[Neurological complications of JC virus infection: A review]. / Complications neurologiques de l'infection par le virus JC : revue générale.

Although human polyomavirus JC (JCV) seroprevalence in the general population is high, its neurological complications are rare and progressive multifocal leukoencephalopathy (PML), a lethal central nervous system (CNS) demyelinating disease, is the most well-known. After an usually asymptomatic primary infection during late childhood, a latent JCV form persists in different sites, notably the kidneys and lymphocytes. Rearrangement of that archetype into the prototypical neurotropic strain can reactivate JCV, thereby enabling its CNS penetration and infection of glial cells. In a context of defective immune defenses (HIV infection, cancer or immunosuppressant therapies) this infection leads to oligodendrocyte death that contributes, via demyelinization, to PML but also, as more recently described, to other CNS complications, e.g., JCV granule cell neuronopathy, meningitis or encephalitis. Clinical manifestations depend on the localization of the lesions. The increasingly widespread use of new immunomodulatory monoclonal antibodies to treat multiple sclerosis and other inflammatory systemic diseases has increased PML frequency in those previously rarely affected entities. Diagnosis relies on magnetic resonance imaging, JCV detection in cerebrospinal fluid and, when necessary, brain histology. PML is often lethal. No specific, evidence-based treatment with clinically relevant efficacy is available. The therapeutic objective is to restore host immune responses to JCV, while avoiding immune-reconstitution inflammatory syndrome.

Advanced multiparametric magnetic resonance imaging of multinodular and vacuolating neuronal tumor.

BACKGROUND AND PURPOSE: Multinodular and vacuolating neuronal tumor (MVNT) of the cerebrum is a rare brain lesion with suggestive imaging features. The aim of our study was to report the largest series of MVNTs so far and to evaluate the utility of advanced multiparametric magnetic resonance (MR) techniques. METHODS: This multicenter retrospective study was approved by our institutional research ethics board. From July 2014 to May 2019, two radiologists read in consensus the MR examinations of patients presenting with a lesion suggestive of an MVNT. They analyzed the lesions' MR characteristics on structural images and advanced multiparametric MR imaging. RESULTS: A total of 64 patients (29 women and 35 men, mean age 44.2 ± 15.1 years) from 25 centers were included. Lesions were all hyperintense on fluid-attenuated inversion recovery and T2-weighted imaging without post-contrast enhancement. The median relative apparent diffusion coefficient on diffusion-weighted imaging was 1.13 [interquartile range (IQR), 0.2]. Perfusion-weighted imaging showed no increase in perfusion, with a relative cerebral blood volume of 1.02 (IQR, 0.05) and a relative cerebral blood flow of 1.01 (IQR, 0.08). MR spectroscopy showed no abnormal peaks. Median follow-up was 2 (IQR, 1.2) years, without any changes in size. CONCLUSIONS: A comprehensive characterization protocol including advanced multiparametric magnetic resonance imaging sequences showed no imaging patterns suggestive of malignancy in MVNTs. It might be useful to better characterize MVNTs.

Multinodular and Vacuolating Posterior Fossa Lesions of Unknown Significance.

Multinodular and vacuolating neuronal tumor of the cerebrum is a rare supratentorial brain tumor described for the first time in 2013. Here, we report 11 cases of infratentorial lesions showing similar striking imaging features consisting of a cluster of low T1-weighted imaging and high T2-FLAIR signal intensity nodules, which we referred to as multinodular and vacuolating posterior fossa lesions of unknown significance. No relationship was found between the location of the lesion and clinical symptoms. A T2-FLAIR hypointense central dot sign was present in images of 9/11 (82%) patients. Cortical involvement was present in 2/11 (18%) of patients. Only 1 nodule of 1 multinodular and vacuolating posterior fossa lesion of unknown significance showed enhancement on postcontrast T1WI. DWI, SWI, MRS, and PWI showed no malignant pattern. Lesions did not change in size or signal during a median follow-up of 3 years, suggesting that multinodular and vacuolating posterior fossa lesions of unknown significance are benign malformative lesions that do not require surgical intervention or removal.

[HIV and the central nervous system]. / Atteintes du système nerveux central et infection par le VIH-1.

