Jacqueline Mikol

Phenotype variability in progranulin mutation carriers: a clinical, neuropsychological, imaging and genetic study

Frontotemporal dementia (FTD), characterized by behavioural and language disorders, is a clinically, genetically and pathologically heterogeneous group of diseases. The most recently identified of the four known genes is GRN, associated with 17q-linked FTD with ubiquitin-immunoreactive inclusions. GRN was analysed in 502 probands with frontal variant FTD (fvFTD), FTD with motoneuron disease (FTD-MND), primary progressive aphasia (PPA) and corticobasal degeneration syndrome (CBDS). We studied the clinical, neuropsychological and brain perfusion characteristics of mutation carriers. Eighteen mutations, seven novel were found in 24 families including 32 symptomatic mutation carriers. No copy number variation was found. The phenotypes associated with GRN mutations vary greatly: 20/32 (63%) carriers had fvFTD, the other (12/32, 37%) had clinical diagnoses of PPA, CBDS, Lewy body dementia or Alzheimers disease. Parkinsonism developed in 13/32 (41%), visual hallucinations in 8/32 (25%) and motor apraxia in 5/21 (24%). Constructional disorders were present in 10/21 (48%). Episodic memory disorders were frequent (16/18, 89%), consistent with hippocampal amnestic syndrome in 5/18 (28%). Hypoperfusion was observed in the hippocampus, parietal lobe and posterior cingulate gyrus, as well as the frontotemporal cortices. The frequency of mutations according to phenotype was 5.7% (20/352) in fvFTD, 17.9% (19/106) in familial forms, 4.4% in PPA (3/68), 3.3% in CBDS (1/30). Hallucinations, apraxia and amnestic syndrome may help differentiate GRN mutation carriers from others FTD patients. Variable phenotypes and neuropsychological profiles, as well as brain perfusion profiles associated with GRN mutations may reflect different patterns of neurodegeneration. Since all the mutations cause a progranulin haploinsufficiency, additional factors probably explain the variable clinical presentation of the disease.

Papillary tumor of the pineal region.

Primary papillary tumors of the central nervous system are rare. We have encountered a series of six papillary tumors of the pineal region with distinctive features that appear to represent a clinicopathologic entity. The tumors occurred in four women and two men, ranging in age from 19 to 53 years. Imaging studies showed a large well-circumscribed mass in the pineal region. The tumors were characterized by an epithelial-like growth pattern, in which the vessels were covered by a layer of tumoral cells. In papillary areas, the neoplastic cells were large, columnar or cuboidal, with a clear cytoplasm. Nuclei, round or infolded, were found generally at the basal pole of tumoral cells. Immunohistochemically, the tumor cells showed strong staining for cytokeratin, S-100 protein, neuron-specific enolase, and vimentin but only weak or no staining for epithelial membrane antigen and glial fibrillary acid protein. Ultrastructural examination of two cases revealed abundant rough endoplasmic reticulum with distended cisternae filled with secretory product, microvilli, and perinuclear intermediate filaments. The morphofunctional features of these papillary tumors of the pineal region, remarkably uniform within this series, are similar to those described for ependymal cells of the subcommissural organ, and the papillary tumors of the pineal region may be derived from these specialized ependymocytes.

Central nervous system immune reconstitution disease in acquired immunodeficiency syndrome patients receiving highly active antiretroviral treatment.

