Arrival Of Pml Cases And An Electron Microscope

Another interdisciplinary contact, which became of considerable importance later on, developed with Veterinary Science. In this Department, Dr. Carl Olson had created a research unit for the study of papilloma viruses, especially of bovine and canine types. A viral oncologist who appreciated the contributions of morphology, he early had acquired an electron microscope. My affiliation with Veterinary Science began in 1957. All such students had to do course work in pathology, and I became their instructor in neuropathology. Over the years I served on at least nine examination committees for M.S. or Ph.D.

candidates, most of them from Dr. Olson's group and others from Dr. Robert Hanson's group which focused on scrapie and transmissible mink encephalopathy.

Meanwhile, in clinical autopsy work, one disease that attracted my particular interest was an acute necrotizing encephalitis with intranuclear inclusion bodies. We observed three such cases from 1957 to 1960 and published the data in 1962. The first case had occurred after head trauma, and I had difficulties with the diagnosis. However, Dr. Stanley Inhorn, a resident engaged in virus research, exhorted me to persist in looking for inclusion bodies. The slow and tedious work was eventually successful, and a herpetic infection could be suggested. With trained eyes the search became much easier in the two following cases. This was a time when immunocytochemistry was not yet part of the diagnostic arsenal.

In 1959, Dr. Sam (Shi-Ming) Chou joined the Department of Pathology as a postdoctoral student with the aim of completing a Ph.D. program in Zoology and Pathology. Supported by the National Multiple Sclerosis Society, he engaged in research in neurolathyrism. By 1962, he had decided that he would choose neuropathology as his career. He opted to take the course that I gave for the neurology residents.

In the fall of 1962, a particularly stimulating consultation case was presented to me by the pathologist of a downtown Madison hospital. The patient, a 33-year-old woman with lupus erythematosus, had died after several weeks of progressive cerebellar disease. The slides showed a multifocal demyelinating disease with a most striking combination of giant tumor-like astrocytes and large numbers of oligodendrocytes with greatly enlarged nuclei deeply stained with hematoxylin. There were no distinct inclusion bodies as one sees with herpes viruses. I was fascinated and knew I had never seen this disease before. I showed the slides to a visiting neuropathologist and he, too, was at a loss. At that time I was in the midst of a very time-consuming experiment with a group of sophomore students. It involved the induction of brain tumors in chicken with Rous sarcoma virus. There was no time for a library search. However, I did show the slides to Dr. Chou, and to my utter surprise, and delight, he brought from his desk a folder with reprints on demyelinating diseases from which he extracted the paper entitled ''Progressive Multifocal Leu-koencephalopathy'' by Astrom, Mancall, and Richardson, Jr. (1958) and Richardson's follow-up paper of 1961. We had no doubt that our consultation case was one of the less than 30 cases of this disease known at that time. Only 2 months later, a 67-year-old woman came to autopsy in our department (A 62393). She had suffered from chronic sinusitis and bronchitis and had developed a left hemiparesis and mental changes during a 7 month period. The clinical diagnosis was multiple infarcts. In the formalin-fixed brain I noticed extensive myelin destruction, and the cytopathology, without doubt, was that of progressive multifocal leukoencephalopathy (PML). We used our sudden wealth of two PML cases for local conferences and teaching exercises.

In 1963, the Pathology Department faculty insisted on the acquisition of an electron microscope to aid various research projects. Dr. Chou, who had learned the technique from Dr. Hans Ris in Zoology, became one of the first users of our RCA EMU 3G instrument (Fig. 2.1). I realized my chance to do some acceptable research at a raised level of morphology. Dr. Angevine had agreed to a sabbatical leave, and Dr. Reese had secured for me a position in the Neuropathology Laboratory of Dr. Harry Zimmerman, at Montefiore Hospital, Bronx, New York. Before thinking of leaving, however, I had to find a colleague who would pitch in for me at home. Dr. Chou graciously consented to help. Thus, in a reciprocal arrangement, I taught him more diagnostic neuro-pathology and he taught me how to run the electron microscope.

In May 1964, another of Dr. Olson's students took his Ph.D. examination, and I was a thesis reader. Among the illustrations for ''The Cytology of Canine Oral Papilloma'' were electron micrographs of cell nuclei with dispersed or aggregated virions. Listed among the references was Dr. Melnick's paper in Science (1962) entitled ''Papova Virus Group.'' In it, he combined the papil-loma and polyoma viruses into one group of oncogenic DNA viruses, capable of producing latent infections. The morphology of virions of this group, in thin sections, had been characterized just within the last few years.

Figure 2.1. The electron microscope, an RCA EMU 3G, in which we first saw the intranuclear virions in brain tissue with progressive multifocal leukoencephalopathy (PML).

In August, one of our autopsy cases showed an extensive esophagitis with distinct intranuclear inclusion bodies. I planned to make up for my lost chance with the encephalitis cases and to search for herpes group virions.

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