key: cord-0035092-z74mk342 authors: Weis, Serge; Sonnberger, Michael; Dunzinger, Andreas; Voglmayr, Eva; Aichholzer, Martin; Kleiser, Raimund; Strasser, Peter title: Infections: Viruses date: 2019-02-12 journal: Imaging Brain Diseases DOI: 10.1007/978-3-7091-1544-2_26 sha: 0b0ef699210285beb93ad3e228cf0ab8350dc419 doc_id: 35092 cord_uid: z74mk342 Viruses can cause meningitis, encephalitis, myelitis, arteritis when affecting the nervous system. Viruses are classified as DNA viruses and RNA viruses. Imaging of viral encephalitis is often nonspecific showing focal or diffuse edema (acute infection) or focal atrophy (chronic infection). Location of the lesion depends on causative agent, thus, HSV encephalitis displays an almost pathognomonic involvement of the limbic system. The various steps in the pathogenesis include entry into the body, delivery of the virus to the target tissue, interaction of virus with target tissue, cytopathogenesis, host responses, immunopathology, virus production in a tissue with release of the virus to other people (contagion), and transmission of viruses. Treatment consists of administration of antiviral drugs which aim at altering virion disruption, attachment, penetration and uncoating, RNA synthesis, genome replication, virion assembly and release. Clinical outcome depends on age of infection, nature of disease, severity of disease, and progression of viral disease. Human immunodeficiency virus (HIV)-1 infection is a serious health problem worldwide as 33 million adults and 2 million children are infected with HIV-1. The brain is often involved which leads to the HIV-associated neurocognitive disorders (HAND) of which asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HIV-associated dementia (HAD) represent various stages. The neuropathologic changes in HIV-1 induced lesions, i.e. HIV-1 encephalitis (characterized by multiple disseminated foci composed of microglia, macrophages, and multinucleated giant cells (MGCs) predominantly located in the cortex, deep gray matter, and the white matter), HIV-1 leukoencephalopathy (diffuse damage to the white matter), lymphocytic meningitis (LM), perivascular lymphocytic infiltration (PLI), vacuolar myelopathy (VM), vacuolar leukoencephalopathy (VL) are described. Therapy might lead to the immune restituiton inflammatory syndrome (IRIS). The sequelae of HIV-1 infection of the nervous system include changes in neuronal number, neuronal size, synapses, dendrites, nerve fibers, astroglia, oligodendroglia, microglia/macrophages, vessels, vascular endothelial cells, and capillaries. Pathogenetic mechanisms deal with the mode of entrance of HIV-1 into the brain, target cells of HIV-1, mechanisms of brain lesions, and interactions between the blood–brain-barrier (BBB) and HIV. Cytomegalovirus infection (CMV), progressive multifocal leukoencephalopathy (PML), Herpes Simplex Virus (HSV) encephalitis, and Tick-borne encephalitis are further described. The diseases caused by viruses are listed in Table 26 .4 while brain diseases caused by viruses are depicted in Tables 26.5 and 26.6. Incidence • 1.5-7 cases/100,000 inhabitants/year, excluding epidemics • True incidence of these infections is difficult to determine because 26 Typical MR imaging patterns of specific viral encephalitides are listed in Table 26 .7. • In HIV-infected patients -Reduced brain perfusion SPECT and reduced FDG-PET uptake of cortical structures (medial frontal, temporoparietal) are described. -FDG shows diffuse hypermetabolism in subcortical and deep white matter, basal ganglia, and thalami in some cases. • In herpes simplex encephalitis -HMPAO showed increased uptake followed by a decrease in tracer uptake in the recovery phase and ECD decreased uptake of the affected temporal lobe (most likely due to disturbed membrane and intracellular metabolism). -FDG-PET shows hippocampal hypermetabolism in the acute phase of herpes simplex encephalitis followed by hypometabolism after 3-9 months, but it is reported, that hypometabolism can persist for years. • Studies with various imaging agents are performed to assess different pathologic steps in neuroinflammation. • No discernible lesion • Hemorrhagic lesion • Necrotic lesion -Vpu: facilitates virion assembly and release, induces degradation of CD4 -Vpr: transport of complementary DNA to nucleus, arresting of cell growth, replication in macrophages -LTR: promoter, enhancer elements Following involvement of the lung (75-85%), the brain is the second most frequently affected organ (60-80%) in HIV-1 infection. Neurological signs and symptoms are seen: • In about 50% of HIV-1-infected patients. • In approximately 10% of the cases, they are the first presentation of the disease. The term "AIDS dementia complex (ADC)" was coined in 1986 (Navia et al. 1986a, b) to describe impaired memory and concentration, psychomotor slowing and behavioral disturbances in 65% of patients, and has been attributed mainly to subcortical damage of AIDS brains (subcortical dementia). The name ADC was later changed into HIV-1-associated cognitive and motor complex with HIV-1-associated dementia complex (motor)/(behavior) (HAD) and HIV-1-associated myelopathy as its severe manifestations