1
The Paradox of Prion Disease
Rosalind M. Ridley and Harry F. Baker
1. introduction
The study of that group of diseases now collectively known as the prion
diseases has always been a source of excitement and argument between scien-
tists. These obscure diseases usually have been of extremely rare occurrence
and have had little impact on the general public. When an epidemic occurs,
however, as in the case of bovme sponglform encephalopathy (BSE) m the
United Kmgdom, the bizarreness of the prion diseases and the profound differ-
ence between them and any other “mfectlous” condition can (and did) lead to
public consternation. Three features of prlon diseases give them an apparently
diabolical quality.
7.1. Their Occurrence Is Largely Unpredictable
1. In
acquired cases there 1s a silent mcubatlon period that can vary from a few
weeks to up to 40 yr, dependmg on the species and the circumstances
2 During the incubation period there are no symptoms and no detectable signs,
e.g., there IS no measurable Immune response that will predict subsequent illness.
3. No mode of transmission could be established for the majority of human cases
that appear to occur “out of the blue.”
1.2. They Exhibit Certain Impossible Properties
In relation to established principles of microbiology, the prion diseases
exhibit certain “impossible” properties.
1 “Infectious” disease seems to arise spontaneously.
2. Inherited cases give rise to a disease that is transmissible but acquired cases do
not produce a heritable disease
From Methods m Molecular Medicrne Prron Dmeases
Edlted by H Baker and R M Rdley Humana Press Inc. Totowa, NJ
1
2

Rciley and Baker
3. Procedures and chemical treatments that specifically destroy nucleic acids (which
all replicatmg organisms possess) do not destroy the mfecttous agent
4 The mfecttous agent can persist m the envtronment almost indetimtely
1.3. They Are Invariably Fatal
1 No treatments have been found that ~111 alter the progression of the disease
2 In animal transmtssion studies, the duratton of symptoms from onset to death can
be as short as a few hours followmg an mcubation period of many months, during
which the animal appears to be completely healthy
These three features have combined to stroke fear into the general publtc,
who regard priori dtseases (perhaps with some justification) as uncontrollable,
mcomprehensible, mdestructable, and incurable. This fear 1s probably only
matched by an excessive dread of radioactivity, which IS similarly imbued with
great “strangeness.” In sharp contrast, the public steadfastly refuses to worry
about “ordmary” factors, such as diet, exercise, and safety, which are known to
have an enormous effect on morbidity.
2. Scientific Investigation
In recent years the screntific investigation of prron diseases has expanded
greatly, leading to strongly held convictions and arguments that have some-
times degenerated into acrimony. Scientists are particularly exercised by the
fact that some accounts of the pathogenesis of prion disease seem to contradict
basic tenets of molecular biology:
1 That proteins are made using information encoded in nucleic acid,
2. That different proteins are encoded by different nucleic acid sequences;
3 That protein synthesis cannot occur without nucleic acid; and
4. That any “agent” that increases m titer must involve rephcatton of nucleic acid.
The central argument has been about “viruses vs genes (or proteins).” As
in other great scientific debates, e.g., “particles vs waves” or “nature vs nur-
ture,” the resolutton of the problem 1s unhkely to be that one vtew is correct
and the other incorrect but that a new way of understanding the phenomenon

allows the dichotomy to dissolve. For many years the body of data on priori
diseases was like a Rubik cube; when one face was intact the others were not.
Thus, rt was easy enough on the basis of experimental transmtssion studies to
make the case for disease being caused by a virus-except that it was not
possible to explain how the majority of cases were “caught.” The transmis-
sible agent appeared to behave like a replicating, infectious agent except
that treatments that destroy nucleic acid did not reduce infectivtty. Further-
more, some human cases clearly were inherited, whereas other cases clearly
were not.
The Paradox of Prion Disease
3
2.1. Misinterpretations
These difficulties m producing a coherent story for prton diseases were com-
pounded by certain mismterpretations of the available evidence.
1 The demonstration of experimental transmissibihty led to the presumption that
all cases were acquired by mfectron.
2 The difficulty in demonstrating contact between cases of human prion disease
led to exaggerated concern about the mfecttousness of the disease. For example,
the apparently higher incidence in cities (probably owmg to sampling and demo-
graphic effects) could be interpreted as meaning that casual contact between
strangers was all that was necessary to transmit disease
3 The not infrequent occurrence of priori disease m another family member of the
proband led to the fear that the disease was transmissible vertically through con-
tamination zn utero or through the incorporation of the agent (perhaps a
retrovnus) m the genome of an acquired case. Where the disease occurred m a
proband and a parent who had been separated for many years the suspicion grew
that transmisston of “agent” had occurred m childhood. Where disease occurred
m a proband and a distant relative who had met for only the briefest of meetings
it was supposed that genetically susceptible people were quite exquisitely vul-
nerable to mfection

4 The transmtssibility of the disease and the apparent rnformatron-carrying prop-
erty of the agent, as demonstrated by the phenomenon of strain of agent m
experimental scrapie, lead to the insistence that failure to find the virus was only
a temporary technical failure rather than evidence that there might not be such an
independent orgamsm m these diseases
The baste phenomenon that the various hypotheses of the etiology of prion
diseases have sought to address 1s experimental transmrsstblltty, and advocates
for each side draw on a number of facts to support then view.
2.2. Evidence in Favor of the Viral Hypothesis
1. The increase m mfectivity titer in brain during disease progression is taken as
evidence of a replicatmg agent
2. No bacteria or other organism can be found so that, by default, the disease is
attributed to a vnus.
3. In experimental transmisston the long incubation period followed by the rapid
course of disease resembles the occurrence of diseases caused by lentivn-uses.
4 Different isolates of priori disease “agent” appear to behave differently in terms
of species specificity, incubation time, and lesion profile on experimental trans-
mtssion to other animals leading to the concept of “strain variation ”
5. The existence of different “strains of agent” is regarded as evidence of an infor-
mattonal, rephcating molecule that is presumed to be composed of nuclerc acrd
6 The familial occurrence of priori disease m humans is explained as a genetic
susceptibility to an infectious agent in the environment.
4
Ridley and Baker
2.3. Evidence in Favor of a Gene (Protein) Hypothesis
8
9
10
11
No vnus particles are associated with infectivity