Central nervous system complications are common in HIV-1 infected patients and occur either as a result of concomitant immunosuppression (opportunistic infections, lymphoma and tumors), as a primary manifestation of HIV infection, or as an adverse effect of therapy (immune restoration and toxicity). These complications contribute largely to patient morbidity and mortality. In the era of highly active antiretroviral therapy (HAART) these disease states have changed in presentation, outcome and incidence. We review in detail the epidemiology, pathogenesis, clinical features, diagnosis, and management of these disorders.

[Sub-cortico-frontal encephalopathy and choreic movements related to recombinant interferon-alpha 2b]. / Encéphalopathie sous-cortico-frontale et mouvements choréiques liés à l'interféron-alpha 2b recombinant.

Interferon (IFN)-alpha is associated with central nervous system (CNS) side effects such as depression and suicide ideation, somnolence, confusion, drowsiness, psychomotor slowing, memory impairment and visual disorientation. More severe complications are uncommon and include frank paranoia, dementia, coma, seizures and neuropathy. With the increasing long-term and extensive use of interferon (IFN)-alpha several new neurologic adverse effects have been recognized. We report on two patients who developed severe subcortico-frontal impairment, associated in one case with choreic movements, after a long-term treatment with IFN-alpha 2b for hematologic malignancies. Our patients rapidly and completely recovered from their cognitive and motor symptoms after the discontinuation of the drug. The same neurologic symptoms reappeared when we attempted to reintroduce lower doses of IFN-alpha in one case. Although little is known regarding IFN-alpha actions in the CNS, several possible mechanisms may underlie its neurotoxicity and might result from complex direct and indirect effects involving brain vasculature, neuroendocrine system, neurotoxic secondary cytokines'release and neurotransmitters.

Neuropathy in diffuse infiltrative lymphocytosis syndrome: an HIV neuropathy, not a lymphoma.

OBJECTIVE: To determine whether CD8 lymphoid infiltrates in nerves of patients with HIV-associated diffuse infiltrative lymphocytosis syndrome (DILS) corresponds to a lymphomatous neoplastic process or to a proliferation of T cells reactional to HIV. BACKGROUND: DILS is characterized by persistent CD8 hyperlymphocytosis and multivisceral CD8 T-cell infiltration, which may affect peripheral nerves. METHODS: Presence of monoclonal T cells and HIV-1 proviral load were evaluated by polymerase chain reaction (PCR) techniques in frozen peripheral nerve samples from six patients with DILS neuropathy and 22 patients with other HIV-associated peripheral neuropathies, including mononeuritis multiplex (MM:6), inflammatory demyelinating polyneuropathies (IDP:6), distal sensory polyneuropathy (DSP:5), and toxic distal sensory polyneuropathy (TDSP:5). RESULTS: Five of six patients with DILS showed no detectable monoclonal T-cell clones in their nerves. Nerve proviral load in DILS (6.8 +/- 0.2 log/10(5) cells) was much higher than in MM (p < 0.008), IDP (p < 0.001), DSP (p < 0.001), and TDSP (p < 0.005). CONCLUSIONS: DILS neuropathy represents a separate entity among HIV-associated neuropathies. It is associated with massive HIV proviral load in nerve and must not be confused with a peripheral nerve T-cell lymphoma.

Peripheral neuropathy in human immunodeficiency virus-infected patients with the diffuse infiltrative lymphocytosis syndrome.

