Wolfgang Zeman

Subacute sclerosing panencephalitis: propagation of measles virus from brain biopsy in tissue culture.

Measles virus was propagated in monolayer cultures established from brain tissue of a patient with subacute sclerosing panencephalitis. Syncytial cells were rendered fluorescent with measles specific antiserums only, by means of an indirect technique. The ultrastructural appearance of the microtubular aggregates was identical in brain tissue and in the cultured cells. Fusion experiments produced a cytopathic effect in humnan embryonic kidney and VERO cell cultures. The virus was identified by hemiagglutination-inhibition, but only in the supernatant of disrupted cultured cells.

Fine structure of the lipid bodies in juvenile amaurotic idiocy

SummaryElectronmicroscopic examination of brain tissue from patients with juvenile amaurotic idiocy (Batten-Spielmeyer-Vogt disease) revealed a highly characteristic fine architecture of the lipid bodies accumulated in the perikarya. These pleomorphic bodies present two different types of internal structure, either a densely granular stroma, or round, oval and tubular membranes giving the cross section a multilocular appearance. There is some suggestion that the bodies might derive from degenerating mitochondria. In all four patients, regardless of age, the lipid bodies were similar in structure but they were distinctly different from the membranous cytoplasmic bodies of infantile amaurotic idiocy (Tay-Sachs disease) as described byTerry andKorey.ZusammenfassungElektronenmikroskopische Studien am Gehirngewebe von vier Patienten mit juveniler amaurotischer Idiotie (Batten-Spielmeyer-Vogtsche Krankheit) ergaben, daß die akkumulierten Lipoide in der Form von cytoplasmischen Organellen vorhanden sind. Diese Lipoidkörper sind pleomorph, von überaus wechselnder Größe, und zeigen zwei Typen von verschiedener interner Strukturierung. Einmal handelt es sich um ein dichtes, granuläres Stroma; in anderen Lipoidkörpern finden sich runde, ovale und tubuläre Membranen, die dem Ganzen ein multilokuläres Aussehen verleihen. Auf Grund gewisser morphologischer Ähnlichkeiten wird die Entstehung der Lipoidkörperchen aus degenerierten Mitochondrien erwogen. Daß ihre Feinstruktur nicht altersbedingt ist, geht daraus hervor, daß die Lipoidkörperchen von einer 9 Jahre alten Patientin mit denen von einer 23 Monate alten Patientin identisch waren. Die Lipoidkörper der juvenilen amaurotischen Idiotie sind grundverschieden von denen der infantilen amaurotischen Idiotie, den sogenannten „membranous cytoplasmic bodies” (Terry andKorey).

Familial alobar holoprosencephaly (arhinencephaly) with median cleft lip and palate: Report of patient with 46 chromosomes

UNDER the term arhinencephuly, Kundratl in 1882 described a spectrum of teratisms characterized by median dysplasia of the face and aplasia of olfactory bulbs and tracts. As the spectrum is currently defined,Z-l cyclopia is the most severely malformed member. Cyclopia has a single-chambered or holistic median eye and a single-chambered (monoventricular ) . holistic prosencephalon which has failed to divide into hemispheres or lobes. In successive teratisms of the spectrum, the holistic prosencephalon or holoprosencephalon differentiates toward hemispheres and lobes, the spectrum finally terminating in a brain that is organogenetically complete except for aplasia of olfactory bulbs and tracts. With the advancing brain differentiation, the dysplastic face and eyes transform toward normality. Since Kundrat’s monograph, the clinical literature on the subject has consisted mainly of scattered case reports, but in recent years the contributions of De Morsier4-4.5 and Yakovlev? have rekindled interest. The intra vitam clinical characteristics of affected infants have now been extensively described.6~7 New morphologic considerations have emphasized the necessity of replacing arhinencephuly with holoprosencephuly as the generic-descriptive term for the teratogenic spectrum.3.6 Attention has been redirected to the association of arhinencephaly-or, as we would term it, lobar hobprosencephuly-with eunuchoidism,4~s*9 as first recorded by Weidenreich in 1914.10 Other endocrine disturbances have been studied in 2 types of alobar holoprosencephaly, cyclopiall and cebocephaly.12 Most recently, cytogenetic studies have shown 13-15 trisomy in patients having alobar13.14 or lobarl5J6 holoprosencephaly in association with other malformations, notably polydactyly. Although the holoprosencephalies are generally regarded as sporadic, familial lobar holoprosencephaly with eunuchoidism is known.

