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PubMed2003

[Ocular complications of the virostatic drug cidofovir].

Cidofovir, a nucleotide analogue virostatic drug is effective in the treatment of herpes virus infections. However, cytomegaly infection is the prime indication due to its adverse effects. There is growing evidence suggesting cidofovir's effectiveness against progressive multifocal leukoencephalopathy (PML) caused by a reactivation of JC-virus. Chronic ocular hypotension which seems to be therapy refractory and anterior uveitis are considered to be the most serious ocular complications of cidofovir. Secondary side effects such as macular folds, retinal or choroidal detachment can result in a permanent loss of vision. Little is known about the pathology of reduced intraocular pressure and only few reports deal with therapeutical attempts to compensate this complication. Abandoning cidofovir presently remains the only therapeutic option. To avoid serious damage it is of utmost importance to monitor all patients undergoing cidofovir administration for signs of anterior uveitis and ocular hypotension.

AIDS-Related Opportunistic Infections↗

PubMedDate not supplied

Role of cytology in the intraoperative diagnosis of central demyelinating disease.

OBJECTIVE: To determine the usefulness of cytology in the intraoperative diagnosis of central demyelinating disorders. STUDY DESIGN: Smears of three multiple sclerosis (MS) plaques and two progressive multifocal leukoencephalopathy (PML) lesions prepared intraoperatively were examined and compared. The cytologic features were contrasted with those of infiltrating astrocytomas. RESULTS: The preparations of demyelinating lesions revealed normal or reactive astrocytes and large numbers of foamy macrophages, the key diagnostic finding. The preparations of the lesions of PML contained virally infected oligodendrocytes. The specific cell types were identified easily because cytoplasmic margins could be distinguished. CONCLUSION: Cytologic preparations of lesions of PML and MS permitted rapid identification of the diagnostic features and distinguished them from infiltrating astrocytomas, the most important lesion in the differential diagnosis. The findings demonstrated the utility of cytology in the diagnosis of central demyelinating diseases.

Adolescent↗

PubMed1992

Occurrence of oligodendrocytes within astrocytes in demyelinating lesions.

We investigated the fine structural details of the presence of apparently newly formed oligodendrocytes within reactive astrocytes in white matter lesions obtained by biopsy from seven cases (3 multiple sclerosis (MS); 3 progressive multifocal leukoencephalopathy (PML); 1 with nonspecific reactive changes next to a sarcoid granuloma). Intact oligodendrocytes were found within astrocytic cytoplasm in two acute MS lesions and also in the reactive white matter lesion. The internalized cells appeared to lie within membrane-bound vacuoles. Formation of rudimentary junctions was observed between the internalized cells and host astrocytes. Sometimes more than one oligodendrocyte was seen in the same astrocyte. Our study suggests that this newly recognized interaction between astrocytes and oligodendrocytes is not restricted to acute MS lesions and probably represents emperipolesis rather than phagocytosis. This apparently nonspecific finding may be expected in any lesion with a proliferation of astrocytes and oligodendrocytes. The precise mechanism of this phenomenon or its functional significance is not entirely clear.

Adolescent↗

PubMed1993

The stereotactic biopsy diagnosis of focal intracerebral lesions in AIDS patients.

Focal intracerebral lesions were biopsied stereotactically in 23 adult HIV-infected patients, the main indication for which was the failure to respond to anti-toxoplasma treatment. A cerebral disease was the initial or main complaint in 19 of them. In 22 of 25 stereotactic approaches, a clear-cut morphological diagnosis could be established (9 primary brain lymphoma, 7 necrotizing toxoplasma encephalitis, 5 progressive multifocal leukoencephalopathy, 1 HIV encephalitis, 3 unspecific tissue changes). In 7 of 8 deceased patients, autopsy confirmed the bioptical diagnosis. The high diagnostic yield was related to the strategy of the stereotactic method and the sample size (3 to 4 consecutive samples along the stereotactic track including the marginal zones, 1 cm long tissue cylinders). Formalin fixation and paraffin embedding of the samples provide the possibility of serial sections and special stainings (immunohistochemistry, in-situ hybridization) and kill the HIV. Stereotactic brain biopsy is a highly accurate diagnostic tool to ascertain the nature of focal intracerebral lesions in selected AIDS patients.

