simplex encephalitis. Histology of partial temporal lobectomy specimen from a 10-year-old boy with chronic granulomatous inflammation complicating herpes simplex virus encephalitis at 4.5 months of age reveals multiple granulomas, some including multinucleated giant cells, with a surrounding infiltrate of lymphocytes and macrophages. The arrow indicates a focus of mineralization. Postoperatively, HSV-1 DNA and elevated titers of HSV IgM antibodies were detected in the CSF. (b). Higher magnification view of the granulomas and foci of mineralization (arrows).

PROGRESSIVE RUBELLA PANENCEPHALITIS

This is a very rare, delayed complication of intrauterine or childhood rubella infection, presenting years later with intellectual impairment, ataxia, seizures, spasticity, and choreoathetosis. The disease progresses slowly over several years until the patient becomes decerebrate and eventually dies. Neuropathologic examination reveals brain atrophy, especially of the cerebellum, and widespread neuronal and white matter destruction with leptomeningeal and perivascular infiltration by lymphocytes and macrophages, severe gliosis, fibrinoid necrosis, and mineralization of small blood vessels. No inclusion bodies are seen.

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)

Until two decades ago, this was a rare disease, predominantly affecting small numbers of patients with leukemias, lymphomas, and renal transplants. Since then, the incidence of PML has increased several-fold, mainly because of its relatively frequent occurrence in patients with AIDS.

MACROSCOPIC APPEARANCES

The cut surface of the fixed brain affected by PML appears asymmetrically pitted by small foci of gray discoloration mixed with larger confluent areas of abnormal parenchyma, which may be centrally necrotic (Fig. 13.5). The lesions tend to be most numerous in the cerebral white matter, but also involve the cerebral cortex and deep gray matter (Fig. 13.5). The cerebellum (Fig. 13.5), brain stem, and much less commonly the spinal cord, may also be involved.

13.5 PML.
(a) Numerous small and larger confluent foci of gray discoloration in the cerebral cortex and white matter. Some of the foci are partly cavitated. (b) In this case there is granularity and focal cavitation of the white matter. (c) Extensive loss of myelin staining in the basal ganglia and hypothalamus. (d) Foci of demyelination in the white matter of the cerebellum.

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

PML is caused by the JC virus, one of two ubiquitous polyomaviruses, the other being BK virus.

Infection in humans is generally asymptomatic.

Latent JC virus is demonstrable in the kidneys and in B cells in the tonsils of most adults and in the brains of some.

PML is thought to result from reactivation of latent JC virus within the CNS or in peripheral tissues, usually as a result of impaired cell-mediated immunity.

JC virus can be detected in circulating B lymphocytes in a high proportion of patients with PML, suggesting that these cells may play a role in viral entry into the CNS.

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

Patients present with focal neurologic deficits including dysarthria, limb weakness, visual disturbances, ataxia, personality changes, and occasionally seizures.

PML usually progresses relentlessly over a few months, resulting in increasing neurologic impairment, dementia, and eventually death.

Treatment of the cause of the underlying immunosuppression (e.g. of AIDS, with highly active anti-retroviral therapy) can lead to remission of PML.

Reconstitution of the immune system (e.g. in the treatment of AIDS) occasionally causes an inflammatory response to the virus in the CNS, with exacerbation of disease.

MICROSCOPIC APPEARANCES

There are multiple foci of demyelination (Fig. 13.6). Some are small and rounded, others confluent, irregular, and occasionally with central necrosis. These lesions contain moderate numbers of foamy macrophages (Fig. 13.6), but only scanty perivascular lymphocytes. Lymphocytic infiltrates may be commoner in PML associated with AIDS and may confer a slightly better prognosis.

