SMJ
2002; 47(5): 100-103
Martin
Zeidler
Neurology
Specialist Registrar
Department of Clinical Neurosciences
Western General Hospital
Crewe Road
Edinburgh
EH4 2XU
Telephone
0131 537 1000 Bleep 5443
Fax
0131 537 1132
E-mail
martinz@globalnet.co.uk
Creutzfeldt-Jakob
disease (CJD) is a rare and usually rapidly fatal neurodegenerative condition
that occurs worldwide. It is characterised clinically by progressive dementia,
ataxia and myoclonus. The classical neuropathological triad is spongiform
degeneration of grey matter, neuronal loss and gliosis.
The
preceding textbook description belies a disorder which has, by a large margin,
the highest interest factor (number of publications per case) of any disease,
1
has spawned a couple of Nobel prizes (one for studying a form acquired by
cannibalism) and is the only human condition that can occur sporadically or as
an infection or due to an inherited genetic mutation (with all forms of this
‘paradoxical trinity’ being experimentally transmissible). Moreover, the
infective agent is highly resistant to decontamination procedures (even
surviving temperatures that can turn tissue to ash
2
),
transmission can occur accidentally via medical procedures (over 260 deaths to
date
3
)
and theoretically persons could unwittingly be asymptomatic carriers of
infection for many years (or even decades). To add to these concerns, there is
no presymptomatic test, no effective treatment and the nature of the infective
agent remains elusive.
And
then, of course, there is bovine spongiform encephalopathy (BSE), the tragic
death of over 110 young people to a related zoonosis (with the worry of a large
future epidemic still looming) and the loss to the UK economy of £5 billion and
counting.
What
causes CJD?
CJD
is a member of a group of conditions collectively labelled transmissible
spongiform encephalopathies (TSEs) by some and prion diseases by others. The
first of this group to be described was sheep scrapie in 1732. The other animal
TSEs have only been recognised in the past 40 years and include transmissible
mink encephalopathy, chronic wasting disease in deer and elk, BSE and feline
spongiform encephalopathy. A major leap forward in understanding the nature of
these disorders came in the 1930s when scrapie was shown to be experimentally
transmissible between sheep, albeit with an incubation period in excess of one
year.
4
This finding supported the later concept of the ‘slow’ transmissible agent,
considered most likely to he a virus (hence these diseases were often referred
to a ‘slow virus diseases’). However, no such virus could be identified, and
infection survived despite tissue being bombarded with ionizing or ultraviolet
radiation, or multiple other insults that would be expected to slay a
conventional virus (or any other living organism).
A
wild, but beautiful, hypothesis emerged in the late 1960s suggesting that the
infective agent may be devoid of nucleic acid and contain only protein. This
theory was championed by the Californian (later Nobel-prize winning) neurologist
Stanley Prusiner who weathered a storm of derision from many of his
contemporaries to show that a protein did indeed play a key role in the
pathogenesis of TSEs. In 1982 he termed this the ‘prion’ protein (PrP),
short for proteinaceous infectious particle with the ‘i’ and the ‘o’
switched for convenience.
5
Prusiner’s deep conviction that this protein was the fundamental part of the
agent was strengthened by the discovery of the gene which codes for PrP on the
short arm of chromosome 20 and the linkage of a mutation of this gene to a
familial form of human TSE called Gerstmann-Sträussler-Scheinker disease.
6
It is now known that PrP is normally a harmless cellular component found in all
animals, but one which twists into a pathological form in the disease state. The
protein-only or prion hypothesis states that when abnormal PrP is produced it
can act as a template for the conversion of more normal PrP to the twisted
pathological form, hence setting in motion a chain reaction that can spread
disease from cell to cell without the need for an infective organism. This
theory has now become the conventional dogma, and elegantly provides a
‘unified theory’ to explain the ‘paradoxical trinity’ of CJD: 1), the
mutations associated with the hereditary TSEs renders PrP inherently unstable,
with a high tendency to fold into the pathological isoform and initiate the
‘chain reaction’, 2) in sporadic disease the initial pathogenic PrP needed
to seed the chain reaction occurs as a rare spontaneous event, and 3) in the
infective form of the disease the inoculated pathogenic PrP initiates the chain
reaction. However, although there is no doubt that prion protein plays a key
role in the pathogenesis of TSEs, the definitive experiment to prove that only
protein is required for infection - converting normal to infective PrP in a test
tube – has not been achieved. Thus the jury is still out on the prion
hypothesis and some still believe that an additional nucleic acid-containing
agent is required for infection.
