Creutzfeldt-Jakob disease is an unusual neurologic disorder, with a prevalence of approximately 1 case per million population, which is about 1/10,000 that of Alzheimer’s disease. Creutzfeldt-Jakob disease has captured widespread attention, in part because of the recent epidemic of bovine spongiform encephalopathy (“mad cow disease”) and the appearance of 139 cases of “new-variant” Creutzfeldt-Jakob disease, including two in North America. The disorder is due to neuronal degeneration resulting from the accumulation of a pathologic isoform (PrPCJD) of the prion protein (PrPC), a normal cellular protein. Eighty-five percent of cases of Creutzfeldt-Jakob disease are sporadic, with familial and iatrogenic cases accounting for the remainder. Patients with familial Creutzfeldt-Jakob disease have mutations in the gene encoding PrPC (PRNP). Iatrogenic Creutzfeldt-Jakob disease is now exceedingly rare; several hundred cases have been reported, mainly in patients receiving either growth hormone or dural grafts derived from human cadavers.
The name of this disease reflects contributions in the 1920s by the German neurologists Creutzfeldt and Jakob. The clinical findings in the original case described by Creutzfeldt were extremely atypical, and modern review of the neuropathological material makes the diagnosis suspect.
Although Jakob’s cases were heterogeneous, at least two had neuropathological features that were consistent with those of sporadic Creutzfeldt-Jakob disease.
The modern conception of sporadic Creutzfeldt-Jakob disease was brilliantly encapsulated by C. Miller Fisher in 1960. He described the disease as a rapidly progressive dementia, often worsening day by day, with death heralded by the onset of a rigid, akinetic, mute state. Dementia was pleomorphic, including profound memory loss, visual illusions and hallucinations, delusions of all types, and dramatic emotional and mood lability. Almost all patients had myoclonic jerks involving the limbs and face, as well as prominent “startle myoclonus” on stimulation. Although a patient could have almost any cortical or cerebral disturbance ever described, Fisher thought that the unique clinical picture was virtually diagnostic.
The clinical findings in cases of new-variant Creutzfeldt-Jakob disease differ dramatically from those in sporadic cases. In patients with new-variant Creutzfeldt-Jakob disease, symptoms develop at a mean age of 26 years – nearly four decades earlier than in patients with sporadic disease – and many patients present with prominent affective symptoms, including dysphoria, irritability, anxiety, apathy, loss of energy, insomnia, and social withdrawal. The diagnosis is usually not suspected until the neurologic symptoms appear, including cognitive impairment, pain and paresthesias, dysarthria, and gait abnormalities. Myoclonus is a late feature, and startle myoclonus is rarely elicited. The predicted epidemic of new-variant Creutzfeldt-Jakob disease has not yet materialized, and the number of cases in the United Kingdom has declined from a peak of 28 in 2000 to 17 in 2002.
A definitive diagnosis of Creutzfeldt-Jakob disease has long been based on the clinical presentation and confirmed by identification in brain tissue of spongiform degeneration, neuronal loss, and astrogliosis. In 1969, Gibbs and Gajdusek demonstrated that brain tissue from patients with Creutzfeldt-Jakob disease could transmit the disorder to primates, making it, like kuru, a “transmissible spongiform encephalopathy.” The diagnosis was greatly facilitated by the ability to identify PrPCJD in immunoblots of unfixed brain tissue or in formalin-fixed, paraffin-embedded brain tissue. Immunodiagnosis of Creutzfeldt-Jakob disease is established with the use of antibodies that recognize both the normal and pathologic isoforms of PrP, with specificity conferred by tissue pretreatment that preferentially degrades the normal protein while sparing the pathologic one.
