Neuropathologic findings in the acquired immunodeficiency syndrome (AIDS)

The acquired immunodeficiency syndrome (AIDS) is characterized by a severe idiopathic deficiency in T-cell mediated immunity. Homosexuals, intravenous drug abusers and Haitians are predominantly affected, predisposing them to opportunistic infections and neoplasms. In this study, the central nervous system (CNS) was examined at autopsy in 29 AIDS patients. Significant CNS complications occurred in 55%, mainly related to opportunistic infections similar to those seen in patients with other causes of immunosuppression. Progressive multifocal leukoencephalopathy (three cases), cytomegalovirus (CMV) encephalitis (five cases), cryptococcal meningitis (four cases), Mycobacterium avium-intracellulare (three cases), and toxoplasmosis (one case) were found. Widespread microglial nodules were observed in 20 patients, 80% of whom had CMV inclusions elsewhere at autopsy. Primary cerebral lymphoma (one case) and lymphomatoid granulomatosis (one case) were present. Subarachnoid (five cases) and intraparenchymal (three cases) hemorrhage was seen although these were not usually clinically significant. A single case of embolic arterial obstruction with cortical infarction was due to non-bacterial thrombotic endocarditis.     

The neuropathology of pediatric acquired immunodeficiency syndrome.

Central nervous system disease has emerged as an important manifestation of acquired immunodeficiency syndrome in both the adult and pediatric populations, with neurologic abnormalities occurring in up to 90% of pediatric patients in some series. Neuropathologic studies, based primarily on the autopsy, have provided valuable insights into the spectrum and pathogenesis of acquired immunodeficiency syndrome-associated neurologic disorders, including primary human immunodeficiency virus encephalopathy and as the spectrum of infectious, neoplastic, and cerebrovascular diseases that may complicate the course of acquired immunodeficiency syndrome. Progressive encephalopathy represents the single most common neurologic disorder in pediatric acquired immunodeficiency syndrome and appears to be caused in most cases by direct infection in brain parenchyma by human immunodeficiency virus. Central nervous system lymphoma and cerebrovascular disease continue to account for most focal central nervous system lesions in the pediatric population. In contrast to adults with acquired immunodeficiency syndrome, opportunistic central nervous system infections remain relatively uncommon in the pediatric population. Our understanding of acquired immunodeficiency syndrome-associated neurologic disease remains far from complete. A plea is made for regular postmortem examination of the central nervous system in all patients dying with human immunodeficiency virus infection.     

Cytomegalovirus infection of the brain in AIDS: a clinicopathological study

Based on neuropathological findings, a retrospective case control study of 39 patients with acquired immune deficiency syndrome (AIDS) and confirmed cytomegalovirus (CMV) infection of the brain is presented. Since 1989, the incidence of cerebral infections in AIDS autopsy material has increased progressively and, in 1994, CMV was the most frequent opportunistic central nervous system (CNS) infection. Of the patients with CMV infections of the brain 16 had one or more coexisting secondary opportunistic and/or tumorous lesions in the CNS. Cerebral involvement by CMV was more frequent in patients with multiple extracerebral organ infections, while 7 among the 39 reported cases showed isolated CMV infection of the brain. The evaluation of the clinical records of 21 patients revealed neuropsychiatric signs and symptoms in 10, while these were absent in 11. All of these patients revealed various types of cerebral lesions related to CMV infection: ventriculitis, focal lesions, and microglial nodule encephalitis. The extent and distribution of cerebral lesions showed no significant correlations with clinical, radiological, or laboratory findings. Further clinicopathological studies are warranted to recognize CMV infections of the CNS and to allow earlier and more efficient treatment of this rather frequent complication of AIDS.     