What
are the clinical features of CJD?
The
typical neurologist sees a patient with CJD every couple of years or so, whereas
a general physician may (but probably won’t) look after one case during their
career and a general practitioner will encounter a patient every 500 years.
However, many clinicians are likely to be asked ‘could it be mad cow disease
doctor?’ Thus, for most us, the main reason for being familiar with the
clinical characteristics of CJD is to be able to rule it out. CJD had
historically been used as a convenient ‘dumping ground’ diagnosis for many
patients with atypical presenile dementias which run a rapid course. However,
over the past 20 years the clinical features of over 1000 cases have been
published, establishing a clear picture of the phenotypical range of disease.
The majority (66%) of cases currently seen in UK are sporadic, about 26% are
variant CJD and the remainder are familial or iatrogenic. A history of growth
hormone exposure, neurosurgery or corneal transplantation characterises the
latter, and many (but far from all) of the familial cases will have other
affected family members, although often with what was considered to be another
form of dementia or psychiatric disorder.
Sporadic
CJD characteristically affects persons in the age range 50-80 and can present
with a protean range of symptoms.
7
However, the vast majority first have (in order of decreasing frequency)
cognitive symptoms, unsteadiness or visual disturbance (including blurring,
field defects).
7
Due to the rapid nature of the disease most suffers will deteriorate over the
space of weeks and will have early objective evidence of cognitive impairment
and soon develop neurological signs, most often in the form of ataxia. Thus a
patient complaining of neurological symptoms, without objective evidence of
cognitive impairment is unlikely to have sporadic CJD, particularly if they fail
to show evidence of cognitive decline over the ensuring weeks.
Variant
CJD typically affects a younger age group (13-45 years),
8
although a case aged 74 has been reported.
9
The early clinical evolution is relatively distinct from sporadic CJD:
presentation is usually with psychiatric symptoms (dysphoria, withdrawal,
anxiety, insomnia, and loss of interest) or less often persistent painful
sensory disturbance (pain, paraesthesia, dysaesthesia or burning in the limbs,
body or face).
10
Neurological signs occur on average about five months from onset, most often in
the form of gait disturbance. At a similar stage, symptoms of cognitive
impairment often occur. All cases that underwent neuropsychometry had clear
abnormalities, although assessments were only performed several months after the
onset of symptoms and therefore it is unclear whether cognitive impairment is a
very early sign. The early psychiatric symptoms of variant CJD are non-specific,
but the failure to develop persistent painful sensory disturbance, unsteadiness
or cognitive impairment after several months argues against the diagnosis.
The
later stages of variant and sporadic CJD are similar, with increasing global
cognitive dysfunction, ataxia, dependency and urinary incontinence, culminating
in the patient becoming bedbound, mute and unresponsive. Involuntary movements,
typically myoclonus, nearly always develop as the illness progresses. A minority
of variant CJD patients developed chorea or dystonia, and some had evidence of
upgaze paresis. The median duration of illness in sporadic and variant CJD is
4.5 and 13 months respectively, the longer duration in the latter being largely
due to the psychiatric prodrome and probably also the ability of younger persons
to survive the complications of debility.
How
can CJD be diagnosed?
Traditionally
the diagnostic armoury for sporadic CJD has consisted of electroencephalography
(EEG – see Figure 1) and
brain biopsy, with post-mortem neuropathology being the gold standard. Although
the latter remains true, the EEG is hampered by poor sensitivity (only about
two-thirds of cases have a characteristic periodic tracing
11
)
and the use of brain biopsy (a potentially dangerous procedure) purely to
confirm a diagnosis of CJD, an untreatable condition, is now frowned upon.