and HIV-1-associated minor cognitive/motor disorder as its mild manifestation (Force 1991). Classification of HIV-associated neurocognitive disorders (HAND) (Antinori et al. 2007) • Asymptomatic neurocognitive impairment (ANI) -No evidence of pre-existing cause. Cognitive impairment must be attributable to HIV and no other etiology (e.g., dementia, delirium). -The cognitive impairment does not interfere with activities of daily living. -Involves at least two cognitive areas (memory, attention, language, processing speed, sensory perceptual, motor skills) documented by performance of >1 standard deviation below the mean of standardized neuropsychological testing. Despite the introduction of antiretroviral therapies with a greater life expectancy of HIV-1infected individuals, epidemiologic data suggest that involvement of the brain in AIDS patients continues to be a frequent autopsy finding. Neuropathological examinations show in up to 95% of the brains changes that may be due to: • primary effect of HIV-1 • probable effect of HIV-1 • opportunistic agents • neoplasias The neuropathological changes seen in the brains (Table 26 .10) and peripheral nerve and skeletal muscle (Table 26 .11) of HIV-1-infected patients are manifold. Since HIV-1 is rarely the cause of focal macroscopic lesions even in severely infected patients, systematic sampling of specimens for histological examination is required. If focal lesions are present, they are almost always due to opportunistic infections, cerebrovascular complications, or neoplasms. General Imaging Features • Brain atrophy and symmetric confluent white matter lesions (periventricular, basal ganglia, centrum semiovale, brain stem, cerebellum), no enhancement HIV-1 encephalitis is characterized by (Fig. 26 .3a-j) • Multiple disseminated foci composed of microglia, macrophages, and multinucleated giant cells (MGCs). The foci are predominantly located in the cortex, deep gray matter, and the white matter. There is no strong correlation between HIVE and the clinical stages of the HAD. Despite the introduction of HAART with a greater life expectancy of infected individuals, epidemiologic data suggest that the prevalence of HIVE is on the rise. HIV-1 leukoencephalopathy is chararcterized by (Fig. 26 Lymphocytic meningitis (LM) is characterized by (Fig. 26 .5a-f) • Significant lymphocytic infiltrates in the leptomeninges. • No opportunistic pathogens are encountered in the meninges. Perivascular lymphocytic infiltration (PLI) is characterized by (Fig. 26 .5g-j) • Significant lymphocytic infiltrates in the perivascular spaces of the brain tissue. • No opportunistic pathogens are encountered in the perivascular brain tissue. It seems that lymphocytic infiltrates in the leptomeninges and in the perivascular spaces of the brain tissue constitute changes occurring in the early stages of the HIV-1 infection. Vacuolar myelopathy is characterized by (Fig. 26 .6a-f) • Numerous vacuolar myelin swellings. • Macrophages in multiple areas of the spinal cord. • Predominant involvement of the dorsolateral spinal tracts. • Some macrophages may be found in the vacuoles. • Might not be specific for HIV-1 since they can occur in the absence of HIV. • The axon is at first unaffected, but it is damaged in the later stages of the disease. • VM might not be specific for HIV-1 Vacuolar leukoencephalopathy is characterized by • Numerous vacuolar myelin swellings in the central white matter. • Some macrophages may be found in the vacuoles. • VL is a rare condition. Brain changes in HIV-1 seropositive, non-AIDS cases include: • Cerebral vasculitis was significantly more frequent and marked in HIV seropositive cases and was often associated with lymphocytic meningitis (Gray et al. 1992 ). • Granular ependymitis, myelin pallor with reactive astrocytosis, and microglial proliferation were also more frequent and more severe in HIV seropositive cases. Immunohistochemistry was negative for HIV-antigens. Highly expressed cytokines (tumor necrosis factor-α, interleukin (IL)-1,4,6) (Gray et al. 1992 ). • Perivascular lymphocytic infiltrates (PLI) as well as lymphocytic infiltrates in the meninges (MLI) were found in 62.8% of the cases. PLI alone was seen in 61% of the cases, MLI alone in 43% of the cases, and the combination of PLI and MLI in 34% of the cases (Weis et al., unpublished data). Children born to HIV-1-infected mothers are in 10-40% of the cases also infected by the virus (Kozlowski et al. 1993) . These children develop symptoms before the age of 2 years. • About 30% of the HIV-1 children develop opportunistic infection or HIV-1 encephalopathy within the first year of life. • Brain growth is impaired leading to intellectual deficiency. • The gross-anatomical analysis shows brains which are too small for the age. • Sometimes atrophic gyri may be noted. In 1995/1996, highly active antiretroviral therapies (HAART) were introduced which combine • nucleoside reverse transcriptase inhibitors (NRTI) -specifically inhibit the viral reverse transcriptase enzyme necessary for DNA chain elongation of the virus • protease inhibitors (PI) -prevent the production of active virus by interfering with the cleavage of proteins necessary for viral