Prothrombotic states in HIV disease and stroke complications

Thirty to 40% of patients with acquired immunodeficiency syndrome (AIDS) have symptoms and signs of neurologic dysfunction. Radiographic and pathologic studies reveal evidence of neurologic involvement in 75% to 90% of cases of advanced-stage human immunodeficiency virus-1 (HIV) disease. Before the introduction of highly active antiretroviral therapies, AIDS dementia complex and opportunistic infections of the central nervous system were frequent causes of global cerebral dysfunction. Focal neurological deficits were most commonly due to toxoplasmosis, primary central nervous system (CNS) lymphoma, or progressive multifocal leukoencephalopathy.Thrombotic events including cerebral infarction and venous thrombosis have been reported in patients with HIV/AIDS. Various hematologic abnormalities have been described that could lead to a hypercoagulable state, including antiphospholipid antibodies; deficiencies of antithrombin III, protein C, and protein S; and increased levels of von Willebrand factor and D-dimer.In the majority of cases of cerebral infarction, there is an associated precipitating event such as opportunistic infection or malignancy. However, vasculopathy has also been described in both adults and children. Furthermore, there are reports of HIV patients with cerebral infarction in whom an HIV-related coagulopathy is identified and other cases where no explanation is found, but only a limited hematologic evaluation has been performed.     

Human immunodeficiency virus (HIV) envelope and core proteins in CNS tissues of patients with the acquired immune deficiency syndrome (AIDS)

Summary Frequency, cellular tropism and relation to pathology of productive infection with human immunodeficiency virus (HIV) in human central nervous system (CNS) were studied. Serial sections of formolfixed and paraffin-embedded CNS tissues from 70 patients (69 with acquired immune deficiency syndrome, AIDS) were immunolabeled with monoclonal antibodies against HIV antigens (Ags) p17, p24, and gp41. Additional and double (immuno)stains were used to identify cell types and opportunistic infectious agents. HIV Ags were detected in 52 cases; they were restricted to cells with characteristics of microglia or macrophages. Anti-gp41, anti-p24, and anti-p17 labeled 50, 33, and 15 cases, respectively. Immunoreactivity for core proteins predominated in mature macrophages and microglia of fully developed lesions; additional immunoreactivity for gp41 was seen in microglia adjacent to, or unassociated with, histopathological lesions. Multifocal and/or diffuse lesions previously suggested as HIV induced because of characteristic histopathology, consistently contained large numbers of cells with HIV Ags (33 cases), confirming their HIV specificity. Isolated labeled microglia without associated pathology, found in seven brains, presumably represent the earliest stage of productive CNS infection by HIV. Lesions of opportunistic infections contained no (34 cases), few (16 cases), or many (4 cases) cells with HIV Ags. These data do not suggest transactivation of local HIV production by opportunistic agents as a frequent event in vivo. Development of specific HIV histopathology appears correlated with the number of productively infected cells.Supported by the Austrian Fund for the Advancement of Scientific Research (P 7154-MED). Major parts of this study were presented at the Vth International Conference on AIDS, June 4–9, 1989, in Montreal, Canada (Th. B. P. 248)     

AIDS dementia: a review of the literature

Mental disturbances associated with acquired immunodeficiency syndrome (AIDS) are related not only to profound psychosocial stress, systemic diseases, and neoplasms or opportunistic infections within the central nervous system (CNS); they are also related to the direct neurotoxicity of the etiologic human immunodeficiency virus (HIV), producing an array of both insidious and acute affective, cognitive, and behavioral dysfunction that can mimic many neuropsychiatric disorders. The precise mechanism of this direct neurotoxicity is not known, nor have the frequency, clinical course, or methods of early diagnosis been clearly established; however, a critique of 56 clinical reviews or case reports regarding approximately 800 subjects suggest that at some point following infection an HIV-induced dementia is extremely common, as are marked histopathological changes throughout the CNS. Treatment strategies are discussed.     

