[Wilson disease]. / La maladie de Wilson.

Wilson disease is an autosomal recessive disorder of copper overload. A principal characteristic of this disease is its wide phenotypic and genotypic variability. Its results from mutations of the ATP 7B gene located on chromosome 13, that encodes a hepatic copper transport protein. More than 300 mutations of this gene have been identified. This protein ensures the transport of copper in the hepatocyte, its incorporation with the apoceruloplasmin and its biliary excretion. The clinical manifestations are heterogeneous as well in their presentation, dominated by the neuropsychiatric and hepatic symptoms, as in the age of the first symptoms. Early recognition and initiation of therapy with chelators or zinc are essential for prognosis. Liver transplantation is indicated in cases with fulminant hepatitis, end-stage liver cirrhosis and should be considered in the therapy resistant neurological forms. A regular follow-up with monitoring of adverse effects of treatment and compliance is essential. Any discontinuation of treatments will involve, within a very variable time, but in constant manner, a reappearance or a reaggravation of the signs. Such relapses are often brutal and can be extremely serious, especially since response to subsequent treatment is often poor.

Kearns Sayre syndrome: an unusual form of mitochondrial diabetes.

Kearns Sayre syndrome (KSS) is a mitochondrial disorder characterized by the emergence before age 20 of progressive external ophthalmoplegia, pigmentary retinopathy, together with other heterogeneous clinical manifestations, including cardiac conduction defects, muscle abnormalities and endocrinopathies. KSS is associated with large heteroplasmic deletions in mitochondrial DNA. We report the case of a 43-year-old woman, with diabetes mellitus as a first manifestation at age 19. Later, she exhibited bilateral ptosis and external ophthalmoplegia with progressive worsening. DNA analysis identified a large mitochondrial DNA (mtDNA) deletion, which confirmed the diagnosis of KSS. By reporting this case with diabetes mellitus as first manifestation, we aim at emphasizing problems of diagnosis in these subtypes of mitochondrial diabetes.

Neuropathology in Europe: an overview.

After a short historical review covering the past 150 years, different aspects of training and practice are considered. Prominent institutes, men and women who have made significant contributions to neuropathology are considered although those still living are not included. There are those countries with neuropathology as a speciality, countries with subspecialty and those countries without neuropathology as a speciality or subspeciality. In order to harmonize teaching, training, examinations and regulations, EURO-CNS (European Confederation of Neuropathological Societies) was founded in 1993. This allowed the recognition of the training charter of neuropathology by the Board of Pathology (1998), the organization of European courses and European congresses, and the achievement of concerted actions simultaneously, recognition of the subspecialty of Neuropathology by the UEMS (Union Européenne des Médecins Spécialistes) Council was obtained in 1997. Data relating to the current position of neuropathology are included and the future of education and the challenges facing neuropathology are discussed.

[Diabetes and mitochondrial cytopathies: pathological studies]. / Diabète et cytopathies mitochondriales: données anatomo-pathologiques.

Maternal diabetes associated with neural deafness is designated as MIDD (maternal inherited diabetes and deafness); it is linked to a A3243G tRNA leucine gene mutation. The disease course is progressive and involvement of other systems is frequent. In most cases, macular pattern dystrophy is present. Muscular lesions are characteristic of mitochondrial myopathies. Mitochondrial abnormalities have also been observed in pancreas, heart, kidney, smooth muscle of the digestive tract with variable heteroplasmy levels. MIDD may present as a single syndrome or is part of MELAS or Kearns-Sayre syndrome.

High frequency of a 30-bp deletion of Epstein-Barr virus latent membrane protein 1 gene in primary HIV non-Hodgkin's brain lymphomas.