AIDS Dementia Complex↗

PubMed1988

Central nervous system dysfunction in acquired immunodeficiency syndrome.

Nearly 40% of AIDS patients develop neurological complications during the course of their illness, and about 10% experience neurological symptoms as the initial manifestations of AIDS. The most common neurological complication (14% of AIDS patients) is human immunodeficiency virus (HIV) encephalopathy, but opportunistic viral and nonviral infections and neoplasms are also quite common; the most frequent among these are cryptococcal meningitis, toxoplasmosis, primary central nervous system (CNS) lymphoma, progressive multifocal leukoencephalopathy, and herpesvirus infections. Most of the nonviral infections and neoplasms are potentially treatable. Neurological syndromes include diffuse and regional encephalopathies, myelopathy, meningitis, intraaxial cranial neuropathies, and retinopathy. About 10% of AIDS patients develop a CNS mass lesion; the chief causes of these lesions are toxoplasmosis and primary CNS lymphoma. Since the clinical profiles of the various diseases overlap to a great extent, differential diagnosis requires a thorough workup, including magnetic resonance imaging or computed tomography brain scanning, examination of the cerebrospinal fluid, and, frequently, brain biopsy. Because AIDS patients have a high incidence of multiple intracranial pathologies, the diagnostic workup may have to be repeated to identify all of the diseases present.

Acquired Immunodeficiency Syndrome↗

PubMed1988

DNA rearrangements in organ-specific variants of polyomavirus JC strain GS.

Variants of JC virus (JCV) strain GS were isolated directly from the central nervous system (variant GS/B) and the kidney (variant GS/K) of a patient with progressive multifocal leukoencephalopathy and were cloned and sequenced. The genomes of the isolates were shown to be nearly identical in the nucleotide sequences of their protein-coding regions, suggesting that both had originated from a single infecting JCV genome. In contrast, the arrangement of the putative elements of transcriptional control revealed considerable differences. The tandemly repeated elements found twice within the enhancer region of JCV GS/B variant were not present in the GS/K variant. The missing elements were replaced by DNA segments containing simian virus 40 and adenovirus E1A core enhancer elements. These differences in the organ-specific GS variants suggest that rearrangements within elements of transcriptional control might be involved in altering the virus-cell interaction in the course of a JCV infection.

Base Sequence↗

PubMed2006

Human demyelinating disease and the polyomavirus JCV.

Many human neurological diseases involve demyelination of the central and/or peripheral nervous systems. These include the hereditary leukodystrophies--which have a genetic basis; multiple sclerosis (MS)--where the underlying cause of demyelination remains unknown; and progressive multifocal leukoencephalopathy (PML)--where the etiology is well-established as being viral. The human neurotropic polyomavirus--JC virus (JCV)--is the etiologic agent of PML, a fatal demyelinating disease of the central nervous system that occurs mainly in immunosuppressed patients, especially those with HIV/AIDS. JCV belongs to the polyomavirus family of tumor viruses that are characterized by non-enveloped icosahedral capsids containing small, circular, double-stranded DNA genomes. Serological studies have shown that JCV is widespread throughout the human population, but infections are usually restricted by the immune system, particularly cell-mediated immunity, causing the virus to enter a latent phase. An important corollary of this is that situations of severe immunosuppression may permit JCV to replicate and are thus a risk factor for PML.

Demyelinating Diseases↗

PubMed2001

Oncogenic potential of human neurotropic virus: laboratory and clinical observations.

