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PRION DISEASES
Within the last few years, Unconventional Slow CNS Infections-the Prion disorders have been described and defined. In 1997 the second Noble Prize was awarded in this field, to Dr. Stanley Prusiner who has championed the concept of the Prion. Our understanding of this group of diseases, began with veterinarian virologist and neuropathologists who earlier in this century described spongiform pathology in scrapie, proved it to be a transmissible disease and developed rodent models which have vastly contributed to our understanding. The veterinary neuropathologist William Hadlow's 1959 letter to Lancet, which pointed out the similarity between Scrapie and the newly described Kuru, and suggested transmission studies of Kuru, specifically in primates, encouraged Gajdusek's Noble Prize winning efforts. Soon after the Kuru work, Klatzo described spongiform pathology in Creutzfeldt-Jacob Disease (C-J disease) which likewise encouraged the successful transmission experiments, by Gajdusek's group. This list is now large and growing. It includes sporadic, transmissible diseases like Kuru and C-J in humans and Scrapie, Mad Cow disease and Mink Encephalopathy in animals. Further, there are familial disorders with autosomal dominant modes of passage within this spectrum. The pathological and clinical phenotypes of the familial diseases appears related to their specific prion protein gene (PRNP) mutation, zygosity at codon 129 of PRNP and other genetic factors. The familial forms of Prion disease maybe viewed either as separate albeit related entities: such as Gerstmann-Straussler-Scheinker syndrome, and Fatal Familial Insomnia (FFI), or as variants of C-J Disease. The case below illustrates several important common histopathological finding in this group of disorders. Such findings must be complemented with appropriate immunological and genetic assay in order to define each case as a prion disorder and either genetic or sporadic. Photograph CJ 1,2,3,4,5 and 6, below, of human autopsy cases depict typical gross and microscopic features of the Prion Diseases. In photo 1, note cerebral cortical atrophy. The microscopic images, taken from grey matter areas, reveal the absence of inflammation which is characteristic, a range of spongiform change, neuronal loss, astrocytosis and typical amyloid plaques. The latter, which are rich in protease resistant PrP protein, are not common in sporadic C-J disease. They were well described in cases of Kuru and are often a feature of familial C-J cases. They appear to be plentiful in recently described English human autopsy cases of presumed Mad Cow Disease.Photographs CJD 1-6:
Fungal Infections
Fungal infections of the nervous system often, but not exclusively, involve immunocompromised individuals. Currently, patients with AIDS are the largest group with CNS fungal infections. Others are risk include the fetus and neonate, poorly controlled diabetic patients, patients with lymphoma and those immunosuppressed for medical purposes, such as transplantation.
The images below (Inf. a, b, and c) are of taken from the autopsy of a poorly controlled acidotic diabetic patient who presented with a bloody nasal discharge, conjunctival edema, exophthalmus and paralysis of the pupil. Note the thickened meninges and thrombosed branches of the anterior cerebral arteries in the coronal section of this patient’s frontal lobes (a). The involved vessels are infected by mucormycoses and secondarily thrombosed. Note the thrombus in the lumen and the blue, infected portion of vessel wall in b. The adjacent high power photomicrograph, "c", depicts an organism apparently dancing within the inflammation.
Photographs Inf. a, b, c:
Another angioinvasive fungal organism is aspergillus. This organism may spread directly to brain, from neighboring structures like the sinuses, or via the hematogenous route from systemic sites of infection. Pulmonary infection is a common source of CNS disease. The setting is usually immunocompromise. The photographs below (Inf. d, e, f and g) depict typical gross (d) , and microscopic images (e, f and g) of this process. They are taken from the brain of an AIDS patient who had pulmonary aspergillosis with secondary sepsis and CNS infection. In the low power microscopic image, "e", note leptomeningeal and parenchymal inflammation and hemorrhage. Vessels within the meninges are thrombosed. Higher power images, "f and g", reveal organisms within the thrombi and within vessel walls. .
Photographs Inf. d, e, f, g:
In the setting of the immunocompromised patient, cryptococcal meningitis may be seen. This type of infection became relatively frequent with the AIDS epidemic. The photographs below depict gross and microscopic findings in such cases( Inf. h, i and j. The gross lesions are quite gelatinous. The surface of the brain is literally slippery. At the microscopic level the infection elicits almost no host response. Perivascular ulcer-like defects filled with organisms are seen within brain.
Photographs Inf. h, i, j:
The neonate is also an immunoincompetent individual, particularly when it comes to cell mediated immunity. The gross photograph below (Inf. k) depicts an infant brain with multiple hemorrhagic abcesses, microabcesses, caused by hematogenously distributed candidiasis.
Photograph Inf. k:
Normal immunocompetent individuals may develop systemic fungal infections with organisms such as coccidiomycosis. The photographs below (Inf. l, m, n and o) depict the brain of a truck driver who happen to drive through the coccidiomycosis rich western part of the USA. He returned with pulmonary coccidiomycosis which lead to chronic, predominantly basilar, leptomeningitis and secondary hydrocephalus due to CSF outlet obstruction. In the gross photograph (l) note the thickened basilar meninges. The microscopic images (m, n and o) reveal granulomatosis meningitis. Note that organisms are seen within multinucleated giant cells (n) and lying freely(o) within areas of inflammation. The basilar distribution of inflammation seen in this case is similar to that observed in casses of tuberculous meningitis. This pattern of meningitis is typical of granulomatous disease. Patients present with complex clinical findings related to inflammation of basilar blood vessels, cranial nerves, and hypothalamus plus slowly evolving hydrocephalus.
Photographs Inf. l, m, n and o:
Protozoal infections
We will show only two infections in this category, amoebiasis and toxoplasmosis.
There are several types of amoebic organisms which may produce CNS infection. The photomicrographs below illustrate a case of cerebral amoebic granulomatous meningoencephalitis which we encountered in a psychotic individual who was apparently immersing his head into the toilet bowl and thus exposing himself to a myriad of possible organisms. The macrophage-like forms in "q" are amoeba.
Photographs Inf p and q:
CNS toxoplasmosis typically occurs in the setting of immunocompromise. It is an important infectious risk for the fetal brain. We see a lot of this infection in our AIDS patients. The photographs below illustrate gross and microscopic findings in patients with AIDS who suffer CNS toxoplasmosis. In the first gross photograph (r) try to ignore the unfortunate highlight and note the large necrotic lesion adjacent to the lateral ventricle. Such lesions often rupture into the ventricle. The second gross picture (s) show a typical "toxoplasmoma", an abcess. The three microscopic images (t,u,and v ) reveal encysted and free organisms and arteritis. Vessel wall inflammation with luminal compromise is typically seen in this ncerotising infection.
Photographs Inf r, s, t, u and v:
