Slow Virus Diseases of the Nervous System

Guest · **posting in usmle forum about Microbiology**

The term "Slow virus infections" refers to the tempo of the DISEASE, not to the growth rate of the virus. Such diseases have a prolonged incubation period (which can be months or years), and a protracted, progressive clinical course.

Slow virus diseases may be caused by conventional viruses or by the unconventional viruses (also known as the unconventional agents or atypical viruses/agents).

The symptoms associated with slow viral/prion diseases of the central nervous system tend to have multiple neurological symptoms and different patients may present with different symptoms.

CONVENTIONAL VIRUSES

Progressive multifocal leukoencephalopathy (PML)

This is a rare, progressive, fatal, demyelinating disease of the CNS which kills oligodendrocytes. It results in memory loss, loss of co-ordination, mentation problems, vision problems, etc.

The disease is caused by certain members of the polyomavirus family, usually JC virus. Serology shows that exposure to JC virus is common, but PML is rare. Patients who develop PML frequently have some abnormality of the immune system. PML develops in up to 5% of patients with AIDS. In AIDS, HAART treatment may be able to stabilize at least some of these patients and their neuroradiological picture may even improve.

PML usually develops in middle age - probably as a result of reactivation of a latent infection. In the disease state there is abundant virus in brain.

Subacute sclerosing panencephalitis (SSPE)

This disease is a rare complication of measles virus infection and develops approximately 1-10 years after the initial infection. It is progressive and fatal and is characterized by mental and motor deterioration. Risk factors include acquiring primary measles at early age.

SSPE is associated with defective forms of the virus in the brain and so it is difficult to isolate infectious virus from patients. Incidence has decreased since the introduction of anti-measles vaccination.

Progressive rubella panencephalitis (PRP):

PRP is a very rare consequence of rubella virus infection and also results in mental and motor deterioration. The initial infection was usually congenital or soon after birth and the onset of PRP occurs at 8-19 years of age. The course of the disease may extend over many years.

UNCONVENTIONAL VIRUSES OR AGENTS:
PRIONS

Some slow diseases of the central nervous system are caused by a group of unusual agents, whose true nature is still controversial. In some ways the agents are like conventional viruses: They are very small, filterable agents that require host cells to grow. They have no capacity for energy generation or protein synthesis.

In some ways, however, they are rather different from viruses for we cannot see any evidence of virus particles in infected tissues or purified preparations of infectious material. No-one has been able to prove that these agents contain nucleic acid. If they contain nucleic acid, it is likely that it is very small and has very little coding capacity. These agents have an unusual resistance to treatments commonly used to inactivate viruses

These unconventional viruses or agents are often called 'prions' - since protein is present in purified preparations of infectious material and treatments which destroy protein destroy infectivity but treatments which destroy nucleic acids do not destroy infectivity.

The question as to whether nucleic acids are part of these agents is still controversial.

These agents:

cause diseases which are confined to the CNS

have a prolonged incubation period

show a slow, progressive, fatal course of disease

show a spongiform encephalopathy

characteristically result in vacuolation of neurons

Diseases caused by these agents (transmissible spongiform encephalopathies) are relatively rare in man, but there is speculation that they may be more common than previously thought and they may have implications in the study of other CNS degenerative diseases

Scrapie

Scrapie is a disease of sheep. It results in behavioral changes, progresses to tremor, ataxia, wasting and death. It is a transmissible disease.

Kuru

Kuru is a disease of man. It causes tremors and ataxia (failure of muscle coordination) and, in later stages, often dementia. It is transmitted by rites for the dead which included autopsy and cannibalism in Fore people in Papua/New Guinea. No-one born since these practices ceased has acquired Kuru. There is no evidence for transmission to fetus, transmission via milk or intimate social contact.

Creutzfeldt-Jakob disease (CJD)

CJD is a disease of man resulting in dementia and also often tremors and lack of motor co-ordination. There are 1-3 cases per million population per annum. The disease can be transmitted to animals in the laboratory. Although the disease have been observed to develop at ages 16-80+ years, it is usually seen at 50-70 years of age. 10% of cases are familial suggesting that a gene apparently makes the individual more likely to develop CJD.

The usual means of transmission is not known but most cases are sporadic and there is no evidence for direct person-person transmission. CJD can be transmitted by medical manipulations: cornea transplants, dura mater transplants, use of improperly sterilized equipment in neurosurgery (sterilization procedures have now been changed to prevent this), human cadaver growth hormone administration (recombinant DNA vector is now used to make human growth hormone).

New variant CJD disease (human BSE); nvCJD, vCJD

A form of CJD has been reported in the United Kingdom in patients who are usually younger (frequently under 40) than is the case for most CJD patients (figure 8A). This disease is also different from the usual CJD in that patients tend to present with psychiatric problems and in that the course of the disease tends to be more protracted. Sufferers may eventually show any or all of the symptoms described above for other human prion diseases. The disease was first seen in 1996 and there is strong evidence to suggest that it is associated with exposure to BSE-contaminated beef. Strong BSE control measures have now been implemented. Autopsy reveals a distinctive neuropathological appearance and more PrP (prion protein) amyloid plaque type deposits than in typical CJD cases.