No immune response to mfectron 1s found m an affected host
No nucleic acid IS associated specifically with infectivity
Infectivity titer is associated with levels of the abnormal isoform of priori protein
known as PrPSC
PrPSC and the normal form of prton protein (PrPc) do not differ m primary struc-
ture, thus negating the need for PrPsc-specific nucleic acid
PrPSC has the primary structure dictated by the PrP gene of the host, thus negating
the need for agent-specific nucleic acid in the production of PrPSC
When priori disease is experimentally transmitted from one species to another the
PrPSC m the recipient has the primary structure of the recipient species, not of the
donor species or agent Agent replication does not, therefore, need to occur for
levels of PrPSC to increase
Most (but not all) of the variation m species specificity, mcubation time, and
lesion profile can be accounted for by variations m the PrP protein of the host and
the homology between that and the PrP protein of the agent (1 e , donor), thus
reducing the variation attributable to “stram of agent ”
Familial prion disease occurs m pedigrees with a mutation m the PrP gene
Transgemc mice carrying mutations m the PrP gene produce a transmissible
spongiform encephalopathy despite being kept m controlled conditions where
accidental contamination with an exogenous agent can be avoided (I)
PrPSC can be reversibly denatured with guamdme-chloride and renatured by
dilutmg out the guamdine chloride If radiolabeled PrPC IS added during the rena-
turation stage, protemase K digestion results m the formation of radiolabeled
proteinase K-resistant fragments of similar size to protemase K-digested PrPSC
from scrapie-affected ammals (2) (and see Caughey et al , this volume) This
suggests that PrPC can be converted directly mto PrPSC by mteraction with other
PrPSC molecules
2.4. Resolution of the Dichotomy
A number of arguments are leading to a resolutton of the dichotomy.
2.4.1. Acquired, Familial, and Sporadic Cases

It is now recognized that cases of prton disease arise m three different
ways-acquired, familial, and sporadic, and that data from one type of case do
not have to be applied to other cases. This resolves the argument between
“mherited” and “acquired” factors in the etiology of different cases
2 4
1 1. ACQUIRED CASES
Acquired cases of prion disease arise because a person or an animal has
ingested or absorbed a quantity of the infectious agent. In humans, the majority
The Paradox of Prion Disease
5
of these acquired cases occurred in Papua New Guinea m the first half of this
century. The disease was known as kuru and spread slowly around various related
ethnic groups of the mdigenous population. Epidemiological analysis imph-
cated funerary practices and the people admitted to cannibalism, especially by
the women and the young children m then care (3). It is now supposed that the
epidemic began with a sporadic case of prion disease. The epidemic has now
almost run its course but the extremely long incubation periods that can occur,
especially following low oral exposure to the agent, means that a few cases
still occur each year.
In the West, prion disease in humans has not been associated with any dietary
practice, but has occurred following the use of human tissue for medical pur-
poses. The largest number of cases (currently approx 100 worldwide) has
resulted from the prolonged use of human pituitary-derived growth hormone.
A few further cases are associated with the use of human dura mater tissue m
reconstructive surgery of the head and a small number of cases have occurred
as a result of contammatron during cornea1 grafting or neurosurgery. In the
latter cases mstruments were used that had previously been used m patients
with priori disease and that probably were still contaminated despite sterihza-
non treatments that were standard at that time. The tissues that have been
implicated m these iatrogemc cases-pituitary gland, dura mater, and cornea-

all come from close to the brain, which is known to have the highest levels of
infectivity.
The largest epidemic of animal priori disease has affected cows m Britam
Bovme spongiform encephalopathy (BSE) was first recogmzed m 1986 and
the number of cases has followed a large distribution with the peak (approx
3500 cases/ma) occurrmg m 1993. The total number of cows affected so far is
approx 150,000 and the epidemic is expected to run beyond the year 2000. The
epidemic is believed to have resulted from changes m the method of rendering
carcasses (including ovine and bovine) for the production of animal food pel-
lets such that the mfectious agent associated with scrapie was not destroyed and
affected the calf population. Subsequently, carcass material from BSE-affected
cattle inevitably would have been incorporated m the calf food pellets, adding
to the infectivity titer of this food preparation. The number of cases occurring
in animals born after the feeding of rummant-derived protein to ruminants was
banned m 1988 has dropped dramatically, mdicatmg that, apart from a possible
very minor level of residual contamination in the system, the epidemic now is
under control. The long incubation period that can occur, however, implies
that there will be several years before the disease is eradicated. In addition to
BSE, the contamination of animal feed has led to a small number of cases of
prion disease m other ammals, notably cats and exotic ungulates, and other
food-related outbreaks have occurred in farmed mink and captive deer
6 Ridley and Baker
2.4.1.2 FAMILIAL CASES
About 15% of cases of human prion disease occur m families where at least
one other family member has been affected and where rt can be established that
a large number of cases have occurred in one family, it can be seen that the
dtsease runs m an autosomal dommant pattern Linkage of disease to a muta-
tion m the PrP gene open reading frame was first estabhshed by Hsrao et al
(4). There are now known to be several point mutations and a number of
expansions m an octapepttde repeat sequence within the PrP gene open readmg

frame (5) that are associated with disease.
2.4 1 3. SPORADIC CASES
Sporadic cases of human prton disease occur, by definition, without any
known antecedent event through which the disease could have been acquired
and without any known family history or mutation m the PrP gene. Some
genetic influence ts now being recognized, however, because most sporadic
cases are homozygous for a common polymorphism in the PrP gene (6)
although, because the disease is exceedingly rare (affecting approx one m a
mullion people worldwtde), the vast majortty of people who share this genetic
feature are not affected.
2 4.1.4. SCRAPIE: ACQUIRED, FAMILIAL, AND SPORADIC CASES
Scrapre in sheep occupres a particularly important position among the prron
diseases because it is a relatively common, naturally occurrmg condition that
shares features of the acquired, inherited, and sporadic ettologtes. It is thought
to be the ortginal source of infection m the BSE epidemic, although this IS
difficult to prove. Persistent efforts to find an eptdemtological or case-con-
trolled association between scrapie and human priori disease, fortunately, have
been unsuccessful.
In the 1960s natural scrapie was reported to occur m a pattern consistent
with autosomal recessive inheritance m at least some breeds of sheep (7). More
recently rt has been shown that m some breeds naturally occurring disease is
linked to polymorphisms m the PrP gene that etther are of partial dommance or
recessive (8), largely vindicating the original observation despite the many
intervening years m whtch the experimental transmisstbility of mouse-adapted
scrapre blinded researchers to the possibrlity that the natural sheep disease
might wholly be genetic. These PrP polymorphisms also are linked to suscep-
tibility to experimental mfection m sheep but it remains unproven whether
linkage to naturally occurrmg disease is because of an influence of the poly-
morphisms on susceptibility to infection m the field or whether the malortty of
naturally occurring cases have a genetic disease, in the absence of any contact

