Final Diagnosis -- Creutzfeldt-Jakob Disease



Creutzfeldt-Jakob disease (CJD) is rare, affecting less than one person in a million per year. Though it has been reported to occur at a variety of ages, the median age of onset is in the seventh decade, as in all of the cases presented here. Likewise, these cases illustrate the range in course of the illness, which can be from a few weeks to eight years. However, the average survival from onset of disease is six months. CJD is uniformly fatal. Most patients succumb to pneumonia or from inanation. Early clinical features can be subtle and include malaise, altered personality, emotional lability, and sleep disturbances. Other findings may include hallucinations or delusional ideation. Later manifestations are a rapidly progressive dementia and ataxia with myoclonus. Patients may become mute, or exhibit cortical blindness, with rigidity and spasticity.

Three clinical subtypes for CJD have been described: subacute, intermediate, and amyotrophic. The subacute form, the most common, is characterized by presence of prodromal symptoms before onset of worsening dementia and ataxia. The intermediate type is marked by a long period in which focal or diffuse neurological signs are present before onset of rapidly progressive dementia. Patient with the rare amyotrophic form of CJD have lower motor neuron signs with neurogenic atrophy of muscle along with dementia.

Diagnosis of CJD is aided by an electroencephalogram (EEG). A characteristic pattern of repetitive sharp waves or slow spikes, followed by synchronous triphasic sharp waves against a background of progressively suppressed cortical activity, is seen in 70% of cases. Computed tomographic (CT) and magnetic resonance imaging (MRI) scans may show cerebral atrophy, but are more helpful to rule out other diseases. The most typical findings for CJD are: (1) rapidly progressive dementia with (2) myoclonus and (3) characteristic EEG abnormalities.

The spongiform encephalopathy of CJD is seen microscopically to exhibit many round to oval vacuoles varying in size from one to 50 microns in size in the neuropil of cortical gray matter. These vacuoles may be single or multiloculated. The vacuoles may coalesce to microcysts. Most cases of CJD also demonstrate neuronal loss and gliosis. In general, the longer the course of the disease, the more pronounced the microscopic changes will be.

CJD is a form of spongiform encephalopathy, which can affect animal species such as sheep and cattle, as well as humans. The forms which affect humans include, in addition to CJD, Gerstmann-Straussler-Scheinker's disease, and kuru. The relationship of human spongiform encephalopathy with animal forms of this disease is not clear, but some recently reported cases of CJD in Britain have occurred in younger patients and in conjunction with prevalent "mad cow disease" caused by bovine spongiform encephalopathy. This suggests the possibility of a relationship, but the rarity of CJD cases precludes compelling epidemiologic evidence.

The agent associated with CJD appears to be a prion protein (PrP), a neuronal cell surface sialoglycoprotein that is encoded by a gene on chromosome 20. It is thought that the PrP is converted via a conformational change to an abnormal form of PrP that is protease-resistant and can accumulate in the central nervous system of affected persons. These abnormal PrP's can be transmitted from a person with spongiform encephalopathy to another person, at least by the evidence from transmission via pituitary extracts, corneal transplants, dural grafts, and contaminated electrodes.

How transmission occurs naturally is not clear, though an acquired mutation of the gene encoding for PrP may account for the appearance of sporadic cases. The abnormal PrP can catalyze the conversion of normal to abnormal PrP. Further evidence for genetic mutation comes from the appearance of familial cases of CJD. About 15% of cases are familial, with clusters reported in Chile, Slovakia, and Italy. Transmission in familial cases appears to be autosomal dominant, and the onset is earlier in life than for sporadic cases.


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