Creutzfeldt-Jakob Disease

Arun Swaminathan, M.B.B.S.
Sachin Kedar, M.B.B.S., M.D.

Basic Information

Definition

Creutzfeldt-Jakob disease (CJD) is a progressive, fatal, dementing neurologic illness caused by an infectious protein agent known as a prion.

Synonyms

Transmissible spongiform encephalopathy
Prion disease
CJD

Other Prion Diseases

Fatal familial insomnia
Gerstmann-Sträussler-Scheinker syndrome (GSS)
Bovine spongiform encephalopathy (“mad cow” disease)
Kuru

ICD-10CM CODES
A81.00	Creutzfeldt-Jakob disease, unspecified

Epidemiology & Demographics

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Incidence of 1 per 1 million population per year
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Peak age 60 yr (range, 16-82 yr); whereas sporadic cases are seen in an older population, the variant subtype is commonly seen in younger patients
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Most common cause of rapidly progressive dementia, with a disease duration of less than 1 year until death.
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5% to 10% familial; remaining cases are sporadic; iatrogenic cases (corneal or liver transplants, dura mater allograft, human pituitary extract, blood or blood product transfusion, reused medical equipment such as EEG depth electrodes) are very rare—about 1%; variant CJD is caused by ingestion of meat from cows with prion disease and is more commonly seen in Great Britain, but cases from Canada, France, Saudi Arabia, and the U.S. have also been reported

Physical Findings & Clinical Presentation

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Cognitive deficits: Patients present with cognitive deficits (dementing illness—memory loss, behavioral abnormalities, higher cortical function impairment), usually a subacute rapid progressive encephalopathy or dementia. Prodromal symptoms such as fatigue, depression, weight loss, and disorders of sleep and appetite may be seen in about one third of patients. Early stages are characterized by confusion with hallucinations, delusions, and agitation.
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More than 80% will have myoclonus—generalized and exaggerated by startle.
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Pyramidal tract signs (weakness), cerebellar signs (clumsiness), and extrapyramidal signs (parkinsonian features) are seen in more than 50% of the cases.
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Less common features include cortical visual abnormalities, abnormal eye movements, vestibular dysfunction, sensory disturbances, autonomic dysfunction, lower motor neuron signs, and seizures.

Etiology

Small proteinaceous infectious particle (prion): Noninfectious prion protein (PrP) is a cellular protein found on the surfaces of neurons. Normal function is not known. This normal protein is converted to a protease-resistant infectious agent by the infectious prion protein.

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Normal prion protein (PRNP) gene is found on human chromosome 20.
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Methionine and valine distribution on codon 129 of the PRNP determines the six clinical phenotypes of CJD.

Diagnosis

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Definite CJD: neuropathologically confirmed spongiform encephalopathy in a case of progressive dementia
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Probable CJD: history of rapidly progressive dementia (<2 yr) with typical EEG and with at least two of the following clinical features: myoclonus, visual or cerebellar dysfunction, pyramidal or extrapyramidal features, akinetic mutism
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Possible CJD: same as probable CJD without EEG findings

Differential Diagnosis

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Other progressive dementias (Alzheimer’s disease, frontotemporal dementia, Lewy body dementia, and vascular dementia)
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Infectious (viral, HIV, fungal, TB, Whipple’s disease)
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Inflammatory or autoimmune (CNS vasculitis, Hashimoto’s encephalopathy, SSPE)
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Metabolic (vitamin deficiency, endocrine)
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Cancers (CNS lymphoma, gliomatosis cerebri, paraneoplastic)
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Other conditions, toxic (heavy metal poisoning)

A clinical algorithm for the evaluation of dementia is described in Section III, “Dementia.”

Workup

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Evaluate for treatable causes of dementia (see section on “Alzheimer’s Disease”).
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Brain biopsy is gold standard for diagnosis but may not be performed because there is no treatment or cure and there is the potential risk of iatrogenic spread.
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Lumbar puncture with spinal fluid analysis for presence of 14-3-3 protein or human prion protein (PrP^Sc).
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Recent guidelines issued by the American Academy of Neurology states that clinicians should order assays for 14-3-3 in patients with rapidly progressive dementia, strong suspicion of sporadic CJD, and an uncertain diagnosis (pretest probability of 20%-90%). The test has a high false-positive and false-negative rate because of its presence in other chronic noninflammatory dementing diseases.

Laboratory Tests

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Presence of periodic sharp wave complexes on EEG in cases of rapidly progressive dementia has a sensitivity of 67% and a specificity of 86%.
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In cases of probable or possible CJD, presence of the 14-3-3 protein in CSF has a 95% positive predictive value with its absence having a 92% negative predictive value. Test for presence of human prion protein (PrP^Sc) in CSF has been reported to be 83% sensitive and 100% specific. Repeated testing for 14-3-3 protein increases the probability of a positive result. Enolase and neopterin in CSF are the other nonspecific markers that may have adjunct diagnostic value.
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Recent reports indicate that testing of nasal brushings using RT-QuIC, an ultrasensitive, multiwall plate–based fluorescence assay involving PrP^CJD–seeded polymerization of recombinant PrP into amyloid fibrils is accurate in diagnosing CJD.
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PRP^Sc can also be detected in urine samples obtained from patients with variant CJD.
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The National Prion Disease Pathology Surveillance Center at Case Western Reserve University performs specific diagnostic tests free of charge and acts as a reporting center to the CDC.

Imaging Studies

MRI scan can show areas of restricted diffusion in the basal ganglia and/or cerebral cortex. MRI diffusion-weighted imaging has a sensitivity of 92.3% and a specificity of 93.8% only in cases of rapidly progressive dementia. T2-weighted imaging may also show subtle hyperintensities in the lenticular nuclei in about 82% of cases.

Treatment

Nonpharmacologic Therapy

Full-time caregiver or nursing home: Social work can be helpful with end-of-life discussions, family counseling, and optimizing appropriate home services. Proper disposal of medical equipment and avoidance of organ transplants from these patients prevent transmission of the disease.

Acute General Rx

No known therapy

Chronic Rx