assembly Effects of the therapy results in: • The frequency of HIV-1-related CNS diseases has been reduced through -the reduction of both viral load in the blood -the reduced continuous penetration of virus into the brain (Tardieu 1999 Larger cohort autopsy studies of HIV-infected patients over longer time periods suggest that, despite the beneficial effects of modern antiretroviral combination therapy, involvement of the brain in AIDS subjects continues to be a frequent autopsy finding (Gray et al. 1988 (Gray et al. , 2003 Jellinger et al. 2000; Langford et al. 2003) (Tables 26.12 and 26.13). Immune reconstitution inflammatory syndrome (IRIS) is a syndrome that emerges when the immune system recovers after an immune deficiency state (Table 26 .14) (Nelson et al. 2017; Chahroudi and Silvestri 2012; McCarthy and Nath 2010) . IRIS is an adverse clinical manifestation that occurs in HIV-infected individuals treated successfully with ART and consists of a paradoxical deterioration of clinical status despite improved CD4-T-cell counts and immunologic conditions. A new variant of HIVE has emerged in the era of HAART as a severe leukoencephalopathy with significant perivascular infiltration of macrophages and lymphocytes which is assumed to be the result of an exaggerated response from a newly reconstituted immune system (Persidsky and Gendelman 2003) . Frequencies for pre-HAART could not be calculated due to lack of original data in their paper • Demyelinating lesions with marked intraparenchymal and perivascular infiltration by macrophages and T-lymphocytes. • In some cases, abundant viral proliferation was identified by immunocytochemistry or in situ hybridization, but in others the infectious agent could only be detected using PCR. • T-lymphocytes were predominantly CD8(+). • In those cases with the more favorable course, inflammation was less severe with marked macrophage activation and a number of CD4(+) lymphocytes. • In the lethal cases, inflammation was severe and mostly composed of CD8(+) cytotoxic lymphocytes. In summary, the following changes of the brain have been described to be due to the HIV-1 infection: • Brain weight (Weis, unpublished data) -no changes • Brain edema (Weis, unpublished data) -no significant difference • Gross-anatomy (Gelman and Guinto 1992) -No apparent macroscopical signs of atrophy are seen by bare visual inspection. -Cerebrospinal fluid (CSF) space greater than two standard deviations above the mean of the age-matched control subjects. -CSF spaces expanded most in the frontal and temporal lobe. • Ventricular system (Weis, unpublished data) (Gelman and Guinto 1992) -Widening of the lateral ventricles. -Ventricular spaces expanded more than the sulcal spaces. • Volume of brain regions (Oster et al. 1993; Subbiah et al. 1996; Weis et al. 1993c) -No significant changes in volume, surface area, mean cortical thickness. -Reduction of the mean volume of the neocortex. -Reduction in volume of the central brain nuclei. -Reduction in volume of the internal capsule. -Mean neocortical thickness was reduced by 12%. -There were no differences in white matter volumes between groups. -The mean volume of the white matter was reduced by 13%. -Mean ventricular volume was increased by 55%. -There were no significant differences between the AIDS groups with and without HIV-associated dementia. • Neuronal number -Cerebral cortex (Ketzler et al. 1990; Weis et al. 1993b) • Loss of neurons in different cortical regions. • Neuronal loss is not be correlated with development of dementing symptoms and of HIV-specific neuropathology. -Basal ganglia • decrease in neuronal density (21%) in the putamen especially in those cases with HIV-1 encephalitis (Everall et al. 1993 ). -Cerebellum • significant reduction of the volume density, the numerical density of neurons as well as neuronal size was apparent in the cerebellar dentate nucleus and in both inferior olivary nuclei (Abe et al. 1996 ) -Substantia nigra • The total number of neuronal cell bodies was 25% lower in AIDS than in agematched controls although the volume density of neuronal melanin did not differ from that of controls because the percentage of pigmented cell bodies was higher and the cell bodies were more fully packed with melanin in AIDS (Reyes et al. 1991 ). • The size of total neurons (pigmented and non-pigmented neurons) and of pigmented neurons was significantly reduced in all investigated nuclei (anteromedial, antero-intermediolateral, posterolateral, and posteromedial nuclei) of HIV-1-infected brains. • Furthermore, the nigral neuronal loss showed no relationship with immunohistochemical detection of HIV-1 antigens (gp41, p24). • The numerical density of non-pigmented large neurons (type II neurons) was significantly increased in HIV-1infected brains suggesting that (1) nonpigmented, dopaminergic neurons or non-pigmented, non-dopaminergic neurons might be relatively preserved in the SN of HIV-1 infection, or (2) that pigmented dopaminergic neurons loose their melanin pigments during the early stages of degeneration, which also might be responsible for functional deterioration (Itoh et al. 2000) . • Neuronal size (Weis et al. 1993b) -no changes in perikaryal size • Synapses (Wiley et al. 1991) -Loss of synapses as shown by a decrease in the immunoreactivity against synaptophysin • Dendrites (Masliah et al. 1992a, b) -Apical dendrites • dilated, vacuolated, and tortuous • decreased length and branching -Basal and oblique dendrites • show the same alterations, but to a lesser extent -Some dendrites present lacunae and filopodia consistent with remodeling. -40-60% decrease in spine density throughout the entire length of dendrites. -Fewer spines on neurons; 55% fewer on the first segment, 40% fewer on the second, 45% fewer on the third, 60% fewer on the fourth, and 65% fewer in the fifth segment. -Aberrant spines in regions of abnormal second-order dendritic branches. • Nerve fibers -White matter • Loss of nerve fibers in the white matter -Corpus callosum (Wohlschlaeger et al. 2009) • Reduced thickness of the myelin sheath of nerve fibers in the corpus callosum. • Calculation of the g-ratio revealed a relative increase in size of the axon and a relative decrease in the myelin sheath thickness. • The data indicated a reduction in the size of nerve fibers and axons as well as thinner myelin sheaths, whereas in other callosal regions axons and myelin sheaths were swollen and enlarged. • These changes were observed in regions which are unaffected, as revealed by light-microscopic analysis of sections stained for myelin. -Optic nerve (Tenhula et al. 1992) • Degeneration was often severe and was scattered throughout all of the AIDSaffected optic nerves. • Despite the approximate 40% loss of axons in the AIDS-affected optic nerves, the mean axonal population was markedly lower than the mean obtained from normal optic nerves (880,000 vs. 1,507,000). • The mean axonal diameters were not markedly different, that the changes may not only be secondary to damage at the retina, but may reflect an AIDS-associated primary optic neuropathy. • Astroglia (Weis et al. 1993a; Ciardi et al. 1990) -no change in the number of all astrocytes (i.e., GFAP-positive and GFAP-negative astrocytes) -reduction of the number of GFAP-negative cells -increase of reactive GFAP-positive astrocytes -not correlated with loss of nerve cells -increase in nuclear size of GFAP-negative and GFAP-positive astrocytes -increase of the size of the cytoplasm of GFAP-positive astroglia -no correlation between the neuronal loss and the pattern of reactive astrocytosis • Oligodendroglia (Esiri et al. 1991) -significant increase in the number of oligodendrocytes associated with mild degree of myelin damage -decrease of oligodendrocytes in severely affected areas -slight increase in immunoreactivity for the enzymes carbonic anhydrase II and 2′,3′cyclic nucleotide 3′-phosphodiesterase -significant increase in the numerical density of transferrin-immunopositive cells of the white matter -an initial reactive hyperplasia which may represent an attempt to repair myelin damage taking place already early during the HIV-1 infection • Microglia/macrophages (Weis et al. 1994) -Activated in gray and white matter of all brain regions. -Activation pattern is not correlated with the presence of HIV-antigen gp41 and p24 in the brain tissue. • Vessels (Buttner et al. 1996; Weis et al. 1996) -Significant increase in the diameter of cortical vessels -Increase of the volume fraction, surface area of vessels -No changes in length density indicating no changes in the number of vessels -Increase of the numerical density of vessels in the gray matter -No changes in the numerical density of vessels in the white matter -Thinning of the basal lamina as seen by electron microscopy -Reduced immunoreactivity for collagen IV and laminin (thinning of the basal lamina) • Vascular endothelial cell (Buttner et al. 1996; Weis et al. 1996) -loss of glycoproteins SBA, UEA-I, and WGA of the endothelial cell membrane -decrease of immunoreactivity for von Willebrand factor (Factor VIII) -no significant differences RCA-I -No changes in size at the electron microscopic level • Capillaries (Weis and Haug 1989) -region-specific changes -increased capillary profile area -increased capillary diameter -decreased basal lamina thickness -increased endothelial cell size -unchanged pericyte size 26.9.9 Pathogenetic Mechanisms 26.9.9.1 Mode of Entrance of HIV-1 to the Brain • HIV-1 is passively carried by T-lymphocytes and monocytes-the "Trojan Horse" hypothesis. • Cell-free HIV-1 particles may also penetrate brain microvascular endothelial cells. • After crossing the BBB into the CNS, macrophages spread productive HIV-1 infection to neighboring microglia. • Microglia serve as -a reservoir for persistent viral infection and replication -a vehicle for viral dissemination throughout the brain -a major source of neurotoxic products that affect glial function, the blood-brain barrier and neuronal function, and finally lead to cell death • Microglia and monocyte-derived macrophages express both the CD4 and chemokine coreceptors (CCR5, CXCR4), the prerequisite for HIV-1 to enter a cell. • The potential role of the cerebrospinal fluid or the choroid plexus as a means for HIV-1 entry in the brain is still unclear. • At the time of primary HIV-1 infection, an acute aseptic meningitis or encephalitis indicates