with agent m the environment. The more recent demonstration that the latter 1s
The Paradox of Prion Disease
7
the case m a proportion of human cases and that transgemc mace carrymg
mutations m the PrP gene (1) or additional copies of normal PrP alleles (9) can
develop prion disease without contact with an exogenous agent make a purely
genetic cause of natural scrapie, in at least some cases, more plausible than was
believed until recently. The possibtlny that natural scrapie may arise without
exogenous infection has, however, been recogmzed by some scientists for
many years (10). One of the arguments in favor of the infection hypothesis of
the eptdemiology of natural scrapie was the high coincidence of scrapte m dam
and progeny that was thought to be indicative of maternal transmission (1 l),
but such a pattern clearly is compatible also with a recessive model, especially
where the flock shares one ram, such that the variance is determined largely by
the status of the dam. Furthermore, although scrapie has been seen m sheep fed
with placentas from scrapie-affected sheep (22) this does not prove that oral
transmission necessarily determines the natural incidence of disease. Indeed, it
is not even clear that the placentas were the source of the disease, since the
only sheep that can be guaranteed to be scrapie-free prior to exposure to
infected tissue come from flocks that are genetically resistant to experimental
infection and that therefore are largely unsuitable as recipients in this type of
experiment. The recent demonstration that scrapie develops in genetically sus-
ceptible sheep born to unaffected, genetically unsusceptible dams followmg
embryo transfer (13) greatly reduces the probable relevance of perinatal events
m natural scrapie. In the origmal experiment, however, the embryo donors had
been challenged with scrapie, therefore further experiments are required to
establish whether this is relevant or whether genetically susceptible animals
resultmg from embryo transfer will develop scrapie without exposure of the
embryo donor to the agent. The time is clearly right for a reevaluation of theo-
ries about the occurrence of natural sheep scrapie in the light of the finding of

dtsease-specific polymorphisms in the PrP gene of sheep and other species and
the demonstration of pathogenic mechanisms that do not require exposure to
the infectious agent. “Naturally occurring scrapie m sheep is not the same as
experimental scrapie in any species. It should be studied, m depth, as a unique
disease” (14).
2.4.2. Transmissible Disease in Genetic Cases
The recent demonstration that genetically manipulated mice spontaneously
can develop neurological disease, which then can be experimentally transmit-
ted to other rodents, has bridged the gap between the two opposing mecha-
msms of “inheritance” and “infection.”
It is well established that disease can be transmitted experimentally to animals
by mtracerebral injection of brain tissue homogenate from affected members
of those families in which typical prion disease 1s inherited as an autosomal
8 Ridley and Baker
dommant. It is also the case that in each family disease is associated with one
of a number of different pathogenic mutations within the open reading frame of
the PrP gene. Currently about 17 such mutations have been described, most of
which appear to be fully penetrant. That an apparently genetic dtsease can
involve a transmissible agent raises the question of whether the gene mutations
are causing disease,
sui generis,
or whether they are predisposing Individuals
to develop disease as a result of mfection with an exogenous agent. The argu-
ment that the genetic mutations are causing disease receives support from the
work on transgemc mace expressing mutant prion protein. These animals spon-
taneously develop neurological disease in adulthood despite bemg protected
from possible Infection with exogenous agents. Furthermore, disease 1s then
transmissible from these animals by serial passage to other animals
(1).
These

expertments suggest that attempts to classify at least some cases of priori dis-
ease as genetic or infectious may be inappropriate.
2.4.3.
ConversIon of Prp to Prpc
Recent experimental findmgs have suggested that the fundamental feature of
pathogenesis in this group of diseases consists of the conversion of a pre-existmg
molecule to a new shape or conformation rather than to
replzcation
of an agent.
2 4 3.1.
THE RELATIONSHIP BETWEEN
PRP~
AND
PRP~~
The most important aspect of molecular pathogenesis is the relationship
between PrPC and PrPSC. A number of important features of this relationship
have been established.
1 PrPC
and
PrPsc are both encoded by the same gene and have the same ammo acid
sequence and relatrve mol wt of 33-35 kDa.
2. PrPC and PrPSC are antrgenically mdtstmguishable.
3 PrPSC IS probably formed by the posttranslational modrficatron of PrPC.
4. PrPC is destroyed completely by proteolytic enzymes but PrPSC IS reduced to a
protease-resistant core of mol wt 27-30 kDa, termed PrP27-30.
5 PrPC IS soluble m the presence of detergent, whereas PrPSC forms msoluble
aggregates
6 Turnover is rapid for PrPc but very slow for PrPSC
7 PrPC 1s found m brain and some other tissues of all mammals, whereas PrPSC is
found only m the brain and, to a lesser extent, other tissues of animals or humans

with prron disease
8 PrPC levels are constant throughout disease, but PrPSC levels m brain rise during
disease progresston in cases of prton disease.
9. PrPSC aggregates have a fibrrllar structure with the tmctorral properties of amy-
loid, whereas PrPC does not aggregate in this way.
10. Levels of PrPSC are associated wtth mfectlvrty titer, whereas no such relationshtp
is seen for PrPc.
The Paradox of Prion Disease 9
2.4.3.2. WHY IS PRP~ CONVERTED TO PRP~~?
Since the conversion of PrPC to PrPSC is irreversible, it would seem that thts
conversion consists of moving from a higher to lower energy state and it is only
the intervening higher activation threshold that prevents the process happening
more frequently. Four factors may contribute to the crossing of this barrier:
1 The
presence of
PrP sc PrP seems to belong to a small group of protems that can
have one of several conformations, the presence of one form predlsposmg the
other molecules to take up that shape (15-17). Such a hypothesis can explain:
a Transmission of disease in the absence of agent-specific nuclerc acid,
b The exponential accumulation of PrPSC durmg disease,
c The observation that, on transmission, the PrPSC in the recipient 1s host coded;
d. The posslbihty that there is more than one self-perpetuating conformation
allowmg for the observation of “strains of agent,” and
e That where the PrP of the donor and host are different, the ability of the donor
PrP to interact with the host PrP will be lessened, leading to the observation
of a “species barrier.”
2. The amino acid sequence of PrP. Mutations in the PrP gene may produce dlffer-
ences m the stability of the secondary structure of the PrP protein such that a
spontaneous increase in the P-pleated sheet content 1s more probable. This could
lead to the occurrence of genetic cases

3 Availability of PrPC Transgenic mice with multiple copies of the normal PrP
gene can develop spontaneous prion disease, those with only one copy show pro-
longed mcubatlon times, and mice with no PrP gene cannot be infected Factors
such as an increase in general metabolic rate, which may inter &a affect the rate
of production and breakdown of PrPC, could occasionally tip the balance toward
the production of PrPsc and therefore contrlbute to the occurrence of prlon dls-
ease m sporadic cases
4 Time. In a dynamic equlllbrium, the probability that a rare event will have
occurred increases with time. The amount of PrPSC required to imtlate the mas-
sive production of PrPsc is not known, but it is likely to consist of a threshold
quantity. Since PrPSC IS not disposed of, the total amount present m one area will
accrue with time. Naturally occurring prlon disease has a characterlstlc age at
onset, which usually IS later m sporadic than inherited cases, but which is con-
fined to middle age and beyond. Whether this reflects the effect of real time or
the effect of age-related changes m the availability of PrPC is not yet clear
2.4.4. Prion Disease and Amyloidosis
The recognition that PrPSC has a propensity to take on the structure described
as “amyloid” has allowed prion diseases to be compared to other amyloldoses
rather than other mfectlous diseases.
PrPc IS a soluble protem containing about 40% a-helical domains and almost
no P-pleated structure PrPSC is largely insoluble with reduced a-helix content
10
Ridley and Baker
(30%) and increased P-pleated structure (43%). The P-pleated content of
PrP27-30 IS even higher (>50%). Pathogemc mutations m the PrP gene are
thought to alter the stability of the tertiary structural relations between the alpha
hellcal structures m the PrP molecule, thereby altering the probablllty that this
structural relationship will break down into a P-pleated sheet conformation
(IS). Protems with high P-pleated content have a propensity to form fibrlls that
themselves aggregate to form large deposits that have the tmctorlal properties

of “amylold.” For example, they exhibit blrefrmgence when stamed with
Congo red and are viewed under polarized light
The most Important CNS amyloldosis occurs m Alzhelmer disease (AD),
which IS characterized by the presence in brain of P-amylold plaques, neu-
rofibrlllary tangles (NFTs), and often cerebral amylold angiopathy (CAA), the
deposition of P-amyloid m cerebral blood vessels Similarities between AD
and prlon diseases include:
1 Approximately 15% of cases of AD and prlon disease occur with an autosomal
dominant pattern of mherttance. In famlhal cases, AD may be associated with
one of several mutations m the gene that makes the precursor protein (amylold
precursor protein, APP) whose modlficatlon produces P-amylold, whereas prlon
disease 1s associated with mutations m the PrP gene (AD also may be associated
with mutations m other genes that interact with the APP gene )
2 AD and prlon disease both have an age at onset largely confined to later middle
age and beyond with onset being earher In familial than m sporadic cases
3 j3-amylold plaques are found in AD, whereas PrP-amylold plaques are seen in
about 20% of cases of prlon disease Even where PrP-amylold plaques are not
visible by light microscopy, electron microscopy reveals that the PrPSC exists m
free fibrlls m the neuropll, suggesting that prlon disease involves amyloldosls
even m cases where plaques are absent (19).
4. In a few cases of prlon disease the degree of CAA and P-amyloid either m sepa-
rate plaques or integrated into PrP plaques IS greater than would be expected by
chance association, suggesting an interaction m the pathogenesls of both types of
amyloldosls.
5 In AD, P-amylold plaques are formed when one of two alternative processing
pathways of APP results m the production of a truncated protem sequence that
takes on a P-pleated sheet conformation. These molecules then polymerize into
fibrlls that aggregate into the characterlstlc form of a plaque In prlon disease,
PrP-amyloid may consist of a truncated form of PrPSC (20) It is, however, not yet
clear whether the crucial difference between PrPC and PrPSC that associates the

latter with mfectlvlty 1s the formatlon of PrPsc into amylold fibrlls or whether PrPSC
exists m a pathogemc form prior to Its subsequent breakdown mto PrP-amylold.
6 Although AD IS not a transmissible disease, the laminar distribution of P-plaques
in the cortex 1s consistent with the spread of pathology around the brain by a self-
sustaining mechanism (21). The mJectlon of P-amylold containing bram into the
brains of monkeys has been found to result m the formation of P-amylold plaques
The Paradox of Prion Disease
II
in cortex (22), suggesting that P-amyloidosis may be transmrssrble under experi-
mental conditions
3. Treatment and Prevention
Perhaps because prion disease in humans is so rare, the amount of effort
devoted to constderatron of treatment for prion disease is but a fraction of the
interest and effort expended m understanding the nature of the disease. How-
ever, several strategies might be considered, some of which will be discussed
in subsequent chapters.
3.7. Genetic Methods
1. The identification of mutations in the PrP gene opens up the possrbihty of genetic
counselmg for affected famrhes, although counselmg for adult-onset disorders 1s
a complex issue Where affected famrhes request it, prenatal genetic testmg can
eliminate the disease from all subsequent progeny
2. Selecting sheep that are resistant to scrapre on the basis of polymorphrsms m the
PrP gene can radically alter the incidence of scrapie m flocks
3 Since mice that lack a PrP gene are not noticeably sick and are resistant to prron
disease, a technique (if rt existed) that blocked PrP gene expression might not
have seriously deleterious effects and would prevent disease in disease-allele
carriers and m those known to be at risk from acquired infection. Such a tech-
nique might also prevent disease progression but would not be expected to reverse
the accumulated damage
3.2. Biochemical Treatments

1. It might be speculated that treatments that decrease the availability of PrPc, either
by reducing PrP synthesis or by speeding up its metabolism, could slow down the
progress of the disease. Alternatively, rt should be borne m mind that centrally
acting drugs that might be intended to relieve some of the symptoms of disease
inadvertently might increase the availability of PrPC and so increase the rate of
disease progression
2 Heterologous PrP molecules can interfere with the process of PrP polymerrzatron
and with the productron of PrPSC in scrapre-infected cell cultures so, in theory,
such molecules might be used to arrest the disease. Such a strategy, however,
only is a remote possibrhty since tt presents considerable difficulties of drug
delivery and, rf an inappropriate PrP molecule was used, it could accelerate the
disease process
3.3. Prevention
Acquired disease can be prevented by an understanding of the procedures
that lead to transmission. For example, kuru has been controlled by a change in
cultural habits. BSE has been reduced by banning the feeding of specified offals
of all species and all ruminant-derived protein to ruminants, although the final
12 Ridley and Baker
eradication of the disease and prevention of its reoccurrence may requn-e
changes m the rendering process, reverting to a sttuatton in which the agent
from any source is destroyed. Iatrogenic human disease may be prevented by a
better appreciation of the risk from brain and related tissue and the recogmtton
that tissue from cases of human prmn disease cannot be excluded from use on
the basis of diagnosis alone because of the posstble msidious onset and atypi-
cal presentatton of the disease.
References
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J (1990) Two alleles of a neural protem gene linked to scrapte m sheep Proc
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Neurobzol 8,25-40
Human Spongiform Encephalopathy
Clinical Presentation and Diagnostic Tests
Rajith de Silva
1. Introduction
The spectrum of human transmlsslble sponglform encephalopathles, or prion
diseases, include sporadic Creutzfeldt-Jakob disease (CJD), familial CJD,
latrogemc CJD, and kuru. Although the disorders are rare and currently untreatable,
estabhshmg the diagnosis 1s of considerable importance for counselmg relatives
and m vfew of the ongomg epldemlologlcal studies. The sclentlfic study of these

disorders has led to significant advances, particularly in the field of molecular
biology. This progress has been accompanied by an expansion in the clnncal
“boundaries” of CJD, so that illnesses such as fatal familial msomma (FFI) now
are included within this group of disorders. In this chapter, the early descrlptlons
of CJD are reviewed The clinical phenotypes of sporadic CJD are described, and
the frequency of common clinical signs is reviewed. Inherited CJD IS discussed,
in relation to classical descrlptlons of conditions such as Gerstmann-Straussler
syndrome (GSS), and more recent descriptions of conditions such as FFI The
clmlcal appearances of iatrogemc CJD cases are described. Diagnostic “pomt-
ers” to the condltlon are discussed. Data from the UK national CJD surveillance
unit 1s presented then, and the differential diagnosis is discussed, based on sus-
pect cases of CJD referred to the unit in which the final neuropathological diag-
nosis 1s not CJD. In conclusion, the common phenotypes of CJD are summarized,
and possible novel diagnostic and therapeutic measures are discussed.
1.1. The Early Descriptions
H. G. Creutzfeldt 1s credited with the first description of the disorder, although
by current diagnostic criteria his case would be highly atypical (I). The patient
From Methods m Molecular Medwne Pnon Dtseases
Edlted by H Baker and PI M Rdley Humana Press Inc , Totowa, NJ
15
16 de Silva
was 23 yr old at presentation, and there was a questionable famtly history of
mental subnormality. In adolescence the patient was noted to be immature and
had behavioral abnormalmes. One year prior to presentation, she was treated
for a skin rash and at that time spastic paraparesis was recorded The latter
improved thereafter, but at presentation there were features of psychiatric dis-
turbance, cerebellar ataxta, and posstbly dystonia During the terminal hospi-
talization, her behavior contmued to be disturbed, and there were a variety of
cognitive deficits, pyramidal and cerebellar signs, and probably myoclonus.
She died m status epilepticus, 2 mo after presentation.

A year later, m 1921, A. Jakob described four cases, at least two of which
had clmical features suggestive of the entity we recognize as CJD (2). A further
case that Jakob considered similar was described in 1923 (3). Over the next 40 yr
there was considerable confusion over nomenclature with at least 12 synonyms
being apphed to this disorder. Of these, three descriptions are worthy of mention.
1.1.1. “Subacute Vascular Encephalopathy”
In 1954 and 1960, Nevin and colleagues m two elegant series described a
total of 10 pattents, all of whom had succumbed to a neurodegenerative pro-
cess of subacute onset and rapid progression (4,5). They drew attention to the
combmation of pyramidal and cerebellar disturbance, the presence of mvolun-
tat-y movements, especially myoclonus, the frequent occurrence of visual fail-
ure, the spectrum of speech disturbances (dysphasia, dyspraxta, and muttsm),
the recurrence of primitive reflexes, and the paratomc rigidity (“Passive move-
ments were resisted “). The assoctatton of the disorder with characteristtc
electroencephalogram (EEG) appearances was indicated, although it was
stressed that the EEG abnormalities were not specific (5) The authors assumed,
on account of the spongtform change noted at neuropathology, that the etiol-
ogy of the disorder was microvascular dysfunction. Despite the erroneous
attrtbutton of causation, these descrtptions remam the most comprehensive
accounts of the clnncal course of sporadic CJD.
1 7.2. Heidenhain’s Syndrome
In 1929 Heidenham reported three cases of rapidly progressive dementia, two of
which had blindness durmg the terminal phase (6). In 1954, Meyer and colleagues
reviewed Hetdenham’s cases and reported a further case (7). The latter was a man
aged 3 8 yr who died 6 mo after the onset of progressive dementia accompanied
by visual failure. On exammation, he was severely demented, appeared to have
a right homonymous hemranopia, had exaggerated limb reflexes on the left,
and was ataxtc. The cerebral spongiform change at postmortem was particu-
larly marked m the occipital lobes. Meyer et al. felt that a variant form of CJD
existed, characterized by rapidly progressive dementia and cortical blmdness

Human Spongiform Encephalopathy
17
1 1 3. Ataxic CJD
In 1965 Brownell and Oppenheimer described four patients with pathologi-
cally confirmed CJD, all of whom had presented with cerebellar ataxia (as had
stx cases they reviewed from the literature) (8). The authors drew attention to
their fourth case, which had a slightly unusual course. A 60-yr-old woman was
seen with a 6-mo history of difficulty walking. The key exammation findings
were gross limb tremor and gait ataxia. At initial assessment, she was “vague
and forgetful” but fully orientated. Within the space of 1 mo she had become
disoriented and demented. By then she was unable to stand or walk without
support. Termmally, she had feeding difficulties and was doubly incontinent.
At the time of death, the suspected diagnosis was (idiopathic) cerebellar
degeneration (lumbar puncture and air encephalography had been normal). The
total duration of illness had been 8 mo. The authors felt that this case of CJD
was unusual m having a course that was for the most part dominated by cer-
ebellar ataxia with dementia being a late feature.
1.2. Kuru
The epidemic of kuru that predommantly affected the Fore-speaking people
of the highlands of Papua New Guinea was recognized as a progressive and
eventually fatal neurodegenerative process mainly affecting the cerebellum
(9,ZU). In R. W. Hornabrook’s 1979 review of the chmcal features of this ill-
ness (based on his experience with 434 cases), the most salient observation
was the remarkable uniformity of clinical features m affected patients (II).
(“A resemblance which could not be closer were they coined from the same
mint” [II].) During a prodrome of 12 mo or more, affected patients would
show transient unsteadiness. At this time minor changes in personality and
mood (mild euphoria, tendency toward fatuousness, and lack of insight) may
have been present. The clinical illness itself was characterized by progressively
worsening ataxia and the mabihty to maintain balance. In the last stages patients

were unable to sit or perform any activity, were grossly dysarthric, and were
unable to swallow. Death ensued 12-18 mo after the onset of the climcal 111-
ness. Dementia probably was present at the terminal stage of disease. Signs of
extrapyramidal disease, rigidity, myoclonus, and seizures were absent. In chil-
dren, the clinical course was more variable and of shorter duration. Bramstem
and bulbar dysfunction appeared to occur more commonly than m adults.
2. Sporadic CJD
Much of the clinical data on sporadic CJD was gathered m the course of
conducting large scale epidemiological studies on CJD all over the world m the
1970s. These used criteria modified from those put forward by Masters et al.
(12). On the whole, only cases that were neuropathologically confirmed (defined
18 de Silva
Table 1
Comparison of Clinical Features
in Large Scale Epidemiological Studies of CJD
W111 and Matthews, Brown et al, Brown et al ,
%, (17) O/o, (13) %, (14)
Clinical picture Onset Course Onset Course Onset Course
Cogmtive Impairment 21 100 64 100 69
Cerebellar dysfunction 19 42 43 61 33
Visual failure 9 13 17 42 19
Pyramidal disease - 79a 2 43 2
Extrapyramidal disease - 3” 2 67 0.5
Lower motor neuron
signs
- 3 04 11 05
Seizures 91b 9 04 8 0
Myoclonus 35C 82 0 88 1
“Presence of rlgldlty alone was classltied as “pyramidal ”
h“Blackout attacks ”

