Download Slow Viral Infections of the Nervous System

Review Article
Slow Viral Infections of the Nervous System *
Richard T. Johnson M.D.
The term "slow infection" was coined originally
in the veterinary literature to describe several trans­
missible diseases of sheep. 1 Two of these diseases,
scrapie and visna, have become the prototypes of
slow infection of the central nervous system (CNS).
After inoculation of sheep with tissues from an in­
fected sheep, a latent period of one or more years
ensues, during which the sheep appears well. This is
followed by the insidious onset of neurological signs
that progress without fever for one to six months and
usually lead to death. Scrapie is characterized prima­
rily by ataxia, and visna by progressive paralysis.
Pathologically, the diseases are quite distinct.
The lesions in scrapie are confined to the CNS, where
there is a proliferation of astrocytes and degeneration
of neurons with cytoplasmic vacuolization.
By
contrast, the CNS lesions of visna are characterized
by inflammation and demyelination. The agents re­
sponsible for these two slow infections also differ
greatly. The scrapie agent has been transmitted to a
wide variety of other animals, but the agent does not
cause cytopathic changes in cell culture, and no virus
particles have been definitely identified in infectious
tissues by electron microscopy. Infectivity of tissue
is remarkably stable upon exposure to physical and
chemical treatments that inactivate classic viruses.
Finally, animals naturally or experimentally infected
with scrapie fail to develop any evidence of an im­
mune response against the agent. 2 Recently a pro­
tein has been associated with infectivity, and a fibril
that could represent the infectious agent has been
identified by electron microscopy. 3,4 In contrast,
visna virus is an enveloped RNA retrovirus. Although
the agent can be transmitted only to sheep, it can be
grown in cell cultures of a varietyof species in which
it causes acute cytopathic changes. Furthermore, in
The Johns Hopkins University Schoolof Medicine, Baltimore,
land 21205, U.S.A.
"Based on a lecture presented at Siriraj Hospital, May 17. 1984.
naturally and experimentally infected sheep, there are
both a humoral and a cell-mediated immune response,
which develop and persist throughout the evolution
of pathological lesions and clinical disease S (Table
1).
During the past 15 years, five chronic human
neurological diseases have been demonstrated to be
slow infections. Two of these, Kuru and Creutzfeldt­
Jakob disease, resemble scrapie pathologically, and
the agents of these diseases have properties similar to
those described for the scrapie agent. The remaining
three diseases, subacute sclerosing panencephalitis,
progressive rubella panencephalitis and progressive
multifocal leukoencephalopathy, resemble visna in
being due to classic viruses capable under specific cir­
cumstances of producing a chronic inflammatory
and/or demyelinating disease in the human CNS.6
Kuru
Kuru is a degenerative disease of the brain limit­
ed to the remote Fore tribal people of the mountains
of eastern New Guinea. Originally described only 25
years ago by Gajdusek and Zigas,' this was the first
human disease demonstrated to be a slow infection.
The disease was most common among adult women,
less common in children (but of equal frequency
among boys and girls), and least common in adult
males.
The disease follows a stereotyped pattern, be­
ginning insidiously with truncal titubations and ataxia
in an otherwise healthy person. The ataxis becomes
progressively more severe until the slightest voluntary
motion leads to violent, uncontrolled, ataxic move­
ments. Late in the course of disease, abnormalities
of extraocular movement and mentation develop.
The disease invariably leads to death in three to 20
months.
During its course, the patient remains
The
spinal fluid shows no abnormality,
afebrile.
Mary­
Pathological changes are confined to the CNS and
consist of an increase of astrocytes and degeneration
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Table 1 The Prototype Slow Infections of Sheep
Saapie
Distribution
Clinical features
Incubation period
Natural
Experimental
Onset
Prominent signs
Course
Cerebrospinal fluid findings
Pathology
Neuropathology
Extraneural
Virus
Host range
Animal
Cell cultures
Immune response
Vma
Worldwide
Classic disease limited to Iceland; other forms
probably worldwide
2 to 7 years
I to 7 years
Insidious, afebrile onset of
neurologic signs
Ataxia
Relentless progression over I to 6
months
2 to 7 years
2 to 5 years
Insidious, afebrile onset of neurologic signs
Paralysis
Progressive or intermittent course of many
months
Normal
Chronic pleocytosis, elevated protein and IgG
Localized to gray matter, with
spongiform changes and no
inflarnmation
None
Localized to white matter, with inflammation
and demyelination
?