13.6 Histology of PML.
(a) Section stained for myelin with solochrome cyanin. (b) Adjacent section stained for axons. Axons traverse the foci of demyelination. The scattered cells with very large nuclei, seen best in (a), are atypical astrocytes. (c) Foamy macrophages, bizarre astrocytes, and very sparse lymphocytes in a region of demyelination. (d) Oligodendrocytes at the edge of a focus of demyelination have enlarged nuclei containing amphophilic viral inclusions (arrows). Note the large atypical astrocyte (arrowhead). (e) Intranuclear polyomavirus particles in PML. (f) Many of the enlarged nuclei within oligodendrocytes near the edge of a focus of demyelination appear immunopositive when labeled with antibody to SV40. Note too the very scanty lymphocytic cuffing of small blood vessels.

A striking feature, particularly in older lesions, is the presence of very large astrocytes with bizarre, pleomorphic, hyperchromatic nuclei (Fig. 13.6). These cells resemble the individual astrocytes that can be seen in glioblastomas. Typical reactive astrocytes are also present.

Mitoses are rare. Those that do occur may appear atypical. However, despite the nuclear pleomorphism, the lesions are easily distinguishable from a neoplasm by their relatively low cellularity and the presence of viral inclusions, which are seen towards the periphery of the foci of demyelination in the enlarged nuclei of oligodendrocytes. The homogeneous amphophilic inclusions (Fig. 13.6) largely fill the nuclei and consist of closely packed polyomavirus particles, which are readily identifiable on electron microscopy (Fig. 13.6). The virus can be demonstrated immunohistochemically (e.g. with SV40 antibody, which also labels JC virus), and viral nucleic acids can be detected and specifically identified by in situ hybridization.

Occasionally, in cases of PML involving the cerebellum, accumulations of cells with large vesicular nuclei and central nucleoli can be seen in the granule cell layer. These probably represent altered granule cells.

Very rarely, astrocytic neoplasms have been reported in PML.

HUMAN T CELL LEUKEMIA/LYMPHOTROPIC VIRUS-1 (HTLV-1)-ASSOCIATED MYELOPATHY (HAM) (TROPICAL SPASTIC PARAPARESIS)

MACROSCOPIC APPEARANCES

In longstanding cases of HAM, there may be meningeal thickening (Fig. 13.7) and atrophy of the spinal cord, particularly in the lower thoracic region. Lateral funicular degeneration may also be visible.

13.7 HAM.
(a) Collagenous thickening of the spinal leptomeninges and the walls of parenchymal blood vessels. (b) Higher magnification reveals thickened leptomeninges and patchy infiltration by lymphocytes in the dorsal root entry zone. (c) Perivascular and parenchymal infiltrates of lymphocytes in the spinal gray matter in HAM. (d) Degeneration of myelinated fibers in the anterior and lateral funiculi of the spinal cord with relative preservation of anterior horn cells.

HUMAN T CELL LEUKEMIA/LYMPHOTROPIC VIRUS-1 (HTLV-1)-ASSOCIATED MYELOPATHY (HAM)

HAM is caused by HTLV-1, which was the first human retrovirus to be identified. As the name suggests, it can also cause adult T cell leukemia.

HTLV-I is endemic in the Caribbean, South America, parts of Africa, southern Japan, the Seychelles, and probably parts of India. HAM is therefore most common in these parts of the world, with prevalence figures of 5–130/100 000 inhabitants.

HTLV-1 infection is transmitted by sexual contact, breast feeding, or blood transfusion. The incubation period varies from 1 year to as long as 25 years, and may depend to some extent on the route of infection; in several reported cases of transfusion-related infection, the incubation period has been less than 2 years.

Patients show clonal expansion of HTLV-I-infected CD4 cells in the peripheral blood.

HTLV-I tax protein induces expression of vascular cell adhesion molecule-1 by infected T-cells and probably promotes entry of small numbers of infected CD4 cells into the CNS – predominantly into the thoracic cord.

The infected CD4 lymphocytes are thought to be the target of a CD8 cytotoxic T lymphocyte-mediated inflammatory reaction.

The damage to axons and myelin may be due to the release of cytokines and other inflammatory mediators, or to direct autoimmune damage to the spinal parenchyma.

