Investigations carried out by a neurologist can be helpful in eliminating other possible psychological illnesses and neurological disorders that may be treatable. Although a definite diagnosis of CJD cannot be made until the brain is examined, these investigations can point toward a possible or probable CJD diagnosis. Figure 4 contains definitions for definite diagnosis, probable diagnosis and possible diagnosis.

Antemortem testing

EEG: An EEG potentially is one of the most useful aids in diagnosing CJD as it may show changes in the brain which are characteristic of the disease. These changes have not been seen in vCJD cases, except a couple very late in their illness.12

Magnetic Resonance Imaging (MRI): In CJD, the MRI scan may look normal except in some cases a certain amount of brain shrinkage (atrophy) may be revealed. MRI is important for ruling out other conditions, such as brain tumor. The MRI may also show relatively specific changes which aid diagnosis, particularly in vCJD.4

Lumbar puncture (Spinal Tap): The presence of the “marker” protein 14-3-3 in the cerebrospinal fluid (CSF) is helpful in diagnosis. Three other “marker” proteins, tau, S100 and NSE, are also occasionally used. Examination of CSF is also done to exclude inflammation or a non-prion infection of the brain as a cause of the symptoms.4

Brain biopsy: If the brain tissue shows characteristic spongiform change or the presence of the abnormal prion protein (PrPSc), then the diagnosis is positive; however, the lack of spongiform change or abnormal prion protein (PrPSc) does not mean a negative diagnosis. Lack of these findings could mean the disease has not affected the part of the brain sampled.4 Furthermore, sporadic and familial fatal insomnia, two other rare prion diseases, often lack spongiform change.13 Brain biopsy is not done routinely because of risk to the patient.4

(Figure 4)

Classifying CJD Diagnosis



Cases in which the abnormal prion protein has been detected in brain tissue (prion proteins may be detected using immunohistochemistry or immunoblot) or histology illustrates characteristic spongiform changes.




Patients with progressive dementia; plus a typical EEG (periodic sharp-wave complexes) during an illness of any duration and/or a positive 14-3-3 CSF assay and a clinical duration to death

of <2 years; plus at least two of the following neurological symptoms: myoclonus, visual and/or cerebellar symptoms, pyramidal and/or extrapyramidal signs or akinetic mutism.




Those fulfilling the above criteria with an illness duration of <2 years but without either the typical EEG abnormalities or positive 14-3-3 CSF assay.



Source: Centers for Disease Control and Prevention: Personal correspondence with Lawrence Schonberger, M.D., M.P.H.



Postmortem testing

Postmortem testing of the brain is necessary to provide a definite diagnosis and definite classification of CJD. Many countries have prion surveillance centers, similar to the National Prion Disease Pathology Surveillance Center in the United States, that solicit brain tissue from deceased individuals suspected of dying from a prion disease and perform diagnostic tests free of charge. These laboratories perform three basic examinations to establish or exclude the diagnosis of a prion disease: histopathology, immunohistochemistry (IHC) and Western Blot. Gene analysis is also performed to determine the subtype of CJD present.


Histopathology: The brain of someone with CJD nearly always shows signs of spongiform change; the brain tissue has the appearance of a sponge when seen under the microscope. Increased number of astrocytes, the cells in the brain which support and supply nutrients to neurons, are often seen in CJD. Often neurons are decreased in number. Plaque deposits of prion protein are seen in only 10 percent of cases of sCJD, virtually all of which belong to the M/V 2 subtype7 (see Figure 5). However, plaques are seen in some cases of familial CJD and iatrogenic CJD caused by growth hormone treatment. In vCJD, where the brain pathology is very characteristic, a particular type of plaque known as a florid plaque is typical of the disease. The florid plaques are round, packed deposits of abnormal prion protein (PrPSc) surrounded by spongiform change.4


Immunohistochemistry (IHC): The presence and distribution of the abnormal prion protein (PrPSc) has been described and correlated to that of the tissue lesions examined histologically.4


Immunoblot/Western Blot: This technique can be highly sensitive for detecting abnormal prion protein (PrPSc). It is often used complementary with IHC because it cannot establish the distribution of the abnormal prion proteins.4

Genetic analysis: Genetic analysis is the most definitive way to establish the presence of familial or genetic CJD. In addition, in order to determine the subtype of CJD, genetic analysis must be conducted to determine the PrP genotype and the presence of the codon for amino acids methionine (M) or valine (V) at position 129 of the human prion protein gene. There are at least six subtypes of sCJD (see Figure 5).


Iatrogenic CJD and sCJD are presently indistinguishable without the clinical history of the decedent.7 Research is underway, however, to develop laboratory techniques to distinguish these illnesses from each other.


Because some early CJD symptoms may be similar to other neurologic diseases, such as Alzheimer’s Disease, it is often necessary for physicians to observe the clinical pattern and duration of the illness before an accurate clinical diagnosis is made. Dr. Harriett Butchko, a physician with postgraduate training in neurology and a principal with an international scientific consulting firm, compared and contrasted the two completely distinct neurodegenerative diseases in “Alzheimer’s Disease vs. Creutzfeld-Jacob Disease”.

In a paper published in the British Medical Bulletin, Pierluigi Gambetti, MD, et. al. describe the different PrP genotypes for sCJD13 (see Figure 5 below).


(Figure 5)


Source: National Prion Disease Pathology Surveillance Center



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