Laboratory Diagnosis in Neurology, 1 Ed.

Creutzfeldt-Jakob Disease

M. Otto

Definition of Creutzfeldt-Jakob Disease

Creutzfeldt-Jakob disease (CJD) was first described by the German neuropathologists Hans-Gerhard Creutzfeldt and Alfons Jakob. It is a rare, transmissible neurodegenerative disease. In addition to the sporadic, familial, and iatrogenic forms, there is a new variant (vCJD) which first occurred in Great Britain in 1996 (Will et al., 1996).

Sporadic CJD

Epidemiology

The incidence of CJD is about 1 per million per year. For Germany, this means about 90 new cases each year.

Etiology

About 10–15% of CJD patients suffer from a genetic form of the disease. Iatrogenic cases have occasionally come about through the use of inadequately sterilized instruments during stereotactic surgery or of infected dura mater or corneal transplants. The greatest number of iatrogenic cases occurred in France as the result of contaminated human growth hormone (hGH). In Germany, where the production of hGH switched to genetically engineered preparations in the 1980 s, no such cases are known.

Clinical Features

The core symptom of CJD is rapidly progressive dementia, although visual or cerebellar symptoms often predominate at the onset of the disease. A change in the personality of the patient has also been reported. For simplicity, Masters et al. (1979) compiled a list of criteria for the diagnosis of sporadic CJD, which in slightly modified form is still in use (Table 11.6). As with other forms of dementia, distinctions are made between neuropathologically confirmed, clinically probable, and clinically possible CJD (WHO 1998).

Diagnosis

Establishing the diagnosis is particularly difficult at the onset of the disease, as there are overlaps with practically all other forms of dementia.

EEG. In addition to clinical symptoms, electroencephalography is used to arrive at a diagnosis. Patients with sporadic CJD show typical periodic triphasic complexes, although these only appear in the course of the disease.

CSF analysis. Distinctly elevated levels of tau protein in CSF can contribute to the diagnosis. Tau protein levels are usually above 1300 pg/mL (Fig. 11.2). A positive CSF 14–3-3 protein immunoblot and markedly elevated S 100B protein levels in both serum and CSF support the diagnosis (Otto et al., 2002). The 14–3-3 protein immunoblot usually becomes positive when tau protein levels reach 1000–1300 pg/mL.

Table 11.6 Criteria for the diagnosis of Creutzfeldt-Jakob disease (CJD) (Masters et al., 1979, modified)

Diagnostic classification

Criteria

Definite

• Neuropathological confirmation, and/or

• Immunocytochemical confirmation, and/or

• Positive for prion protein (Western blots), and/or

• Positive for scrapie-associated fibrils (prion rods)

Probable

• Progressive dementia, and

• Typical EEG changes (periodic sharp-wave complexes), or

• SDS-PAGE/immunoblot positive for 14–3-3 protein, and

• At least two of the following four clinical features:

– Myoclonus

– Impaired vision or cerebellar symptoms

– Pyramidal/extrapyramidal dysfunction

– Akinetic mutism

Possible

• Progressive dementia of less than 2 years, and

• Two of the above-mentioned 4 clinical features, but

• Abnormal EEG (or EEG not available)

Other

• The criteria above are not met completely

Genetics. Despite the rarity of CJD, intense research activity has made it possible to define at least six different phenotypes of sporadic CJD. The polymorphism for methionine and valine at codon 129 of the prion protein (PrP) is clinically important. (PrPC is the normal cellular form; PrPCJD is the pathological form in humans and PrPSc in animals.) Homozygotes are clearly overrepresented in the sporadic form of CJD relative to the normal population. In the case of vCJD, only methionine homozygotes (MM) are known. Depending on the electrophoretic migration of the protein-Kresistant part of PrPCJD, a type 1 and a type 2 of the prion protein can be distinguished. The possible combinations between PrP types 1 and 2 and the polymorphism at codon 129 correspond to the neuropathologically and clinically distinct subtypes of CJD (Fig. 11.3). Patients of the methionine/methionine type 1 (MM1) phenotype have a distinctly different course of spontaneous CJD than patients of the valine/valine type 2 (VV2) phenotype.

Neuroimaging. Proton-weighted and T2-weighted images often show hyperintense areas in the basal ganglia. For early diagnosis, the sensitive diffusion-weighted MRI is suitable. It is interesting that patients with a negative 14–3-3 protein immunoblot frequently show prominent changes on MRI.

Variant CJD

Epidemiology

So far, no cases of vCJD are known in Germany. Most patients with vCJD are younger than those with the sporadic form—although patients of 60 years and older have recently been described. In the younger age group, the classic sporadic form of CJD is extremely rare.

Clinical Features

Patients with vCJD show clear differences from patients with sporadic CJD. Psychiatric symptoms (behavioral abnormalities, depression, anxiety) predominate in the early stage (Table 11.7). Some patients develop distal dysesthesia. All patients show ataxia and develop progressive dementia. At about 14 months, the duration of illness before death is twice as long as in the classic sporadic form of CJD.

Diagnosis

So far, all vCJD patients have been homozygous for methionine at codon 129 of the prion protein. T2-weighted MRI often reveals hyperintense areas in the pulvinar. The patients also show elevated CSF levels of tau protein and S 100B. Tau protein levels are usually above 600 pg/mL.

References

Otto M, Wiltfang J, Cepek L, et al. Tau protein and 14–3-3 protein in the differential diagnosis of Creutzfeldt-Jakob disease. Neurology 2002;58:192–197

WHO. Consensus on criteria for sporadic CJD. Geneva: WHO; 1998.

Will R, Ironside JW, Masters CL, et al. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 1996;347:921–925

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Fig. 11.2 Boxplot of tau protein levels in the CSF of patients with Creutzfeldt-Jakob disease (CJD), other forms of dementia, and nondemented controls. The boxplot shows the 10th, 25th, 50th, 75th, 90th percentiles and outlying values. The bar represents the level at which the 14–3-3 protein immunoblot becomes positive.

image

Fig. 11.3 Classification of sporadic Creutzfeldt-Jakob disease on a molecular basis. M, methionine; V, valine.

Further Reading

Kretzschmar HA, Neumann M. Neuropathological diagnosis of neurodegenerative and dementia diseases. Pathologe 2000;21:364–374

Poser M, Zerr I, Schroeter A, et al. Clinical and differential diagnosis of Creutzfeldt-Jakob disease. Arch Virol Suppl 2000;16:153–159

Table 11.7 Diagnostic criteria for variant Creutzfeldt-Jakob disease (vCJD)

I

A

Progressive neuropsychiatric disease

 

B

Duration of disease > 6 months

 

C

Routine examinations do not yield an alternative diagnosis

 

D

No evidence of iatrogenic CJD

 

E

No evidence of familial CJD

II

A

Early psychiatric symptoms

 

B

Persistent painful sensory symptoms

 

C

Ataxia

 

D

Myoclonia or choreatic symptoms or dystonia

 

E

Dementia

III

A

EEG does not show pattern typical of sporadic CJD (or EEG is not possible)

 

B

MRI shows bilateral symmetric signal intensity in the pulvinar

IV

A

PrPCJD-positive tonsil biopsy

Definite vCJD

IA and neuropathologic confirmation of vCJD

Probably vCJD

I and 4 out of 5 symptoms from II, III A, III B

and IV A; or

I and IV A

Possible vCJD

I and 4 out of 5 symptoms of II and III A