Fortunately two readily available techniques have now been shown to be useful in
separating true CJD cases from suspects with final alternative diagnoses. The
first is lumbar puncture and the second MRI brain scanning. Typically patients
with CJD have neither an excess of white cells nor oligoclonal bands in the
cerebrospinal fluid (as TSEs are not ‘inflammatory’ disorders), but about
one-third have a raised protein, a non-specific finding. However, the detection
of one particular protein, called 14-3-3 (an indicator or neuronal death) has
now been shown in multiple studies to be a highly sensitive (~94%) and specific
(~84%) marker of sporadic CJD.
11
Unfortunately this test is less sensitive (~50%) in detecting variant CJD.
12
However, recent work has reported that elevated CSF tau has a comparably high
sensitivity and specificity in both sporadic and variant CJD (92% vs. 80% and
97% vs. 94% respectively).
12
CSF analysis of these two brain-specific proteins is performed at the CJD
Surveillance Unit in Edinburgh (contact Dr Alison Green 0131 5373075), but
should only be performed on patients with suspected CJD as the specificity will
fall if used as a screening test.
MRI
shows bilateral high signal on long-repetition time sequences (proton density
and T2-weighted) in the striatum (caudate and putamen) in about two-thirds of
sporadic CJD cases (see Figure 2),
but only 7% of controls.
13
In variant CJD a different pattern is seen with the pulvinar of the thalamus
showing prominent bilateral hyperintensity relative to other grey matter, a
finding observed in over 80% of the cases tested and as yet no suspected cases
with a final alternative diagnosis (see
Figure 2). Fluid attenuated inversion recovery (FLAIR) is a relatively new
form of MR imaging that is more sensitive than conventional sequences in
sporadic and variant CJD.
14
Diffusion-weighted imaging (DWI), another novel technique, appears even better
than FLAIR in sporadic CJD,
14
but too little data is available in variant CJD is assess its utility at
present.
The
recognition of the usefulness of CSF 14-3-3 and MRI in sporadic and variant CJD
respectively led to their inclusion in recently revised WHO clinical diagnostic
criteria (see Figure 3 and Figure
4).
15,16
Tonsil biopsy is a somewhat more controversial procedure, given its invasive
nature, that has been shown to be useful in variant but not other forms of CJD:
in the former immunostaining for the abnormal form of PrP is usually positive, a
finding that is claimed to be highly specific.
17
I believe that tonsil biopsy should only be considered in patients with a strong
suspicion of variant CJD in whom MRI is negative.
CJD:
the future?
It has been argued that CJD is the best understood of all neurodegenerative conditions, and certainly great strides have been made in understanding this disease in the past few decades. Despite this, the ‘wish list’ for future breakthroughs is long, and includes a screening test for presymptomatic cases, a method to exclude infectivity in blood and other tissues, non-invasive diagnostic tests highly accurate early in the clinical course, an effective treatment and, ‘the holy grail’, identification of the exact nature of the transmissible agent. Some believe that recent efforts to develop highly sensitive assays for PrP will be rewarded with a blood test for affected and presymptomatic individuals in the next few years. However, such views may be over-optimistic as it is not clear whether most patients with CJD have any potentially detectable abnormal PrP in the blood. We should also be cautious in raising our hopes too high after recent reports of patients being treated with quinacrine. 18 This compound has been reported to ‘cure’ neuroblastoma cell lines infected with scrapie, but it is giant leap from the Petri dish to the hospital ward, and perhaps, a leap that should not have occurred without promising results from in-vivo animal studies. Still, it is encouraging that (well-funded) scientists are prepared, against what seems like massive odds, to search for a cure for a rare neurodegenerative disease rather than dismissing this as alchemy. But what of the search for the holy grail? Scientists from California and Edinburgh’s Neuropathogenesis Unit are leading the hunt, but have different ideas as to what they might find: the Americans believing that the agent will contain only protein and the Scots being sceptical of this view. Who will turn out to be right is anyone’s guess, but what is certain is that unlocking the secret of the TSE agent will lead to new ideas for diagnostic tests and therapy, and will likely be helpful in our understanding of the more common disorders in which protein conformation seems to play an important role, such as Alzheimer’s disease. 19
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