So far 149 people have been reported with vCJD in the UK plus 6 in France and 1 each in Ireland, Italy and the US. We do not know if we are seeing the beginning of a major outbreak or whether these will be the majority of cases of this disease ever seen. There is also concern because there appears to be more infectious agent in the peripheral tissues, especially the lymphoreticular tissue of patients with vCJD than with normal CJD. This raises questions about sterilization of surgical instruments etc. and the possibility of iatrogenic spread. This is also one of the reasons that the United States is concerned and conservative about protecting the blood supply (by screening out those who have spent considerable time in the UK or Europe). There is a possibility that vCJD agents may have been transmitted by blood transfusion in two cases – but this has not been proven.

Gerstmann-Sträussler-Scheinker syndrome [GSS]

GSS is a disease of man and has symptoms that are Kuru-like. It is a familial disease and is often regarded as a genetically transmitted subclass of CJD cases. This disease can be transmitted to laboratory animals.

Fatal Familial Insomnia (FFI)

FFI is a disease of man and results in progressive untreatable insomnia, loss of circadian rhythm, endocrine disorders, motor disorders, dementia. Again it is a familial (inherited) disease that can be transmited to animals in the laboratory. In this form of the disease, it seems that hypothalamus function may be the initial target.

PRION PROTEIN

Preparations of highly purified infectious material contain large amounts PrP. This is coded for by a host cellular gene and is a cell surface glycophospholipidylinositol (GPI)-anchored protein. Its normal function is not known. The infectious form has the same amino acid sequence and the same post-translational modifications as the normal form, but has a different conformation in diseased tissue. The normal form contains a lot of alpha-helix, whereas the disease-associated form contains a lot of beta-pleated sheet. The disease-associated form is known as PrPRES since it is more resistant to protease or as PrPSC since it was first found in scrapie infections.

Why is a protein infectious?

One hypothesis is that the resistant form can convert the normal form to the resistant form, which will then be able to convert more normal to resistant itself, and thus the rate of conversion will gradually amplify as the concentration of resistant form increases. At least some of this conversion appears to occur extracellularly.

Acquired cases

Acquired cases may be due to being infected with the resistant form, which then may convert the person’s normal form to the PrPSC, and the process will gradually amplify as above.

Sporadic cases

Sporadic cases may be due to spontaneous conversion of normal to resistant form, and this process is then amplified as the resistant form recruits more normal form to the resistant form. Sporadic cases may also be due to somatic mutation, which makes the PrP more likely to undergo the spontaneous conversion to the resistant form, or may be acquired by an unknown mechanism.

Familial/hereditary cases

In familial cases, mutations in the PrP gene have been observed. In the inherited form of this disease, the mutated form of the protein might have a greater likelihood of spontaneously changing to the resistant form and then the same recruitment process would occur. For at least some of these mutations, it appears that everyone who gets the mutant gene eventually develops CJD/GSS if they live long enough. The nature of the mutations in the inherited form can affect the clinical course of the disease.

IMMUNE RESPONSE

These unconventional viruses/agents do not cause an inflammatory response. They do not induce interferon. There is no antibody response against these agents. Hence it is not possible to screen people for exposure to these agents by looking for antibodies.

TREATMENT

To date, the prion diseases have been invariably fatal. Classic CJD usually results in death within a few months of the symptoms becoming obvious. The average time from symptoms becoming obvious to death in vCJD is longer - about sixteen months. Due to the poor prognosis for CJD patients, various drugs have been tested for efficacy but, so far, they seem to offer little if any positive effects, and if they were real they were very transient; moreover side effects of these drugs can be very serious.

Another approach has been to make antibodies which inhibit prion formation in mice. Part of the excitement here is because it seems that if one stops further PrPSC formation, cells can actually dispose of the PrPsc which has already formed. This approach has not yet been tried in humans.

One aspect to remember is that if there are drugs which slow progress, even if they do not cure someone with symptoms. They may be of use in the familial forms where they could be given before symptoms develop. This is a very new area in prion disease.

DIAGNOSIS

During life, a probable diagnosis is based on the clinical picture. EEG can provide useful supportive evidence in some cases. The wide range of symptoms and disease course make diagnosis difficult and prion diseases are often misdiagnosed. The final diagnosis is usually made from post-mortem examination of the brain. A brain biopsy can be used. Serology is of no use since the patient does not show an immunological response.

In the case of vCJD, a positive diagnosis can sometimes be made due to the presence of PrPSC in peripheral lymphoid tissue; for example, tonsil biopsies have been used. One can make antibodies to PrPSC by using mice that have had the PrP gene deleted and are therefore not tolerized to the protein. These antibodies can then be used in a Western blot type of assay if enough prion material can be obtained from the patient.

TRANSMISSIBLE ENCEPHALOPATHIES AND OTHER DISEASES

Amyloid plaques are seen in other CNS diseases - but the major components of amyloid plaques seen in, for example, Alzheimer's disease are NOT made of the same material as those seen in Kuru, CJD, GSS. It is possible that the way in which prion diseases interfere with the function of cells in the CNS may pinpoint crucial processes in the CNS whose disturbance leads to progressive degeneration of nervous tissue.