Cancer is a multi-step disease involving a series of genetic alterations that result in the loss of control of cell proliferation and differentiation. Such genetic alterations could emerge from the activation of oncogenes and the loss or malfunctioning of tumor suppressor gene activity. Our understanding of cancer has greatly increased through the use of DNA tumor viruses and their transforming proteins as a biological tool to decipher a cascade of events that lead to deregulation of cell proliferation and subsequent tumor formation. For the past ten years our laboratory has focused on the molecular biology of the human neurotropic papovavirus, JCV. This virus causes progressive multifocal leukoencephalopathy, a fatal neurodegenerative disease of the central nervous system in immunocompromised patients. JCV is a common human virus that infects more than 80% of humans but does not induce any obvious clinical symptoms. The increased incidence of acquired immune deficiency syndrome and the use of immunosuppressive chemotherapy have dramatically raised the incidence of PML. The coincidental occurrence of malignant astrocytes and oligodendrocytes in PML patients, coupled with the induction of glioblastoma in JCV-infected nonhuman primates, provides intriguing speculation on the association between JCV and CNS malignancies. In this report we discuss clinical data and laboratory observations pointing to the direct involvement of JCV in cancer.

Animals↗

PubMed1981

Multifocal varicella-zoster virus leukoencephalitis temporally remote from herpes zoster.

Two patients with cancer, one with Hodgkin's disease and the other with a granulosa cell tumor of the ovary, developed a progressive, eventually fatal infection of the central nervous system exhibiting multifocal symptoms and signs. Pathologically, gross abnormalities of the brain resembled those in progressive multifocal leukoencephalopathy (PML), with discrete and confluent plaque-like lesions concentrated in the white matter, particularly along the gray-white junction. Microscopically, pathological changes differed distinctly from those associated with PML; in addition to confluent foci of white matter injury characterized by early demyelination and subsequent necrosis, prominent Cowdry type A eosinophilic intranuclear inclusions were noted in oligodendrocytes, astrocytes, and neurons. By electron microscopy, intranuclear spherical particles consistent in size and appearance with herpesvirus nucleocapsids were found within the lesions. Immunoperoxidase studies detected varicella-zoster virus (VZV) antigens in infected cells, implicating this virus as the responsible agent despite a lapse of many months between the cutaneous herpes zoster and onset of cerebral symptoms in both patients.

Adult↗

PubMed1992

The efficacy of image-guided stereotactic brain biopsy in neurologically symptomatic acquired immunodeficiency syndrome patients.

A prospective series of 50 neurologically symptomatic human immunodeficiency infected patients with intracranial lesions who underwent image-guided stereotactic brain biopsy is presented. Patients were diagnosed with primary central nervous system lymphoma (14 patients), progressive multifocal leukoencephalopathy (14 patients), toxoplasmosis (13 patients), human immunodeficiency virus encephalitis (3 patients), infarction (2 patients), and 1 patient each with metastatic adenocarcinoma, metastatic melanoma, cryptococcoma, and atypical mycobacterial infection. Two of the patients with toxoplasmosis had a second intracranial abnormality. Two biopsies resulted in either descriptive diagnosis only or were nondiagnostic; the definitive diagnostic efficacy of image-guided stereotactic biopsy was thus 96%. No deaths were incurred as a result of biopsy. Four intraoperative or postoperative hemorrhages occurred; in only 1 patient was there a residual neurological deficit related to the surgery. Image-guided stereotactic biopsy may thus be considered both safe and effective in this patient population.

Acquired Immunodeficiency Syndrome↗

PubMed2003

Dystonia in AIDS: report of four cases.

Dystonia is a rare complication of acquired immune deficiency syndrome (AIDS). We report four such cases related to three different causes. Cases 1 and 2 both developed dystonia secondary to biopsy-proven progressive multifocal leukoencephalopathy. One had left arm dystonia, whereas the other had bilateral upper limb dystonia. One patient had associated akinesia and rigidity. Imaging demonstrated frontal and/or parietal white matter lesions but no basal ganglia abnormalities. Case 3 developed hemidystonia and cervical dystonia from biopsy-proven toxoplasmosis with a lesion in the thalamus. Case 4 suffered from AIDS dementia complex and developed cervical dystonia while taking risperidone therapy. We also review previously reported cases of dystonia in AIDS patients with the same causes and discuss the issue of increased vulnerability of the basal ganglia to HIV infection which, in turn, leads to increased sensitivity to neuroleptics. When dystonia is seen in AIDS patients, its pattern may be a clue to the ultimate cause.