HUMAN T CELL LEUKEMIA/LYMPHOTROPIC VIRUS-1 (HTLV-1)-ASSOCIATED MYELOPATHY

Age of onset is usually 25–60 years.

HAM causes progressive spastic paraparesis and sphincter disturbance, and most patients are chair-bound within 10 years.

Backache is common.

HAM can cause sensory disturbances in the legs.

A history of other sexually transmitted disease(s) is often elicited.

MICROSCOPIC APPEARANCES

An infiltrate of lymphocytes and macrophages is seen in the leptomeninges and parenchyma of the spinal cord (Fig. 13.7), and is most marked in the lower thoracic region. Hyaline thickening of small blood vessels is a prominent feature. Intramyelinic vacuolation and demyelination may be evident early in the course of disease, but soon progress to symmetric degeneration and gliosis involving the long tracts in the spinal cord (Fig. 13.7). The degeneration tends to be most severe in the lateral columns. The anterior and less commonly the posterior columns may also be involved. The neurons are relatively well preserved (Fig. 13.7). Sparse viral nucleic acids may be detectable within the spinal cord by in situ hybridization or by polymerase chain reaction. Adventitial fibrosis and scanty perivascular inflammation have been observed in the cerebral white matter and less commonly in the cerebellum and brain stem.

HUMAN IMMUNODEFICIENCY VIRUS (HIV) INFECTION

HIV was first recognized as a cause of human disease, especially profound immunosuppression resulting from impaired cell-mediated immunity, in the early 1980s. Although other subtypes exist, most human disease results from infection with HIV-1 (referred to below simply as HIV), which is now almost universally accepted as the major cause of acquired immune deficiency syndrome (AIDS). HIV infection is pandemic, although the prevalence varies worldwide.

HUMAN IMMUNODEFICIENCY VIRUS

HIV is a retrovirus of the Lentivirus subfamily. Like other retroviruses it is an enveloped positive-strand RNA virus (Fig. 13.8). It has a characteristic ultrastructural appearance (Fig. 13.9). Transmission of infection occurs by:

13.8 Schematic diagram of an HIV virus.

13.9 Ultrastructural appearance of HIV virions in a lymphocyte culture.
Several virions are present; in each, note the virus envelope surrounding a truncated, cone-shaped core (arrows). Virus particles have irregular granular ‘knobs’ on their surfaces, barely visible at this magnification. Virions are typically 115–120 nm in diameter.

Vaginal or anal intercourse in 70–80% of cases.

Intravenous drug injection in 5–10% of cases.

Infected mother to child transmission in 5–10% of cases.

Healthcare or occupational exposure in rare cases, e.g. following accidental inoculation of large aliquots of HIV (in research workers), accidental ‘needle stick’ with contaminated blood, or puncture by an infected instrument during an AIDS autopsy.

Transmission through blood transfusion, at one time accounting for 3–5% of cases, is now very rare in industrialized nations, as potential donors are screened exhaustively and blood supplies monitored rigorously.

Viral entry into T lymphocytes or macrophages is mediated by binding of the Env envelope glycoprotein to CD4 receptors on the cell surface. DNA provirus is synthesized from the RNA genome by the viral enzyme reverse transcriptase, which is packaged within the core particle of the virus and released on its entry into the cell. The provirus enters the nucleus and integrates at random sites in the cellular genome.

Once a patient is infected, ‘clearance’ does not occur except in very rare circumstances. With combination antiretrovital therapy (cART), viral titers in blood may decline to barely detectable levels in some patients. The CNS, where virus can reside within infected macrophages/microglia even while blood levels of HIV are essentially undetectable, thus represents a reservoir for HIV from which systemic re-infection may later occur.

HIV infection in the bloodstream is detected by serology or by polymerase chain reaction (PCR) assay for HIV nucleic acids; the latter is far more sensitive than the former – there is a ‘window’ of several weeks after primary infection during which a person may have HIV in the blood but remain seronegative, a fact of major importance in screening potential blood donors.

