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.     

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.     

Pathology of the central nervous system in patients infected with the human immunodeficiency virus (HIV): a Report of 252 autopsy cases from Brazil

The central nervous system (CNS) was studied in 252 HIV-infected patients from the States of Rio de Janeiro and Sgo Paulo in Brazil, the regions with the highest incidence of AIDS in the country. We compared the frequency and morphology of opportunistic infections and CNS changes caused by the HIV, with those described in other series and briefly analysed the risk factors involved in our cases. There were CNS lesions in 230 cases (91.3%), 30 (11.9%) with multiple infections and/or turnours. Most infections were opportunistic (65.4%), including 15.4% viral and 50% bacterial, fungal or protozoal infections. The most frequent was toxoplas-mosis (34.1%), followed by cryptococcosis (13.5%), cytomegalovirus (CMV) infection (7.9%) and nodular encephalitis (6.7%). Primary lymphomas were observed in 4% of the cases and HIV encephalitis or leukoencephalopathy in 10.7%. Other opportunistic and HW associated lesions were present in a limited number of cases and there were also vascular and non-specific lesions. Our study confirms the high frequency of CNS lesions in HIV infected patients. They are morphologically similar to those previously described. However, the higher incidence of toxoplasmosis and cryptococcosis, a lower incidence of viral opportunistic and HIV-associated lesions, and the presence of rarer lesions such as histoplasmosis and chagasic encephalitis, differ from other series, and may reflect geographical and/or socio-economic factors.     

Central nervous system lymphoma in the acquired immunodeficiency syndrome

Primary central nervous system (CNS) lymphomas were studied in fifteen autopsied patients with the acquired immunodeficiency syndrome (AIDS). Using the working formulation for non-Hodgkin's lymphomas, the tumors were classified as large cell (7 patients), mixed large and small cell (6 patients), small cleaved cell (1 patient), and unclassifiable (1 patient). The mixed lymphomas displayed unusual features characterized by a high mitotic rate and the presence of numerous medium-sized cells (5 to 10 mus), not classifiable using the working formulation. Focal T cell and lymphoplasmacytoid B cell infiltrates accompanied lymphoma cells at the periphery of and remote from solid tumor masses in 9 cases. Immunohistochemical analysis of the lymphomas suggested B cell neoplasms. All of these patients had concurrent CNS and systemic cytomegalovirus (CMV) infections. The CNS infections were of both viral (CMV, human immunodeficiency virus (HIV), varicella zoster virus (VZV), progressive multifocal leukoencephalopathy (PML) and non-viral (toxoplasmosis, candidiasis) etiology. In the general AIDS population at our institution, the autopsy incidence of CNS infections and systemic CMV was 63% and 60%, respectively. In contrast, the incidence for both these entities was 0% in otherwise healthy, non-AIDS patients with CNS lymphoma supports the hypothesis that viral infection plays a role in the pathogenesis of CNS lymphoma in the immunocompromised. Polyclonal lymphoplasmacytoid B and T cell infiltrates accompanying lymphoma may produce diagnostic difficulties on surgical biopsy. As these infiltrates were a frequent feature in this study, we caution that their recognition does not argue against the presence of CNS lymphoma.     

The epidemiology of human immunodeficiency virus-associated neurological disease in the era of highly active antiretroviral therapy

Highly active antiretroviral therapy (HAART) is effective in suppressing systemic human immunodeficiency virus (HIV) viral load and has decreased mortality rates and the incidence of systemic opportunistic infections in patients with acquired immunodeficiency syndrome (AIDS). Multiple studies now suggest that the incidence rates of HIV-associated neurological disease and central nervous system (CNS) opportunistic infections also are decreasing. Since the introduction of HAART in 1996, the incidence of HIV dementia has decreased by approximately 50%. The mean CD4 cell count for new cases of HIV dementia is increasing, but it remains as a complication of moderate-advanced immunosuppression. The incidence of HIV-associated distal sensory polyneuropathy has decreased, although the incidence of antiretroviral drug-induced toxic neuropathy has increased. However, as patients with AIDS live longer as a result of HAART, the prevalence of peripheral neuropathy in HIV-seropositive patients may be increasing. The incidence rates of CNS opportunistic infections (cryptococcal meningitis, toxoplasmosis, progressive multifocal leukoencephalopathy) and primary CNS lymphoma have decreased since the introduction of HAART. As patients develop increasing resistance mutations to antiretroviral drugs and with subsequent decline in CD4 cell counts, in the near future, the incidence of HIV-associated neurological disease may begin to rise.     