A subset of human immunodeficiency virus (HIV)-infected patients develop persistent CD8 hyperlymphocytosis and a Sjogren's syndrome-like syndrome associated with multivisceral CD8 T-cell infiltration, known as the diffuse infiltrative lymphocytosis syndrome (DILS). Patients with DILS tend to have higher CD4 cell counts, fewer opportunistic infections, and longer survival times than other HIV-infected patients. Peripheral nerve involvement in DILS has been poorly documented. We studied 12 HIV-infected patients with CD8 hyperlymphocytosis, DILS, and clinical signs of peripheral neuropathy. Two of 4 patients who were HLA typed were HLA-DR5 and 1 was HLA-DR6. All patients had the sicca syndrome and multivisceral involvement. The neuropathy was acute or subacute, always painful, and symmetrical in 8 cases. Electrophysiology was consistent with axonal neuropathy in 10 of 12 patients. Nerve biopsy showed marked angiocentric CD8 infiltrates without mural necrosis (12 of 12), and abundant expression of HIV p24 protein in macrophages (12 of 12). The HIV genome was detected by polymerase chain reaction in nerve homogenates. Zidovudine therapy was associated with improvement in 6 of 6 patients and steroid therapy was beneficial in 4 of 5 patients. No T-cell lymphoma was observed during follow-up, but 2 patients developed a primary B-cell lymphoma. We conclude that DILS neuropathy represents HIV-associated neuropathy, characterized by marked CD8 infiltration and abundant HIV in nerve, that improves with zidovudine or steroid therapy, and probably reflects a systemic host-determined and antigen-driven response to HIV.

AIDS-associated cytomegalovirus infection mimicking central nervous system tumors: a diagnostic challenge.

We reviewed cases of cytomegalovirus (CMV) infection of the central nervous system (CNS) that initially masqueraded as tumors in 37 of 543 consecutive patients infected with human immunodeficiency virus (HIV) and CMV who were seen at the Pasteur Institute Hospital and Saint-Louis Hospital (Paris) between 1992 and 1994. We detail the clinical features of three patients who presented with ring-enhanced space-occupying lesions mimicking CNS tumors. They were all profoundly immunodepressed (mean CD4 cell count, 13/mm3). Magnetic resonance imaging (MRI) showed enlargement of the spinal cord in one case, consistent with a space-occupying lesion and showing gadolinium enhancement; in the other two cases, ring-enhanced mass lesions were seen in the cerebral hemispheres. In all three cases marked edema and a mass effect were present. Image-guided stereotactic biopsies confirmed the diagnosis of CMV infection. The three patients' conditions improved with specific therapy. MRI showed enhanced focal intraparenchymal lesions consistent with marked focal necrosis, probably related to the severity of immunodepression, as HIV infection had been diagnosed several years previously. CMV infection should be considered as a cause of ring-enhanced space-occupying mass lesions in patients with HIV-1 infection. Earlier identification of these unusual tumorlike forms of CMV infection by means of MRI should result in improved outcome.

AIDS-associated progressive multifocal leukoencephalopathy revealed by new-onset seizures.

PURPOSE: To describe the clinical features of new-onset seizures in HIV-1-infected persons with progressive multifocal leukoencephalopathy (PML), and to discuss potential mechanisms. PATIENTS AND METHODS: Forty-nine consecutive HIV-1-infected patients with PML attended our institutions between January 1988 and September 1993. We retrospectively analyzed cases with seizures as the presenting symptom of PML. RESULTS: Twenty percent of the HIV-1-infected patients with PML presented with new-onset seizures of various types, generalized or partial. None of them met the criteria of the AIDS dementia complex or had a concomitant opportunistic infection. Their mean CD4 cell count was < 60/mm3. Brain magnetic resonance imaging showed areas of increased signal intensity on T2-weighted images in 9 cases, and atrophy in only 1 case. Lesions most often involved subcortical white matter in parieto-occipital or frontal lobes, but 2 patients had posterior fossa lesions. Image-guided stereotactic brain biopsies in 8 cases and postmortem examination in 2 confirmed the diagnosis of PML. Typical histological lesions were observed in all cases, and positive immunolabelling of oligodendroglial nuclei was obtained in all cases with the polyclonal antibody directed against late SV40 antigens. Putative causative factors for the seizures include demyelinated lesions adjacent to the cerebral cortex acting as irritative foci, axonal conduction abnormalities, or disturbances of the neuron-glia balance. CONCLUSION: These cases illustrate that PML should be considered as a possible cause of new-onset seizures in patients with HIV-1 infection.

Cerebral glial tumors and human immunodeficiency virus-1 infection. More than a coincidental association.