Human immunodeficiency virus (HIV) leukoencephalopathy and the microcirculation

We studied the brains of three patients with acquired immune deficiency syndrome (AIDS), all of whom developed subacutely progressive dementia unassociated with opportunistic infection or neoplasm in the central nervous system. Computed tomographic (CT) scans of the head revealed cortical atrophy, ventricular dilation, and diffuse hypodensity of the centrum semiovale. On microscopic examination, the cerebral and cerebellar white matter in all cases showed diffuse and focal, angiocentric regions of myelin pallor, focal vacuolization, and extensive gliosis. Variable axonal loss and axonal spheroids were evident. The microvasculature showed striking changes, including mural thickening, increased cellularity, and enlargement and pleomorphism of endothelial cells with variable numbers of macrophages and multinucleated giant cells (MNGC), which often contained hemosiderin pigment. Human immunodeficiency virus type 1 (HIV-1) antigens were identified immunocytochemically within perivascular macrophages and MNGC and in some microglial cells. We suggest that the morphologic abnormalities of the microcirculation may be associated with an alteration of the blood-brain barrier. The increased vascular permeability could contribute to damage and loss of the white matter including both myelin and axons, and result in subcortical cerebral atrophy. The HIV-1 infected cells present in relation to the microvasculature may play a role in mediating the vascular injury.     

Progressive tumefactive inflammatory central nervous system demyelinating disease in an acquired immunodeficiency syndrome patient treated with highly active antiretroviral therapy

We report here a case of progressive tumefactive inflammatory central nervous system (CNS) demyelinating disease in a human immunodeficiency virus (HIV)-seropositive patient treated with highly active antiretroviral therapy (HAART). Biopsy revealed diffuse macrophage and perivascular T-lymphocytic infiltrates with severe demyelination and relative axonal sparing. The disease progressed in a centrifugal fashion, to involve bihemispheric cerebral white matter, with subsequent central necrotic changes and atrophy. Treatment with HAART was discontinued, and inflammatory disease was treated with subcutaneous interferon (IFN)β-1a. Massive brain edema was controlled with courses of intravenous corticosteroids. Following fulminant monophasic disease, the patient stabilized with no evidence of disease progression over long-term follow up. We propose that immune response reconstituted by HAART can unmask an autoimmune response in susceptible individuals, analogous to the enhanced immune response to the preexisting acquired immunodeficiency syndrome (AIDS) opportunistic infections. Therapeutic options are considered.     

Neuropsychiatric manifestations of AIDS-spectrum disorders

Psychiatric symptoms among patients with acquired immune deficiency syndrome (AIDS) may be functional reactions to contracting a fatal and stigmatizing disease or may be secondary to malignancies and opportunistic infections in the central nervous system (CNS). More recent evidence indicates that HTLV-III, the virus that causes AIDS, directly infects the CNS and may cause psychiatric symptoms before signs of immunodeficiency, cognitive impairment, or neurological abnormalities emerge. AIDS-related organic mental syndromes may mimic functional disorders such as chronic mild depression and acute psychosis. Both of these common presentations are illustrated with detailed case reports, and diagnostic and management guidelines are provided.     

Neurological complications and concomitants of AIDS

A survey of the literature of neurological manifestations associated with the acquired immune deficiency syndrome (AIDS) shows a broad disease spectrum affecting approximately one third of the patients in large hospital series. The complications include focal cerebral lesions caused by abscesses, lymphomas, leucoencephalopathy or infarcts as well as encephalitis, meningitis and myelitis. Most opportunistic infections of the central nervous system presumably are caused by toxoplasma gondii, cytomegalovirus and cryptococcus neoformans. One tenth of all patients have neurological disease as their initial symptom of AIDS. The diagnosis should always be considered in patients at risk and in males with an unusual neurological history or with a peculiar CT scan of the brain. Besides the opportunistic complications of AIDS, LAV/HTLV-III itself probably attacks the nervous system and gives rise to concomitant lesions of the long tracts of the spinal cord with ataxia, paresis and spasticity and to subacute encephalopathy and peripheral nerve abnormalities as well.     

