NEUROPATHOLOGY FOR MEDICAL STUDENTS
Presented by William I. Rosenblum, MD
CHAPTER 5--PATHOLOGY OF CNS INFECTIONS
Section 4: Viral Infections, Rickettsial Infections, and Prion Diseases
This chapter contains four interrelated sections. The other three sections are:
PRETEST: Answers can be found in the text of this section or click on link at end of questions
INFECTIONS CHARACTERIZED BY A LYMPHOCYTIC REACTION
These are sometimes called serous infections because the subarachnoid space appears hydropic and watery instead of being filled with pus or gelatinous, fibrous material as in a granuloma. Besides this serous meningitis characterized by a lymphocytic response, the viruses and rickettsia may produce a diffuse encephalitis also characterized by lymphocytic exudate.
In addition to lymphocytic cuffing of vessels (image above), neuronophagia is also seen. This is illustrated in the next figure. (arrows).
Dead or dying neurons are surrounded by or covered by clusters of microglia which appear to be devouring the affected cells. Collections of microglia [unfortunately called "glial" nodules] unrelated to individual neurons are also prominent in rickettsial infections, where the nodules are known as typhus nodules. In addition to a lymphocytic response, neuronophagia, and glial nodules, viral and rickettsial meningoencephalitis may also be characterized by a non-specific astrocytosis. Besides these histologic characteristics common to many viral and rickettsial infections, certain viral diseases are characterized by cytoplasmic or nuclear inclusion bodies not found in rickettsial disease, while some rickettsial infections are characterized by a vasculitis not observed in viral disease. We will now discuss selected viral and rickettsial diseases.
HERPESVIRUS INFECTIONS OF THE NERVOUS SYSTEM
A variety of herpes virus serve as important infectious agents of the human nervous system. The four most common are discussed below:
Herpes simplex encephalitis is the most important single cause of sporadic viral encephalitis. Herpesvirus Type I, the same strain that causes "cold sores" and is harbored latently in the trigeminal ganglion, is responsible for encephalitis in adults and children. It produces a necrotizing and hemorrhagic necrosis (image below) with a predilection for the temporal lobe and limbic system. In this photo the cingulate gyri are involved. These are connected to the limbic system which originates in the hippcampi and this linkage may explain involvement of the cingulate gyri in this case.
In addition to the lymphocytic and microglial response mentioned in the previous section, characteristic large, eosinophilic nuclear inclusions are often seen (image below).
Herpes virus Type II, which is responsible for genital or venereal herpes, may cause an overwhelming encephalitis which devastates the brains of some infants born to infected mothers. It has been uncommon in adults. However the incidence of HSV2 infection of the brain is increasng and may be related to increased frequency of oral sex which can transfer to the mouth a virus normally found in the genitalia. The virus may then find its way to the brain through nerve pathways .
 HERPES ZOSTER
Herpes zoster is caused by the same agent which is responsible for chicken-pox (varicella-zoster virus) and may occur years after the childhood exanthem. In this entity, however, the sensory ganglia of the spinal or cranial nerves are reservoirs fo rthe virus which may become active years after taking up its position in the reservoir. Spread down the axon then results in the vesicular rash and pain in the affected dermatome[s]. In the affected ganglia, a hemorrhagic necrosis and a typical lymphocytic infiltration are found. In a limited number of cases, the infection may encroach upon the central nervous system, causing a transverse myelitis, or more rarely, an encephalitis.
 CYTOMEGALIC INCLUSION DISEASE The causative herpesvirus is present without clinical infection in the majority of adults and may be transmitted transplacentally. In neonates and debilitated persons, it may produce a severe encephalomyelitis. The calcific lesions are usually seen in a periventricular location and typical cytoplasmic inclusion bodies may be present in neurons and glia.
The black material in the image above is calcium deposited in a juxtaventricular zone of necrosis. Sometimes the calcification can be seen radiologically. In AIDS, it may be present as a more fulminant, necrotizing condition (See below).
OTHER VIRAL DISEASES
 RUBELLA AND INTRAUTERINE INFECTION: Intrauterine infection with viruses can affect the fetal nervous system. One effect is microcephally which, along with cataracts and deafness, may result from infection by rubella virus of unimmunized mothers during pregnancy.
 POLIOENCEPHALOMYELITIS: Caused by the polio virus this virus selectively effects the gray matter of cord and brain stem. The selectivity of the virus probably is the result of similarity between molecules on the surface of the virus and "receptors" on the affected neurons. A similar mechanism but with different molecules involved may account for preferential infection of temporal lobe and Purkinje cells by rabies virus. At the beginning of this chapter there is a figure illustrating neuronophagia of neurons in the cord, with accompanying lymphocytic infiltration. That figure comes form a case of polio.