Factors that lead to progression from ‘simple’ HIV infection to AIDS are not yet fully understood, and the time interval between the two may be many years. Neurologic disease in people infected with HIV may result from:

Direct infection of the CNS by HIV.

Systemic factors and miscellaneous (non-specific) conditions related to cachexia, metabolic derangement, hypoxia, and other diverse abnormalities that can result from chronic HIV infection treatment.

Since 1995/1996, following the introduction of combination anti-retroviral therapy (cART), the prognosis of patients with HIV infection has improved dramatically, rendering it a chronic illness for many patients in industrialized nations. Patterns of CNS neuropathology and systemic opportunistic infections (OIs) and neoplasms have also been markedly altered by the use of cART, e.g. there has been a decrease in cases of Kaposi sarcoma, extra-CNS protozoal, and CNS viral infections. Ironically, a decline in the numbers of autopsies on HIV-infected patients over the past 5–10 years has limited our understanding of the neuropathologic consequences of cART. In parts of the world where HIV infection and AIDS are most prevalent (e.g. sub-Saharan Africa), there is limited access to cART or medicines for treating the major OIs; in these regions, patient survival is tragically short.

EPIDEMIOLOGIC ASPECTS OF HIV INFECTION

By the early 2000s, an estimated 60 million people worldwide had been infected by HIV-1, of whom approximately 20 million had died. The approximate numbers of people infected with HIV in different geographic regions are as follows (accuracy of the estimates varies, depending upon the means of case ascertainment):

>65 million worldwide by 2009.

>1 million in North America.

1.3–1.5 million in Latin America.

At least 23–25 million in sub-Saharan Africa.

6–7 million in South-east Asia.

An estimated 650 000 in China (2008).

500 000 in western Europe.

360 000 in the Caribbean.

12 000–13 000 in Australia and New Zealand.

In some popul ations, e.g. India and the People’s Republic of China, AIDS is a growing problem with increasing numbers of new cases, even as the spread of AIDS and HIV infection appears to have reached a plateau in North America and Europe.

HIV-1 clade B is the most common subtype causing HIV infection in the industrialized world.

DEFINITION OF AIDS

AIDS is a clinical syndrome associated with HIV infection and defined since 1 January 1993 by the Centers for Disease Control, Atlanta, in very specific terms, as follows:

A patient with AIDS is an HIV-infected person with CD4-positive T lymphocytes totaling less than 200/μL, or accounting for less than 14% of all T lymphocytes, who also has one of 23 specific (AIDS-associated or AIDS-defining) illnesses (e.g. cryptosporidiosis, Kaposi sarcoma, various fungal and viral infections, HIV encephalopathy or dementia, wasting syndrome, pulmonary tuberculosis, recurrent pneumonia, or invasive cervical cancer).

DIRECT HIV INFECTION OF THE CNS

MACROSCOPIC APPEARANCES

The brain may appear normal or show diffuse atrophy with modest ventriculomegaly (Fig. 13.10) and ill-defined gray discoloration of the centrum semiovale.

13.10 Macroscopic appearance of brain in AIDS dementia/subacute encephalitis of AIDS.
(a) Brain slice from a 39-year-old man with multiple complications of HIV infection including widespread microglial nodule encephalitis and vacuolar myelopathy. Note the mild diffuse cortical atrophy and ventricular enlargement with blunting of the angles of the lateral ventricles. (b) Brain slice from another patient, in a coronal plane similar to that in (a), showing slightly more prominent atrophy of the deep white matter, and blunting of the angles of the lateral ventricles. Cavum septum pellucidum was an incidental finding.

MICROSCOPIC APPEARANCES

Histology reveals the following abnormalities in various combinations, sometimes defined by the descriptive terms ‘subacute encephalitis of AIDS’ or ‘HIV leukoencephalopathy’:

Widespread low-grade inflammation, with microglial nodules and perivascular lymphocyte cuffing (Fig. 13.11). MGNE (microglial nodule encephalitis) is however not specific for direct infection with HIV and is also a feature of many OIs, including CMV, toxoplasmosis, and certain fungal infections.