central nervous system invasion. • The point in time when the migration of HIV-1-infected lymphocytes into the brain takes place is not known. It has been shown that, at the time of seroconversion, HIV-1 can be detected in the CSF; this is the time when, clinically, a subacute meningitis develops, thus, suggesting that HIV-1 enters the CNS at a very early stage of the disease. • Opportunistic infectious agents or drugs of abuse disturbing the BBB may further attract more HIV-1-infected T-lymphocytes and macrophages into the brain. The cells in the brain identified to contain HIV-1 are: • The development of brain lesions due to opportunistic infections and lymphomas might be explained by the lack of a competent immunologic defense system. • One might assume that the changes described in Sect. 26.5.8 might result by direct infection with HIV-1. -However, it has been shown that neither neurons, nor astrocytes nor endothelial cells are infected with HIV-1. -Thus, these changes more probably result from indirect toxic factors that are produced either by infected multinucleated giant cells or by activated microglia. • Neuronal dropout occurs in brain regions -That are free from any neuropathological changes. -Neuronal damage in AIDS was, at least, partly due to apoptosis. -No correlation was found between the presence and severity of neuronal loss or of neuronal apoptosis and a history of cognitive disorders. -No correlation between the presence of HIV-1 proteins and neuronal loss. • The reactive astrogliosis was not correlated with the loss of nerve cells, indicating that this reaction pattern is rather a response to toxic factors secreted into the brain tissue. • The number of activated microglia/macrophages is significantly increased in all brain regions. This activation of microglia is not correlated with the presence of HIV-1 antigen in the brain tissue. Activated microglia/macrophages, rather than MGCs, most probably secrete toxic factors. • The neurotoxicity associated with HIV-1 infection is mediated, in part, through -cytokines -arachidonic acid metabolites -produced during cell-to-cell interactions between HIV-1-infected brain macrophages and astrocytes • Pathobiological events underlying the neurodegenerative processes in HIV-1-associated dementia are believed to begin with productive infection of monocytes/macrophages by HIV-1. -Peripheral activation causes the differentiation of macrophages to produce a variety of immune products that lead to the upregulation of adhesion molecules on brain microvascular endothelial cells and the expression of adhesins on the monocyte-macrophage cell surface. -After penetration of the BBB, the differentiated brain macrophages and microglia can be vehicles for viral dissemination throughout the brain and focal reservoirs for productive HIV-1 replication. -The neurotoxic events in the brain are caused by neurotoxins produced by these cells which are primed by HIV-1 and secondarily activated by factors such as immune stimuli or by T-cells trafficking through the nervous system. -The primed and immune-activated brain macrophages/microglia secrete a variety of factors which affect neural and glial function and eventually lead to CNS inflammation. -A pro-inflammatory cytokine response from blood-derived monocytes/macrophages, microglia, and astrocytes is amplified and leads finally to neurodegeneration. -Immune neurotoxic factors may contribute to the breakdown of the BBB and affect the generation of chemokines, leading to transendothelial migration of monocytes into the brain perpetuating the inflammatory cascade. -As a result of the neurotoxic activities of activated macrophages/microglia, astrocytes may suppress or increasemacrophages/microglia secretory functions and toxicity, depending on the astrocytic functional status. -Cytolytic T-lymphocytes serve to eliminate infected cells, but are lost in late-stage HIV-1 disease, allowing the virus-induced, neurodegenerative response to continue unabated. • Other factors include: -viral proteins -CA 2+ channels -NMDA receptors -chemokines and cytokines • Expression of developmental proteins (Malik and Eugenin 2016) : -Dickkopf homolog 1 (DKK1): upregulated -Rho-associated, coiled-coil containing protein kinase 2 (ROCK2)-upregulated -Low density lipoprotein receptor-related protein-associated protein 1 (LRPAP1)upregulated -Low density lipoprotein receptor-related protein 5-like (LRP5L)-downregulated -Low density lipoprotein-related protein 12 (LRP12)-upregulated -Low density lipoprotein receptor-related protein 8, apolipoprotein e receptor (LRP8)-downregulated -Catenin (cadherin-associated protein), alphalike 1 (CTNNAL1)-upregulated -Catenin, beta-like 1 (CTNNBL1)downregulated -Catenin (cadherin-associated protein), delta 1 (CTNND1)-downregulated -Catenin (cadherin-associated protein), alphalike 1 (CTNNAL1)-upregulated -Glycogen synthase kinase 3 beta (GSK3B)downregulated -Wingless-type MMTV integration site family, member 10A (WNT10A)downregulated • For more details, see (Zayyad and Spudich 2015; Singh 2016; Ru and Tang 2017; Rao et al. 2014; Malik and Eugenin 2016; Lamers et al. 2016; Joseph et al. 2016; Chen et al. 2014; Carroll and Brew 2017) . Interactions