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protein Proc Nat1 Acad Scl USA 91,713s7143.
19 Jeffrey, M , Goodslr, C M , Bruce, M , McBride, P A , Scott, J. R , and Halllday,
W G. (1994) Correlative light and electron microscopy studies of PrP locahsatlon
m 87V scraple. Bram Res 656, 329-343.
20. Tagliavml, F , Prelli, F , Ghlso, J , Bugiam, 0 , Serban, D , Prusmer, S B , et al.
(199 1) Amyloid protein of Gerstmann-Straussler-Scheinker disease (Indiana km-
dred) 1s an 11 kd fragment of prion protein with an N-termmal glycme at codon
58 EMBOJ 10,513-519
21. Pearson, R C A., Esln, M M., Hlorns, R. W , Wilcock, G K., and Powell, T P
S (1985) Anatomical correlates of the distribution of the pathological changes m
the neocortex m Alzhelmer disease. Proc Natl. Acad Scz USA 82,453 l-4534
22, Baker, H. F , Rldley, R. M , Duchen, L W., Crow, T. J., and Bruton, C J. ( 1994)
Inductlon of P-amylold m primates by inJection of Alzhelmer™s disease bram
homogenate: comparison with transmission of sponglform encephalopathy Mol
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 1sof 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 casesare described. Diagnostic “pomt-
ers” to the condltlon are discussed.Data from the UK national CJD surveillance
unit 1spresented then, and the differential diagnosis is discussed, based on sus-
pect casesof CJD referred to the unit in which the final neuropathological diag-
nosis 1snot 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 1scredited 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
casethat 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
stressedthat 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 casesof rapidly progressive dementia, two of
which had blindness durmg the terminal phase (6). In 1954, Meyer and colleagues
reviewed Hetdenham™s casesand reported a further case(7). The latter was a man
aged 38 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
17
Human Spongiform Encephalopathy

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 stagespatients
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 casesthat 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 ,
O/o,(13) %, (14)
%, (17)
Clinical picture Onset Course Onset Course Onset Course
Cogmtive Impairment 21 100 64 100 69 100
Cerebellar dysfunction 19 42 43 61 33 71
Visual failure 9 13 17 42 19 42
Pyramidal disease - 79a 2 43 2 62
Extrapyramidal disease - 3” 2 67 0.5 56
Lower motor neuron signs - 3 04 11 05 12
Seizures 91b 9 04 8 0 19
Myoclonus 35C 82 0 88 1 78
“Presence of rlgldlty alone was classltied as “pyramidal ”
h“Blackout attacks ”
˜“Involuntary movements ”


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,
19
Human Sponglform Encephalopathy

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: caseswith 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 caseshave 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 SubJectm 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 caseswith
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 ISdescribed almost exclusively m the Japa-
nese literature, and is characterized by extensive whzte matter degeneration m
cases of CJD. There 1sprobably 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 casealong 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
21
Human Spongiform Encephalopathy

case along with mne other cases m the literature sharmg slmllar clinical and
pathological features (27). With the inclusion of seven further caseswith 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

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