Creutzfeldt-Jakob Disease

What is Creutzfeldt-Jakob disease?

• Creutzfeldt-Jakob disease (CJD) is a rapidly progressive, invariably fatal neurodegenerative disorder believed to be caused by an abnormal isoform of a cellular glycoprotein known as the prion protein. CJD occurs worldwide and the estimated annual incidence in many countries, including the United States, has been reported to be about one case per million population.

Clinical Features• Nonspecific prodromal symptoms occur in about a third of patients with CJD and

may include fatigue, sleep disturbance, weight loss, headache, anxiety, vertigo, malaise, and ill-defined pain. Most patients with CJD present with deficits in higher cortical function. These deficits almost always progress over weeks or months to a state of profound dementia characterized by memory loss, impaired judgment, and a decline in virtually all aspects of intellectual function. A few patients present with either visual impairment or cerebellar gait and coordination deficits. Frequently the cerebellar deficits are rapidly followed by progressive dementia. Visual problems often begin with blurred vision and diminished acuity, rapidly followed by dementia.

• Other symptoms and signs include extrapyramidal dysfunction manifested as rigidity, masklike facies, or (less commonly) choreoathetoid movements; pyramidal signs (usually mild); seizures (usually major motor) and, less commonly, hypoesthesia; supranuclear gaze palsy; optic atrophy; and vegetative signs such as changes in weight, temperature, sweating, or menstruation.

Myoclonus

• Most patients (90%) with CJD exhibit myoclonus that appears at various times throughout the illness. Unlike other involuntary movements, myoclonus persists during sleep. Startle myoclonus elicited by loud sounds or bright lights is frequent. It is important to stress that myoclonus is neither specific nor confined to CJD and tends to occur later in the course of CJD. Dementia with myoclonus can also be due to Alzheimer's disease (AD), dementia with Lewy bodies, corticobasal degeneration, cryptococcal encephalitis, or the myoclonic epilepsy disorder Unverricht-Lundborg disease.

Diagnosis• The constellation of dementia, myoclonus, and periodic electrical bursts in an

afebrile 60-year-old patient generally indicates CJD. Clinical abnormalities in CJD are confined to the CNS. Fever, elevated sedimentation rate, leukocytosis in blood, or a pleocytosis in cerebrospinal fluid (CSF) should alert the physician to another etiology to explain the patient's CNS dysfunction.

• Variations in the typical course appear in inherited and transmitted forms of the disease. fCJD has an earlier mean age of onset than sCJD. In GSS disease, ataxia is usually a prominent and presenting feature, with dementia occurring late in the disease course. GSS disease typically presents earlier than CJD (mean age 43 years) and is typically more slowly progressive than CJD; death usually occurs within 5 years of onset. FFI is characterized by insomnia and dysautonomia; dementia occurs only in the terminal phase of the illness. Rare sporadic cases have been identified. vCJD has an unusual clinical course, with a prominent psychiatric prodrome that may include visual hallucinations and early ataxia, while frank dementia is usually a late sign of vCJD.

Laboratory Tests• The only specific diagnostic tests for CJD and other human prion diseases

measure PrPSc. The most widely used method involves limited proteolysis that generates PrP 27-30, which is detected by immunoassay after denaturation. The conformation-dependent immunoassay (CDI) is based on immunoreactive epitopes that are exposed in PrPC but buried in PrPSc. In humans, the diagnosis of CJD can be established by brain biopsy if PrPSc is detected. If no attempt is made to measure PrPSc, but the constellation of pathologic changes frequently found in CJD is seen in a brain biopsy, then the diagnosis is reasonably secure (see "Neuropathology," above). The high sensitivity and specificity of cortical ribboning and basal ganglia hyperintensity on FLAIR and diffusion-weighted MRI for the diagnosis of CJD have greatly diminished the need for brain biopsy in patients with suspected CJD. Because PrPSc is not uniformly distributed throughout the CNS, the apparent absence of PrPSc in a limited sample such as a biopsy does not rule out prion disease. At autopsy, sufficient brain samples should be taken for both PrPSc immunoassay, preferably by CDI, and immunohistochemistry of tissue sections.

• T2-weighted (FLAIR) MRI showing hyperintensity in the cortex in a patient with sporadic CJD. This so-called "cortical ribboning" along with increased intensity in the basal ganglia on T2 or diffusion-weighted imaging can aid in the diagnosis of CJD.

Care of Cjd Patients• Although CJD should not be considered either contagious or communicable,

it is transmissible. The risk of accidental inoculation by aerosols is very small; nonetheless, procedures producing aerosols should be performed in certified biosafety cabinets. Biosafety level 2 practices, containment equipment, and facilities are recommended by the Centers for Disease Control and Prevention and the National Institutes of Health. The primary problem in caring for patients with CJD is the inadvertent infection of health care workers by needle and stab wounds. Electroencephalographic and electromyographic needles should not be reused after studies on patients with CJD have been performed.

• There is no reason for pathologists or other morgue employees to resist performing autopsies on patients whose clinical diagnosis was CJD. Standard microbiologic practices outlined here, along with specific recommendations for decontamination, seem to be adequate precautions for the care of patients with CJD and the handling of infected specimens.

Prevention and Therapeutics• There is no known effective therapy for preventing or treating CJD. The finding that

phenothiazines and acridines inhibit PrPSc formation in cultured cells led to clinical studies of quinacrine in CJD patients. Unfortunately, quinacrine failed to slow the rate of cognitive decline in CJD, possibly because therapeutic concentrations in the brain were not achieved. Although inhibition of the P-glycoprotein (Pgp) transport system resulted in substantially increased quinacrine levels in the brains of mice, the prion incubation times were not extended by treatment with the drug. Whether such an approach can be used to treat CJD remains to be established.

• Like the acridines, anti-PrP antibodies have been shown to eliminate PrPSc from cultured cells. Additionally, such antibodies in mice, either administered by injection or produced from a transgene, have been shown to prevent prion disease when prions are introduced by a peripheral route, such as intraperitoneal inoculation. Unfortunately, the antibodies were ineffective in mice inoculated intracerebrally with prions. Several drugs, including pentosan polysulfate as well as porphyrin and phenylhydrazine derivatives, delay the onset of disease in animals inoculated intracerebrally with prions if the drugs are given intracerebrally beginning soon after inoculation.