Allelic origin of the abnormal prion protein isoform in familial prion diseases.

The hallmark of prion diseases is the presence of an aberrant isoform of the prion protein (PrP(res)) that is insoluble in nondenaturing detergents and resistant to proteases. We investigated the allelic origin of PrP(res) in brains of subjects heterozygous for the D178N mutation linked to fatal familial insomnia (FFI) and a subtype of Creutzfeldt-Jakob disease (CJD178), as well as for insertional mutations associated with another CJD subtype. We found that in FFI and CJD178 subjects, only mutant PrP was detergent-insoluble and protease-resistant. Therefore, PrP(res) derives exclusively from the mutant allele carrying the D178N mutation. In contrast, in the CJD subtype harboring insertional mutations, wild-type PrP was also detergent-insoluble and likely to be protease-resistant. Our findings indicate that the participation of the wild-type PrP in the formation of PrP(res) depends on the type of mutations, providing an insight into the molecular mechanisms underlying the phenotypic heterogeneity in familial prion diseases.

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.

[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.

Simultaneous progressive multifocal leukoencephalopathy, Epstein-Barr virus (EBV) latent infection and cerebral parenchymal infiltration during chronic lymphocytic leukemia.

We report a non-HIV patient who had B chronic lymphocytic leukemia (CLL) with progressive multifocal leukoencephalopathy (PML) and diffuse cerebral leukemic parenchymal infiltration in the presence of JC virus and Epstein-Barr virus (EBV) cerebral co-infection. Multiple subcortical hypodensities lining the cortico-subcortical junction were present within the white matter on computerized tomography (CT) scan, with large areas of high signal intensity on T2-weighted sequences on magnetic resonance imaging (MRI). JCV DNA was identified in peripheral blood nuclear cells and cerebrospinal fluid polymerase chain reaction (PCR) DNA/DNA hybridization plus Southern blot analysis. Frontal stereotactic biopsy confirmed the diagnosis of PML by immunocytochemistry, in situ hybridization (ISH) with JC Enzo probe and electron microscopy. Leukemic B cells with the same phenotype as leukemic blood cells were disseminated in the demyelinated areas. They were labeled by anti-latent membrane protein and by BamHl W EBV probe after ISH. Adhesion and activation molecules were positive for CD23. Autopsy showed diffuse visceral leukemic infiltration without acutization. EBV-transformed B lymphocytes would favour JCV penetration and/or intracerebral reactivation of previously latent JCV infection with further development of simultaneous PML and cerebral CLL infiltration in an immunosuppressed patient.

[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.

The juvenile and chronic forms of GM2 gangliosidosis: clinical and enzymatic heterogeneity.

We report the cases of 5 patients from 2 sibships with the "adult" or chronic form of GM2 gangliosidosis and 2 patients from another sibship with the juvenile form. We demonstrated hexosaminidase A deficiency in all cases but in 1 sibship the enzymatic profile was identical to that in Tay-Sachs disease, whereas in the remaining 2 families it was that of the B1 variant. There was no correlation between the clinical features and the enzymatic profile. Hexosaminidase A deficiency should be considered in unexplained progressive neurologic disorders of childhood and adolescence, including isolated dementia. EMG evidence of anterior horn cell involvement in association with neurologic or cognitive deterioration may be a diagnostic clue in the juvenile forms.

Recurrent optic neuromyelitis with endocrinopathies: a new syndrome.

We report a new syndrome that we call "recurrent optic neuromyelitis with endocrinopathies" in eight Antillean women from Martinique and Guadeloupe Ocular involvement was either monocular or binocular, whereas myelopathy was acute or subacute. In seven patients, myelopathic symptoms recurred, and in six patients, visual problems recurred. Spinal cord involvement was a consistent band-like pseudo-syringomyelic dissociated sensory loss. All eight patients had endocrinopathies consisting of amenorrhea, galactorrhea, diabetes insipidus, hypothyroidism, or hyperphagia. Spinal cord MRI revealed cavitation-like images. Various immunosuppressant treatments had little effect on the uniformly deteriorating course, ending in blindness and paraplegia. Six patients died within 5 years of onset, and an autopsy in one patient showed multiple demyelinizing lesions of the spinal cord with thickened blood vessels walls without evidence of inflammation. These cases appear to constitute a syndrome distinct from MS and from classic Devic's syndrome, not only because of the association with endocrinopathies but because of the stereotypy of the recurrences, the absence of MRI lesions in the cerebral white matter, and the unusual image of cavitation of the spinal cord. The syndrome is also distinct from HTLV-I-associated paraparesis, which is endemic in the West Indies.

