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The History of TSE (Prion Diseases) Caring for a loved one with CJD Getting tested for the CJD Mutation
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SPORADIC CJD Sporadic CJD occurs in a random distribution all over the world, and has no known genetic or environmental cause. It apparently arises from a one-in-a-million spontaneous conversion of a normal cellular protein (encoded by a gene on chromosome 20) into an abnormal 3-dimensional shape, or configuration. Once converted, the abnormal molecule is thought in some way to compel normal molecules of newly synthesized protein to assume the same abnormal configuration, leading to aggregated deposits in and around cells of the central nervous system, and causing neuronal degeneration and symptomatic disease. Sporadic CJD chiefly affects people between 50 and 75 years of age, but can occur as early as adolescence, and as late as the 9th decade of life (by which time it may be mistaken as 'senility'). The age distribution of a large series of cases referred to the National Institutes of Health is shown in Figure 1. Symptoms We
need only look at the brains of deceased patients to understand the great
variety of neurological symptoms and signs that can be seen in CJD.
To the naked eye, the brain usually has a somewhat shrunken
appearance (atrophy) because of the severe loss of nerve cells.
Under the microscope (Figure 2), the loss of cells and spongy degeneration
can
be seen to affect virtually every area of the brain, but with an
unpredictably ‘patchy’ distribution.
One or more regions of the cerebral cortex are always affected to
some degree, and two other regions of the brain are usually also involved:
the deep lying basal ganglia and caudate nuclei, and the cerebellum, both
of which moderate body movements and coordination. In
a majority of patients, the onset of illness involves some form
of mental deterioration or emotional disturbance.
More often than not the earliest symptom is a simple loss of
memory, and is more likely to be noticeable in younger than older
patients, whose mental lapses are often attributed to aging.
Sometimes the patient is the first to notice this change, sometimes
family or friends, and sometimes associates at work. Other signs of mental deterioration may also occur, ranging
from subtle losses of reasoning ability to episodes of confusion about
time or place, or even to gross hallucinations.
Emotional abnormalities may occur in the form of depression or
anxiety, or as bizarre or uncharacteristic behavior. Many
patients become aware of physical abnormalities at about the same time as
(or even before) the onset of mental or emotional abnormalities.
Typically, the first signs involve difficulty in walking or
climbing stairs (gait ataxia). Incoordination can
also affect other body movements, for example, an inability
to manipulate eating utensils, or to speak clearly.
Another physical disturbance that often occurs coincident with or
shortly after the onset of mental symptoms involves vision.
At first, this may be just a vague sense of blurred or
‘clouded’ vision and not infrequently leads the patient to visit an
eye doctor. A more dramatic
symptom is dizziness, or even vertigo, which is usually accompanied by
rapid horizontal eye movements (nystagmus).
Other, less common visual disturbances are a change in color
perception, or partial paralysis of eye movements. These
three broad categories of symptomatic disease – mental or emotional
deterioration, incoordination (especially of gait), and visual
disturbance, alone or in combination – represent the earliest
abnormalities in the great majority of patients with CJD, and their
progressive severity over a matter of a few weeks is almost always cause
for an initial medical contact (Table 1).
Examination at this time may reveal surprisingly few objective
physical signs, in spite of symptoms that to the patient are obvious, and
this early disproportion between symptoms and signs has been responsible
for a great deal of criticism of the medical profession by the families of
patients with CJD, who ask (in retrospect) why the diagnosis was not
considered earlier. The
answer is that several more common diseases (especially Alzheimer’s
disease) can mimic the early symptoms and signs of CJD, so that the
physician is obliged to rely on the passage of time and progression of
disease to winnow away these equally plausible alternative diagnostic
possibilities. As
the disease evolves, the mental and emotional deterioration progress to a
global dementia, incoordination advances to the point of inability to walk
or sit or take care of oneself, and visual symptoms may progress to
apparent blindness. Additional
physical abnormalities also become evident, especially involuntary
movements, most often in the form of muscle twitching (myoclonus) often
first noticed at night but later becoming continuous, and less frequently
as the twisting or writhing movements of choreoathetosis, the repetitive
tremors of Parkinsonism, or even as classical epileptic seizures.
Muscle weakness or paralysis, or sensory symptoms such as pain,
numbness, or ‘pins and needles’ occur in a minority of patients.
Towards the end of the clinical course, the patient lies in a mute,
unresponsive and often rigid state of bedridden helplessness that is
terminated by either a fatal infection or aspiration, usually within a few months
after the onset of illness (Figure 3). Historically,
certain distinctive clinical patterns were recognized and given individual
names such as Heidenhien’s variant (dementia with prominent visual
symptoms), or Brownell-Oppenheimer variant (dementia with prominent
cerebellar symptoms), and more recently a form of CJD with prominent
insomnia has been reported as ‘Fatal Insomnia’.