Often interstitial pneumonia
RNA retrovirus
Sheep, goat, mice, hamster,
primates, and many others
None
None
Only sheep
Sheep, goat, bovine, and other cells
Humoral and cell-mediated immune responses
Modified fromjohnson,6 p.238.
of vacuolated neurons with a total lack of inflamma­
tion.
Because of the similarities in epidemiology, cli­
nical course and pathology between scrapie and kuru,
brain tissue from patients dying of kuru was inoculat­
ed into primates for long-term observation. After an
incubation period of 18 months to four years, a simi­
lar disease developed in chimpanzees. This disease
subsequently has been transmitted from chimpanzee
to chimpanzee and to several other species. The
agent can be transmitted with serial dilutions, proving
that it replicates within the host. As with scrapie,
however, the agent has not been seen by electron
microscopy, does not induce cytopathic changes in
cell cultures, is resistant to many physical and chemi­
cal treatments that usually inactivate viruses, and fails
to evoke a demonstrable immune response in man or
experimental host,"
Although kuru was the commonest cause of
death in the Fore tribe in the late 1950s and early
1960s, its incidence then declined, particularly among
children, in whom it has now disappeared. This decli­
ning incidence coincided with the suppression of can­
nibalism in this primitive culture, and circumstantial
evidence strongly indicates that kuru was transmitted
in the practice of ritual cannibalism,"
Creutzfeldt.Jakob disease
Creutzfeldt-Jakob disease is a presenile dementia
characterized by rapid mental deterioration, myoclo­
nic jerking and other inconstant neurological signs.
The incidence of the disease is approximately one per
million per year. In contrast to kuru, this is a world­
wide disease of apparently uniform distribution. For
approximately 10 to 15 per cent of patients, how­
ever, the disease occurs in families with pedigrees that
suggest autosomal dominant inheritance,"
Dementia develops rapidly; dissolution of in­
tellect can be seen from week to week leading to
severe dementia within six months of onset. Demon­
tia is associated with a variety of abnormal signs. The
most characteristic and constant is myoclonus, which
often is stimulus-sensitive. In addition, blindness,
amyotrophy, ataxia, chorea, athetosis, and pyramidal
tract signs can be seen with variable frequency.l" The
patient remains afebrile, and the cerebrospinal fluid
shows no abnormality. The electroencephalogram
becomes abnormal early in the disease and may show
a characteristic pattern of diffuse slowing with supe­
rimposed bursts or sharp waves. Eighty per cent of
the patients die within 12 months of onset, although
some linger for up to eight years. Pathologically,
J Infect Dis Antimicrob Agents
changes are limited to the nervous system and re­
semble those seen in scrapie and kuru but with greater
involvement 'of the cerebral cortex and less of the
cerebellum.
Despite the fact that in clinical and epidemiolo­
gical features Creutzfeldt-Jakob disease differs from
the other spongiform encephalopathies, the similar
pathological findings stimulated experiments to trans­
mit the disease to chimpanzees. After an incubation
period of 17 to 71 months, the disease in chimpan­
zees simulates the disease in man," Studies of the
nature of the agent again show the same unusual fea­
tures found in Scrapie and kuru, and the same small
fibril found in scrapie has been identified by electron
microscopy. 3
The mode of spread of the disease is unknown,
but that it can be transmitted with tissues of familial
cases suggests the importance of genetic factors or the
possible vertical transmission of the agent. The
failure to find increased incidence in medical person­
nel, laboratory investigators or spouses of patients
suggests a lack of significant communicability. On
the other hand, person-to-person transmission has
occurred. One patient developed the disease 18
months after a corneal transplant from another pa­
tient who was proven to have it; the disease develop­
ed in two young patients less than two years after
cerebral corticography using the same electrodes pre­
viously used in a patient with Creutzfeldt-Jakob dis­
ease; and the illness may be more frequent within two
years after neurosurgical procedures."
