VIROLOGY - CHAPTER TWENTY THREE
SLOW VIRUS DISEASES OF THE NERVOUS SYSTEM
Dr Margaret Hunt
Department of Pathology, Microbiology and Immunology
University of South Carolina School of Medicine
Let us know what you think
Edited and illustrated by Dr Richard Hunt
to subacute/chronic diseases of the central nervous system.
unconventional agents associated with subacute diseases of the central
The term "Slow virus infections"
to the tempo of the DISEASE, not to the growth rate of the virus. These 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 manifestations. Different patients may present with very different
Brain in progressive multifocal leucoencephalopathy
Brain in progressive multifocal leucoencephalopathy ©
Bristol Biomedical Image Archive. Used with permission
This is a rare, progressive, fatal,
demyelinating disease of the CNS that kills oligodendrocytes (figure 1 and 2). 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. However, not all
HIV-positive PML patients show an obvious response to HAART with respect to PML.
PML may be due to reactivation of a JC virus latent infection, probably in
the kidney. There is also abundant virus in brain.
Another polyoma virus, BK
virus, can establish a latent infection in the kidney and under conditions
of immune suppression be reactivated and may cause severe urinary tract
infections. It is not associated with PML. There has been a
suggestion (2006) that BK virus might play a role in prostate cancer.
Subacute sclerosing panencephalitis
This disease is a rare complication of measles virus
infection and develops approximately 1 to 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 an 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 is a very rare consequence of rubella
virus infection and also results in mental and motor deterioration. The initial infection
congenital or soon after birth and the onset of PRP occurs at 8 to 19 years of age.
The course of the disease may
extend over many years.
Other slow virus infections
Human immunodeficiency virus and
AIDS. See HIV/AIDS section
UNCONVENTIONAL VIRUSES OR AGENTS:
Comparison of the properties of conventional viruses and 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 other ways, however, they are rather different from
viruses; for example, 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 (figure 3 and 4).
Properties of unconventional viruses
Transmissible spongiform encephalopathies
Spongiform change in CJD consists of numerous rounded vacuoles within the neuropil which occur both singly and in confluent groups, distorting the cortical
cytoarchitecture. © The UK Creutzfeldt-Jakob Disease Surveillance Unit
These unconventional viruses or
agents are often called 'prions'
- since protein is present in purified preparations of infectious
material and treatments that destroy protein destroy infectivity. In contrast, treatments
that destroy nucleic acids do not destroy infectivity. This protein is
known as PrP (prion protein). The question as to whether nucleic
acids are part of these agents is still controversial; many people think that
the infectious material is protein only.
cause diseases that 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
can cause formation of fibrillar aggregates, which contain PrP
and have amyloid-like characteristics
Diseases caused by these
spongiform encephalopathies (figure 5)) 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. They may be acquired,
inherited, or occur sporadically.
Scrapie is a disease of sheep. It
results in behavioral
changes, progresses to tremor, ataxia (failure of muscle coordination), wasting and death. It is a transmissible
BSE, otherwise known as mad cow disease is a prion-caused disease
that results in progressive neurological degeneration in cattle. The first
cases were identified in 1986 in the United Kingdom with infections probably
having occurred in the 1970’s. Transmission probably occurred as a result of
feeding cows with meat and bone meal from other BSE-infected cows (an
infection that might have arisen spontaneously) or with meat and bone from
Scrapie-infected sheep. Control of the disease has resulted from banning
BSE peaked in the United Kingdom in 1992 when new cases were being reported
at more than 1,000 per week but because of control measures, the rate of new
infections has fallen to 1 to 2 per year.
In North America, there have been 24 cases of BSE (through February 2015) of
which 20 have been in Canada
Kuru Information Page
Creutzfeldt-Jakob Disease Fact Sheet
Prion protein immunostaining showing amyloid plaques.
© The UK Creutzfeldt-Jakob Disease Surveillance Unit
Kuru is a disease of man. It causes
tremors and ataxia
and often, in later stages, 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. In the United States, there are 1 to
2 cases per million
population per annum but cases may go undiagnosed. The disease can be transmitted to animals in the laboratory.