~“Involuntary movements ”
100
71
42
62
56
12
19
78
as “detimte”), or those with characteristic EEG appearances and appropriate
clinical features (designated “probable”) were included in these analyses.
2.7. Ages of Onset and Disease Durations
In Brown’s 1986 study (23) the mean age of onset was 6 1 5 yr (range 1983),
and the mean disease duration was 7.4 mo (median 4.0). In hts larger series of
1994 (based on 300 cases, all of whom had been experimentally transmitted to
nonhuman primates) (I#), the subgroup of sporadic cases (n = 234) had a mean
age of onset of 60 yr (range 16-82, median 60) and a median disease duration
of 4 5 mo (range l-130, mean 8).
2.2. Clinical Courses
In a previous review of clinical characteristics, Cathala and Baron referred
to a prodromal clmtcal stage m a third of patients, conslstmg of nonspectfic
features such as fatigue, sleepmg dtfficulties, wetght loss, headaches, malaise,
and “sensations” (IS). However, Knight has argued persuasively that these
symptoms are “. . . common, nonspecific, and often noted later, when develop-
ments have lent them retrospective and possibly spurious sigmficance” (16).
Symptoms and signs at the start and during the course of CJD m the larger
series are summarized m Table 1 With respect to the debut of their illnesses,
30-40% of these patients had cognitive impairment alone, 30-40% had neuro-
logical dysfunction m isolatton (most commonly cerebellar ataxla or cortical
blindness), and 20-30% had mixed features. As can be observed in Table 1,

Human Sponglform Encephalopathy
19
inevitably there 1s some variation m the reported frequency of features, but
several general conclusrons can be drawn. First, dementia almost always was
present during the course of tllness. Second, myoclonus, which was rarely
present at the onset, was frequently noted durmg the course of disease. Third,
features of cerebellar, visual, pyramidal, and extrapyramidal dysfunction were
noted regularly but were not universal. Finally, features of lower motor neuron
dysfunction and convulsions were rare presenting features, and were unusual
even during the course of illness. As the disease progresses, multifocal central
nervous system (CNS) dysfunction is the norm, and is accompamed by the
recurrence of primitive reflexes and, later, akinetic muttsm. Terminally, the
patients are rigrd, mute, and unresponsrve, and may have abnormal resprratron.
It is appropriate at this juncture to consider some atypical, variant forms of
sporadic CJD: cases with either very long or short durations of tllness, so-called
“amyotrophic” CJD, and “panencephalopathic” CJD.
2.2.1. Extreme Disease Durations
Will and Matthews described an “intermediate” group of patients with a mean
disease duration of 33.4 mo (I 7), who accounted for 6% of their series These
cases exhibited three distmct types of disease progresston: a form of CJD m
whrch there was slow but mexorable progression, a form m which a slow
neurodegeneratrve process was followed by a rapid terminal phase, and (most
rarely) a rapid early course that was followed by a protracted terminal phase m
which there was little further declme. It is of note that two of the 12 pattents
considered by these authors had a family history of neurodegeneration. Brown
and colleagues’ seminal analysts of CJD of long duration m 1984 (18), also is
complicated by the inclusion of famihal cases. The observation that these cases
are difficult to differentiate from other chronic dementmg processes (particu-
larly Alzhetmer’s drsease) nevertheless, is valid. In his later NIH series (14),
4% of sporadrc cases (n = 9) had Illness duratrons longer than 2 yr. Of the

previously identified subtypes, there were three each in the slow, slow-fast,
and fast-slow groups.
In contrast, some CJD cases have a rapidly progressive course, with an onset
and evolutron resembling stroke. In a recent survey, approx 6% of cases m the
UK CJD database (covering the period 1970-1994) were found to have this
phenotype (29). That a smgle neurodegenerative process can exhrbrt such
diverse behavior is clmically fascmatmg, but merely may represent the extremes
of btologrcal behavior of this disorder in humans.
2.2.2. Amyo trophlc CJD
As Indicated in the previous eprdemrologtcal studies, signs of lower motor
neuron dysfunction do occur in CJD, but they are uncommon and do not occur
20 de Sllva
m the absence of more wrdespread corttcal and cerebellar disease. Further-
more, then presence at the start of the clinical illness is extremely unusual.
Salazar et al reviewed this SubJect m 1983, and came to the conclusion that
“. . . the great majortty of cases involving syndromes of dementia and early
onset of LMN (lower motor neuron) stgns are clmtcally and pathologtcally
distinct from the typical cases of CJD and do not represent transmtssible dts-
ease caused by unconventional viruses as presently understood” (20). They
based then concluston on the negattve transmission studies they performed,
and also on the atyprcal neuropathologtcal appearances. The most consistent
feature of the latter examinations was atrophy (with neuronal loss and ghosis)
m the frontotemporal cortex. It is now recognized that frontotemporal atrophy
is the pathologtcal hallmark of the dementia that somettmes accompanies motor
neuron dtsease (21). It is our view that “amyotrophic CJD” is a misnomer, and
that this entity m the maJority of cases represents motor neuron dtsease with
dementia. In the previous series of Salazar et al., only two out of 33 cases with
dementia and early LMN stgns transmitted: Both had chronic pertpheral
neuropathies and also typical CJD brain histology. They probably represented
cases of CJD that had developed by chance m mdividuals with chronic

neuropathtes
2.2.3. Panencephalopathic CJD
This pathologtcal variant of CJD IS described almost exclusively m the Japa-
nese literature, and is characterized by extensive whzte matter degeneration m
cases of CJD. There 1s probably no difference m the clmical presentations of
these patients, although reports have implicated a longer duration of disease,
and evidence of corttcal atrophy and white matter disease (on CT and MRI) m
these cases (22,23). A further report has implicated the coextstence of amylotd
plaques on neuropathological exammation (24).
3. Familial CJD
In 1928 Gerstmann described an unusual inherited cerebellar disorder. A
25-yr-old woman developed ataxia, dysarthria, and personality change, and on
review a year later had more pronounced ataxta and dementia (25). Over the
next 5 yr (leadmg to death) the pattent exhibited “pseudobulbar disturbance of
swallowmg,” nystagmus (lateral and upgaze), limitation of upgaze, hypotoma,
intention tremor, dtmmtshed reflexes, and bilaterally upgomg plantar responses
In a subsequent publicanon (26), the detatled clmical and pathological features
of this case along with the family history (there were seven other affected mem-
bers) were described. The pathological appearances were dominated by
argyrophilic plaques throughout the brain, and minima1 spongtform change.
In their landmark pubhcation m 198 1, Masters et al. reviewed Gerstmann’s
Human Spongiform Encephalopathy
21
case along with mne other cases m the literature sharmg slmllar clinical and
pathological features (27). With the inclusion of seven further cases with lden-
tlcal phenotypes referred to the authors’ laboratory for transmlsslon expen-
ments, they concluded that the mean age of death m these cases was 48 yr
(range 29-62) and that the mean disease duration was 59 mo (range 13-l 32).
The key clinical features were characterized as cerebellar incoordination, pyram-
idal signs, and dementia, with myoclonus as an inconstant finding. The slow

