Colorado Surveillance Program for Chronic Wasting Disease Transmission to Humans Lessons from 2 Highly Suspicious but Negative Cases

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OBSERVATION Colorado Surveillance Program for Chronic Wasting Disease Transmission to Humans Lessons From 2 Highly Suspicious but Negative Cases

C. Alan Anderson, MD; Patrick Bosque, MD; Christopher M. Filley, MD; David B. Arciniegas, MD; B. K. Kleinschmidt-DeMasters, MD; W. John Pape, BS; Kenneth L. Tyler, MD

Objective: To describe 2 patients with rapidly progres- Interventions: Clinical evaluation, neuropathological sive dementia and risk factors for exposure to chronic examination, and genetic testing. wasting disease (CWD) in whom extensive testing ne- gated the possible transmission of CWD. Results: Neuropathological and genetic assessment in the 2 patients proved the diagnoses of early-onset Alz- Design/Methods: We describe the evaluation of 2 heimer disease and a rare genetic prion disease. young adults with initial exposure histories and clinical presentations that suggested the possibility of CWD trans- Conclusion: No convincing cases of CWD transmis- mission to humans. sion to humans have been detected in our surveillance program. Patients: A 52-year-old woman with possible laboratory exposure to CWD and a 25-year-old man who had consumed meat from a CWD endemic area. Arch Neurol. 2007;64:439-441

PONGIFORM ENCEPHALOPA- been demonstrated in other tissues, in- thies are a family of degen- cluding skeletal muscle, saliva, and blood erative disorders affecting a of clinically ill CWD-infected deer.5,6 Ex- variety of human and mam- posure to CWD prions could potentially malian species. Issues con- occur through consuming meat or tis- cerningS possible cross-species transmis- sues from infected animals; while process- sion have captured scientific and public ing game; or through unusual pathways attention following the outbreak of a form such as ingesting antler velvet, which is of Creutzfeldt-Jakob disease with un- used in Asian cultures as a traditional usual clinical and histopathological fea- medicine. tures. Now known as variant Creutzfeldt- Chronic wasting disease was first de- Author Affiliations: Jakob disease, the disease was identified scribed as an endemic disease in free- Departments of Neurology in young adults in the United Kingdom and ranging herds of mule deer (Odocoileus (Drs Anderson, Bosque, Filley, linked to consumption of meat from cattle hemionus), white-tailed deer (Odocoileus Arciniegas, Kleinschmidt- infected with bovine spongiform encepha- virginianus), and mountain elk (Cervus ela- DeMasters, and Tyler), lopathy.1 phus nelsoni) in a contiguous area encom- Psychiatry (Drs Anderson, Filley, and Arciniegas), Two other spongiform encephalopa- passing northeastern Colorado, south- Pathology (Dr Kleinschmidt- thies affecting mammals whose meat is western Nebraska, and southeastern DeMasters), Medicine consumed regularly by humans are scra- Wyoming, where disease prevalence av- (Dr Tyler), Microbiology pie in sheep and chronic wasting disease erages 5% in mule deer.7 Subsequently, (Dr Tyler), and Immunology (CWD) in some cervid species. Despite CWD has been found in wild deer in (Dr Tyler); University of more than 200 years of exposure to the Illinois, Kansas, Minnesota, New Mexico, Colorado School of Medicine, scrapie agent in sheep, no evidence of scra- New York, South Dakota, Utah, West Denver; Denver Veterans Affairs pie transmission to humans exists, al- Virginia, Wisconsin, Alberta, and Sas- Medical Center, Denver though this risk cannot be completely ex- katchewan and in captive, ranched deer (Drs Anderson, Filley, cluded.2 Whether humans are susceptible and elk in 10 American states and 2 Ca- Arciniegas, and Tyler); Denver Health Medical Center, Denver to CWD is not known. As with all spon- nadian provinces. The origins of the dis- (Dr Bosque); and Colorado giform encephalopathies, CWD is marked ease are obscure. The earliest recognized Department of Public Health by accumulation of an abnormal isoform cases of CWD occurred in captive deer in and Environment, Denver of the normal brain protein known as the a research facility in Colorado in 1967, and (Mr Pape). prion protein.3,4 Infectious prions have also indirect evidence indicates that the dis-