Epstein-Barr virus and the nervous system

The neurological complications of Epstein-Barr virus infection include viral meningitis, encephalitis and neuromuscular complications. The introduction of cerebrospinal fluid polymerase chain reaction for Epstein-Barr virus DNA has improved diagnosis of these conditions and of primary central nervous system lymphoma in acquired immune deficiency syndrome, and has enabled cerebrospinal fluid monitoring of therapy. Prognosis remains good for most Epstein-Barr virus-related neurological complications; for primary central nervous system lymphoma in acquired immune deficiency syndrome the prognosis is still poor.     

Central nervous system toxoplasmosis in acquired immunodeficiency syndrome: An emerging disease in India.

With the incidence of patients infected with human immuno-deficiency virus (HIV) increasing in India, the central nervous system (CNS) manifestations of the disease will be seen more frequently. The CNS may be primarily afflicted by the virus or by opportunistic infections and neoplasms secondary to the immune suppression caused by the virus. In India, although mycobacterium tuberculosis has been reported to be the most common opportunistic infection, toxoplasmosis may become as common owing to the ubiquitous nature of the protozoan. Since an empirical trial of medical therapy without histopathological diagnosis is recommended, the true incidence of this condition may remain under estimated. The role of ancillary tests such as radiology and serology in the initial diagnosis of this condition remain crucial. This report highlights two patients who were diagnosed to have acquired immuno-deficiency syndrome (AIDS) only after the biopsy of the intracranial lesion was reported as toxoplasmosis. Presently all patients for elective neurosurgery are tested for HIV antigen. The management protocol to be followed in a known patient with AIDS presenting with CNS symptoms is discussed in detail. The value of ancillary tests is also reviewed.     

Cognitive deficits associated with human immunodeficiency virus encephalopathy

The encephalopathy associated with direct nervous system infection by the human immunodeficiency virus (HIV) has been recognized as one of the major debilitating aspects of the acquired immunodeficiency syndrome (AIDS) and of pre-AIDS conditions. A comprehensive neuropsychological examination of symptomatic HIV-infected subjects without opportunistic cerebral disease demonstrated a distinctive pattern of cognitive deficits marked by prominent attentional impairment. Evidence of organizational and reasoning impairments also was observed, but language, visual-spatial, and memory consolidation abilities were relatively preserved. The findings suggest a profile of impairment similar to other cognitive syndromes involving dysfunction of predominantly anterior brain structures and projections and suggest a rationale for psychostimulant drug treatment.     

Central nervous system AIDS

The retrovirus that causes the acquired immunodeficiency syndrome (AIDS) has two targets: the immune system and the nervous system. Central nervous system (CNS) manifestations of AIDS are protean. This review describes the opportunistic infections and malignancies that affect the nervous system in AIDS, and discusses the syndromes resulting from primary infection of the CNS by the AIDS virus. Possible mechanisms of CNS injury are cited as well as potential predictors of neurologic expression of AIDS.     

Central nervous system lymphomas and immunodeficiency

Primary lymphomas of the central nervous system (CNS) may sometimes be associated with some immunological abnormalities, including renal or cardiac transplants, some congenital and acquired immunodeficiencies, immunoinflammatory diseases and immunosuppressive treatments. A relatively high incidence of cerebral lymphomas has been particularly noticed in renal or cardiac transplantation patients and in those with acquired immune deficiency syndrome (AIDS), two conditions which are today observed with increasing frequency. The different congenital and acquired immunodeficiencies associated with cerebral lymphomas and the pathogenetic connections between the two conditions are discussed from a large review of the literature.     

Early brain changes in HIV infection: neuropathological study of 11 HIV seropositive, non-AIDS cases.

