New discovery: mycoplasma attacks blood vessels in brain

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She pulled off 2 big disease findings

By Wahlberg,608-252-6125,dwahlberg@... Wisconsin

Wisconsin State Journal,Madison,WI-April 20,2008

2<http://www.madison.com/wsj/home/local/282360>

e Zu Rhein has twice done what few scientists do once: make

key discoveries about a new disease.

But that second discovery, of a rare brain disease that she reported

in December at the age of 87, is just one of the remarkable things

about Zu Rhein's life.

Zu Rhein, a native of Germany, spent her childhood playing in

castles. Her father was property manager for King Ludwig of Bavaria.

She studied medicine in Munich during World War II while the city was

being bombed by Allied planes. After the war, she worked as a

pathologist at a U.S. Army Hospital.

In 1954, she took a job teaching pathology at UW-Madison. Though she

retired in 1995, she has continued reporting to her campus office to

conduct research and read and write scholarly articles.

" I want to keep informed, " Zu Rhein said recently from her office,

crammed with new and tattered books and journals but void of a

computer (there is an electric typewriter). " It 's just my lifestyle.

I 'm a very curious person. "

Zu Rhein reported her first discovery in 1964. She found the virus

responsible for a disease that had been identified not long before:

progressive multifocal leukoencephalopathy, or PML. The brain disease

mainly affects people with compromised immune systems, including

those with cancer, transplants or AIDS.

She became known as an expert on PML. In 1991, a doctor from Neenah

sent her brain tissue from a 56-year-old Wisconsin woman who had

apparently died of PML. He asked her to confirm the cause of death.

But when Zu Rhein looked at the tissue under a microscope, she

didn 't see the telltale signs of PML. Instead, she saw heaps of

membrane-less bodies eating away at the linings of tiny blood vessels.

" I had never seen those before, " she said. " It was bizarre. "

Zu Rhein painstakingly analyzed the tissue for months, using an

electron microscope. The infectious agent was too large for a virus,

she concluded. It appeared to be a mycoplasma, a one-cell bacterium

known to invade the lungs and cause walking pneumonia.

But this mycoplasma was attacking blood vessels in the brain.

She wanted to alert the scientific world. But she hadn 't heard of

other cases and didn 't want to publish a report about just one case.

Eventually, Dr. Powers, a pathologist at the University of

Rochester in New York, received tissue from two similar patients -- a

41-year-old man from South Carolina and a 67-year-old man from

Georgia.

The men, like the Wisconsin woman, had gradually lost their ability

to walk, talk and eat before dying. One was thought to have Lyme

disease.

Powers and Zu Rhein compared notes and found that the tissue from the

men was similar to that from the Wisconsin woman.

In December, they published their findings about the three cases in

the Journal of Neuropathology and Experimental Neurology.

Dr. Sobel, a pathologist at Stanford University who is editor

of the journal, called the report a " significant contribution " to

the field.

The findings " are very strongly suggestive of something new, " he

said. " Obviously, more cases and more molecular diagnostic work is

needed, but that is how new diseases are generally discovered. "

Zu Rhein, who turned 88 this month, plans to keep studying the

mysterious disease.

" I will probably not live to see this clarified, " she said. " But

I 'm happy that I have been so lucky in my research. "

Wisconsin State Journal

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A Novel Cerebral Microangiopathy With Endothelial Cell Atypia and

Multifocal White Matter Lesions: A Direct Mycoplasmal Infection?

Zu-Rhein, e M. MD; Lo, Shyh-Ching MD, PhD; Hulette,

M. MD; Powers, M. MD

Journal of Neuropathology & Experimental Neurology. 66(12):1100-1117,

December 2007.

http://www.jneuropath.com/pt/re/jnen/abstract.00005072-200712000-

00006.htm;jsessionid=LLdcwDhRpYVPS6GWFnRwKGTr2F3rCpyQXqQLgBfmhBv8Gh1Q9

zwc!670793751!181195628!8091!-1

Abstract:

We present 3 sporadic cases of a subacute to chronic, progressive

motor (i.e. weakness, ataxia, spasticity, dysarthria, and dysphagia)

and cognitive disorder in adults of both sexes, without proven

immunocompromise or malignancy. Neuroimaging studies revealed tiny

calcifications with atrophy of the cerebrum, pons, and midbrain in 1

patient, cerebral atrophy in another, and cerebral atrophy and

periventricular white matter hyperintensities in the third. Clinical

diagnoses included cortico-pontine-cerebellar degeneration, mixed

neurodegenerative disorder, progressive supranuclear palsy, diffuse

Lewy body disease, and Lyme disease. One atrophic brain revealed

widely disseminated, millimeter-sized gray lesions in cerebral white

matter and obscured anatomic markings of the basis pontis. The most

conspicuous microscopic feature in all was capillaries with focally

piled up endothelial nuclei, some of which appeared to be

multinucleated, or enlarged, hyperchromatic crescentic single nuclei.

Although seen mostly without associated damage, they were also noted

with white matter lesions displaying vacuolation, demyelination,

spheroids, necrosis, vascular fibrosis, and mineralization; these

were most severe in the basis pontis. Immunostains and probes to

herpes simplex virus-I, -II, and -8; adenovirus, cytomegalovirus,

varicella-zoster, Epstein-Barr virus, measles, JC virus, and herpes

hominis virus-6 were negative. Electron microscopy revealed no

virions in endothelial cells with multilobed or multiple nuclei and

duplicated basal laminae.

However, mycoplasma-like bodies, mostly 400 to 600 nm in size, were

found in endothelial cell cytoplasm and capillary lumina. Platelets

adhered to affected endothelial cells. Polymerase chain reaction and

immunohistochemistry of fixed samples for Mycoplasma fermentans were

negative; other species of Mycoplasma remain viable pathogenic

candidates.

, American Association of Neuropathologists, Inc.

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