Electroencephalography in AIDS and AIDS-related complex

EEG records from 47 patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) were reviewed retrospectively to correlate EEG findings with neurologic abnormalities. Abnormal EEGs were found in 22 of 33 (67%) patients with AIDS and 5 of 14 (36%) patients with ARC. Among 27 patients with abnormal EEGs, there were 9 patients with dementia, 10 with opportunistic infections of the CNS, and 6 with no apparent neurologic disease. AIDS dementia was associated with intermittent or continuous slowing, often most prominent anteriorly. Focal slowing or sharp activity was usually found in patients who had focal CNS processes, such as cerebral toxoplasmosis and CNS lymphoma. These findings suggest the EEG can be a useful diagnostic test for evaluating patients with AIDS and ARC, particularly when these patients present with seizures, psychiatric symptoms, or cognitive dysfunction. The significance of abnormal EEGs in patients who are neurologically asymptomatic is unknown.     

HIV-associated cerebral toxoplasmosis -- review and retrospective analysis of 36 patients

Highly active antiretroviral therapy (HAART) has resulted in a reduction of morbidity and mortality in HIV-associated cerebral opportunistic infection.Before HAART, up to 50% of all HIV-infected patients in Europe developed cerebral toxoplasmosis, an encephalitis caused by reactivation of Toxoplasma gondii infection.Although potent therapeutical options exist, the prognosis is still poor. We describe the course of 36 AIDS patients with cerebral toxoplasmosis and present a review of clinical signs, diagnosis, therapy, and survival times.The main criteria for differential diagnosis from other secondary neuromanifestations such as primary CNS lymphoma, progressive multifocal leukencephalopathy, abscesses, and ischemic infarctions are described. Indications and problems of stereotactic biopsy are discussed.     

Coinfection of the central nervous system by cytomegalovirus and herpes simplex virus type 1 or 2 in AIDS patients: autopsy study on 82 cases by immunohistochemistry and polymerase chain reaction

We evaluated the frequency and histopathological features of concomitant infections of the central nervous system (CNS) with cytomegalovirus (CMV) and herpes simplex viruses type 1 or 2 (HSV1/2) in a large series of patients who had died from AIDS. Eighty-two autopsy cases with a histological diagnosis of CMV necrotizing encephalitis were examined retrospectively. CMV and HSV1/2 were detected by immunohistochemistry (IHC) with poly- and monoclonal antibodies and by nested polymerase chain reaction (PCR) for HSV 1 and 2 on DNA extracted from paraffin blocks. PCR for a β-globin genomic sequence was performed in all IHC-positive cases to verify the integrity of extracted DNA. Concomitant CMV/HSV infections were demonstrated by IHC in 13 cases (16%); using monoclonal antibodies, HSV1 was found in 9 cases and HSV2 in 4 cases. In half of the cases, HSV1- or HSV2-positive cells represented more than 25% of immunopositive CMV cells. In all 13 cases, double immunochemical staining showed cells containing both CMV and HSV antigens. PCR for HSV1 and 2 was positive in only 7 of 13 cases (5 HSV1 and 2 HSV2). In the remaining 6 negative cases PCR for β-globin was also repeatedly negative. HSV1 or 2 infection can be demonstrated by IHC in a significant proportion of AIDS cases with necrotizing CMV encephalitis. Nested PCR for HSV1 and 2 on DNA extracted from formalin-fixed and paraffin-embedded autopsy tissues was positive in only slighty above 50% of IHC-positive cases. Received: 28 November 1995 / Revised, accepted: 26 February 1996     

Neuropathology of the acquired immune deficiency syndrome (AIDS): report of 39 autopsies from Vancouver, British Columbia.