13.11 Microglial nodule encephalitis.
This is a characteristic finding in the brains of patients who die with HIV infection, and may be due to an identified agent (e.g. HIV, CMV, toxoplasmosis), though occasionally no causal micro-organism is found. Inflammatory foci contain varying numbers of microglia, some lymphocytes and (often) surrounding astrocytes. (a) Small microglial nodule (MGN, arrow) within brain parenchyma. (b) Subpial microglial nodule (arrows), one of many identified in a patient who had severe AIDS dementia and harbored a ‘neurotropic’ strain of HIV. Note slightly more prominent cytoplasm of component cells in the MGN. This is a characteristic finding in the brains of patients who die with HIV infection, and may be due to an identified agent (e.g. HIV, CMV, toxoplasmosis), though occasionally no causal micro-organism is found. Inflammatory foci contain varying numbers of microglia, some lymphocytes and (often) surrounding astrocytes. (c) Poorly defined region of microglial activation. (d–f) Compact collections of microglia, including one in the substantia nigra (e). The presence of multinucleated cells in (d) (arrows) and (f) is strong evidence for HIV infection of the brain. (g) Loosely defined collection of microglia, associated with vacuolation of the surrounding neuropil.

Leukoencephalopathy with patchy demyelination and variable gliosis of white matter, often with associated gliosis of deep central gray matter (Fig. 13.12).

13.12 HIV leukoencephalopathy.
This is characterized by pallor of myelin staining, and mild to moderate white matter astrocytic gliosis as illustrated in (a). Arrows indicate the junction between cortex, at right, and subcortical white matter, at left. Astrocytic gliosis is also often noted in the deep central gray matter (b).

Multinucleated cells, usually pericapillary, with scant cytoplasm (morulae) or abundant cytoplasm (true giant cells) (Fig. 13.13), in which HIV antigen can be demonstrated with antibody to gp41 or p24 (Fig. 13.14). Even without immunohistochemistry, the multinucleated cells are sufficiently characteristic to allow a diagnosis of HIV encephalitis provided that other causes of granulomatous inflammation with giant cell formation are ruled out. HIV antigen may also be demonstrable in microglial cells without characteristic ‘giant cell’ morphology (Fig. 13.15).

13.13 Multinucleated cells, characteristic of HIV infection of brain (HIV-GC).
Parenchymal HIV-GC are indicated by arrows in each frame. The cells may be associated with MGNs (a) or have a morular appearance (c). The cells contain variable amounts of eosinophilic or foamy cytoplasm, and tend to aggregate around blood vessels (especially capillaries), as in (b): the arrowheads indicate several intraluminal HIV-GC. (d) HIV-GC adjacent to a CNS lymphoma.

13.14 HIV brain infection.
(a) Immunohistochemical demonstration of HIV p24 antigen in scattered microglia/macrophages and multicleated cells. (b) and (c) HIV-immunoreactive cells with more typical microglial morphology. In (b), they are prominent in a perivascular distribution (arrow).

13.15 Potential mechanisms by which HIV enters the nervous system and causes neuronal injury.
Macrophages and lymphocytes, expressing CD4 and CCR5 or CXCR4 are infected in the periphery and subsequently cross the blood–brain (or blood–nerve) barrier. Once in the nervous system, other cells of macrophage/microglial lineage are infected or are induced to release potential neurotoxins, including cytokines, chemokines, matrix metalloproteinases (MMPs), quinolinic acid, glutamate, and nitric oxide. To a limited extent, astrocytes are also infected; this may influence neuronal survival. Inset shows a potential signaling pathway in microglia/macrophages, involving HIV gp120 induction of MMP expression through CCR5 and subsequent activation and nuclear translocation of the transcription factor, STAT-1. (Diagram reproduced by courtesy of Dr Chris Power, University of Calgary, Canada, and the Canadian Journal of Neurological Sciences.)