BACKGROUND: The authors describe the clinical and morphologic patterns in four patients with acquired immune deficiency syndrome (AIDS) who developed intracranial glial tumors. METHODS: This retrospective study reports 70 patients at various stages of human immunodeficiency virus-1 (HIV-1) infection who underwent stereotactic brain biopsy for an intracerebral space-occupying lesion. RESULTS: Of these patients, four had glial tumors: one astroblastoma, two astrocytomas, and one glioblastoma. Glial tumors probably arise from a complex interplay of factors; possibilities include the activation of a dominant oncogene or viral inactivation of a tumor suppressor gene by a viral promoter (like the tat protein), impairment of immune defenses (which facilitates the growth of astrocytomas in acute lymphoblastic leukemia), production of cellular growth factors, cytokines, possible infection of glial cells by HIV, and the potentiation of a coinfectious agent. CONCLUSIONS: These cases illustrate that glial tumors should be considered in the differential diagnosis of brain masses in HIV-1 infection, especially because specific treatment for these tumors is available. Moreover, the occurrence of glial tumors in AIDS patients is not only an important event from a clinical point of view, but may also have implications for the pathogenesis of tumors in AIDS.

[Central serotonin receptors. Principal fundamental and functional aspects. Therapeutic applications]. / Récepteurs centraux de la sérotonine. Principaux aspects fondamentaux et fonctionnels. Applications thérapeutiques.

Serotonin (5-HT) is a central neurotransmitter and a neuromodulator. This amine is involved in many physiological functions and pathological disorders. Most of its effects are mediated by specific 5-HT receptors. In the first part of this paper, the present knowledge of 5-HT receptors is reviewed in terms of both pharmacology and molecular biology. In the second part, the functional properties of 5-HT receptors are analyzed and their involvement in pathophysiological processes is discussed. Most 5-HT receptors belong to the G-protein-coupled receptor family (5-HT1, 5-HT2 and 5-HT4 receptors), whereas one is a member of the ligand-gated ion-channel receptor family (5-HT3 receptor). 5-HT1 receptors are characterized by their high affinity for 5-HT and comprise several subclasses. Most are negatively coupled to adenylate cyclase but the 5-HT1C subtype is linked to phospholipase C activation and resembles the 5-HT2 receptor. By contrast, the newly identified 5-HT4 receptor is positively coupled to adenylate cyclase. Most 5-HT receptors have now been cloned, but their physiological roles are not completely understood. Better knowledge of 5-HT receptors has already led to the development of new drugs, such as buspirone, a 5-HT1A partial agonist devoid of benzodiazepine-like properties for the treatment of generalized anxiety. Anxiolytic properties have also been reported for 5-HT2 and 5-HT3 receptor antagonists. A new and potent anti-migrainous drug, sumatriptan, has recently been selected among compounds obtained by research on the 5-HT1D receptor. This key receptor controls the release of monoamines, amino acids and peptides, and new drugs are expected in the near future. The therapeutic potential of 5-HT3 antagonists is impressive, as these compounds have potent antiemetic, promnesic and antipsychotic properties in various animal models. Two such drugs have already been marketed for the prevention of radiation-induced emesis (ondansetron and granisetron) and are more potent than the antidopaminergic drugs. Many other data suggest that 5-HT receptors might be involved in other illnesses. Some drugs are in the development phase but identification of the relevant receptor is often difficult. Furthermore, the lak of specific ligands for some receptors clearly hinders functional correlations.

[Cerebral glioblastoma: a new complication of HIV-1 infection]. / Glioblastome cérébral: nouvelle complication de l'infection par le VIH 1.

A new case of supratentorial malignant glioma is reported in an HIV-1 infected male homosexual. Tumours of the nervous system account for only 5 to 10 percent of neurological complications of AIDS, and most of them are lymphomas or metastases from Kaposi's sarcomas. In fact, HIV-1 is a neurotropic lentivirus, not transforming by definition. Our patient had a frontal tumoral syndrome resistant to the conventional anti-toxoplasmic treatment. Pathological examination of a tumoral fragment obtained by stereotactic biopsy showed that according to the WHO criteria the tumour was a glioblastoma. The mechanism through which HIV infection results in malignant transformation of astrocytes is conjectural. There is no consensus on whether the virus is located in glial cells, but the transgenic animal technique suggests that the tat gene might play a certain role. Other hypotheses concerning the indirect neurotoxicity of HIV have been put forward, notably that of viral coinfection with viruses of the papova group.