In point of fact, CJD comprehends a nearly continuous spectrum of
neurologic and psychiatric symptomatology, and although physicians and
scientists are constantly tempted by the exercise of classification, the
continuing use of these sobriquets is both confusing and illogical. Laboratory
aids to diagnosis
A
good history and physical examination are sufficient to make a correct
diagnosis fairly early in the course of illness in nearly all patients
with the typical features of CJD, and at least raise a suspicion
in most patients with an atypical illness.
However, we now have three laboratory tests that provide valuable
assistance in difficult or uncertain cases. The
first of these tests, electroencephalography (EEG), has been used for many
years as a supplementary examination in patients with neurological
disease. In CJD, a periodic
sharp wave pattern occurs in two thirds of cases, and in its most
characteristic form of electrocardiogram-like regularity is seen in very few other
diseases (Figure 4). A less
definite but still suggestive periodic pattern is called ‘burst wave
suppression’, in which short periods of comparative electrical silence
are broken by a quick succession of sharp waves. The
second test requires a special analysis of the spinal fluid for the
presence of a protein designated as ‘14-3-3’ that is released from
damaged or dying nerve cells, and is detectable in over 90% of patients
with CJD. As with the EEG, it is not entirely specific, and can be
detected in some patients with other disorders such as viral encephalitis,
the acute oxygen deficiency often associated with strokes, and
Alzheimer’s disease. Apart
from Alzheimer’s disease, these disorders can usually be easily
distinguished from CJD by the clinical history and routine spinal fluid
examination. The
third test, magnetic resonance imaging (MRI), has only recently been
appreciated as a useful radiological aid to the diagnosis of CJD. In about 80% of cases, an increased signal can be seen to
‘light up’ the basal ganglia on one or both sides of the brain (Figure
5). Because radiologists are
usually searching for asymmetrical radiological changes, the significance
of these often bilateral bright spots was overlooked for many years. They may also be seen in cases of Wilson’s disease and in
carbon monoxide poisoning, disorders that are readily distinguished
clinically from CJD. None of these tests is sensitive enough to identify every case of CJD, and none is entirely specific for the diagnosis (Table 2); however, if two or all three of them are positive, the diagnosis is virtually certain to be CJD, no matter how atypical the illness, and no matter what the clinical supposition. Because of the availability of this battery of laboratory tests, brain biopsy is no longer needed or advised in the diagnostic evaluation of suspected cases of CJD. Prevention
and therapy No effective therapy for TSE has yet been discovered, although attempts have been made to prevent or treat infections in experimental animal models for decades, and several laboratories continue to work intensively on the problem. Sporadic TSE remains the pre-eminent problem because it accounts for about 90% of all cases, and because it appears to arise from within the brain itself, thus negating any strategy based on blocking the entry of the infectious agent from outside the brain. For this form of TSE, the most plausible strategy resides in the development of ‘beta blockers’ – drugs that slow down the formation of beta-sheeted ‘prion’ protein, or that accelerate or re-route its normal metabolic pathways. A number of such drugs are presently under investigation for both CJD and Alzheimer’s disease, and a few are showing promise of not only arresting the disease process in experimental models, but in some cases, reversing the process, which would be especially valuable for patients in whom the disease has already led to significant mental and physical impairment. Table
1. Clinical
characteristics of sporadic Creutzfeldt-Jakob disease
Based
upon the NIH series of 232 experimentally transmitted cases. Table
2. Laboratory
aids in the diagnosis of transmissible spongiform encephalopathy.
Note:
cerebral
biopsy is shown only for comparison - it is no longer either necessary or
recommended as a diagnostic procedure.
Figure legends Figure 1. Age at onset of illness in 232 cases of sporadic CJD referred to the National Institutes of Health. Figure 2. Comparison of the microscopic appearance of normal brain (left side) and CJD brain (right side). Note the many vacuoles ( 'sponginess') of the CJD brain. Figure 3. Duration of illness in 232 cases of sporadic CJD referred to the National Institutes of Health. Figure 4. Electroencephalograms (EEGs) of two patients with sporadic CJD. Lower tracing shows the highly specific periodic sharp wave pattern; upper tracing shows a less specific but suggestive 'burst-suppression' pattern. Figure
5.
Magnetic resonance image (MRI) of a patient with sporadic
Creutzfeldt-Jakob disease. The
right basal ganglia (arrow) is abnormally bright. Back To Top Back To Front Page |
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