We examined 11 brains of human immunodeficiency virus (HIV) seropositive cases who died from unnatural causes (10 intravenous drug abusers who died from heroin overdose and 1 homosexual dead from a gunshot injury); 10 brains of HIV seronegative heroin addicts who died from overdose and 1 seronegative drug abuser who died from gunshot injury served as controls. Complete postmortem examination did not show evidence of acquired immune deficiency syndrome (AIDS) or AIDS related complex. Terminal changes including nerve cell ischemia, edema and diffuse vascular congestion were observed in all cases. Perivascular pigment deposition with macrophages was a constant finding in drug addicts and was probably related to chronic intravenous injection. In contrast, cerebral vasculitis was significantly more frequent and marked in HIV seropositive cases and was often associated with lymphocytic meningitis. Granular ependymitis, myelin pallor with reactive astrocytosis and microglial proliferation were also more frequent and more severe in HIV seropositive cases. Immunocytochemistry was negative for HIV antigens. Our study further supports the view that early central nervous system changes occur in HIV infection.     

Neuropathology of progressive multifocal leukoencephalopathy]

Progressive multifocal leukoencephalopathy (PML) is caused by opportunistic infection of JC virus which belongs to Papovavirus, and presents with progressive demyelinating lesion in the central nervous system. PML was originally reported as a rare complication of hematologic disorders, but later greatly increased in number in association with acquired immunodeficeincy syndrome (AIDS). Original neuropathological features of PML consist of demyelination lacking inflammatory reaction or necrosis, accompanying oligodendroglial nuclear inclusions in the periphery of demyelination. The lesion is preferentially localized to gray-white junction of the cerebral hemisphere and manifests as characteristic demyelinating lesion, called scallopping. Detection of JC virus is essential for the final diagnosis of PML and is achieved via immunohistochemical detection of JC virus with antibodies raised against their components, ultrastructural demonstration of virions characteristic of JC virus, or detection with in-situ hybridization of the genome of JC virus. JC virus can replicate only in oligodendroglial cells, but astrocytes are frequently infected by the virus. The resume of immunological function through therapeutic intervention develops new pathology in PML, exhibiting severe inflammatory reaction with edema and necrosis. This new pathological feature is called immune reconstruction syndrome and clinically presents with severe progression in symptoms of the central nervous system. Nevertheless, treatment of PML is directed for the elimination of the viruses by host immune system. The modification of the above immune reconstruction syndrome is essential for successful outcome of such therapeutic trial.     

Central nervous system involvement in patients with acquired immune deficiency syndrome (AIDS)

Central nervous system involvement occurred in 28 of 121 patients with acquired immune deficiency syndrome (AIDS). The major risk factor in this AIDS population was intravenous drug abuse (64%). A neurologic symptom or disability was the principal reason for hospitalization in 16 cases (57%). Three patients had primary lymphoma of the brain and the remainder had opportunistic infections. Patients with focal neurological features usually had toxoplasmosis. Progressive headache and meningeal signs occurred with cryptococcosis. A progressive subacute dementia was probably due to cytomegalovirus. Other infections included atypical mycobacteria, candida, herpes zoster and possible progressive multifocal leukoencephalopathy.     

Progressive multifocal leukoencephalopathy in purine nucleoside phosphorylase deficiency

Progressive multifocal leukoencephalopathy is a demyelinating disease caused by JC virus, an opportunistic infection of the central nervous system. Although the majority of cases are infected with the human immunodeficiency virus (HIV), other immunocompromised patients are also at risk. Purine nucleoside phosphorylase is an enzyme in the purine salvage pathway that reversibly converts inosine to hypoxanthine and guanosine to guanine. Purine nucleoside phosphorylase deficiency is a combined immunodeficiency with a profound cellular defect. Neurologic abnormalities are salient features of this syndrome. We describe for the first time a patient with this rare disorder presented with progressive multifocal leukoencephalopathy.     

Emerging viral infections

Unique disorders appear episodically in human populations and cause life-threatening systemic or neurological disease. Historical examples of such disorders include von Economo encephalitis, a disorder of presumed viral etiology; acquired immune deficiency syndrome, caused by the human immunodeficiency virus; and severe acute respiratory syndrome, caused by a member of the coronavirus family. This article describes the factors that contribute to the emergence of infectious diseases and focuses on selected recent examples of emerging viral infections that can affect the nervous system of infants, children, and adolescents.