Clinicopathologic correlation of these neuropathologic changes with ‘HIV-associated dementia/cognitive-motor deficit’ is, unfortunately, imprecise – i.e. the CNS of demented patients may show minimal structural abnormalities, whereas individuals with neuropathologic stigmata of ‘subacute encephalitis’ may not have had demonstrable cognitive impairment. HIV-associated dementia probably reflects neuronal dysfunction resulting from a combination of effects mediated through several cellular mechanisms, only some of which are understood. While cART is effective in restoring immune function and decreasing blood levels of HIV, it seems less effective in improving HIV-associated cognitive abnormalities in affected patients, despite reversal of abnormalities as seen, for instance, in proton MRI scans.

DEMENTIA DUE TO HIV INFECTION OF THE BRAIN

A dementing illness with memory and personality changes may be a presenting feature of AIDS and is also one of the ‘AIDS-defining’ illnesses (see above). This has received various descriptive names including AIDS–dementia complex, HIV-related cognitive–motor deficit, subacute encephalitis of AIDS, HIV encephalitis, AIDS/HIV-related encephalopathy, minor neurocognitive disorder, HAND (HIV-associated neurocognitive disorder), and HIV-associated dementia (HAD). The relationship between minor neurocognitive disorder and HAD is conceptually analogous to that between amnestic mild cognitive impairment and Alzheimer’s disease.

The reported frequency is extremely variable, depending upon the research interests of a given AIDS treatment center, and:

Exceeded 50% of patients in some early series, but is much less common now in most centers.

Has become less common since the widespread use of antiviral agents, particularly cART combination therapy, which includes anti-nucleosides and protease inhibitors. However, while the incidence of HAD has declined, its prevalence is increasing, as prolonged survival among HIV-infected patients becomes more common.

HAD shows variable clinical progression. A history of IV drug injection, or presentation with prominent psychomotor slowing tends to be associated with more rapid neurologic deterioration. When brains of these ‘rapid progressors’ are examined at autopsy, they show more abundant macrophage activation.

PATHOGENESIS OF DIRECT HIV INFECTION OF THE CNS

In the CNS, HIV infects mainly microglial cells or macrophages (Fig. 13.15). ‘Neurotropic’ strains of HIV show a predilection to infect CNS macrophages, or monocytes, which eventually cross the blood–brain barrier into the brain, i.e. they are not ‘neuronotropic’. HIV tropism is also determined by which chemokine receptor the virus utilizes as a co-receptor, i.e. CXCR4 on T-lymphocytes, and CCR5 on macrophages. Various methods have been used to show convincingly that HIV can also infect circumscribed populations of astrocytes, dysfunction of which may then contribute to HAD pathogenesis. Infection of neurons has not been conclusively demonstrated, except in tissue culture experiments. An increase in trafficking of monocytes from blood to brain may have a role in HAD pathogenesis; sequences of the HIV gp160 gene (which encodes the HIV envelope protein) isolated from cerebral white matter are more closely related to those from bone marrow than from other tissues. HIV-infected lymphocytes/macrophages may also enter the CNS via the choroid plexus. CSF levels of HIV RNA, when high (>1 000 000 copies/mL) appear to be a reasonable predictor of brain HIV levels, although the level of HIV neuroinvasion does not consistently relate to the degree of neurological damage (i.e. the neurovirulence).

Macrophage/microglial infection by HIV results in the secretion of:

Cytokines such as tumor necrosis factor (TNF), matrix metalloproteinases, and interleukins (e.g. IL-1, IL-6).

Other potentially damaging chemicals such as nitric oxide, superoxide anion, hydroxyl radical, peroxides, and quinolinate.

The HIVgp120 viral protein may itself be neurotoxic.

Activated microglia/macrophages may also, however, have some neuroprotective/neurotrophic effects, e.g. through preventing glutamate-mediated neurotoxicity.

There is selective and regional vulnerability of CNS neuronal populations to HIV infection. This vulnerability is probably determined by chemokine receptor profiles, glutamate receptor densities, and concentrations of calcium-binding proteins on neuronal membranes.

Apoptosis has been observed in neurons, astrocytes, and endothelial cells in brain tissue from AIDS patients. Its role in the pathogenesis of HAD is controversial.

The neuropathologic substrate of the resulting encephalopathy has been extensively studied:

Initial attention focused on a leukoencephalopathy or leukoencephalitis as the cause of neurologic deterioration.

The emphasis has recently been on neocortical abnormalities such as neuron, synapse, and dendrite loss – these may in part result from retrograde/trans-synaptic changes caused by HIV-mediated injury of deep white matter or gray matter.

There has been much debate as to whether HIV encephalopathy and dementia are related to the viral burden within the CNS, or the secretion of cytokines and other damaging substances by a relatively circumscribed population of infected cells.

The level of interferon-α correlates with the degree of neurocognitive impairment.

Direct HIV infection of brain is a relatively more common cause of neurologic deterioration in HIV-positive infants and children than in adults with HIV, in whom opportunistic infections and other miscellaneous conditions are more often responsible.

The use of cART has led to a substantial decrease in most opportunistic infections, although their frequency may be underestimated because of the decline in autopsy examinations in such cases.

Vacuolar Myelopathy

MACROSCOPIC AND MICROSCOPIC APPEARANCES: The vacuolar myelopathy resembles subacute combined degeneration of the spinal cord (Fig. 13.16) (see Chapter 21). There is vacuolation of the spinal white matter in the posterior columns and lateral corticospinal tracts, most pronounced in the thoracic segments. Breakdown of myelin, and later axons, is accompanied by an accumulation of macrophages containing debris.

13.16 Vacuolar myelopathy of AIDS.
This resembles subacute combined degeneration of the spinal cord. (a) Note vacuolar change in the posterior columns. (b) There may also be vacuolar change in the lateral corticospinal tracts, but usually to a lesser extent than in the dorsal columns.

VACUOLAR MYELOPATHY

Vacuolar myelopathy affects up to 25% of people with AIDS and causes spastic paraparesis, ataxia, and incontinence.

The cause is unclear. It may result from direct infection of macrophages within the spinal cord or an indirect mechanism not associated with productive HIV infection.

BIOMARKERS OF NEURO-AIDS

Several markers in CSF and peripheral blood correlate with the presence or complications of HIV-associated disease of the CNS (this list excludes abnormalities on structural and functional imaging, which are of obvious importance).

HIV viral load in CSF: associated with extent and severity of neurological disease, including HAD.

β2-microglobulin in CSF: associated with progression of HAD.

Soluble CD14 (sCD14) in blood: associated with HIV disease progression; may be higher in cognitively impaired patients.

Neopterin in CSF: increased in patients with opportunistic infections and HAD.

Quinolinic acid in CSF: increased in patients with opportunistic infections and HAD.

Leptin in CSF: reduction may be associated with cognitive impairment in HIV patients.

Osteopontin in blood: may correlate with HAD.

S-100β, neurofilament proteins and tau in CSF: markers of brain damage (in the case of neurofilament protein and tau, specifically of neuronal damage.

Necrotizing leukoencephalopathy

Rarely, HIV infection of the CNS produces a severe necrotizing leukoencephalopathy (Fig. 13.17). A severe leukoencephalopathy, characterized by intense perivascular macrophage and lymphocyte infiltration and high levels of HIV in the CNS, has been described in rare individuals receiving cART. This may result, in part, from an exaggerated response of the reconstituted immune system to HIV antigens.

13.17 Necrotizing leukoencephalopathy associated with HIV infection.
(a) Patchy necrosis (arrows) of the internal capsule. (b) Dystrophic calcification and reactive (gemistocytic) astrocytes in a focus of white matter necrosis. (c–e) All sections are from the brain of a patient who had severe HIV encephalitis with numerous HIV-immunopositive cells throughout the brain. In (c) there is prominent vacuolation of the white matter. Other regions contained large collections of foamy macrophages (d,e), among which were HIV-immunoreactive cells: arrows in (e).