A characteristic 30-base pair (bp) deletion (del) in the 3' end of the Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) gene, coding for the C-terminal NF-kappa B activation domain, has been identified in various lymphoproliferative disorders and nasopharyngeal carcinomas. In the single report to date of human immunodeficiency virus primary brain lymphomas (HIV-PBLs), del-LMP1 was noted in seven cases out of nine. The present study was designed to identify this deletion in a series of 31 diffuse large B-cell HIV-PBLs, with the aim of determining its possible oncogenic action. The presence of EBV was confirmed by EBER mRNA in situ hybridization. After genomic extraction from frozen tissue, two 20-base oligonucleotide primers flanking the site of the 30-bp deletion were used. DNA sequencing of the polymerase chain reaction (PCR) products confirmed an identical segment spanning 30-bp and 69-bp, frequently associated with mutational hotspots in 19 cases (61%). A role for del-LMP1 in the oncogenic potential of EBV in systemic proliferations is a matter of debate. Its high incidence suggests that the oncogenic mechanism of LMP1 in the brain might differ significantly from that in systemic lymphoid proliferations, and might be enhanced by HIV infection.

Intramedullary abscess resulting from disseminated cryptococcosis despite immune restoration in a patient with AIDS.

We report on a case of cryptococcal intramedullary abscess, which occurred three years after a disseminated cryptococcosis and two years after a lymph node cryptococcal recurrence in a HIV-infected patient who exhibited a long-standing immune restoration. At the time of diagnosis, CD4(+) lymphocyte-count was 640x10(6)/l and HIV viral load was undetectable. Spinal involvement is rare during cryptococcosis of the central nervous system. As far as we are aware, there is only one case of proven intramedullary cryptococcal abscess reported in the literature and this case is then the second one. The significant and sustained increase in CD4 count following effective antiretroviral therapy was probably associated with only a partial immune restitution that did not allow to avoid the occurrence of the cryptococcal medullar abscess. Finally, this case raises the question of when to stop secondary prophylaxis of cryptococcal disease after increase in CD4 cell count under antiretroviral therapy.

Reversible leukoencephalopathy in cerebral amyloid angiopathy presenting as subacute dementia.

This report concerns a 71-year-old woman who had rapid progressive dementia along with myocloni and increased blood pressure. Cranial computed tomography and magnetic resonance imaging scans showed bilateral widespread white matter changes with mass effect. A brain biopsy revealed an amyloid angiopathy in leptomeningeal as well as cerebral cortex arteries. After 2 months of antihypertensive treatment, a dramatic improvement of cognitive functions and a spectacular regression of leukoencephalopathy were observed. We suggest that hypertensive encephalopathy may worsen or reveal cerebral amyloid angiopathy.

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.

Changes in AIDS-related lymphoma since the era of highly active antiretroviral therapy.

HIV infection is associated with a high incidence of AIDS-related lymphomas (ARLs). Since the use of highly active antiretroviral therapy (HAART), the incidence of AIDS-defining illnesses has decreased, leading to a significant improvement in survival of HIV-infected patients. The consequences of HAART use on ARL are under debate. This study compared the incidence and the characteristics of ARL before and after the use of HAART in a large population of HIV-infected patients in the French Hospital Database on HIV (FHDH) and particularly in 3 centers including 145 patients with proven lymphoma. Within the FHDH, the incidence of systemic ARL has decreased between 1993-1994 and 1997-1998, from 86.0 per 10 000 to 42.9 per 10 000 person-years (P < 10(-30)). The incidence of primary brain lymphoma has also fallen dramatically between the periods, from 27.8 per 10 000 to 9.7 per 10 000 person-years (P < 10(-11)). The analysis of 145 cases of ARL in 3 hospitals showed that known HIV history was longer in the second period than in the first period among patients with systemic ARL (98 versus 75 months; P <.01). Patients had a higher number of CD4 cells at diagnosis during the second period (191 versus 63/microL, P = 10(-3)). Survival of patients with systemic ARL also increased between the periods (from 6 to 20 months; P =.004). Therefore, the profile of ARL has changed since the era of HAART, with a lower incidence of systemic and brain ARL. The prognosis of systemic ARL has improved.

[Atypical CADASIL phenotypes and pathological findings in two new French families]. / CADASIL: aspects phénotypiques inhabituels et observations anatomo-pathologiques dans deux nouvelles familles françaises.

