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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.
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.
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.