Subacute sclerosing panencephalitis
This disease, also described in the literature as
subacute inclusion encephalitis, nodular panencepha­
litis and subacute sclerosing leukoencephalitis, is a
rare, late complication of measles virus infection.
The disease has an incidence of about one per million
children per year. It has been reported between the
ages of 2 and 32 with an average age of onset of
seven to eight years. Males are affected three times
more often than females, and there is a curiously high
preponderance among males of rural origins.
The temporal course of the disease is variable,
but it commonly progresses through three stereo­
typed stages. The onset usually is insidious, with be­
havioral problems and decline in school performance.
Over weeks to months, dementia becomes evident.
The second stage of the disease is characterized by
disturbed motor function, particularly the develop­
ment of myoclonic jerks. Seizures occur in some pa­
tients, and retinopathy, 0 ptic atrophy, cerebellar
ataxia and dystonia may develop. In the third stage,
the child lapses into a stuporous, rigid state with
autonomic instability. In the typical patient, the
course is ingravescent with death in one to three
years. In approximately 10 per cent the disease leads
Vol. 1 No.2 Apr. ~ Jun. 1984
87
to death in three months; in another 10 per cent
there may be protracted survival for 4 to 10 years.
Particularly in this latter group, prolonged periods of
stabilization and transient periods of objective im­
provement can be seen. Fever and headache are not
present. The cerebrospinal fluid, although usually
acellular, shows an elevation of IgG with oligoclonal
bands demonstrating its limited heterogeneity.
Serum and spinal fluid antibody titers to measles are
high and with a distorted ratio that indicates local
synthesis of antibody within the eNS. The electroen­
cephalogram may show a characteristic pattern of
periodic synchronous bursts of high-voltage slow and
sharp waves,"
Pathological abnormalities are seen in both gray
and white matter. There is a mild leptomeningitis,
and small cuffs of lymphocytes and plasma cells are
found around cerebral vessels. Gliosis is present with
varying degrees of demyelination, and eosinophilic
intranuclear inclusion bodies are found in both glial
cells and neurons. Because of these inclusions, a her­
pesvirus was long suspected. Electron microscopic
studies of cerebral biopsies, however, showed the in­
clusions were composed of particles resembling the
nucleocapsids of paramyxoviruses, and immunofluo­
rescent staining revealed the presence of measles virus
antigen. Nevertheless, the isolation of measles virus
from the brains of patients with subacute sclerosing
panencephalitis requires the establishment of cell
cultures from brains of patients with the disease and
subsequent co-cultivation with other cells. Both in
the brains of the patients with the disease and in the
cultures, there is a paucity or absence of the matrix
(M) protein, a protein necessary for the enveloping
and maturation of measles virus." Whether this re­
presents a defective replication of measles virus in the
neural cells or a mutation of measles virus permitting
persistence is unclear, but cell culture studies suggest
the defect may represent defective translation." Al­
though there is no treatment for the disease, prophy­
lactic use of measles vaccine causes a tenfold decrease
in the development of subacute sclerosing panencep­
halitis."
Progressive rubella panencephalitis
Recently, a similar slow progressive panencepha­
litis has been associated with rubella virus. This is an
extremely rare disease; only 10 cases have been
described. Seven bore the stigmata of congenital
rubella and three apparently followed acquired rubel­
la. All patients have been male.
The children develop normally within limits of
static congenital defects until eight to 19 years of age
when deterioration of schoolwork and behavior
signals an insidious onset of intellectual deterioration
similar to the early stage of subacute sclerosing
panencephalitis. Ataxia is the most frequent and pro­
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minent neurological sign. Spasticity and dysarthria
develop late. Some patients have myoclonus; optic
atrophy and retinopathy also are seen. Headache
and fever are absent. Cerebrospinal fluid in most
cases shows some increase in mononuclear cells with
protein elevation and a striking elevation of IgG that
largely represents antibody against rubella virus
synthesized within the CNS.16
The pathology is quite distinct from that of sub­
acute sclerosing panencephalitis. Similar inflamma­
tion of meninges and perivascular spaces with variable
degrees of demyelination occurs, but inclusion bodies
are absent. In contrast, perivascular PAS positive
material is prominent, indicating mineralization simi­
lar to that seen in congenital rubella encephalitis.
