[Progressive multifocal leukoencephalopathy. Demyelinating viral disease--common complication of AIDS]. / Progressiv multifokal leukoencefalopati. Demyeliniserande virussjukdom--vanlig komplikation till aids.

PML is a chronic, progressive, fatal disease in the CNS of humans. Characteristic pathologic features are spotty demyelination, enlarged oligodendrocytes with nuclear inclusions, and transformed astrocytes. It is caused by the polyoma virus JCV, which has worldwide distribution and usually is harmless. In some individuals with impaired cell-mediated immunity, most commonly in aids, virus changes into a pathogenic form. Hence, PML is a slow, viral, opportunistic infection. The infection is productive in astrocytes and destructive in oligodendrocytes. Lysis of the latter causes demyelination. The discovery of PML in 1958 opened the door to extensive research in several fields of biomedicine.

The development of neuropathology at the Massachusetts General Hospital and Harvard Medical School.

Few institutions have shaped neuropathology as a discipline as profoundly as Massachusetts General Hospital (MGH) and Harvard Medical School. Their fascination over many decades is due to a unique accumulation of excellent, intellectually stimulating neurologists with a sincere interest in the morphologic and pathogenetic basis of nervous system diseases. Their approach was strictly case oriented and clinico-pathological conferences were developed to the highest standard. In this review, the foundations of neuropathology in Boston are recounted.

Early pathological changes in progressive multifocal leukoencephalopathy: a report of two asymptomatic cases occurring prior to the AIDS epidemic.

Serial sections of formalin-fixed, paraffin-embedded blocks from two asymptomatic, non-AIDS cases of progressive multifocal leukoencephalopathy (PML) were stained with a double-label immunocytochemical method for detection of glial fibrillary acidic protein and JC virus (JCV) capsid proteins and with luxol fast blue/hematoxylin-eosin. In case 1 small, rounded lesions of about 1-mm diameter were seen within a restricted area in the posterior part of the superior frontal gyrus of both cerebral hemispheres, suggesting an early manifestation of the disease. Fully developed demyelinated lesions of the classical type with JCV-infected oligodendrocytes appeared in the white matter and along its border with the cortex. Less-well-developed lesions, believed to be precursors to the fully developed ones, were seen in the gray and white matter. Of special interest were areas which contained small collections of enlarged, glial fibrillary acidic protein (GFAP)-positive astrocytes without capsid antigen and which seemed to lack destruction of myelin as judged from the appearance of matching serial sections stained for myelin. Large lesions in the brain of case 2 showed the well-known features of advanced PML. The close relation between some astrocytes and oligodendrocytes with viral antigen raises the possibility of early intercellular passage of virus. Vacuolation, seen within or near lesions in both cases, has previously been noted in the CNS infected by HIV, but not in PML. It is suggested that PML, a disease of both oligodendrocytes and astrocytes, may actually begin in astroglial cells which, under the influence of a restricted JCV infection, become reactive, express GFAP and pass on virus to the more highly susceptible oligodendrocytes with which they are in contact.

The early development of the neopallial wall and area choroidea in fetal rats. A light and electron microscopic study.

The telencephalic wall was studied by light and electron microscopy in 11-13 day old fetal rats (E11-13). A few specimens from E14-16 were also included for comparisons. Two areas were selected: the dorso-lateral convexity of the hemispheric vesicles, called the neopallial wall, and the area choroidea, the posterior part of the telencephalic roof which unites the two hemispheres. Our observations and a review of the literature have shown that on E11-12 the neopallial wall, the telencephalic roof, and the hippocampal anlage between them form a continuous, nonstratified, cohesive monolayer of columnar and mitotic cells, which essentially is similar to epithelial monolayers elsewhere in the body. This simple structure is modified late on E12 or early in E13 in the neopallial wall when postmitotic neurons appear and migrate in order to form the cortical plate. However, bipolar radially oriented cells, which span the entire width of the wall, still predominate. These cells, now called radial glial cells, increase greatly in number and length during the period of neuronal migration. The cuboidal cells in the neural tube, the columnar cells in the early neopallial wall, and the radial glial cells in the period of neuronal migration have the same basic structure. They are axially polarized epithelial cells which are characterized by the following basic features. They have an elongated bipolar shape which is maintained by a cytoskeleton of longitudinally oriented microtubules. Opposite ends are different structurally and functionally. Thus, the apical ends, connected by tight junctions, face the fluid-filled cavity while the outer ends, covered by a basal lamina, face mesenchymal tissue including blood vessels. A polarization of cytoplasmic organelles is also evident, e.g. the Golgi apparatus has always a supranuclear position. During the early development of the telencephalon this basic epithelial structure is maintained but is modified locally in order to serve various functions. The columnar/radial glial cells in the neopallial wall are elongated and slender, have a narrow Golgi apparatus, profiles of RER and vesicles, relatively few ribosomes, and show a few examples of micropinocytosis. These cells grow continuously in length during development. On the other hand, the cells in the area choroidea have a low columnar or cuboidal shape, which does not change during development. The inner portion (between the nucleus and the ventricle) contains a voluminous Golgi apparatus, many mitochondria, RER cisternae which contain electron-dense material, SER, and many vesicles. The inner ends of the cells project into the ventricular cavity as bulbous or apical protrusions which contain many organelles, especially MVBs.(ABSTRACT TRUNCATED AT 400 WORDS)

Preparation of fetal rat brains for light and electron microscopy.