evolution of illness was felt to be the main differentiating feature of this group
of patients from those with sporadic CJD.
Molecular biology has had an enormous impact on this form of CJD. After the
demonstration of a pathogemclty-associated point mutation at codon 102 of the
prion protein gene (PRNP) in patients with this phenotype (28), the Identical
mutation was identified m Gerstmann’s original family (29). DNA extracted from
archival material on the first described case of familial CJD (“Paul Backer,” by
Klrschbaum rn 1924 [3U/) recently has revealed a point mutation at codon 178
of PRNP (32). To date, some 19 different point mutations and extra basepalr
msertlons of the PRNP open reading frame have been associated with cases of
familial CJD. Although specific clmlcal phenotypes are not consistently noted
with individual mutations, some general observations can be made.
3.1. Gerstmann-Strtiussler Syndrome
Although the clinical and pathological syndrome (described earlier) 1s clas-
sically associated with the codon 102 Pro-Leu change, mdlvlduals carrymg
this mutation even within the same pedigree will manifest highly variable phe-
notypes. For example, m the German “Sch”pedigree the clinical illness broadly
was that of GSS, but individual cases exhibited features as diverse as anxiety
and poor concentration, trtubation, and myoclonus (32). The evaluation of the
impact of other sites within the genome on this phenotyplc varlabllrty 1s m
progress, but m a recent attempt the common polymorphism at codon 129 was
not found to be mfluential(33).
Confusingly, point mutations at codons 117, 198, and 2 17 are also associ-
ated with the pathological features of GSS. In the case of the latter two, the
characteristic multicentric plaques are accompanied by neurofibrillary tangles
(“the Indiana variant”), but probably are indistinct from GSS clmlcally (34).
The codon 117 mutation has also been described m association with a so-called
“telencephallc” form of CJD, m which dementia 1s accompamed by pyramldal
and extrapyramidal features, and variable cerebellar signs (35).
3.2. Familial CJD Resembling Sporadic Disease

The point mutations at codons 200, 2 10, and 178 are associated with CJD
that resembles sporadic CJD clinically. The last, however, is not associated
22 de Silva
with characterrsttc EEG appearances. Even m the case of the first (the explana-
tion for the high inctdence of CJD among Libyan-born Jews) perusal of the
chmcal features of a large pedigree revealed considerable phenotypic hetero-
geneity, including rarmes (for CJD) such as demyelinating polyneuropathy (36)
3.3. Fatal Familial Insomnia
The Asp-Asn change at codon 178 of the PRNP open reading frame has also
been linked with an unusual neurodegenerattve process (3 7), first descrrbed m
1986 (38). A 53-yr-old man first presented with progressive msomma and
dysautonomia. A prevtously sound sleeper, he could sleep only for 2-3 h at
night He became Impotent and had loss of libido. There was eptsodtc sahva-
tron, lacrimatton, and rhinorrhoea, and he exhibited orthostatrc diaphoresrs,
pyrexla, dtfficultres with mlcturttion, and consttpatron Two months later, he
could only sleep for 1 h, and he was frequently dtsturbed by vivid dreams. He
developed progressrve dysarthrta, mtentron tremor of his limbs, and gait ataxla.
Examination at this stage revealed mtosts, cerebellar signs, and brisk tendon
reflexes He was noted to lapse mto a stuporose state tf left alone, m which he
performed complex and apparently purposeful gesturing and breathed notslly.
He could be awakened quickly by light strmuh. As his condmon progressed,
there were oculomotor disturbances (limitation of upward gaze and saccadtc
movements), myoclonus, and irregular breathing patterns Termmally he
became confused and disoriented, had episodes of motor agttatron, and exhibited
severe truncal dystomas. The total duration of his Illness was 9 mo. HIS EEG was
never characteristic of CJD, but revealed diffuse slow waves and later became
isoelectric. His dreamlike states comctded with EEG desynchronizatlon, but
phystological EEG patterns of sleep were absent. A pharmacologtcal response
to a short-acting benzodiazepine antagonist could be demonstrated both clini-
cally and electrophystologically There were at least four other affected mem-

bers in his pedigree, mcludmg two affected sisters. Study of the famtly m greater
detail revealed that insomnia, dysautonomza, dysarthria, ataxia, myoclonus,
andpyramidal szgns mvarlably werepresent m affected members. Memory and
attention deficits were mimmal m the early stages, but tended to progress with
time. During “sleep” there was loss of slow-wave and rapid-eye-movement
phases, The mean age of onset was 49 yr, and the mean duration was 13 mo.
3.4. CJD Associated with Extra Repeat Insertions
Extra mserttons of a variety of sizes have been described m the octapeptrde
repeat region of the PRNP open reading frame. The phenotyprc descrrptrons of
these cases resemble CJD, with two notable exceptions. First, m a large pedl-
gree reported from the South East of England with a 144-basepair msertion,
there was striking dtverslty m the clinical phenotypes of affected cases (39)
Human Spongiform Encephalopathy
23
Diagnoses, such as General Paralysis of the Insane, “spinal sclerosis,” “cere-
bral softening,” cerebral thrombosis, dementia praecox, Parkmsonrsm,
Huntington disease, Pick disease, and Alzhelmer disease, had been attached to
affected members of the pedigree through the ages. This was accompanied by
considerable variation m the neuropathologlcal features of cases With respect
to the molecular biology, an important pomt of note was the stablhty of the
expanded sequence over five successive generations. This contrasts with
expansions of trinucleotlde repeat sequences m successive generatlons, which
are associated with the phenomenon of antlclpatlon m associated neuro-
degenerative disorders, such as Huntington disease (40). Antlcipatlon 1s not a
feature of inherited CJD. The age at death in this pedigree was affected by the
common polymorphism at codon 129. The mutation was always carried on an
allele encoding methlonine at this site; cases homozygous for methlonme had a
significantly younger age at death than heterozygous cases (42).
Second, in then- report on a case of dementia associated with a 2 16-basepatr
insertion, Duchen et al. argued that the presence of neurltlc plaques staining