This finding suggests the deposition of immune com­
plexes, and immune complexes containing rubella
virus have been found in high titers in serum and
occasionally in spinal fluid of these patients," How
this infection remains quiescent for many years, and
then becomes active and causes lesions localized in
the CNS, remains unknown. No cases have been re­
lated to the rubella virus vaccine, but data are insuffi­
cient to exonerate the vaccine virus definitely.
Progressive multifocalleukoencephalopathy
Progressive multifocal leukoencephalopathy is a
subacute demyelinating disease that usually develops
in patients with preexisting disorders of the reticu­
loendothelial system such as leukemia, lymphoma or
sarcoidosis. It can occur in patients who have been
immunosuppressed therapeutically or after organ
transplantation, and has been observed in children
with primary immunodeficiencies." Recently the dis­
ease has been seen with great frequency in patients
with the acquired immunodeficiency syndrome."
The neurological disease can occur at any time
during the course of the underlying disease. Onset
usually is insidious, with signs and symptoms suggest­
ing multifocal disease. Paralysis, mental deteriora­
tion, visual loss and sensory abnormalities are com­
mon. Ataxia is less common, as are focal signs of
brainstem or spinal cord involvement. Patients re­
main afebrile and headaches are infrequent. The dis­
ease usually follows a progressive course to death in
three to six months. Cerebrospinal fluid generally is
normal, with no pleocytosis and no elevation of pro­
tein content. Computerized axial tomography may
show multiple radiolucent areas in the white matter,
A definite diagnosis can only be made pathologically.
There are obvious areas of demyelination of varying
size, most prominent in the subcortical white matter.
Histologically, these foci show a relative sparing of
axons with loss of oligodendrocytes and myelin. Oli­
godendrocytes surrounding the foci are enlarged with
large intranuclear inclusion bodies.
Within' the
demyelinated foci, astrocytes are enlarged, often are
bizarre and contain mitotic figures. Inflammatory
cells usually are not prominent."
The presence of inclusion bodies and their
occurrence against a background of disorders associat­
ed with impaired immunologic responses led to the
initial speculation that the disease might be caused by
an opportunistic viral infection. Electron microsco­
pic examination in almost all cases has shown parti­
cles in the oligodendrocyte inclusions resembling
small papovaviruses." In the majority of cases, the
virus has proved to be a human papovavirus called JC
ViruS. 18,21 This virus subsequently has been found to
be a common infectious agent in man, with most peo­
ple acquiring antibody in childhood. It has not been
associated with any other disease, however. Whether
this disease represents a primary infection of an im­
munologically compromised patient or reactivation of
a latent or persistent papovavirus infection remains
unknown.
Other chronic neurological diseases
Since viruses can cause disease after a long in­
cubation period, can cause disease with a subacute or
relapsing course, and can give rise to noninflammato­
ry pathological changes, a possible role of slow infec­
tions has been entertained for a variety of chronic
neurological diseases. Some cases of chronic focal
epilepsy in the Soviet Union have been related to per­
sistent tick-borne virus infections following acute en­
cephalitis; but this has not been shown in chronic
focal encephalitis occurring in other geographic
areas," Because of the noninflammatory degeneration
seen in spongiform encephalopathies, a possible viral
etiology for amyotrophic lateral sclerosis also has
been suspected, as it has been in Parkinson's disease
and other forms of subacute dementia. Even greater
speculation has occurred about the possibility of a
viral cause of multiple sclerosis. Although there is no
definitive evidence to incriminate a specific virus, the
epidemiological evidence indicates that multiple
sclerosis follows an early life exposure, and serologi­
cal data show abnormal immune responses to viral
antigens,"
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