The need for brain tissue to confirm the diagnosis of sporadic Creutzfeldt-Jakob disease has been a major impediment to definitive diagnosis before death. Ancillary tests, including electroencephalography (EEG), magnetic resonance imaging (MRI), and cerebrospinal fluid analysis, facilitate the diagnosis but suffer from problems with specificity and sensitivity. The presence of periodic sharp-wave complexes on EEG supports the diagnosis, but these findings can also occur in other disorders. Patients with sporadic Creutzfeldt-Jakob disease may have abnormal patterns of hyperintensity in the basal ganglia on diffusion-weighted MRI sequences, but the specificity and sensitivity of these patterns remain uncertain. Many patients with sporadic Creutzfeldt-Jakob disease have abnormal proteins in their cerebrospinal fluid, most notably the 14-3-3 protein. The specificity of this finding may be as high as 95 percent, but the sensitivity ranges from 45 to 85 percent.
The diagnosis of Creutzfeldt-Jakob disease has been greatly enhanced by the establishment, in 1997, of the National Prion Disease Pathology Surveillance Center at Case Western Reserve University. In addition to its surveillance activities, the Center performs, free of charge, a variety of key diagnostic tests, including Western blots on frozen brain tissue to detect protease-resistant PrP, immunohistochemical tests for PrP on fixed tissue, analysis of DNA extracted from blood or brain tissue for PRNP, and analysis of cerebrospinal fluid for 14-3-3 protein.
For the treatment of moderate pain or moderately severe pain including arthralgia, headache, myalgia, dental pain following oral surgery such as extraction of impacted molars or chronic conditions such as low-back pain, bone pain and cancer-related pain.
Maximum Dosage Limits:
- Adults: 100 mg/dose PO or 400 mg/day PO.
- Elderly >= 75 years: 100 mg/dose PO or 300 mg/day PO.
- Elderly 65 – 74 years: 100 mg/dose PO or 400 mg/day PO.
- Adolescents >= 16 years: 100 mg/dose PO or 400 mg/day PO.
- Adolescents 13 – 15 years: Maximum dosage has not been determined.
- Children: Maximum dosage has not been determined.
The recognition that patients with new-variant Creutzfeldt-Jakob disease have PrPCJD in extraneural sites, including lymphoreticular tissues, has led to the use of tonsil biopsy as an important diagnostic test for this disease. Unfortunately, similarly detectable lymphoreticular reservoirs are not present in sporadic cases of the disease. In this issue of the Journal, Zanusso and colleagues (pages 711-719) report positive immunostaining for pathologic PrP in the cytoplasm and dendrites of olfactory receptor neurons in postmortem specimens of olfactory mucosa from nine of nine patients with sporadic Creutzfeldt-Jakob disease; none of the samples from age-matched control subjects or from control patients with other neurodegenerative diseases were positive. This finding could not be confirmed by detection of PrPCJD in immunoblots of olfactory mucosa lysates unless they were pretreated with phosphotungstic acid to precipitate PrPCJD, a procedure with uncertain implications for specificity.
If confirmed, the results of this study provide evidence of “peripheral” localization of PrPCJD in sporadic Creutzfeldt-Jakob disease and point to the possibility that nasal biopsy could facilitate the diagnosis of sporadic Creutzfeldt-Jakob disease, just as tonsil biopsy has done for new-variant Creutzfeldt-Jakob disease. Although there is no effective therapy for Creutzfeldt-Jakob disease, a sensitive and specific early diagnostic test would greatly facilitate future clinical trials. Clinical studies are currently in progress to evaluate compounds that may inhibit the conversion of PrPC to its pathologic isoforms, including testing of the acridine and phenothiazine derivatives quinacrine and chlorpromazine. Studies in transgenic mice suggest that some forms of PrPC may resist conformational conversion into pathologic isoforms. Overexpression of these “dominant negative” prion proteins can prevent or dramatically retard the development of scrapie in mice, supporting the hypothesis that interference with the conversion of PrPC to its pathologic state represents a potential therapeutic target.
The finding of PrPCJD in nasal neuroepithelium raises intriguing questions about the pathogenesis of sporadic Creutzfeldt-Jakob disease. Does PrPCJD accumulate in nasal neuroepithelium as a consequence of its accumulation in and spread from the brain? Might the nose even serve as a potential portal of entry for infection, as the gastrointestinal tract does in kuru and new-variant Creutzfeldt-Jakob disease?
From the Department of Neurology, University of Colorado Health Sciences Center, and the Denver Veterans Affairs Medical Center – both in Denver.