between the blood-brain barrier (BBB) and HIV (Hong and Banks 2015) Mechanisms involving the BBB in HIVinfection • Passage of HIV cell-free virus across the BBB -Transcytotic (mannose 6 phosphate receptor dependent) -Paracellular (tight junction dissolution) • Passage of HIV-1 proteins (gp120, Tat) across the BBB • Increased immune Ccll trafficking across the BBB -Activated and infected T cells -Activated and infected monocytes • Transport of cytokines across the BBB • Induction of cytokine release from barrier cells • Increased BBB leakiness • Brain-to-blood efflux of antivirals -Protease inhibitors by P-glycoprotein -AZT by organic ion transporter • Altered BBB transporter expression and function (e.g., P-glycoprotein) • Neurovascular unit effects Therapeutic effects on involved pathways are illustrated in Table 26 .15. • In general, there are no gross-anatomical changes. • Rarely, some small areas of necrosis are seen lining the ventricles, i.e., necrotizing ependymitis. Microscopic Features (Fig. 26 .8a-j) • Microglial nodules are seen scattered throughout the nervous system. • Large cells containing inclusion bodies are found within the microglial nodules. • The microglial nodules located in the gray and white matter are usually not surrounded by a necrotic area. • Along the periventricular spaces CMVcontaining cells are found within the necrotic areas. John Cunningham Virus (JCV) is a member of the Polyomaviridae family Polyomaviruses BK and JC are ubiquitous. • Are 45 nm in diameter. • Contain less than 5000 base pairs. • Genomes of BK and JC are closely related. -divided in early, late, and non-coding regions • JC virus etiological agent of the progressive multifocal leukoencephalopathy (PML) • JC is an ubiquitous, neurotropic virus: -50-90% of adult healthy individuals have been exposed to this virus. -19-27% of those people shedding JCV in their urine. • The seroprevalence increases with age but acquisition of this virus is not associated with a clinical syndrome. • JC binds to sialylated carbohydrates and serotonin receptors to enter glial cells by endocytosis. • DNA genome is uncoated and delivered to the nucleus. • The pre-AIDS era -Impaired vision • homonymous hemianopsia -Motor weakness • hemiparesis or hemiplegia -Changes in mentation: • personality change • difficulty with memory • emotional lability The differences between progressive multifocal leukoencephalopathy (PML), progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome (PML-IRIS) and multiple sclerosis (MS) with regard to anatomical, neuropathological, and MRI features are shown in Table 26 .17. Prognostic factors of the evolution of progressive multifocal leukoencephalopathy have been described (Gheuens et al. 2013) a, b) . The virus is demonstrated by immunohistochemistry mainly in neurons (c, d) Macroscopic Features (Fig. 26.13a Tick-borne encephalitis (TBE) is an infection of the central nervous system (CNS) caused by tick-borne encephalitis virus (TBEV) and transmitted by ticks, with a variety of clinical manifestations (Table 26 .18). The incidence of TBE in Europe is increasing due to an extended season of the infection and the enlargement of endemic areas. Causative agents: • General Imaging Features • MRI and CT often normal, rarely lesions in thalamus, cerebellum, or basal ganglia • Virus enters the vector (mosquito or tick) while it is feeding on the blood of an infected host. • Is transmitted to other hosts in the salivary secretions of the vector. • Natural hosts are birds or small mammals (rodents). • Humans are dead-end hosts. • Virus replicates at the site of host inoculation. • Spreads to regional lymph nodes and other lymphoreticular tissues. • Disseminates hematogenously to systemic tissues (CNS). Degeneration of the cerebellar dentate nucleus and the inferior olivary nuclei in HIV-1-infected brains: a morphometric analysis Progressive multifocal leukoencephalopathy Progressive multifocal leukoencephalopathy. Continuum (Minneapolis, Minn) 18(6 Infectious Disease Epidemiology of tickborne encephalitis (TBE) in Europe and its prevention by available vaccines Neuroimaging of HIV-associated neurocognitive disorders (HAND) Cranial viral infections in the adult Updated research nosology for HIV-associated neurocognitive disorders HSV-induced apoptosis in herpes encephalitis Congenital cytomegalovirus infection Herpes simplex infections of the nervous system Neuroimaging of herpesvirus infections in children Progressive multifocal leukoencephalopathy and immune reconstitution inflammatory syndrome (IRIS) New insights on human polyomavirus JC and pathogenesis of progressive multifocal leukoencephalopathy Immune surveillance and response to JC virus infection and PML The clinical features of PML Progressive multifocal leukoencephalopathy Classifying PML risk with disease modifying therapies The pathogenesis of progressive multifocal leukoencephalopathy PML diagnostic criteria: consensus statement from the AAN Neuroinfectious Disease Section HSV antiviralscurrent and future treatment options HSV LAT and neuronal survival Herpes simplex virus-1 encephalitis in adults: pathophysiology, diagnosis, and management Herpes simplex virus latency: the DNA repair-centered pathway Vascular changes in the cerebral cortex in HIV-1 infection. II An immunohistochemical and lectinhistochemical investigation Neonatal herpes simplex virus infections: past progress and future challenges The host cell response to tick-borne encephalitis virus HIV-associated neurocognitive disorders: recent advances in pathogenesis, biomarkers, and treatment IRIS: the unfortunate rainbow of HIV Neuropathogenesis of HIV-associated neurocognitive disorders: roles for immune activation, HIV blipping and viral tropism The involvement of the cerebral cortex in human immunodeficiency virus encephalopathy: a morphological and immunohistochemical study Progressive multifocal leukoencephalopathy in HIV-1 infection HIV-associated neurocognitive disorder Maternal and neonatal herpes simplex virus infections HIV disorders of the brain: pathology and pathogenesis Herpes simplex virus: the interplay between HSV, host, and HIV-1 Magnetic resonance imaging and spectroscopy of the brain in HIV disease Tickborne encephalitis virus and the immune response of the mammalian host HIV-1-associated neurocognitive disorder: epidemiology, pathogenesis, diagnosis, and treatment HIV and antiretroviral therapy in the brain: neuronal injury and repair Fate of oligodendrocytes in HIV-1 infection A review of neuronal damage in human immunodeficiency virus infection: its assessment, possible mechanism and relationship to dementia Molecular biology, epidemiology, and pathogenesis of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain Nomenclature and research case definitions for neurologic manifestations of human immunodeficiency virus-type 1 (HIV-1) infection Immune reconstitution inflammatory syndrome unmasking or worsening AIDS-related progressive multifocal leukoencephalopathy: a literature review Microglia in human immunodeficiency virus-associated neurodegeneration HIV infection and dementia Morphometry, histopathology, and tomography of cerebral atrophy in the acquired immunodeficiency syndrome The neuropathogenesis of HIV-1 infection Progressive multifocal leukoencephalopathy: why gray and white matter Brain imaging abnormalities in CNS virus infections Herpes simplex encephalitis: an update Alarmins and central nervous system inflammation in HIV-associated neurological disorders The neuropathology of the acquired immune deficiency syndrome (AIDS). A review Early brain changes in HIV infection: neuropathological study of 11 HIV seropositive, non-AIDS cases The changing pattern of HIV neuropathology in the HAART era What goes around, comes around-HSV-1 replication in monocyte-derived dendritic cells Update on PML: lessons from the HIV uninfected and new insights in pathogenesis and treatment Neuroimaging studies of the aging HIV-1-infected brain Neuroimaging of natalizumab complications in multiple sclerosis: PML and other associated entities Role of the immune system in HIV-associated neuroinflammation and neurocognitive implications Imaging findings in tick-borne encephalitis with differential diagnostic considerations Common and uncommon imaging findings in progressive multifocal leukoencephalopathy (PML) with differential diagnostic considerations HIV-1 tat-mediated calcium dysregulation and neuronal dysfunction in vulnerable brain regions Neuronal damage of the substantia nigra in HIV-1 infected brains Immunology of progressive multifocal leukoencephalopathy Neuropathology and general autopsy findings in AIDS during the last 15 years New strategies against drug resistance to herpes simplex virus HIV-1 induced CNS dysfunction: current overview and research priorities Tick-borne encephalitis Neuroimaging of infections Neuroimaging of infections of the central nervous system Pathways to neuronal injury and apoptosis in HIV-associated dementia Loss of neurons in the frontal cortex in AIDS brains Neuropathogenesis of central nervous system HIV-1 infection Neurologic complications in persons with HIV infection in the era of antiretroviral therapy Central nervous system in pediatric AIDS. Results from Neuropathologic Pediatric AIDS Registry The meningeal lymphatic system: a route for HIV brain migration? Changing patterns in the neuropathogenesis of HIV during the HAART era MR imaging in human rabies Neuroimaging in rabies HIV-associated neurologic disorders and central nervous system opportunistic infections in HIV Genetic, transcriptomic, and epigenetic studies of HIV-associated neurocognitive disorder Tick-borne encephalitis HIV, antiretroviral therapies, and the brain HIV-related neurotoxicity Oligodendrocyte injury and pathogenesis of HIV-1-associated neurocognitive disorders Overcoming drug resistance in HSV, CMV, HBV and HCV infection Blood-brain barrier abnormalities caused by HIV-1 gp120: mechanistic and therapeutic implications Mechanisms of HIV neuropathogenesis: role of cellular communication systems Targeting the brain reservoirs: toward an HIV cure Update on neuroimaging in infectious central nervous system disease Spectrum of human immunodeficiency virus-associated neocortical damage Cortical dendritic pathology in human immunodeficiency virus encephalitis Neurologic consequences of the immune reconstitution inflammatory