Neuropathological findings from 39 acquired immune deficiency syndrome (AIDS) autopsies of primarily neurologically symptomatic patients and 7 brain biopsies from AIDS patients performed at St. Paul's Hospital, Vancouver, British Columbia are reported. Autopsy findings included human immunodeficiency virus-1 (HIV)-type multinucleated giant cell (MNGC)-associated encephalitis seen in 17 patients, toxoplasmosis in 7 patients, and cytomegalovirus encephalitis and/or microglial nodule-associated nuclear inclusions in brain parenchyma in 9 patients. Central nervous system lymphoma was identified in 11 autopsy patients and in 4 of 7 brain biopsies. Infectious processes including HIV encephalitis were seen in 10 of 11 autopsied patients with lymphoproliferative lesions in the brain parenchyma, while 40% of patients without lymphoma had HIV-type MNGC or opportunistic infections. CNS lymphoma was not significantly increased in incidence in patients with a clinical history of zidovudine treatment, but increased duration of survival after the diagnosis of AIDS was associated with increased incidence of lymphoma in both untreated and zidovudine-treated patients. Patients displaying HIV MNGC within microglial nodules had a shorter mean duration of survival after diagnosis of AIDS than those patients with HIV encephalitis with dispersed MNGC, white matter vacuolation, and gliosis.     

NEUROPATHOLOGY OF ACQUIRED IMMUNODEFICIENCY SYNDROME

The nervous system is involved in the acquired immunodeficiency syndrome (AIDS) by infections and infestations, by neoplasms, and by several diseases of uncertain pathogenesis. The most common pathological abnormalities are the changes associated with the HIV agent itself, the 'HIV subacute encephalitis'; the most specific change is demyelination with multinucleate giant cells. Cytomegalovirus (CMV) is the most common secondary virus, but progressive multifocal leucoencephalopathy (PML) is more frequently seen at biopsy. Toxoplasmosis is the most common cause of abscess formation, but fungal infections, especially by cryptococcus, are more often the cause of meningitis. Mycobacterial infections and other opportunistic organisms are relatively rarely seen in the CNS. A vacuolar myelopathy of unknown pathogenesis is seen in AIDS; it involves the dorsal and lateral columns and the thoracic spinal cord most prominently. Endarteritis of unknown cause with resultant infarction is seen in children. Primary CNS lymphoma accounts for a major percentage of the lymphomas seen in AIDS; they are high grade tumours, are most often multiple, and are of B-cell origin. Metastatic Kaposi's sarcoma is very rare. Several peripheral neuropathies occur in AIDS, and recently a myopathy with small rod bodies has been reported.     

Neuropathology of acquired immunodeficiency syndrome (AIDS): an autopsy review

In the brains and spinal cords of 153 adult patients dying with acquired immunodeficiency syndrome (AIDS) at New York and Memorial Hospitals a subacute encephalitis with multinucleated cells was present in 28% of all patients. This encephalitis was characterized by multinucleated cells primarily located in the white matter and associated with myelin pallor and sparse infiltrates of rod cells, macrophages, gemistocytic astrocytes and lymphocytes. The incidence per 12 month period ranged from 0 to 43% and significantly increased between 1983-84 (14%) and 1984-85 (43%). Recent virologic and pathologic studies suggest that this encephalitis may be caused by direct LAV/HTLV-III infection of the central nervous system (CNS). Cytomegalovirus encephalomyelitis and toxoplasmosis were the most common opportunistic infections (26% and 10%, respectively). Progressive multifocal leukoencephalopathy, herpes simplex ventriculitis, varicella-zoster leukoencephalitis and fungal infections were infrequent (less than 3% each). A nonspecific encephalitis with microglial nodules and with mild white matter changes occurred in 17%, vacuolar myelopathy in 29% and CNS lymphoma in 6%. Less than 20% of patients had either normal brains or terminal metabolic encephalopathies. This survey shows that neuropathologic complications of AIDS are frequent. Infections are the most common complication and are caused by probable LAV/HTLV-III infection, or by opportunistic organisms.     