Severe encephalitis resulting from coinfections with HIV and JC virus.

We observed 3 cases of progressive multifocal leukoencephalopathy (PML) among frozen CNS samples obtained at autopsy from 102 adult AIDS patients. In 2 patients, PML was associated with severe HIV encephalitis. In those 2 cases, the areas of extensive JC-induced demyelination were massively infiltrated by HIV infected macrophages/microglial cells with evidence for localized increase of HIV encephalitis in PML lesions. Using immunohistochemistry and in situ hybridization, we demonstrated that each virus infects, in a latent or productive fashion, different CNS cell populations. Therefore, the extension of HIV encephalitis could not be related to an intracellular transactivation of 1 virus by the other. However, the results are consistent with dissemination of viral infection by the recruitment of HIV-infected macrophages to damaged areas of the brain. This phenomenon might be generalized to other pathogens that are frequently associated with HIV CNS infection. Early detection and treatment of opportunistic CNS lesions could be important to prevent extension of HIV encephalitis.

Cerebrotendinous xanthomatosis: treatments with simvastatin, lovastatin, and chenodeoxycholic acid in 3 siblings.

We report 3 sisters treated for cerebrotendinous xanthomatosis. We treated one, with a severe neurologic form of the illness, with chenodeoxycholic acid, then lovastatin and simvastatin. These drugs had different efficacy and tolerance, but induced no clinical improvement. Her sisters, without neurologic symptoms, received chenodeoxycholic acid, which normalized the cholestanol level. Optimal treatment of this illness must begin before there is significant clinical symptomatology.

Thrombotic carotid megabulb: fibromuscular dysplasia, septae, and ischemic stroke.

The proximal internal carotid artery is most commonly spared in cerebral fibromuscular dysplasia. The authors report the cases of three young black patients with stroke and carotid megabulbs with fibrous components, two of whom had superimposed thrombi.

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.

Calcitonin genes (I and II) expression in human nervous and medullary thyroid carcinoma tissues.

The calcitonin gene family comprises two main genes: CALC I which encodes for calcitonin (CT) mRNA in thyroid and calcitonin gene-related peptide I (CGRP I) mRNA in neuronal tissues and CALC II gene which encodes for CGRP II mRNA only. Recently, in normal thyroid and in medullary thyroid carcinoma (MTC), we detected an additional splicing pathway involving the splicing of exon 4 to exon 5 and leading to the expression of a third CALC I mRNA: CT mRNA II. In the present study, we analyzed by polymerase chain reaction the expression of CT mRNAs I and II, CGRP I and II mRNAs in MTC and in human tumors of the nervous system (3 pituitary adenomas, 3 astrocytomas, 2 schwanomas). In pituitary tissues, CGRP II expression was constant and easily detectable in comparison to other tissues. CT mRNA II signal was very low, but clearly detectable after a reamplification indicating that the factors responsible for the splicing of exon 4 to exon 5 are poorly operative in neuronal tissues.

Connections of latero-dorsal nucleus of the thalamus. II. Experimental study in Papio papio.

Modifications of the latero-dorsal (L.D.) nucleus of the thalamus have been observed earlier in man in relation to limbic lesion of various etiologies. Our proposal was to determine the role of L.D. in memory disturbances. We attempted to study the connections of L.D. in Papio papio baboon after surgical lesion using silver impregnations as well as traditional techniques. We found three afferent pathways: from the fornix, the posterior cingulate and the parietal cortex (area 7). The most important is the afferent system from the fornix, it terminates in the antero-dorso-medial part of L.D.; the other two afferent pathways have a postero-lateral projection in L.D. The three efferent systems to parietal cortex, cingulate and fornix were not delineated in this study. It was concluded that the antero-dorso-medial portion of L.D. is connected to the limbic system and the ventro-postero-lateral portion integrated into a large parieto-cingulo-parahippocampal circuit to which it is joined by direct and indirect projections with several relays. These connections have important implications, perhaps, in our understanding of memory disturbances.

[Lesion of the lateral dorsal thalamic nucleus and alcoholic Korsakoff syndrome]. / Atteinte du noyau lateral dorsal du thalamus et syndrome de Korsakoff alcoolique.

