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.     

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.     

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.     

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.     

Central nervous system opportunistic infections in developed countries in the highly active antiretroviral therapy era

A marked decrease in incidence has been observed for most central nervous system (CNS) opportunistic infections (OIs) after the use of highly active antiretroviral therapy (HAART) in developed countries. However, the spectrum of these OIs in acquired immunodeficiency syndrome (AIDS) patients has remained almost unchanged. CNS toxoplasmosis, cryptococcosis, tuberculosis, and progressive multifocal leukoencephalopathy (PML) remain the most frequent ones. Primary CNS lymphoma should be included in the differential diagnosis of all cases with focal lesions. Final diagnosis is currently made by combining neuroimaging techniques (single-photon emission computed tomography [SPECT], positron emission tomography [PET], magnetic resonance imaging [MRI] and/or computed tomography [CT] scan) and molecular studies of cerebrospinal fluid (CSF) and therapeutical response. Stereotactic biopsy should only be performed in the case of atypical lesions or nonresponse to recommended treatments. After treatment of the acute phase, lifelong maintenance therapy is necessary to prevent OI recurrences. Once HAART is initiated, some patients can develop a clinical worsening of some CNS OIs with or without atypical neuroimaging manifestations. This paradoxical worsening is known as the immune reconstitution inflammatory syndrome (IRIS) and it results from reconstitution of the immune system's ability to recognize pathogens/antigens in patients with prior OIs and low CD4+ T-cell counts. In this context, IRIS can be seen in patients with CNS cryptococcosis, tuberculosis, or PML. On the other hand, HAART-induced immune reconstitution can improve the prognosis of some untreatable diseases such as PML, and can allow maintenance therapy of some CNS OI to be safely discontinued in patients with high and sustained CD4+ T-cell response.     

Aspergillus infection of the central nervous system in patients with acquired immunodeficiency syndrome

Infections of the central nervous system in patients with the acquired immunodeficiency syndrome are common. Of the many microorganisms that have been implicated, infection with Aspergillus is rare. We describe three patients with Aspergillus infection of the nervous system. Two patients had cerebral lesions due to Aspergillus flavus, and one patient had Aspergillus fumigatus infection of the spinal cord. Diagnosis of the infections was difficult, and therapy appeared to be ineffective.     

Central nervous system immune reconstitution inflammatory syndrome in AIDS: experience of a Mexican neurological centre

Background

Highly active antiretroviral therapy (HAART) restores the inflammatory immune response in AIDS patients and it may unmask previous subclinical infections or paradoxically exacerbate symptoms of opportunistic infections. Up to 25% of patients receiving HAART develop immune reconstitution inflammatory syndrome (IRIS). We describe six patients with IRIS central nervous system (CNSIRIS) manifestations emphasizing the relevance of CSF cultures and neuroimaging in early diagnosis and management.

Methods

Patients with CNSIRIS were identified among hospitalized HIV-infected patients that started HAART from January 2002 through December 2007 at a referral neurological center in Mexico.

Results

One-hundred and forty-two HIV-infected patients with neurological signs were hospitalized, 64 of which had received HAART, and six (9.3%) developed CNSIRIS. Five patients were male. Two cases of tuberculosis, two of cryptococcosis, one of brain toxoplasmosis, and one possible PML case were found. IRIS onset occurred within 12 weeks of HAART in five patients. Anti-infective therapy was continued. In one case, HAART was temporarily suspended. In long-term follow-up the clinical condition improved in all patients.

Conclusions

CNSIRIS associated to opportunistic infections appeared in 9% of patients receiving HAART. Interestingly, no cases of malignancy or neoplasm IRIS-related were found. Frequent clinical assessment and neuroimaging studies supported diagnosis and treatment. Risk factors were similar to those found in other series.     

Isolated central nervous system aspergillosis in the acquired immunodeficiency syndrome.

Aspergillus infection involving the central nervous system are unusual, but should be included in the differential diagnosis in patients with the acquired immunodeficiency syndrome and neurologic signs and symptoms. Of the few reported AIDS cases with central nervous system aspergillosis, the majority have had focal brain abscesses. We report an atypical case that presented as a basal meningitis with pontine infarction secondary to invasive Aspergillus sinusitis.     

Central nervous system infection in a murine retrovirus-induced immunodeficiency syndrome

Astrocyte-enriched primary glial cultures (AGC) from C57BL/6 mice were found to be highly susceptible to infection with the replication competent components of LP-BM5, consisting of the ecotropic and mink cell focus-inducing (MCF) helper murine leukemia viruses (MuLVs). The presence in infected AGC of defective LP-BM5 MuLV genome, a critical component for induction of the disease referred to as murine AIDS, was confirmed by Southern blot hybridization using a probe reactive with the p12 gag sequence of the 4.9 kb defective genome. Electron microscopic studies demonstrated C-type retrovirus particles in both astrocytes and microglial cells. In vivo studies demonstrated that the ecotropic MuLVs and the defective genome could be detected within AGC obtained form either 14-day-old mice following intraperitoneal inoculation or 7-day-old mice following intracranial inoculation. These findings suggest that: (1) the central nervous system (CNS) infection is present at an early stage in murine AIDS, (2) both astrocytes and microglial cells are possible CNS targets in which helper MuLVs replicate, and (3) these cells can harbor the defective genome that is a critical component for disease induction.     

Serologic evidence of human immunodeficiency virus infection of the central nervous system in African patients with acquired immunodeficiency syndrome

The intrathecal synthesis of antibodies to human immunodeficiency virus (HIV) was determined by 3 different immunoassays in 15 African patients with pre-acquired immunodeficiency syndrome (AIDS) and AIDS. Isoelectric focusing together with affinity-mediated immunoblot were found to be superior to enzyme-linked immunosorbent assay and Western blot in providing information not only about the antigen specificity of locally produced antibodies but also about their clonal distribution. In 9 of the subjects, HIV-specific oligoclonal bands were demonstrable with higher frequency or intensity in the cerebrospinal fluid than in the autologous serum, indicating autochthonous synthesis of HIV-related antibodies.     