 RABIES (HYDROPHOBIA): Usually rabies is transmitted through bites of rabid dogs, but skunks, raccoons, foxes, bats and other warm blooded animals also transmit the disease. Ten days to one year after inoculation, if rabies vaccine is not administered, flu-like symptoms develop followed by marked agitation, excruciatingly painful spasms of the throat muscles, violent convulsions, coma and death. The only specific findings superimposed on the usual histologic picture of encephalitis are eosinophilic cytoplasmic inclusions (Negri bodies) within neurons (arrows, image below).Temporal lobe neurons and cerebellar Purkinje cells are frequent sites of attack.
 ARBOVIRUS (EPIDEMIC) ENCEPHALITIS Meningoencephalitis may be produced by a number of viruses but when we think of "encephalitis" we usually call to mind epidemics caused by mosquito and tick borne arboviruses. The predominant animal reservoir consists of birds. The clinical picture includes fever, headache, stiff neck, and lethargy which may proceed to coma and death.
There are several types of arboviruses which produce meningoencephalitis but in this country the predominant ones are those of western equine, eastern equine, and St. Louis encephalitis. Of these eastern equine encephalitis is the most lethal, but fortunately, the least often seen. More recently of course we have the West Nile virus which may turn out to be the most common cause of encephalitis produced by viruses in this country.
ROCKY MOUNTAIN SPOTTED FEVER AND TYPHUS--These are rickettsial diseases that are borne respectively by ticks and lice. Rocky Mountain spotted fever is common not only in the western but also the eastern United States, including Virginia, while typhus is rarely seen in this country.Following the severe headache, myalgia, and skin rash that are seen early in these diseases, some patients develop symptoms and signs of encephalitis. Histologically, the picture is similar to that of viral encephalitis. However, in rickettsial encephalitis, the glial nodules [ "typhus nodules"] mentioned earlier may also be present. These are nodules of microglia often clustered around capillaries with swollen endothelium (image below). The typhus nodule may also appear as a clump of microglia without a central capillary.
Slow virus encephalitides are produced by viruses that reside in the body for long periods of time before attacking the nervous system. Also, their clinical course is somewhat slow (subacute). Moreover, they produce varied patterns of destruction in the CNS that are atypical of most viral encephalitides.
 SUBACUTE SCLEROSING PANENCEPHALITIS [SSPE]: This condition is a result of infection with measles. Both gray and white matter are affected by lymphocytic inflammation and destruction of tissue. Clinical signs may begin months after infection. The responsible agent has been called a "modified" measles virus. It is of interest to note that in routine measles there is a high incidence of encephalitis, either clinical or subclinical. The relationship of this to SSPE is uncertain.
 PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY [PML]: This disease may or may not be a slow viral disease--we really do not know because we are not sure when the virus actually entered the CNS of affected people. Usually the disease affects persons with compromised immune status, including AIDS victims. Many of the earliest reported cases were in "alcoholics". These were reported before AIDS was recognized. We might speculate that such persons were really among the earliest AIDS victims and were not recognized as such or we may suggest simply that some alcoholics have compromised immune systems. The lesions of PML characteristically show infected oligoglia at the margins of destructive lesions in white matter [white=leuko]. These infected oligos have dense and often greatly enlarged nuclei [also dense] which contain the papova virus which can be visualized by electron microscopy. There may also be bizarre astroctyes which may even look malignant but in fact are not. The causative agent is the JC virus, a papovavirus [has nothing to do with Jakob Creuzfeldt disease].
 AIDS: Should we call this a "slow viral" disease when the brain is affected ? Again we do not know precisely when the virus enters the brain so we cannot state with certainty what the incubation period is. Clinical findings are diverse but can include dementia. The histologic hallmark is a multinucleate giant cell that appears form from histiocytes or microglia and may be the only histological manifestation of infection. It is believed that the infected cells enter as monocytes from the blood stream. The basis of neuronal dysfunction is a subject of current dispute. Many workers have failed but some have succeeded in demonstrating viral infection of neurons. Those who fail suggest that neuronal dysfunction and death is due to cytokines released from infected monocytes.
Investigation of these diseases has thus far led to two Nobel prizes.The first prize was given for the discovery that this new kind of disease existed in humans and animals. The second prize, given decades later, was for the discovery that these diseases are caused by a potentially transmissible agent which is neither virus, bacteria or rickettsia and which contains no nucleic acid.