syndrome (IRIS) HIV and viral protein effects on the blood brain barrier The brain and HAART: collaborative and combative connections Defining nervous system susceptibility during acute and latent herpes simplex virus-1 infection The risk of progressive multifocal leukoencephalopathy in the biologic era: prevention and management Immune system involvement in the pathogenesis of JC virus induced PML: what is learned from studies of patients with underlying diseases and therapies as risk factors The AIDS dementia complex: II The AIDS dementia complex: I. Clinical features Immune reconstitution inflammatory syndrome (IRIS): what pathologists should know Progressive multifocal leukoencephalopathy (PML) associated with HIV Clade C-is not uncommon Controversies in HIV-associated neurocognitive disorders Cerebral atrophy in AIDS: a stereological study Progressive multifocal leukoencephalopathy: current treatment options and future perspectives Mononuclear phagocyte immunity and the neuropathogenesis of HIV-1 infection Herpes simplex virus type-1: replication, latency, reactivation and its antiviral targets Viral and cellular factors underlying neuropathogenesis in HIV associated neurocognitive disorders (HAND) Nigral degeneration in acquired immune deficiency syndrome (AIDS) Central nervous system infectious diseases mimicking multiple sclerosis: recognizing distinguishable features using MRI An inquiry into the molecular basis of HSV latency and reactivation Herpes simplex encephalitis: from virus to therapy HIV-associated synaptic degeneration Imaging of topographic viral CNS infections Tick-borne encephalitis: pathogenesis and clinical implications Macrophages, chemokines and neuronal injury in HIV-1-associated dementia Astrocyte activation and apoptosis: their roles in the neuropathology of HIV infection Progressive multifocal leukoencephalopathy: a review of the neuroimaging features and differential diagnosis Neuronal stress and injury caused by HIV-1, cART and drug abuse: converging contributions to HAND HIV-associated neurocognitive disorder-pathogenesis and prospects for treatment Natalizumab-associated PML: challenges with incidence, resulting risk, and risk stratification Imaging features of CNS involvement in AIDS Imaging manifestations of progressive multifocal leukoencephalopathy Overview on the tricks of HIV tat to hit the blood brain barrier Review of tick-borne encephalitis and vaccines: clinical and economical aspects HIV-1 and its causal relationship to immunosuppression and nervous system disease in AIDS: a review Update on progressive multifocal leukoencephalopathy Stereological analysis of cerebral atrophy in human immunodeficiency virus-associated dementia EAN consensus review on prevention, diagnosis and management of tick-borne encephalitis Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis HIV-1-related central nervous system diseases Morphometric comparisons of optic nerve axon loss in acquired immunodeficiency syndrome Herpes simplex virus establishment, maintenance, and reactivation: in vitro modeling of latency Novel neuroimaging methods to understand how HIV affects the brain Cytomegalovirus infections of the adult human nervous system Oxidative stress and the HIV-infected brain proteome Pathological findings in the central nervous system of AIDS patients on assumed antiretroviral therapeutic regimens: retrospective study of 1597 autopsies Astrocyte elevated gene-1 (AEG-1) and the A(E)Ging HIV/ AIDS-HAND PET brain imaging in HIVassociated neurocognitive disorders (HAND) in the era of combination antiretroviral therapy MRI features of Japanese encephalitis MRI-imaging and clinical findings of eleven children with tick-borne encephalitis and review of the literature The chameleon of neuroinflammation: magnetic resonance imaging characteristics of natalizumab-associated progressive multifocal leukoencephalopathy Capillaries in the human cerebral cortex: a quantitative electronmicroscopical study Astroglial changes in the cerebral cortex of AIDS brains: a morphometric and immunohistochemical investigation Neuronal damage in the cerebral cortex of AIDS brains: a morphometric study Macroscopic morphometry of human brains in neurodegeneration Activation of microglia in HIV-1 infected brains is not dependent on the presence of HIV-1 antigens Vascular changes in the cerebral cortex in HIV-1 infection: I. A morphometric investigation by light and electron microscopy Herpes simplex viruses: mechanisms of DNA replication Pathogenesis of progressive multifocal leukoencephalopathy-revisited Diagnostic assays for polyomavirus JC and progressive multifocal leukoencephalopathy Neocortical damage during HIV infection Central nervous system damage, monocytes and macrophages, and neurological disorders in AIDS A cultured affair: HSV latency and reactivation in neurons White matter changes in HIV-1 infected brains: a combined gross anatomical and ultrastructural morphometric investigation of the corpus callosum Neurological complications of tick borne encephalitis: the experience of 89 patients studied and literature review Neuropathogenesis of HIV: from initial neuroinvasion to HIV-associated neurocognitive disorder (HAND)