Highly active antiretroviral therapy (HAART)-induced immune restoration has been very beneficial for acquired immunodeficiency syndrome (AIDS) patients. In rare instances, HAART may induce a paradoxical clinical deterioration due to an immune reconstitution inflammatory syndrome (IRIS). This syndrome has been described with a wide variety of systemic infections and, in the central nervous system, with Cryptococcus neoformans infection, cytomegalovirus retinitis, and progressive multifocal leukoencephalopathy (PML). The authors have examined brain tissue in eight cases of IRIS: two autopsy cases and three biopsy cases of HIV encephalitis with IRIS and one autopsy case and two biopsy cases of PML with IRIS. All the patients presented with clinical deterioration following initiation of HAART and imaging showed contrast enhancement of the lesions. The symptoms regressed in four patients whereas the other four patients died. Neuropathological examination revealed severe inflammatory and demyelinating lesions with marked intraparenchymal and perivascular infiltration by macrophages and T lymphocytes. In some cases abundant viral proliferation was identified by immunocytochemistry or in situ hybridization, but in others the infectious agent could only be detected using PCR. T lymphocytes were predominantly CD8(+). In those cases with the more favorable course, inflammation was less severe with marked macrophage activation and a number of CD4(+) lymphocytes; in contrast, in the lethal cases inflammation was severe and mostly composed of CD8(+) cytotoxic lymphocytes. We conclude that HAART-induced paradoxical aggravation of HIV encephalitis or AIDS-related PML due to IRIS is reversible in most cases but may be lethal in others. In fatal cases, fulminant viral infection and/or acute perivenous leukoencephalitis may result from a dysregulation of the CD8(+)/CD4(+) T-cell balance.

Dissociated optic nerve fiber layer appearance of the fundus after idiopathic epiretinal membrane removal

PURPOSE To report the appearance of the fundus, that is seen frequently after removal of an idiopathic epiretinal membrane and which we refer to as the dissociated optic nerve fiber layer appearance. DESIGN Interventional, noncomparative retrospective case series. PARTICIPANTS One hundred consecutive patients with an epiretinal membrane who underwent pars plana vitrectomy and epiretinal membrane peeling in one eye. METHODS Only patients with an idiopathic epiretinal membrane or a membrane associated with a peripheral retinal tear, but without retinal detachment, were considered for this study. Sixty-one patients met these criteria for one eye. Preoperative and postoperative best-corrected visual acuity and preoperative and postoperative blue filter fundus photographs were reviewed. Histopathologic specimens of epiretinal membranes were available for 14 eyes. MAIN OUTCOME MEASURES The postoperative incidence of the dissociated optic nerve fiber layer appearance on blue filter photographs, visual acuity changes, and the presence of internal limiting membrane in epiretinal membrane specimens. RESULTS The postoperative incidence of this feature on blue filter fundus photographs was 43%. No difference was found between eyes with or without this feature concerning the average preoperative and postoperative best-corrected visual acuity or the average change in visual acuity. Internal limiting membrane was present in all 14 epiretinal membrane specimens available. Five of these 14 patients concerned exhibited a dissociated optic nerve fiber layer appearance and 9 did not. CONCLUSIONS The dissociated optic nerve fiber layer appearance occurred frequently after removal of an epiretinal membrane. As far as we know, this feature has not been previously reported. It consisted of numerous arcuate striae within the posterior pole in the direction of the optic nerve fibers and slightly darker than the surrounding retina. This feature had no functional effect noticeable by the patient and did not preclude good visual recovery. The small number of histologic samples and the impossibility of quantifying the area of internal limiting membrane peeled off did not allow us to supply proof that this feature is due to the extensive peeling of the internal limiting membrane, although this is the most likely hypothesis.

Brain Damage After Heat Stroke

Cerebellar syndromes and radiologic cerebellar atrophy after hyperpyrexia have occasionally been reported, mostly in neuroleptic malignant syndromes, but neuropathologic studies are extremely rare. We studied 3 patients (a 74-year-old woman, a 63-year-old man, and an 80-year-old man) who had heat stroke during heat waves in France. One patient had generalized seizures and died 28 hours after admission. The other patients survived one month and 2 months after admission; both had palatal myoclonus, and in one case, magnetic resonance imaging showed high signal intensity in the cerebral peduncles. The main neuropathology in the 3 cases was severe diffuse loss of Purkinje cells associated with heat shock protein 70 expression by Bergmann glia. In situ end labeling was negative in surviving Purkinje cells, suggesting that the mechanism of neuronal death was not apoptosis. Degeneration of Purkinje cells axons resulted in myelin pallor of the white matter of the folia and of the hilum of the dentate nuclei. DNA internucleosomal breakages were identified by in situ end labeling in the dentate nuclei and centromedian nuclei of the thalamus and were associated with degeneration of the cerebellar efferent pathways: superior cerebellar peduncles, decussation of the superior cerebellar peduncles (Wernekinck commissure), and dentatothalamic tract. These findings suggest that the mechanisms of neuronal death in the dentate nuclei and centromedian nuclei of the thalamus was different from that in Purkinje cells and more likely resulted from deafferentation. Ammons horn and other areas susceptible to hypoxia were spared. These observations confirm the selective vulnerability of Purkinje cells to heat-induced injury and involvement of the cerebellar efferent pathways in palatal myoclonus.