Enzymuria in Gentamicin-Induced Kidney Damage

To assess their potential value as early indicators of gentamicin-induced kidney damage, lysosomal hydrolases were measured in the 24-h urines of rats receiving 30 or 60 mg of gentamicin per kg per day for 15 days. Proteinuria, urine osmolality, blood urea nitrogen, and creatinine clearance were also measured. Kidney tissue was examined by both light and electron microscopy. Beta-galactosidase, beta-n-acetyl-hexosaminidase, and alpha-fucosidase were sensitive indicators and were significantly elevated above control values by day 3 at both doses (P < 0.01). Proteinuria, urine osmolality, and tests reflecting glomerular filtration rate were later indicators of nephron damage. Changes by light microscopy were detected on day 5. Necrosis was most prominent in the proximal convoluted tubules on day 10. Electron microscopy revealed numerous cytosomes with myeloid bodies within the proximal tubular epithelium on day 5. Lysosomal enzymuria appears to be an early manifestation of gentamicin nephrotoxicity and may possibly be related to the lysosomal abnormalities seen on electron microscopy. Images

Pathology of the torsion dystonias (dystonia musculorum deformans).

THE PATHOLOGY of the torsion dystonias, or dystonia musculorum deformans as these disorders are frequently referred to, is still a controversial subject. In a recent review of degenerative disorders of basal ganglia, Dreese and Netsky1 state “Patients with the syndrome of dystonia musculorum deformans may be divided into two pathologic groups. The larger group includes all instances of inflammation or neoplastic diseases and recognized pathologic entities such as hepatolenticular degeneration or the syndrome of Hallervorden-Spatz. Pathologic study of this group reveals a wide range of disorders causing the syndrome. The smaller group, here designated idiopathic dystonia musculorum deformans, is characterized anatomically by degenerative loss of neurons, often associated with secondary gliosis and status marmoratus.” This statement is contrasted by the conclusion of Zeman and Dyken2 that “Detailed histologic studies on the brains of two patients with dystonia niusculorum deformans did not reveal specific alterations which would account for the clinical manifestations. A critical evaluation of 18 autopsy studies reported in the literature points in the same direction. Muscle biopsies on two patients likewise revealed non-specific alterations. I t therefore appears safe to state that the pathology of dystonia musculorum deformans is unknown.” The controversy results in part from the loose definition of the terms torsion dystonia or dystonia musculorum deformans, and to resolve the issue, a more rigid definition will be presented and the evidence on which these divergent statements are based will be reviewed.

Reflections on the etiology and pathogenesis of subacute sclerosing pan encephalitis

THE ELECTRON MICROSCOPIC demonstration of pseudomyxovirus in the brain tissue of a patient with subacute sclerosing panencephalitis (SSPE) and the subsequent observation of rising measles antibody titers during the course of the disease2 seem to have firmly established the etiology of this puzzling malady of the central nervous system. Before the implications of these findings are discussed in more detail, I will dwell briefly on some historical developments which have led to the delineation of SSPE and draw a sketch of its clinical manifestations. An excursion into the historical development of the concept of SSPE provides an arresting glimpse into what may be called the autistic thinking of pathologists, for the disease was described under at least five and possibly six different headings, each of which implied a separate nosological entity. I t was suggested by Lumsdem that Schilder was one of the first to put a pertinent case on record in 1924.3 Preoccupied as he was with his efforts to delineate a diffuse primary demyelinating disease from the heterogeneous group of diffuse sclerosis, Schilder identified his case as ‘‘encephalitis periaxialis diffusa,” unaware of the fact that his two previous observations493 represented two entirely different nosological entities. Bodechtel and GuttmannG reported a case under the title “Diffuse encephalitis with sclerosing inflammation of the hemisphere white matter,” certainly the most inclusive but also the clumsiest terms yet devised. Dawson7VR described two more cases, termed “epidemic” and “lethargic encephalitis,” but subsequently called “inclusion body encephalitis.” Whereas his neuro-pathologic predecessors had based their histopathologic examination on celloidin embedded hemisphere sections, Dawson, a general pathologist, relied on small H&E stained paraffin sections. Using these to the best advantage by high-powered light microscopy, he discovered the intranuclear inclusion bodies but did not mention the typical demyelination and gliosis of the white matter. Pette and DGring studied five cases of encephalitis. They were impressed by the generalized involvement of the brain tissue with inflammatory lesions and introduced the term “panencephalitis”; however, only their cases 3 and 5 seem to have been instances of SSPE. Van BogaertloJl stressed the discrepancy between the enormous astrocytic proliferation and the lesser degree of demyelination in the white matter by the designation ‘hbacute sclerosing leukoencephalitis.” Though this term neglects the usually marked and often pathognomonic lesions in the gray matter, it enjoys worldwide usage. From 1948 on, various investigators adduced piecemeal evidence that all the conditions mentioned above represented actually one entityl2-I4 and re-examination of van Bogaert’s 21 cases revealed intranuclear inclusion bodies in five.15 Thus, it appears that Dawson’s inclusion body encephalitis, van Bogaert’s subacute sclerosing leukoencephalitis, and the panencephalitis of Pette and Doring, those terms being most frequently fnund in present texts as representing different entities,