Although the disease have been observed to develop at ages 16 to 80+ years, it is
usually seen at 50 to 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)
A new form of CJD was reported in
the United Kingdom, in patients who were usually younger (frequently under 40;
average age at death: 28 years) than is the case for most CJD patients (average age of death: 68 years) (figure 8A). This disease
was also different from the
usual CJD in that patients tended to present with psychiatric problems and in that
the course of the disease tended to be more protracted. This disease is known as
variant Creutzfeldt-Jakob disease or vCJD.
vCJD patients may eventually
show any or all of the symptoms described above for other human prion diseases 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 (figure 7 and 9) than in typical CJD cases.
As of 2014, there have been over
220 cases of vCJD reported around the world. 177 people have
been reported with vCJD in the UK, all of whom have died (figure 8b), 27 in France, 4 in Ireland,
the United States and 1
each in Canada, Japan, Portugal, Spain and the Netherlands (the people
from Canada, Japan and the US were probably exposed while living in the UK). The
peak year of the UK epidemic was 2000 when there were 27 people diagnosed with
vCJD and 28 deaths from the disease.
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.
Further peaks are possible in different genetic groups but there has, so far,
been no evidence of another wave of vCJD. 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 in the United Kingdom. In
both cases, the blood had not been leuko-depleted; it is thought leuko-depletion
might decrease the chances of transmission by blood transfusion.
Age Distribution of CJD in UK: CJD and vCJD 1994-2001 USDA
Number of deaths due to CJD in UK 1990-2003
Medulla of the BSE affected cow: Vacuoles are seen in one neuron and in the
neuropiles. Astrocytes with small
nucleus proliferate. No inflammatory cells infiltrae in the brain. Left x100, Right x200
Dr. M. KUBO NIAH, Japan
Immunocytochemistry for PrP in the cerebellum shows strong staining of a
kuru- type plaque (centre) with multiple smaller plaques in the granular layer and abundant pericellular deposition in the molecular layer
© The UK Creutzfeldt-Jakob Disease Surveillance Unit/The
Immunocytochemistry for PrP in the thalamus shows several large multicentric plaques
(centre) with perivacuolar and synaptic deposition in
the surrounding neuropil ©
The UK Creutzfeldt-Jakob Disease Surveillance Unit/The Lancet
syndrome (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
Fatal Familial Insomnia 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
transmitted to animals in
the laboratory. In this form of the disease, it seems that hypothalamus function may be
the initial target.
Preparations of highly purified
infectious material contain large amounts PrP (figure
9 and 10). 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 form to the resistant form; 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 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
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
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.
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 that
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.
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, MRI can be useful in diagnosis. A positive diagnosis can sometimes
be made due to the presence of PrPSC in peripheral lymphoid tissue;
for example, tonsil biopsies have been used. It is possible to 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.
The prion protein PrP (encoded by a cellular gene
and made in normal cells) can exist in two forms. In diseased tissue the
protease-resistant form (PrPsc) with a lot of beta-pleated
sheet accumulates as 'amyloid plaques'
Simplified model for prion disease.
PrPsc, the protease-resistant
form of the molecule, acts as a 'template'. It associates with the helical form
allowing the latter to be converted to the beta-pleated sheet resistant form
(presumably by lowering the energy barriers that normally prevent this
happening). There are now two molecules of the resistant form that can act as a
template and so the process accelerates
How can this model explain the sporadic, acquired or inherited form of the
disease? The conversion from the alpha helical to the beta-sheet form may occur
spontaneously, though very rarely (sporadic). The conversion
may be catalyzed by PrPsc that comes from some
exogenous source (acquired). Germ line mutations may make spontaneous
conversion more likely (inherited). Somatic mutations may make
spontaneous conversion more likely (sporadic). In this case, the mutant
form could start the process of conversion and the resulting PrPsc
molecules would then convert the normal form from surrounding cells
Why are there differences in prion diseases? There may be subtle differences in
the protease-resistant form (PrPsc) of the prion protein according to
the source of the PrPsc or the mutation
involved. As indicated in the figure, the two related but subtly different
forms of PrPsc convert the normal form to
their own conformation. Thus, the final PrPsc product
that accumulates depends on the form that initiated the process
This explanation may also be applied to the inherited
forms. Different mutations may predispose the PrPsc
adopt slightly different protease-resistant forms spontaneously
TRANSMISSIBLE ENCEPHALOPATHIES AND
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 etc. Amyloid refers to the staining properties, and many glycosylated
protein aggregates can have similar staining properties.
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. Understanding the nature of the pathogenesis of
prions may help understanding of other CNS diseases.
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