Acquired Immunodeficiency Syndrome↗

PubMed1986

A comparison of imaging, clinical, and pathologic aspects of space-occupying lesions within the brain in patients with acquired immune deficiency syndrome.

Patients with acquired immune deficiency syndrome (AIDS) often have central nervous system mass lesions. Since clinical signs, symptoms, and results of imaging techniques are generally nonspecific, brain biopsy has been considered to be the optimal method for establishing a definitive diagnosis. In an effort to define better the imaging characteristics of such lesions, we retrospectively analyzed 24 patients with AIDS who had intracerebral space-occupying lesions, with subsequent definitive histologic diagnosis and/or a diagnostic response to empiric therapy for toxoplasmosis. We employed computerized tomography (CT), double-dose-delay CT (DDD-CT), and nuclear magnetic resonance imaging (NMRI) of the brain. Sixteen patients had toxoplasmosis, seven had high-grade non-Hodgkins lymphoma, and one had progressive multifocal leukoencephalopathy that was due to herpes simplex virus II (HPML). Toxoplasmosis generally occurred as multiple, small (2 cm or smaller), hypodense or isodense lesions with variable enhancement. Malignant lymphomas appeared as single lesions, always larger than 3 cm, which were isodense or hyperdense, with internal enhancement. The combined radiologic criteria of size, multiplicity, and pre- and postcontrast appearance were useful in differentiating these two pathologic processes. The best single discriminant of toxoplasmosis versus lymphoma was the average lesion size of less than 3 cm. In our experience, diagnostic brain biopsy may be averted when lesions typical of toxoplasmosis are seen. DDD-CT and NMRI may be useful in identifying lesions that are not seen optimally on routine CT.

Acquired Immunodeficiency Syndrome↗

PubMed2004

Meningoencephalitis and demyelination are pathologic manifestations of primary polyomavirus infection in immunosuppressed rhesus monkeys.

The human polyomavirus JC (JCV) is the etiologic agent of progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the CNS that occurs in immunosuppressed individuals. Because polyomavirus-induced CNS pathology usually occurs as a result of the reactivation of latent virus, little is known about the disease manifestations of a primary polyomavirus-induced disease in man. To model such a primary infection, SV40-negative rhesus monkeys were immunosuppressed by infection with the virus SHIV-89.6P and then superinfected with the polyomavirus SV40. The animals developed CNS pathology characterized by both demyelination and meningoencephalitis. This observation suggests that a primary polyomavirus infection can be associated with an inflammatory CNS process. These data shed new light on the pathogenic mechanisms of primate polyomaviruses in the immunocompromised host.

Animals↗

PubMed1978

Electron microscopic studies of cerebrospinal fluid sediment in demyelinating disease.

Cerebrospinal fluid specimens from 31 patients with multiple sclerosis (MS) and 2 with progressive multifocal leukoencephalopathy (PML) were subjected to ultracentrifugation, and the resulting pellets were examined in an electron microscope. Cell types seen in the pellets included lymphocytes, occasional plasma cells, polymorphonuclear leukocytes, monocytes, eosinophils, lipid-laden macrophages, and fibroblasts. The most interesting noncellular elements were extracellular myelin fragments, recognizable by their characteristic alternation of major dense lines and intraperiod lines. Myelin fragments were seen in the CSF from 7 of 9 patients with MS in exacerbation involving areas other than the optic nerve. These fragments were not observed in 4 specimens from patients with acute attacks manifested by optic neuritis. Myelin fragments were present in 1 of the 2 patients with PML. These observations indicate that a portion of the myelin destruction seen in MS and PML occurs extracellularly, with release of myelin fragments and degradation products into the CSF.