To study cellular shapes, growth patterns, and fine structure during early stages of CNS development in rat embryos, preparative procedures were evaluated and modified to meet two criteria: 1) Coronal semithin sections should reveal undeformed telencephalic hemispheres that were symmetrically expanded on both sides of midline structures and were surrounded by contiguous mesenchyme. 2) In electron micrographs, cells should have intact, undistorted surface membranes, evenly distributed nucleoplasm and well preserved cytoplasmic organelles. To meet these criteria, 378 fetuses with a gestational age of 11-20 days (E11-E20) were used to test and modify procedures for anesthesia, embryo removal and handling, dissection, fixation, dehydration, and embedding of the embryonic CNS. Most specimens were in an early stage of development (E11-E13), which, in case of the neopallial wall, is the preneural period. The tests produced methods that met the above criteria and identified the most common artifacts and their causes. Deformities of the cerebral hemispheres and separations between the brain and its coverings were usually caused by trauma during embryo removal and during handling before fixation. Changes in cellular volumes, especially swelling during fixation and dehydration, were the most important causes of histological artifacts. The procedures and methods that consistently produced the best light and electron microscopic preservation of the E11-E13 rat CNS are described. Fixation was best when the brains were treated with glutaraldehyde and s-collidine buffer, followed by osmium tetroxide in s-collidine buffer. A surprisingly beneficial effect of sodium chloride in the dehydrating alcohol was noted.

Transneuronal changes in the optic tectum following eye enucleation in the newborn rat.

Following unilateral eye enucleation, degenerated neurons were observed in the affected tectum. However, dead cells also were present in the ipsilateral tectum, i.e., on the side which does not receive input from the enucleated eye. Further, the degeneration pattern observed in the experimental animals was similar to that observed in control unoperated animals. From these results we concluded that within the period studied, eye enucleation does not cause cell death to the neurons onto which the optic tract projects. Rather, the dead cells observed in the tectum are due to normal cell death that occurs in embryological development. The reduction in volume that occurs to the affected tectum following eye enucleation is attributed to an absence of the optic tract rather than to a neuronal loss.

Treatment of mouse muscular dystrophy with the protease inhibitor pepstatin.

Dystrophic mice were treated for 5 weeks beginning at 3 weeks of age with 20 ugm per day of pepstatin, a potent inhibitor of cathepsin D. Mortality was less and weight gain greater in pepstatin treated mice than in controls. Muscle bulk was greater and hind lamb contractures were reduced in treated mice. Mean muscle fiber mass was significantly increased by pepstatin treatment. Inhibition of muscle protease may be the mechanism by which pepstatin slows the tempo of progression of mouse muscular dystrophy.

Cell death in the optic tectum of the developing rat.

The death of cells was studied by light microscopy in the optic tectum of normal, developing rats. Normal cell death in the tectum during development has previously been described in chickens but not in a mammal. The total period of cell death was from the 20th embryonic day through the 11th postnatal day. During this period the number of dying cells was comparatively small for the first 2 days, reached a peak at birth and then decreased over the next 11 days. In comparison to the number of surviving cells the number of dead cells in each section was small. The dead cells appeared to be randomly distributed in all layers of the optic tectum.

Characteristics of myosin in nemaline myopathy.

Electron-microscopic, morphometric, histochemical and biochemical studies were carried out on muscle biopsies from a patient with the characteristic clinical and pathological findings of nemaline myopathy. The mean fiber diameter was decreased, and the vastus lateralis muscle biopsy consisted exclusively of slow twitch (Type I) fibers. Quantitative biochemical investigations revealed significantly low calcium uptake and ATPase activity of the fragmented sarcoplasmic reticulum and decreased myosin ATPase activity. The electrophoretogram of myosin showed an abnormality in the light chain pattern which could not be explained by a disproportion of normal fiber types.

Mononucleosis-associated subacute sclerosing panencephalitis.

A thirteen-year-old girl died of subacute sclerosing panencephalitis (SSPE) which occurred as part of a complex encephalitic illness related to acute infectious mononucleosis. The cerebrospinal fluid (CSF) Epstein-Barr virus (EBV) fluorescent antibody (FA) titer was 1:64. Electron microscopic examination revealed 17 nanometer (nm) diameter paramyxovirus-like nucleocapsids in brain sections and 90 nm diameter herpes virus-like enveloped particles in negatively stained brain tissue extracts. Indirect FA staining of cerebral cortex sections demonstrated both measles and EBV antigenic material. EBV antigenic material has not previously been demonstrated in brain tissue. The proportion of B lymphocytes among the patient's peripheral blood lymphocytes was significantly increased as compared to normal controls, while the T lymphocyte percentage was normal. It is suggested that defects in cellular immunity associated with infectious mononucleosis may have been responsible for activation of latent measles-like virus. This is the tenth reported case in which two viruses have been associated with SSPE. This is the third instance in the authors' experience in which acute EBV infection has occurred coincident with the development of SSPE.

The initial lesion in experimental allergic neuritis. A phase and electron microscopic study.

Experimental allergic neuritis (EAN) was produced in rats by the intradermal injection of an emulsion of peripheral nerve in Freund's adjuvant. Early lesions in perfused sciatic nerves were studied by phase, light, and electron microscopy at intervals up to 15 days following immunization. Circulating lymphocytes attached focally to the inner surface of blood vessels, primarily venules, to initiate parenchymal lesion formation. Attached cells had the hand mirror configuration typical of the motile lymphocyte. They subsequently flattened against the endothelial surface and then traversed the vascular wall by sinking into and passing through the cytoplasm of endothelial cells. The transgressor and transgressed cell membranes were intact and both cells retained their integrity. Lymphocytes began to transform and divide intravascularly; these events accelerated extravascularly. Although the migrating cells became larger and more pleomorphic in the perivascular regions, their essential character was in keeping with an origin from circulating lymphocytes. In many lesions, there was fluid with protein, possibly produced by the transformed extravascular cells. The described cellular events precede tissue damage and are likely instrumental in the myelin destruction which follows