Atypical phenotypes of CADASIL and corresponding anatomical data in two cases are described in 6 members of 2 new French families. In the first family, 4 cases in the same kindred were probably affected, two of them with a predominant psychiatric presentation, two others with dementia and a pseudo-bulbar syndrome of progressive evolution. No history of migraine or ischemic event were documented in any. In the propositus, the diagnosis was documented by skin biopsy, Notch 3 gene mutation and autopsy after the patient had died when 67 years old, 8 years after onset. Brain examination showed a widespread leukoencephalopathy with subcortical infarcts. Characteristic granular lesions of the small arteries of the brain and other organs were observed. In the second family, two cases are reported. One patient died when 63 years old after a subacute evolution mimicking intracranial hypertension. The anatomical diagnosis was retrospectively proven typical of CADASIL with Notch 3 immunostaining of arterial smooth muscle cells. The other case had a progressive evolution over 20 years of limb paresthesia with a mild spasticity diagnosed as a progressive form of multiple sclerosis. It was followed by a pseudo-bulbar syndrome and a mild subcortical dementia without acute ischemic attack. The diagnosis was confirmed by skin biopsy and mutation of the Notch 3 gene. This report illustrates

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.

[Post-traumatic Korsakoff's syndrome: clinical and anatomical report]. / Syndrome de Korsakoff post-traumatique: étude anatomo-clinique.

Clinical and anatomical report of a post traumatic amnestic syndrome (Korsakoff's syndrome), associating anterograde amnesia persisting for fifteen years, with temporal disorientation, false recognitions, initially intense transitory confabulation and secondarily bursts of confabulation, intact remote memory and persistence of old learnings. Death after twelve years from mesenteric infarction. Anatomically, post-traumatic sequellae are limited to both cingulate gyri in their anterior part. This cingula involvement is easy to understand if one knows that post-traumatic Korsakoff's syndrome appears after severe cranial traumatisms, with at least three days of coma, and develops constantly, even if transitory, after long duration comas with 20 to 30 days of loss of consciousness. Anatomical explanation depends on the fact that Korsakoff's syndromes from various etiologies need, to be produced, a bilateral damage of the limbic circuit and that severe head traumatisms, when dying early in the evolution without possibility of a neuro-psychological investigation, have always a destruction of corpus callosum or cingulate gyri or both, resulting from crushing of these structures by the edge of the faulx cerebri. Consistent with these constatations, it is logical that a Korsakoff's syndrome develops after severe head traumas with bilateral lesions of the limbic circuit and especially of the cingulate gyri. But anatomical evidence remains rare, because early fatal evolution does not permit psychological evaluation and, reversely, long survivals who may die from another pathology would not have brain examination. We prefer the name of "Korsakoff's syndrome" rather than that of "amnesic syndrome" to denominate the anterograd amnesia (amnésie des faits récents) encountered in nutritional disorders due to B1 deficiency in true Korsakoff's disease, but also with other etiologies such as cerebral tumours, vascular cerebral disorders, post-commital anoxia, herpetic encephalopathy, head traumas, all of them developing amnesia for recent events, formerly classified under the title of "korsakowian syndrome" or "mental syndrome of Korsakoff" and more recently under the denomination of "amnesic syndrome". But whatever is the etiology of the memory disorder, the amnesic syndrome remains identical and the advanced small differences, such as euphoria in alcoholics or mood depression in tumours, are often fallacious, so that the only way of differentiation deals with accessory symptoms such as intracranial hypertension in tumours, sudden onset in vascular etiologies or polyneuritis in B1 deficiency. Post-traumatic Korsakoff's syndrome joins with this scheme, for its clinical aspect is so similar to that of nutritional disorders that it might be difficult to reach the exact diagnosis when an alcohol addict develops, after a head trauma, an amnesia which could be the consequence of the trauma but also of a nutritional disorder developed after the accident with inadequate parenteral treatment. Our case, which is the first well documented observation of this disease reported with long clinical survey and final pathological examination, was presented in 1981 at a joint meeting of the French and Dutch neurological societies. It gives the proof of the importance, in limbic circuit, of the cingulate gyri. A comparison is made with four other clinical cases of post traumatic amnestic syndrome with MNR procedures which show, for two of them, cingula lesions explaining the clinical features, for one of them a bilateral lesion of Ammon's homs and for the last one extra-limbic lesions, with destruction of the inferior part of both frontal lobes, associated with a possible deafferentation of the right cingula cortex.

[Histological data in inflammatory myositis]. / Anatomo-pathologie des maladies musculaires inflammatoires.