positively for P-amylold protein and ‘c protein indicated that this case repre-
sented a transition (neuropathologlcally, at least) between CJD and Alzhelmer
disease (42). From the clmical perspective, however, this patient’s illness was
entirely compatible with familial CJD.
3.5. Some Unusual Mutations, and Conclusions on Familial CJD
Two recent mutations described m cases of famlhal CJD from Japan are
associated with a Pro-Leu change at codon 105, and an amber mutation at codon
145 Almost uniquely for cases of CJD (sporadic or famlhal), patients carrying
the former mutation presented with spastic paraparesis (43). Dementia eventu-
ally supervened, but there were no cerebellar features or myoclonic Jerks The
latter mutation was associated (in a single patient) with a slowly progressive
dementia of >lO yr duration (44)
Familial CJD encompasses a wide variety of clmlcal syndromes, some of
which have highly unusual features, such as dysautonomia and spastic
paraparesis. There is considerable overlap of clinical features associated with
individual PRNP mutations, and the variability of clinical features
wdhin
pedi-
grees cannot be accounted for consistently by the common polymorphism at
codon 129. Famlhal CJD may be associated with longer disease durations than
sporadic cases. This would account for the higher prevalence of famlhal cases
among series of CJD patients with long disease durations.
4. latrogenic CJD
Although rare, forms of iatrogenic CJD are of considerable clinical and pub-
lic health importance. In particular, the disease phenotype appears to be mflu-
24
de Silva
enced by the route by which the agent of mfecttvity gains entry mto the host.
Cases where “peripheral” (outside the CNS) moculatton has taken place
(recipients of contaminated human pmutary-derived hormones) are character-

ized by a progressive cerebellar ataxia, wtth little or no cogmttve impairment
and the absence of charactertsttc EEG findings (4.5). The disease phenotype m
these mdividuals IS remarkably homogeneous, and mevttable compartsons with
the clmical course of kuru have been made. In addition to exhibiting relent-
lessly progressive truncal and limb ataxia, patients demonstrate a characteris-
tic change m then personalmes, appearing apathetic and unconcerned about
then predtcament. As then disease progresses, more CJD-like features emerge.
hmb rigtdity, myoclonus, startle responses, and akmetic mutism are all apparent
The clinical course of patients who have had the CJD agent inoculated cen-
trally have had disease phenotypes consistent with sporadic CJD However, rn a
recent report, four “Lyodura” recipients who had grafts placed in their posterior
fossae were descrtbed (46). They had presented with cerebellar syndromes (all
four were ataxic at presentation, and three were dysarthnc), possibly owing to
the proximity of the cerebellum to the site of graft placement, but m our opinion the
disease phenotypes were distinct from those with peripherally inoculated iatrogemc
CJD. One patient had characteristic periodic sharp wave complexes on the EEG
5. Diagnostic Tests
5.
I. Electroencephalography
In the large epidemiological studies referred to prevtously, the EEG was found
to be the most useful dtagnosttc test for CJD. However, because the inclusion
crtterta for these studies included characteristic EEG appearances, there has been
a tendency for over-ascertainment of this feature. Also, gtven the subJective
nature of EEG interpretation, there may have been some variatton m the types of
abnormalities included in the drfferent series. Will and Matthews found character-
istic EEG abnormahttes m 84% of “subacute” cases (I 7). In their “mtermedtate”
group (with a longer disease duration) the EEG was typical in only two out of nine
cases Brown et al report “pertodic” EEG appearances m 60-80% and “triphasic
I cycle/second” m 48-56% (I 3,14). In our experience, an EEG showing periodic
sharp wave complexes m the approprtate clinical setting is vzrtually diugnostlc of

CJD. Anecdotal reports of false positive diagnoses have usually arisen from the
mcorrect assessment of EEGs, and the maccurate descrtption of nonspecific EEG
findmgs as “characteristic” of CJD. However, a proportion of CJD patients
never mamfest typical EEG appearances, reducing the sensitivity of this test.
5.2. Liver “Function” Tests
In the large eptdemtological series, routme biochemistry and hematology
usually were normal, with the exceptton of liver functton tests (32 out of 80 cases
Human Spongiform Encephalopathy
25
in Will and Matthews’ study). These amounted to mild elevations of hepatlc
enzymes, and overt liver failure was not observed. Although serial measure-
ments rarely have been reported, the lmpresslon gained
IS
that the elevations
are transient (4 7,48).
5.3. Neuroimaging
Computerized tomography m CJD 1s usually normal but sometimes atrophy
is found, especially m cases with protracted Illnesses Radiology reports may
overemphasize any degree of cortical atrophy in view of the clinical history of
dementia. MRI abnormalltles have been reported m CJD. The extensive white
matter degeneration reported by Uchmo et al may be specific for the Japanese
panencephalopathic variant of CJD (49). In reports from Western countries,
high T2-signal lesions m the basal ganglia have been described (50,5 I) In our
experience these abnormalities are not universal; nor are they necessarily asso-
ciated with basal ganglia dysfunction. Magnetic resonance spectroscopy (for
N-acetylaspartate) has been disappointing as an early diagnostic tool (52).
5.4. Cerebrospinal Fluid
Exammatlon of the cerebrospmal fluid (CSF) m patients with CJD
IS
some-

times abnormal. Extrapolatmg from Will and Matthews’ data, the CSF protein
was >0.4 g/L m 45% of cases where it was examined. The protein content
rarely exceeds 1.0 g/L, and a leukocyte response is absent. A pair of novel
proteins m the CSF, Identified by two-dlmenslonal electrophoresls, has been
described m CJD (53,54), but may not be specific for this condition (see note
added m proof)
6. Data from the UK National Surveillance Unit
Surveillance of CJD has been ongoing in the UK since 1990, and affords an
opportunity for the systematic collection of clmrcal data on patients with this
disorder. Cases designated “defimte” and “probable” using criteria modified
from Masters et al. are Included m the survey (55). During the first 4 yr of the
study, 144 sporadic and 14 famlhal cases of CJD were Identified. The ages of
onset and disease durations of these patients are tabulated m Table 2. As can be
seen, patients with familial disease tend to present approx 10 yr earlier than
sporadic cases, and have a disease duration approximately twice as long.
The frequency of chmcal features during the course of illness m sporadic cases
was entirely consistent with the previous surveys. The detailed chmcal questlon-
naire, however, enabled a closer scrutiny of patients’ presenting features. It
emerges that at presentation, approx 40% of patients with CJD have some aspect
of cognitive dysfunction m isolation, 30% present with cerebellar ataxla alone,
10% have a combmatlon of cognitive and cerebellar dysfunction, and IO%