These diseases produce a variety of symptoms reflecting involvement of cerebrum [e.g. dementia in Jakob Creuzfeldt disease], spinal cord [e.g. Gerstmann-Strassler disease], or certain portions of the cerebrum [familial fatal insomnia]. PRIONS are polypeptides [i.e. proteins]. They are abnormally folded forms of a prion protein that occurs normally spans cell membranes. The normal function of the protein is unknown. The abnormal folding results in beta pleated sheets hence the abnormal prion has tinctorial properties of amyloid. Abnormal folding is encouraged by genetic alterations--polymorphisms--on the gene for the normal prion protein. Such changes account for familial cases of prion diseases. Abnormal folding may also arise from a spontaneous "stochastic" event-- an extremely rare occurrence which may account for sporadic--i.e.. non familial cases. Cannibalism in New Guinea explains the transmission from person to person of the first prion disease--Kuru--to be recognized in humans. Prion diseases may also be iatrogenic as when unidentified cases of Creuzfeldt-Jacob disease are transmitted from contaminated electrodes placed in the recipients brain, or by corneal or dural transplants or pituitary hormone obtained from infected hosts.So-called "mad cow disease" is really a variant of Creuzfeldt-Jacob. It is caused by an abnormal prion that causes disease in cows. This prion was transmitted from cows to humans via the food chain [meat] . Normally there is a "species barrier" which prevents prions causing disease in one species from causing disease in another species. Mad-cow [Variant Jakob Creuzfeldt Disease] is a rare example of crossing the species barrier.Thus far it has been restricted to humans with a particular polymorphism of the prion gene. This polymorphism apparently increases susceptibility to the binding of the foreign prion to the normal prion of the new host, thus resulting in the cascading increase of abnormal prions in that host..
The abnormally folded prion protein acts as a template converting the hosts normal prion proteins to the abnormally folded form. Once abnormal folding has occurred the abnormal prion attaches to a normal prion by an unknown mechanism and causes it to take up the abnormal configuration. Each newly folded, abnormal form in turn may cause its neighbors to fold abnormally in an ever widening cascade. The abnormally folded forms are resistant to digestion by proteases and hence are sometimes denoted with the superscript "pr" standing for "protease resistant". The accumulation of many abnormal prions in the tissue then causes neuronal death also by an unknown mechanism.
In addition to Kuru there are several other human diseases caused by prions. These include--Creutzfeldt-Jakob disease, Gerstmann--Straussler--Sheinker disease and fatal familial insomnia. The distribution of the lesions with the CNS is different in each disease. This difference in localization of the disease appears to be related to the sites at which the abnormal prion accumulates. Prion peptides [proteins] are glycosylated and the sites of glycosylation appears to differ from "strain" to strain of the prion. The glycosylated prions act as if the host tissue contains receptors which preferentially bind one prion strain or another. Thus the glycosylation pattern appears to determine where in the CNS the prions tend to accumulate.
.Although neuronal death is the ultimate outcome of the disease it is usually diagnosed in histologic sections because it produces small vacuoles resulting in a spongiform appearance. Hence Jakob Creuzfeldt disease is sometime called a spongiform encephalopathy.The vacuoles may occur in grape-like clusters. In light microcscopy they appear to be extracellular, although they often appear to be indenting neurons. This is a clue to the fact that they are, in fact, intracellular as shown by electron microscopy. They frequently involve dendritic cytoplasm. In addition to spongiform changes--whose existence and distribution is variable from case to case and from one type of prion disease to another-there is also astrocytosis. Thus the ideal trio of findings for diagnostic purposes would by spongiform change, astrocytosis and neuronal loss. The loss of neurons is the most difficult of the three findings to identify except in severe cases. In the figure below the upper left panel shows the spongiform change characteristic of many prion diseases including Jacob Creuzfeldt. The pericellular holes may be artifact but the grape like clusters of holes are real. In the upper right panel the arrows point to "kuru plaques". These are round masses that stain like an amyloid and are, in fact, masses of prions. Such plaques, especially in the cerebellum as seen here, are found in Kuru and in variant JC [mad cow disease]. They are unusual in ordinary JC. The lower panel show the masses of prion stained with relevant antibody.
Although it is transmissible, prion disease is not infectious in the usual sense. Transmission must involve puncture of the host and usually this means direct penetration of the brain or of its extension, the eye. Ingestion is another means of transfer however only a small proportion of monkeys, fed infected brains, developed the disease. This resistance might account for the failure of much greater numbers of persons in England to get the variant JC disease, since approximately 50% have the polymorphism which conveys susceptibility. There are no definite cases of transfer by needle puncture and the incidence of JC in health care workers is not higher than that in the rest of the population. The prion is not killed by formalin but is killed by formic acid and by bleach. Alzheimer's disease is the usual alternative diagnose for demented persons in whom JC was "suspected". However the duration of JC is usually less than two years and you should be very skeptical of any suggestions by clinicians concerning the probability of JC disease if the duration of illness exceeded 2 years.