In 2001, Stanley Prusiner’s laboratory at the University of California, San Francisco (UCSF)1
demonstrated the potential therapeutic efficacy of both quinacrine and chlorpromazine in an experimental model of prion disease. This finding led to a dramatic increase in referrals for suspected prion disease to UCSF, and over the past 6 years we have conducted comprehensive evaluations on 178 cases of suspected prion disease or RPD (). We made a conclusive diagnosis in 95.5% of these patients, whereas in 4.5%, the diagnosis was dementia, leukoencephalopathy, or encephalopathy of unknown origin. Sixty-two percent of all patients had prion disease, which was sporadic in 75% (72% were pathology proved), genetic in 22%, and acquired in 3% (variant or iatrogenic). In 38% of the RPD patients, we diagnosed a nonprion condition; typically, these cases were diagnostically complex, defying diagnosis despite evaluations by multiple physicians before assessment at UCSF. The breakdown of specific diagnoses for these non-prion RPD cases is shown in .
Fig 1 Diagnosis of University of California, San Francisco (UCSF)–evaluated rapidly progressive dementia (RPD) referrals (N =178) from August 2001 to September 2007. Pie chart showing the percentile of broad categories for final diagnoses of patients (more ...)
Nonprion Diagnoses of Patients in University of California, San Francisco Cohort Initially Suspected of Having Creutzfeldt–Jakob Disease
The largest group of nonprion patients in the UCSF cohort had neurodegenerative diseases, which were found in 14.6% of all cases, accounting for 39% of all nonprion cases. These nonprion dementing conditions included frontotemporal dementia (FTD), corticobasal degeneration (CBD), Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), and progressive supranuclear palsy. All of these dementias can resemble CJD because of the overlap of motor, behavioral, psychiatric, and cognitive manifestations. These disorders sometimes present in a fulminant form, developing over months, with death occurring in less than 3 years.2–4
For nonprion disorders, dementia of unknown cause was the third most common diagnosis, accounting for 4.5% of all and 12% of nonprion cases.
Autoimmune conditions were the second most common group, representing 8.4% of the entire cohort (22% of nonprion cases), and included antibody-mediated limbic encephalitis (LE) associated with cancer (paraneoplastic) or occurring without cancer (non-paraneoplastic), Hashimoto’s encephalopathy (HE), multiple sclerosis, and neurosarcoidosis. HE was diagnosed by identification of highly increased anti-thyroglobulin or anti-thyroperoxidase antibodies in the serum and exclusion of other diseases (including untreated thyroid disease). Antibody-mediated autoimmune syndromes were associated with antibodies directed against the brain. Patients in the autoantibody group often had antibodies in their cerebrospinal fluid (CSF) and/or serum, several of which may not yet be available through commercial testing but can be identified in academic research laboratories. Four RPD patients had encephalitis, but the agent (enterovirus) was identified in only one.5
In the other three patients, the cause was presumed to be viral, but despite thorough evaluation, no virus could be identified. We identified toxic-metabolic causes of RPD in three cases, including methylmalonic academia, encephalopathy secondary to alcohol intoxication, and methotrexate toxicity.
In four patients, we identified encephalopathies associated with cancer (three had lymphoma) but without evidence of autoantibodies. These cases did not immediately suggest cancer or lymphoma, but they had MRI, T2-weighted, white matter hyperintensities that often were contrast enhancing. Virtually all the lymphomas (systemic or central nervous system [CNS]) required biopsy for diagnosis, because CSF evaluation (cytology) and other studies were nondiagnostic. The main subtypes of RPD and the varied conditions that led to a misdiagnosis of CJD are discussed in the following section.