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What is Creutzfeldt-Jakob disease?• Creutzfeldt-Jakob disease (CJD) is a rapidlyprogressive, invariably fatalneurodegenerative disorder believed to becaused by an abnormal isoform of a cellularglycoprotein known as the prion protein. CJDoccurs worldwide and the estimated annualincidence in many countries, including theUnited States, has been reported to be aboutone case per million population.
Clinical Features• Nonspecific prodromal symptoms occur in about a third of patients withCJD and may include fatigue, sleep disturbance, weight loss, headache,anxiety, vertigo, malaise, and ill-defined pain. Most patients with CJDpresent with deficits in higher cortical function. These deficits almostalways progress over weeks or months to a state of profound dementiacharacterized by memory loss, impaired judgment, and a decline invirtually all aspects of intellectual function. A few patients present witheither visual impairment or cerebellar gait and coordination deficits.Frequently the cerebellar deficits are rapidly followed by progressivedementia. Visual problems often begin with blurred vision and diminishedacuity, rapidly followed by dementia.• Other symptoms and signs include extrapyramidal dysfunction manifestedas rigidity, masklike facies, or (less commonly) choreoathetoidmovements; 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, ormenstruation.
Myoclonus• Most patients (90%) with CJD exhibit myoclonus thatappears at various times throughout the illness. Unlikeother involuntary movements, myoclonus persistsduring sleep. Startle myoclonus elicited by loud soundsor bright lights is frequent. It is important to stress thatmyoclonus is neither specific nor confined to CJD andtends to occur later in the course of CJD. Dementiawith myoclonus can also be due to Alzheimers disease(AD), dementia with Lewy bodies, corticobasaldegeneration, cryptococcal encephalitis, or themyoclonic epilepsy disorder Unverricht-Lundborgdisease.
Diagnosis• The constellation of dementia, myoclonus, and periodic electrical bursts inan afebrile 60-year-old patient generally indicates CJD. Clinicalabnormalities in CJD are confined to the CNS. Fever, elevatedsedimentation rate, leukocytosis in blood, or a pleocytosis in cerebrospinalfluid (CSF) should alert the physician to another etiology to explain thepatients CNS dysfunction.• Variations in the typical course appear in inherited and transmitted formsof the disease. fCJD has an earlier mean age of onset than sCJD. In GSSdisease, ataxia is usually a prominent and presenting feature, withdementia occurring late in the disease course. GSS disease typicallypresents earlier than CJD (mean age 43 years) and is typically more slowlyprogressive than CJD; death usually occurs within 5 years of onset. FFI ischaracterized by insomnia and dysautonomia; dementia occurs only in theterminal phase of the illness. Rare sporadic cases have been identified.vCJD has an unusual clinical course, with a prominent psychiatricprodrome that may include visual hallucinations and early ataxia, whilefrank dementia is usually a late sign of vCJD.
Laboratory Tests• The only specific diagnostic tests for CJD and other human prion diseasesmeasure PrPSc. The most widely used method involves limited proteolysisthat generates PrP 27-30, which is detected by immunoassay afterdenaturation. The conformation-dependent immunoassay (CDI) is basedon immunoreactive epitopes that are exposed in PrPC but buried in PrPSc.In humans, the diagnosis of CJD can be established by brain biopsy if PrPScis detected. If no attempt is made to measure PrPSc, but the constellationof 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 gangliahyperintensity on FLAIR and diffusion-weighted MRI for the diagnosis ofCJD have greatly diminished the need for brain biopsy in patients withsuspected CJD. Because PrPSc is not uniformly distributed throughout theCNS, the apparent absence of PrPSc in a limited sample such as a biopsydoes not rule out prion disease. At autopsy, sufficient brain samplesshould be taken for both PrPSc immunoassay, preferably by CDI, andimmunohistochemistry of tissue sections.
• T2-weighted (FLAIR) MRI showing hyperintensity in the cortex in a patient with sporadicCJD. This so-called "cortical ribboning" along with increased intensity in the basal ganglia onT2 or diffusion-weighted imaging can aid in the diagnosis of CJD.
Care of Cjd Patients• Although CJD should not be considered either contagious orcommunicable, it is transmissible. The risk of accidental inoculation byaerosols is very small; nonetheless, procedures producing aerosols shouldbe performed in certified biosafety cabinets. Biosafety level 2 practices,containment equipment, and facilities are recommended by the Centersfor Disease Control and Prevention and the National Institutes of Health.The primary problem in caring for patients with CJD is the inadvertentinfection of health care workers by needle and stab wounds.Electroencephalographic and electromyographic needles should not bereused after studies on patients with CJD have been performed.• There is no reason for pathologists or other morgue employees to resistperforming autopsies on patients whose clinical diagnosis was CJD.Standard microbiologic practices outlined here, along with specificrecommendations for decontamination, seem to be adequate precautionsfor 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 findingthat phenothiazines and acridines inhibit PrPSc formation in cultured cells led toclinical studies of quinacrine in CJD patients. Unfortunately, quinacrine failed toslow the rate of cognitive decline in CJD, possibly because therapeuticconcentrations in the brain were not achieved. Although inhibition of the P-glycoprotein (Pgp) transport system resulted in substantially increased quinacrinelevels in the brains of mice, the prion incubation times were not extended bytreatment with the drug. Whether such an approach can be used to treat CJDremains to be established.• Like the acridines, anti-PrP antibodies have been shown to eliminate PrPSc fromcultured cells. Additionally, such antibodies in mice, either administered byinjection or produced from a transgene, have been shown to prevent prion diseasewhen prions are introduced by a peripheral route, such as intraperitonealinoculation. Unfortunately, the antibodies were ineffective in mice inoculatedintracerebrally with prions. Several drugs, including pentosan polysulfate as well asporphyrin and phenylhydrazine derivatives, delay the onset of disease in animalsinoculated intracerebrally with prions if the drugs are given intracerebrallybeginning soon after inoculation.