The authors report a clinico-pathological study dealing with the limbic nuclei of the thalamus in 11 cases of Korsakoff syndrome of alcoholic aetiology. There is no parallelism between the involvement of the latero-dorsal nucleus (L.D.), the medio-dorsal nucleus, the pulvinar and the importance of the retrograde amnesia. The mamillary bodies are always affected. The latero-dorsal nucleus was modified in 9 cases out of 11, the medio-dorsal in 7 cases and the pulvinar in 6 cases. In contrast, the anterior nucleus is normal. The frequency of the involvement of the L.D. is an argument to relate this nucleus with the limbic system. But the lesion of this nucleus is inconstant whereas that of the mamillary bodies is always observed.

A typical presenile dementia. Report of an anatomo-clinical case and review of the literature.

A clinico-pathological report is given of a case of dementia of frontal type with EEG changes, associated with a diffuse neuronal loss, subcortical gliosis and laminar spongiosis in the superficial part of the 2nd cortical layer. The authors discuss the cortical biopsy and the post-mortem findings in their case. They draw a comparison between their case an two conditions known as "progressive sub-cortical gliosis" and "Kraepelin's disease" which might be a single entity "atypical presenile dementia".

Familial juvenile parkinsonism with multiple systems degenerations. A clinicopathological study.

An unusual case of familial multisystemic degeneration is reported. Two siblings had juvenile parkinsonism, areflexia, and retinal degeneration of slow progression. The main neuropathological findings in case 1 were pallidoluysian, nigral, dentate, and dorsal columns degeneration. The authors draw a comparison between this case and juvenile parkinsonism, dentato-rubro-pallido-luysian atrophy, and spino-cerebello-nigral degeneration.

Fatal systemic carnitine deficiency with lipid storage in skeletal muscle, heart, liver and kidney.

A fatal case of systemic carnitine deficiency is reported. The patient suffered from slowly progressive muscle weakness since early childhood. After the age of 17 years her weakness progressed more rapidly until her death at the age of 20. A pregnancy during the last year of the patient's life was followed by rapid deterioration in her condition. An episode of renal insufficiency occurred at the age of 17 years and hepatomegaly, increased BSP dye retention and intermittent ketoacidosis were present during the last month of her life. Biopsy and autopsy specimens of muscle showed a lipid storage myopathy. Type 1 fibers were selectively severely affected, and many Type 1 fibers were atrophic. Abundant large mitochondria, some also containing abnormal inclusions, were also present in the muscle fibers. At autopsy there was marked accumulation of sudanophilic lipid deposits in all hepatocytes, in the renal tubular epithelial cells, and a patchy increase of lipid material was found in the myocardial fibers. There was marked carnitine deficiency in the patient's liver as well as muscel, while the carnitine palmityltransferase activities in these tissues were abnormally high. The basic metabolic abnormality is assumed to be a defect in carnitine biosynthesis.

Familial mitochondrial myopathy with cataract.

A 62-year-old female had severe progressive ophthalmoplegia associated with facial, pharyngeal and limb muscle involvement. When 40, she had undergone surgery for bilateral cataract present for about 20 years. Biopsies of skeletal muscles indicated myopathy; histochemistry and electron microscopy gave evidence of abnormal mitochondria in type I fibres. Bilateral cataract needing surgical treatment at 32 was the prominent symptom in her daughter, then with only mild facial weakness. Despite absence of ophthalmoplegia, similar pathological changes were observed in an inferior oblique muscle. The child of the former, a 10-year-old clinically healthy boy, had been surgically treated for a bilateral cataract at the age of 3. As indicated by a review of literature, cataract is not an exceptional occurrence in this particular type of ocular myopathy and therefore should be included within its multisystem associations. The same HLA haplotype (A2-B21) was found in the three patients.

Esthesioneuroblastoma with intracranial extension.

The authors present five cases of olfactory neuroblastoma with intracranial extension operated on in the Department of Neurosurgery in collaboration with otorhinolaryngologists. This tumor is most frequently reported as growing inside the nasal cavities, and it can extend to the paranasal sinuses. Cases presenting initially as intracranial tumors have been infrequently reported. At present, histological diagnosis of this tumor is aided by the use of electron microscopy and immunocytochemistry. Total resection combined with radiation therapy remains the most satisfactory treatment.