Inflammatory muscular diseases of adult and child consist of dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM). Muscular biopsy takes a seminal place in their diagnosis, through analysis of the topography and clustering of individual histological lesions: endomysial, perimysial and perivascular inflammation, muscular necrosis with regeneration, fibre modifications, fibrosis, micro-angiopathy. They can be associated with collagen diseases or malignant tumors that usually precede them. IBM seems somewhat apart among inflammatory myopathies, being characterised by the association of neurogenic and myogenic features and the presence of vacuoles containing filaments with an accumulation of proteins previously reported in Alzheimer's disease (beta amyloid protein, tau, ubiquitin,.). Inflammation is of various intensity, lacking in familial IBM (hereditary inclusion body myopathy) that otherwise shares the same histologic characteristics as sporadic forms. Other inflammatory muscular diseases: focal myositis, eosinophilic polymyositis, are less frequent. Macrophagic myofasciitis, viral myositis and drug induced myositis are discussed in other articles.

So-called malignant and extra-ventricular neurocytomas: reality or wrong diagnosis? A critical review about two overdiagnosed cases.

Central neurocytoma (CN) is described as a rare intra-ventricular benign neuronal tumor of the brain. Two primary tumors first diagnosed as malignant and extra-ventricular neurocytomas are reported here. Histologically, the tumor of the first patient, a forty-one-year-old man, consisted of monotonous cells with round nuclei, but no fibrillar background. The second tumor, in a nineteen-year-old girl, showed areas of moderately pleomorphic round cells, with numerous rosettes and ganglion cell differentiation, in an abundant fibrillary network. Both presented calcifications. Mitoses were more frequent in recurrences and spinal locations than in the primaries. All tumors stained strongly for synaptophysin, and GFAP was partly positive in the first case only. Patients received post-surgical radiotherapy and were still alive eight and six years, respectively, after initial surgery. The interpretation of atypical cases, such as ours is not easy: the diagnoses finally retained were oligodendroglioma in the first case and ganglioneuroblastoma in the second case. Furthermore, neurocytomas atypical either by their unusual topographical or histological presentation or by their poor prognosis, have been frequently entitled in this way on synaptophysin positivity. So, we were prompted to reassess the entity of CN, seventeen years after the first description, to re-appreciate the reality of anatomo-clinical variants and to discuss the value of synaptophysin positivity in these tumors. In conclusion, it seems preferable to individualize true classical CN, which has a favorable outcome, from so-called extra-ventricular, atypical and anaplastic, clinically malignant neurocytomas for which complementary treatment is required.

Progressive multifocal leukoencephalopathy and oligodendroglioma in a monkey co-infected by simian immunodeficiency virus and simian virus 40.

A rhesus monkey experimentally inoculated with simian immunodeficiency virus (SIV) mac251 was killed 42 months later because of poor general condition. CD4 lymphocyte count which was 3,430/mm3 before inoculation, had decreased to 638/mm3 2 months before death. Neuropathological examination revealed changes characteristic of progressive multifocal leukoencephalopathy (PML) in the white matter of the cerebral hemispheres and brain stem. In situ hybridization was negative for JC virus but markedly positive for simian virus 40 (SV40) in the nuclei of many oligodendrocytes. Many oligodendrocytes also expressed p53. Within an area involved by PML, there was a densely cellular tumor with honeycomb appearance and elongated vessels characteristic of oligodendrogliomas. Within the tumor in situ hybridization for SV40 and immunocytochemistry for p53 were negative. Opportunistic infection by SV40 has been occasionally reported in experimentally SIV-infected monkeys resulting in PML or malignant astrocytoma. Association of JC virus-induced PML and astrocytomas has been reported in three human cases without AIDS. In those cases, as in our monkey, polyomaviruses (SV40 or JC virus) were expressed in the areas with PML but not in the glial tumor. Association of PML and oligodendroglioma has not been reported previously to our knowledge. The relationship between oligodendrocyte proliferation and polyomavirus infection of oligodendrocytes is unclear. Our findings suggest that binding of the viral protein to p53 may result in inactivation of the pro-apoptotic protein favoring the proliferation of a randomly occurring tumoral clone of oligodendrocytes.