Ventriculoencephalitis (Figs 13.25, 13.26) visible macroscopically or on imaging studies as ‘sugar icing’-like material lining the ventricular surfaces, with hemorrhagic necrosis of adjacent brain parenchyma.

13.25 Necrotizing CMV ventriculoencephalitis.
(a) There is congestion and focal hemorrhagic necrosis of peri-ventricular tissue adjacent to the ependymal lining (arrows). (b) A more posterior coronal slice through the same brain shows similar features (arrows), as well as acute hemorrhage into the choroid plexus, epithelial cells of which are frequently infected by CMV.

13.26 Necrotizing CMV ventriculoencephalitis and associated CMV encephalitis.
(a) The ventricular cavity (barely visible at right of figure) is surrounded by a thick layer of inflamed, partly necrotic ependymal and subependymal tissue. (b) Within this periventricular tissue, cytomegalic cells are prominent. (c) Elsewhere within the brain, isolated cytomegalic cells (e.g. arrow) are seen, often with minimal surrounding inflammation.

Meningoradiculitis and myelitis (Fig. 13.27) with a clinical presentation simulating Guillain–Barré syndrome. This is often due to CMV-associated vasculopathy, with microvascular thrombi in and around the nerve roots.

13.27 CMV radiculitis in an AIDS patient who presented with an acute polyradiculitis, resembling Guillain–Barré syndrome.
(a) The nerve roots show a moderately severe chronic inflammatory infiltrate within which (b) are typical CMV inclusions (arrow). (c) Foci of necrosis are associated with microthrombi (arrow) in small meningeal arteries harboring CMV in their walls.

Rarely, widespread infection of microvascular endothelial cells (Fig. 13.28) that sometimes also involves the peripheral nerve and skeletal muscle, including epineurial/epimysial tissues.

13.28 CMV infection of endothelial walls.
(a) In the brain (arrow). (b) In the epineurium (arrow).

Foci of demyelination.

There is evidence of occasional coinfection of single cells by HIV and CMV.

Varicella-zoster virus (VZV): This is much less common than CMV infection, but also produces heterogeneous neurologic manifestations, including:

Leukoencephalopathy and leukoencephalitis with sharply demarcated necrotizing lesions.

Encephalitis involving the visual system.

Brain stem encephalitis.

Myeloradiculitis (Fig. 13.29).

13.29 VZV infection of nerve roots and brain.
(a) Radiculitis. Immunostained VZV-infected cells (arrows) in a nerve root. (Courtesy of Professor Françoise Gray, Hôpital Raymond Poincare, Paris, France.) (b) Ventriculitis. Arrows indicate ventricular lining that was heavily infected with VZV. Small ependymal intranuclear inclusions are barely visible at this magnification. Subependymal region shows only slight rarefaction, and minimal inflammation (contrast the appearance of CMV ependymitis, Fig. 13.26).

Ventriculitis (Fig. 13.29).

Vasculitis or non-inflammatory vasculopathy.

Other herpesviruses infections: Herpes simplex encephalitis occurs rarely in patients with AIDS, while Epstein–Barr virus infection is associated with primary CNS lymphoma in AIDS patients (see below and Chapter 42). The role of human herpesvirus-6 in the pathogenesis of AIDS-related neurologic syndromes has not yet been defined. Another herpesvirus, designated human herpesvirus-8 (HHV8) or Kaposi’s sarcoma-associated herpesvirus (KSHV), has a role in the pathogenesis of Kaposi’s sarcoma and primary effusion (body cavity-based) lymphomas, but not directly in the development of neurologic disease.

The neuropathology of PML is described on p.325.

Other viral infections of the CNS that have rarely been reported in patients with AIDS include adenovirus encephalitis (Fig. 13.30) and measles inclusion body encephalitis (see p.323).