Varicella-zoster virus vasculopathy and central nervous system immune reconstitution inflammatory syndrome with human immunodeficiency virus infection treated with steroids

Immune reconstitution inflammatory syndrome (IRIS) is widely recognized and rarely involves the central nervous system (CNS). Patients with acquired immunodeficiency syndrome (AIDS) are at an increased risk for developing CNS-IRIS upon initiation of highly active antiretroviral therapy (HAART). This syndrome can be fatal and requires extreme vigilance in determining if a treatable underlying opportunistic infection exists. We report here a case of varicella-zoster virus (VZV) vasculopathy and CNS-IRIS in a human immunodeficiency virus (HIV)-infected patient who required prolonged steroid treatment for clinical stabilization. There are no established treatment regimens for IRIS and the use of corticosteroids in this syndrome remains controversial. Similar to our patient, severe cases of CNS-IRIS may benefit from high-dose intravenous corticosteroid treatment followed by an oral prednisone taper.     

The effect of highly active antiretroviral therapy on outcome of central nervous system herpesviruses infection in Cuban human immunodeficiency virus-infected individuals

With the rapid progress in the development of highly active antiretroviral therapy (HAART), the observed patterns in human immunodeficiency virus (HIV) encephalitis has changed, allowing herpesvirus (HV) infection to be controlled. HAART was first administered to HIV patients in Cuba in 2001. Consequently with the aim of investigate the behavior of the HVs causing neurological disorders in this population in the post-HAART era, the authors perform a clinical evaluation by a multiplex nested polymerase chain reaction (PCR) assay for simultaneous detection of human HVs--herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), human herpesvirus 6 (HHV-6), and Epstein-Barr virus (EBV). The authors studied 241 samples of cerebrospinal fluid (CSF) received at the Sexually Transmitted Diseases Laboratory between 2001 and 2005 inclusive. Of the 241 CSF studied, 10.4% resulted positive for HV infections. Of these, 92% of patients were acquired immunodeficiency syndrome (AIDS) individuals at the C3 stage. CMV (44%), EBV (28%), and dual-HV (16%) infections were the most important agents identified. The principal clinical manifestations were fever, headache, vomiting, and focal abnormalities; the latter being associated with an increased risk of death. A statistically significant result was observed when central nervous system (CNS) disease evolution was compared between patients who were under HAART against those who were not, before they developed encephalitis. It was therefore concluded that it is more likely that HIV individuals receiving HAART have a better recovery of CNS infections than those who are not receiving it.     

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.     

Case of highly active anti-retroviral therapy-induced immune reconstitution inflammatory syndrome in AIDS-related progressive multifocal leukoencephalopathy]

A 44-year-old man presented with difficulties in gripping a ball with the left hand upon playing tennis. He developed muscle weakness involving the left limbs, as well as memory decline, with subsequent gradual worsening of such symptoms. Cranial MRI showed multiple high intensity lesions in the white matter on T2-weighted imaging and FLAIR imaging. Serologic testing was positive for HIV infection and laboratory studies revealed a CD4+T cell count of 103 cells/microl and a plasma HIV-1 RNA load of 240,000 copies/ml. Accordingly, the diagnosis of AIDS was made. Although the initial result of DNA amplification by PCR for detection of the JC virus with CSF was negative, PML was suspected because of the presence of multifocal white matter lesions. Four weeks after the commencement of highly active anti-retroviral therapy (HAART), the HIV-1 RNA load was decreased from 680,000 to 480 copies/ml, although the CD4+T cell count was unchanged. JC virus DNA became positive at the second examination. Five weeks after the commencement of HAART, general fever, disturbance of consciousness, and brain edema suddenly developed, and the patient died within two days. Histological examination of the autopsied brain revealed demyelination and reactive gliosis within the white matter and JC virus antigen was detected in oligodendrocytes, consistent with a diagnosis of PML. The most striking feature was an intense perivascular infiltration by CD8+T cells with proteinaceous fluid exudation, suggesting an occurrence of HAART-induced immune reconstitution inflammatory syndrome. Immune reconstitution inflammatory syndrome should be considered as a fatal complication of HAART in patients with AIDS-related PML.     

Influence of highly active antiretroviral therapy on persistence of HIV in the central nervous system

PURPOSE OF REVIEW: The epidemiology of HIV infection is changing rapidly in the era of highly actively antiretroviral therapy, as the use of such therapy is increasing in all countries. This has had a significant impact on the neurological manifestations of HIV infection, posing new challenges in diagnosis and treatment. This review provides a critical analysis of the recent literature on the impact of highly actively antiretroviral therapy on HIV-related neurological complications and changes in treatment strategies. RECENT FINDINGS: It is becoming clear that the brain is an important reservoir for the virus, and neuroinflammatory and neurodegenerative changes may continue despite the adequate use of highly actively antiretroviral therapy. Although this antiretroviral therapy has had a significant impact on the severity of HIV dementia, cognitive impairment persists. With improvement in the immune status following treatment with antiretrovirals, in rare cases the brain can become a target of the immune reconstitution. SUMMARY: Highly actively antiretroviral therapy may need to be optimized in patients with HIV-associated cognitive impairment to achieve maximal central nervous system penetration; however, this therapeutic strategy may not be sufficient for halting the process. In some instances, the antiretroviral drugs themselves may become the problem. New strategies for neuroprotection that also target host genes which control HIV replication are being developed.