Cell Count↗

PubMed2004

Exclusive induction of tau2 epitope in microglia/macrophages in inflammatory lesions-tautwopathy distinct from degenerative tauopathies.

Tau2 antibody recognizes a phosphorylation-independent epitope that is pathologically modified as tau protein is phosphorylated to form neurofibrillary tangles of Alzheimer's disease (AD). Similar modification of tau2 epitope can be induced even in the absence phosphorylation of tau, as we first demonstrated in ischemic foci and in glial cytoplasmic inclusions (GCIs) of multiple system atrophy. This modification of tau2 epitope is distinguishable from those observed in degenerative tauopathies because (1) it is a conformational change, which is reversible upon exposure to a detergent; (2) it shows an absence of fibrils composed of phosphorylated tau protein; and (3) it is characterized by the lack of immunohistochemical labeling by anti-tau antibodies other than tau2. In this study, we expanded this observation to inflammatory foci of different pathologies (human immunodeficiency virus encephalopathy, progressive multifocal leukoencephalopathy or multiple sclerosis) by examining formalin-fixed, paraffin-embedded sections immunostained with a panel of anti-tau antibodies. It was found that tau2 was the only anti-tau antibody that immunolabeled microglia/macrophages in these lesions, and this immunoreactivity was reversibly diminished upon exposure to a detergent. Exclusive apparition of tau2 immunoreactivity in these cells without neurofibrillary pathology may be a secondary event shared with ischemic foci and GCIs. It is, however, related to a unique conformational state of tau, possibly grouped under the name of "tautwopathy", that may represent an initial stage of tau deposition distinct from degenerative tauopathies characterized by fibrils composed of phosphorylated tau protein.

AIDS Dementia Complex↗

PubMed1999

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.

AIDS-Related Opportunistic Infections↗

PubMed1987

Formalin fixed brains are useful for magnetic resonance imaging (MRI) study.

We carried out magnetic resonance imaging (MRI) studies on human brains which had been fixed in formalin solution for over 2 years and had been proven neuropathologically to be cases of multiple sclerosis (MS), progressive multifocal leukoencephalopathy (PML), and Balo's concentric sclerosis (Balo). Using spin echo (SE) and inversion recovery (IR) pulse sequences to detect demyelinated lesions in a living person with MS, the demyelinated lesions of the fixed brains in cases of MS, PML and Balo definitely re-appeared, although T1 and T2 in the gray and white matter were reduced following fixation. High signal areas on the SE images corresponded not only to the characteristic distribution of demyelinated lesions in the white matter but also to sparse myelin, gliosis and mild perivascular cuffing in the white matter around the demyelinated foci in cases of the fixed MS, PML and Balo brains. On the IR images, only MS plaques were evident. This MRI study of fixed brains proved useful to elucidate clinicopathological correlations.

Adolescent↗

PubMed1989

Direct isolation and characterization of JC virus from urine samples of renal and bone marrow transplant patients.

JC virus DNA was extracted from urine-derived cells of bone marrow and renal transplant patients and cloned directly into the plasmid vector pBR322. These clones represent the first JC virus isolates obtained directly from individuals that did not have progressive multifocal leukoencephalopathy (PML). Three of the clones appeared to be identical to the prototype JC virus Mad 1, and the fourth clone was identical to the type II JC virus variant Mad8-Br. Importantly, the same JC virus strains have been identified both in the urine of non-PML patients and in the brain tissue of PML patients. These results indicate that different organs may be infected with the same JC virus subtype and implies that an adaptation process involving the alteration of viral regulatory signals is not required in the pathogenesis of PML. Furthermore, both a type I and a type II variant were obtained from the same patient, suggesting that an individual may be infected with more than one strain of JC virus at a given time.

BK Virus↗