Direct evidence for a chronic CD8+-T-cell-mediated immune reaction to Tax within the muscle of a human T-cell leukemia/lymphoma virus type 1-infected patient with sporadic inclusion body myositis

ABSTRACT Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) infection can lead to the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), concomitantly with or without other inflammatory disorders such as myositis. These pathologies are considered immune-mediated diseases, and it is assumed that migration within tissues of both HTLV-1-infected CD4+ T cells and anti-HTLV-1 cytotoxic T cells represents a pivotal event. However, although HTLV-1-infected T cells were found in inflamed lesions, the antigenic specificity of coinfiltrated CD8+ T cells remains to be determined. In this study, we performed both ex vivo and in situ analyses using muscle biopsies obtained from an HTLV-1-infected patient with HAM/TSP and sporadic inclusion body myositis. We found that both HTLV-1-infected CD4+ T cells and CD8+ T cells directed to the dominant Tax antigen can be amplified from muscle cell cultures. Moreover, we were able to detect in two successive muscle biopsies both tax mRNA-positive mononuclear cells and T cells recognized by the Tax11-19/HLA-A*02 tetramer and positive for perforin. These findings provide the first direct demonstration that anti-Tax cytotoxic T cells are chronically recruited within inflamed tissues of an HTLV-1 infected patient, which validates the cytotoxic immune reaction model for the pathogenesis of HTLV-1-associated inflammatory disease.

Deletion of mitochondrial DNA in patient with chronic tubulointerstitial nephritis.

We report a mitochondrial DNA deletion (2.6 kb) in a boy with tubulointerstitial nephritis in whom chronic renal failure and leukodystrophy subsequently developed. Elevated lactate values in plasma and cerebrospinal fluid were suggestive of a defect in the mitochondrial respiratory chain. High amounts of deleted mitochondrial DNA were present in muscle and cerebral white matter. On the basis of this observation, we suggest giving consideration to genetic defects of oxidative phosphorylation in any attempt to determine the origin of unexplained chronic tubulointerstitial nephritis, especially when seemingly unrelated organs are involved.

Primary central nervous system malignant non–Hodgkin's lymphomas from HIV-infected and non-infected patients:expression of cellular surface proteins and Epstein-Barr viral markers

The increased incidence of primary central nervous system malignant non–Hodgkins lymphomas (PCNSL) in HIV– and non–HIV–infected patients and the demonstration of Epstein–Barr virus (EBV) in these tumours may indicate relationships between PCNSL and EBV. Consequently expression of EBV–induced antigens and cellular markers were studied in 11 HIV–infected and seven non–infected patients by in situ hybridization (ISH) and immunocytochemistry in monoclonal B cell PCNSL. In HIV–infected patients EBV genome was present in 9/11 cases, LMP in 11/11 cases and EBNA2 in 10/11 cases. The expression of adhesion and activation molecules was low or absent. In HIV non–infected patients, EBV genome was present in 5/7 cases, with LMP in 4/7 cases. EBNA2 was never detected. All these lymphomas expressed LFAlbeta. Whatever the population, no lytic cycle EBV markers were detected. Compared with other types of EBV lymphomas, our results suggest a different EBV latency state in primary B cell lymphomas of the CNS from HIV–infected or non–infected patients.

Sporadic Inclusion Body Myositis in a Patient with Human T Cell Leukemia Virus Type 1-Associated Myelopathy

Sporadic inclusion body myositis is a disease of unknown pathogenesis in which a viral etiology has long been suspected. We report a case that occurred in a patient with human T cell leukemia virus type 1-associated myelopathy. The diagnosis was confirmed by histopathological studies of the deltoid muscle. Nucleic acids amplification and in situ hybridization indicated the presence of integrated proviral DNA and viral mRNA transcripts in the lesions.

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.