Neuropathology of the acquired immune deficiency syndrome (AIDS): a report of 135 consecutive autopsy cases from Switzerland

Summary Neuropathological changes were studied in a consecutive autopsy series of 135 cases, comprising 73% of all patients who died of AIDS in Switzerland between April 1981 and December 1987. Central nervous system involvement was found in 119 patients (88%), 19 of which had multiple concomitant intracerebral lesions. Among the non-viral opportunistic infections, encephalitis due toToxoplasma gondii was most frequent and occurred in 35 patients (26%), followed by central nervous system infection withCryptococcus neoformans, which was found in five patients (4%). Cytomegalovirus (CMV) encephalitis was present in 14 patients (10%). Disseminated microglial nodules without morphological or immunocytochemical evidence of CMV was encountered in 18 patients (13%). However, in all but two of these patients there was evidence of extracerebral CMV infection, suggesting that CMV was responsible for these nodular encephalitides. Nine patients (7%) had progressive multifocal leukoencephalopathy (PML); in five of these, demyelination was associated with extensive tissue destruction and cyst formation. HIV-associated encephalopathy was observed in 21 patients (16%) and showed two characteristic morphological patterns: progressive diffuse leukoencephalopathy (PDL) and multifocal giant cell encephalitis (MGCE). PDL was observed in 13 cases and characterized by diffuse pallor and gliosis of the cerebral and cerebellar white matter with scattered multinucleated giant cells, but without significant inflammatory response. MGCE was found in eight patients and characterized by clusters of numerous multinucleated giant cells, rod cells, macrophages, lymphocytic infiltrates and occasional necroses. In our view, PDL and MGCE represent the two opposite variants of HIV-induced encephalopathies, with overlapping intermediate manifestations.     

Acquired immune deficiency syndrome in childhood

Central nervous system (CNS) involvement is very frequently observed in pediatric AIDS. Clinical manifestations include encephalopathy, cognitive deficits, acquired microcephaly, neurological signs, myelopathy, and peripheral neuropathy. Neurological complications can be related to opportunistic viral infections such as encephalitis, atypical aseptic meningitis, progressive multifocal leukoencephalopathy, and myelitis. Nonviral syndromes include: toxoplasmosis, cryptococcal meningitis, candidiasis, Mycobacterium tuberculosis meningitis, and Mycobacterium avium subacute encephalitis. Bacterial infections, tumors, cerebrovascular complications, and peripheral neuropathies are not frequently observed in pediatric AIDS. The most severe complications of HIV infection is encephalopathy resulting from HIV infection of brain tissue. Direct HIV invasion of the CNS has been demonstrated. Clinical features of HIV encephalopathy are classified into three categories: (1) normal neurological findings; (2) static encephalopathy; and (3) progressive encephalopathy. AIDS dementia complex can be differentiated from the predominance of behavioral and cognitive disabilities.     

Opportunistic infections of the central nervous system during HIV-1 infection (emphasis on cytomegalovirus disease)

Toxoplasma encephalitis, cryptococcal meningitis, progressive multifocal leukoencephalopathy (PML), and cytomegalovirus (CMV) encephalitis are the most common opportunistic infections of the central nervous system (CNS) in HIV-infected patients. They occur at variable degrees of immunosuppression, and their diagnosis is based on a systematic evaluation with includes, in a definite order, ongoing prophylactic therapies, extraneurological signs, neuroimaging and CSF studies, and an anti-Toxoplasma therapeutic trial. Concurrent neurological HIV-CNS disease (such as the AIDS dementia complex) is frequent. The development of reliable molecular biology techniques such as the polymerase chain reaction and their application to the CSF have made the diagnosis of virus-related opportunistic infections much easier and has limited the need for cerebral biopsy. The incidence of opportunistic infections has decreased since the introduction of recent antiretroviral therapeutic strategies. Received: 15 July 1998 Accepted: 24 July 1998     