Deficiency of α-L-Fucosidase

A new form of α-L-fucosidase deficiency has been found in a 20-year-old severely retarded male. Additional signs include angiokeratoma corporis diffusum and anhydrosis. The skin lesion is due to an accumulation of residual bodies, presumably containing oligosaccharides and glycoproteins, in endothelial cells and fibrocytes. The enzyme activity in blood relatives indicates that the disease is inherited as a simple autosomal recessive trait that segregates according to Mendelian principles. Because the enzyme activity in the heterozygotes was consistently below that of normal controls, the carriers of the trait in this family could be ascertained.

On the ultrastructural diversity and essence of residual bodies in neuronal ceroid-lipofuscinosis

In 4 patients with neuronal ceroid-lipofuscinoses (NCL) (3 patients with the junvenile type, 1 patient with the late infantile type), the ultrastructural spectrum of residual bodies in the central and peripheral nervous system presented curvilinear profiles in all cases and regions investigated and many more ultrastructural patterns within and beyond regions commonly accessible to biopsy, probably due to age dependence, local tissue and cellular biochemical factors. Sampling from basal ganglia especially yielded combined curvilinear-fingerpint bodies, from peripheral ganglia additional membranous bodies. Residual bodies in NCL were present in almost every cell type, similar to the distribution of regular lipofuscin. Although the classical subgroups of NCL contain electronmicroscopically well defined residual bodies, permitting distinction of the late infantile type from the juvenile type, the ultrastructural differences are more of a quantitative than of a qualitative nature. However, they are not pathognomonic. N.m.r. spectra of ceroid and lipofuscin support the concept of their biochemical similarity, and argue against the proposition that they contain a single major component.

The Morphogenesis and Biochemical Characteristics of Ceroid Isolated from Cases of Neuronal Ceroid-Lipofuscinosis

Two distinctly different groups of disorders have emerged from the conditions generically classified as amaurotic familial idiocies. One is characterized by grossly abnormal profiles for cerebral sphingolipids, for example the GM1 and GM2 gangliosides. The other group is composed of patients with normal sphingolipid profiles, but with neuronal accumulation of lipopigments of the ceroid-lipofuscin type. The sphingolipidoses have been shown by a number of investigators to meet the classic concept of Hers (1965) for lysosomal diseases. This view has been repeatedly reinforced by continuing studies which show the lack or reduction of specific hydrolases, resulting in the accumulation of biochemical compounds which cannot be degraded to metabolically utilizable substances. The concept of lysosomal diseases has led many investigators to search for a single accumulating lipid or a deficient hydrolytic enzyme unique to neuronal ceroid-lipofuscinoses. Since many of the lysosomal disorders became better understood by the elucidation of the chemical properties of a specific lipid, present in unphysiologically large quantities, the pronouncement by Donahue et al. (1966) before this group, that the “chemical analysis of cytoplasmic lipopigment granules (from the brains of patients with Batten’s disease) will contribute little towards an understanding of this disease” was decidedly unwise. Although it is correct, that autofluorescent lipopigments lack chemical specificity and result from a great variety of pathogenetic situations (Porta and Hartroft, 1969), Donahue et al. (1966) failed to recognize the distinct possibility, that certain repetitive patterns in the chemical composition and ultrastructure of these residual bodies may indicate a specific formative pathogenesis. On the strength of this argument, we developed methods to isolate lipopigments in pure preparations and the first results have proved already the soundness of this concept. As it turned out, the previously held concept of a close relationship between lipofuscin and ceroid had to be abandoned and replaced by the theses that these classes of lipopigment are distinctly different entities, albeit both represent residual bodies and both contain polymeric substances (Siakotos et al., 1970).

The control of variables in radiopathological studies on mammalian nervous tissue.

SummaryAn experimental x-irradiation technique for small rodents is described which exposes the segments T2 to T4 of the spinal cord. By keeping the volume of the irradiated tissue small in comparison with the total body volume, the predominant effect of the irradiation is a delayed necrosis of the spinal cord. Abscopal and somatic effects are thus reduced, as shown by the normal weight-curves following the irradiation. This technique permits the obtaining of reproducible lesions after a narrowly defined latency period, thus making possible longitudinal studies on pathogenesis and evolution of delayed radionecrosis of the spinal cord. Since the gaseous environment can be manipulated, studies on the oxygen-effect were carried out and preliminary results are reported.