Hidden in plain view: emergence of progressive multifocal leukoencephalopathy after treatment of CNS toxoplasmosis

Multiple CNS infections can coexist in advanced AIDS, but are most commonly reported in autopsy case studies. We describe the case of an HIV+ individual, who was first diagnosed with CNS toxoplasmosis, confirmed by brain biopsy. After initiation of combined anti-retroviral therapy (cART) and successful treatment of CNS toxoplasmosis, he developed worsening neurological symptoms and was subsequently diagnosed with progressive multifocal leukoencephalopathy. Retrospective analysis of the MRI scans indicated that PML was already present early on but was interpreted as edema associated with CNS toxoplasmosis. Clinicians should be aware that multiple pathologies may coexist in the brain of immunosuppressed individuals and that PML may develop and worsen despite the use of cART.     

Cerebral toxoplasmosis and AIDS. Clinical, neuroradiological and immunological findings in 15 patients.

Cerebral toxoplasmosis is the most common cause of focal CNS disease complicating AIDS and its incidence ranges from 3% to 40% of such patients. This opportunistic infection is generally due to reactivation of chronic toxoplasmosis as a consequence of severe immune deficiency. We present the clinical, neuroradiological and immunological findings of 15 AIDS patients with cerebral toxoplasmosis. All patients had focal neurological signs. CT-scan (13 cases) and NMR (2 cases) showed single or multiple mass lesions and edema. Serum IgG anti-Toxoplasma antibodies were positive in 14 patients; CSF specific IgG were positive in 5 out of 7 studied patients, while serum and CSF specific IgM were negative in all subjects. The intrathecal synthesis of anti-Toxoplasma antibodies were high in all 7 patients. A presumptive diagnosis of cerebral toxoplasmosis is based on the focal cerebral signs and neuroradiological findings. It is more frequently confirmed by the improvement of the clinical and neuroradiological picture during the treatment with pyrimethamine-sulphadiazine or clindamycin.     

Neurotoxoplasmosis and AIDS. Cerebrospinal fluid analysis in 96 patients.

The behavior of CSF inflammatory pattern in patients with AIDS and/or toxoplasmosis of the CNS is studied in 176 patients, divided in three groups. In the first group, 96 patients with toxoplasmosis and AIDS are considered; in the second group, 50 patients with toxoplasmosis without AIDS; in the third group, 30 AIDS patients without toxoplasmosis nor any other opportunistic infection. It is possible to conclude that patients with toxoplasmosis associated to AIDS exhibit CSF inflammatory pattern similar to patients with neurotoxoplasmosis without AIDS, except in respect to gamma globulin rates for which a cumulative effect can be detected.     

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.     

CSF in 85 patients with AIDS and CNS cryptococcosis.

In an eight years time period (July 1984-June 1992) CSF samples of 40718 patients were studied, and 610 were from patients with AIDS clinically diagnosed and immunologically confirmed through HIV antibodies detection. Among opportunistic infections detected in them 85 were CNS cryptococcosis. For the purpose of this study the CSF of these 85 patients are the AIDS group of CNS cryptococcosis. For comparison, CSF data from 50 patients with CNS cryptococcosis but without AIDS were taken (non-AIDS group); in this group, 22 patients were immunosuppressed after renal transplant. In AIDS group, the more frequent CSF findings were: yeast presence at direct exam (Fuchs-Rosenthal cell counting chamber), growing of the yeast in cultures, and gamma globulins increase. In non-AIDS group were more frequent: hypercytosis, neutrophil cells presence, and total protein increase. Differences between the two groups are discussed taking into account CNS/CSF immune changes induced by HIV infection. It is concluded that in CNS cryptococcosis of patients with AIDS the CSF evidenced more extensive signs of the fungal opportunistic infection than signs of inflammatory response to the infection. The latter were more prominent among patients of the non-AIDS group of CNS cryptococcosis.     

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.