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 slowing. Other laboratory studies were unremarkable. Ce- rebrospinal fluid findings were unremarkable except for a weakly immunostaining 14-3-3 protein band, an inde- terminate finding for the diagnosis of prion disease. Ge- netic testing of the prion protein gene was normal, re- vealing methionine homozygosity at codon 129. Brain biopsy results were negative for the presence of protease- resistant prion protein but showed definite Alzheimer disease with numerous neuritic plaques and tau-positive neurofibrillary tangles (Figure). Further analysis of brain tissue at the National Prion Disease Pathology Surveil- lance Center was negative for prion disease by Western blot analysis. Subsequent investigation by the state department of health revealed the patient had worked in an area of the laboratory that conducted necropsies on domestic animals and had never been assigned to the Figure. High-power photomicrograph illustrating the numerous neuritic CWD testing laboratory. The Colorado Department of plaques, silver-positive neuropil threads, and neurofibrillary tangles seen on brain biopsy in patient 1 (modified Bielschowsky silver stain, original Public Health and Environment could not confirm that magnification, ϫ600). the technician had ever worked with deer and elk tissues. ease may have been present in wild deer from around that time.8 The mode of spread of CWD is not fully under- CASE 2 stood, but epidemiological studies point to horizontal transmission in herds, and histopathological evidence ex- This 25-year-old right-handed man had a 4-month his- ists for an oral route of exposure.9 tory of progressive gait disturbance, myoclonus, hallu- cinations, slowed cognition, impaired attention, and memory loss. He had hunted deer and elk in a CWD en- METHODS demic area of southern Wyoming and cooked and ate the field-dressed meat. His family history was significant in In conjunction with the Colorado Department of Public Health that his mother had died of a dementing disease at age and Environment human prion disease surveillance program, 40 years, although there was neither a clinical diagnosis in 2001 the University of Colorado School of Medicine established a protocol for conducting thorough clinical evaluation, nor an autopsy. Brain magnetic resonance imaging find- neuropathological assessment, and prion protein testing to as- ings were unremarkable, and electroencephalography sess the possibility of CWD transmission to humans. The main demonstrated 1-Hz high-amplitude periodic sharp wave purpose of the surveillance program is to identify patients with complexes. Other laboratory studies had negative re- an atypical neurological or neuropsychiatric presentation, un- sults. Testing for the 14-3-3 protein had positive results, usual epidemiological features for prion disease such as young but the cerebrospinal fluid was otherwise unremark- age, and significant exposure to potentially CWD-infected deer able. The diagnosis of Gerstmann-Stra¨ussler-Scheinker or elk. The program involves urgent review of potential cases syndrome, a familial prion disease, was confirmed with of human prion disease, and 5 to 10 cases have been screened a detailed autopsy examination and referral of the brain each year. The vast majority of these cases did not suggest hu- to the National Prion Disease Pathology Surveillance Cen- man CWD. This report details 2 peculiar cases we encoun- tered as part of this surveillance in which CWD transmission ter. Autopsy brain tissue showed the presence of protease- was suspected based on initial assessments and which prompted resistant prion protein by Western blot analysis. Genetic a detailed investigation. evaluation revealed the P102L mutation in the prion protein gene with methionine/valine heterozygosity at codon 129. REPORT OF CASES

CASE 1 COMMENT

A 52-year-old right-handed woman presented with a No cases of CWD transmission to humans have been de- 1-year history of progressive memory loss, language im- tected to date. Colorado has implemented a multifac- pairment, visuospatial disturbance, and myoclonus. She eted program to assess the human health risk, if any, of related that she had been a histology technician in a labo- exposure to CWD. This includes making human prion ratory that processed tissue specimens from deer and elk disease a physician-reportable condition, conducting in- with CWD and had handled specimens without wear- vestigations and autopsies on all suspected prion dis- ing gloves. Both she and her family expressed signifi- ease cases, and initiating epidemiological studies on the cant concerns about the possibility of transdermal trans- incidence of human prion disease. Several cases with atypi- mission of CWD. Her family history was negative for cal features investigated as part of this project have been dementia and other neurologic disorders. Brain mag- previously reported,4,10,11 including our second case in a netic resonance imaging showed mild diffuse volume loss, review of prion disease in young patients.4 This patient and electroencephalography demonstrated mild diffuse was presented in an abstract by our group in 200310 and

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 was then included in a review article published in 2004,4 Arciniegas, Kleinschmidt-DeMasters, Pape, and Tyler. prior to completion of our 5-year summary report; this Drafting of the manuscript: Anderson, Filley, Kleinschmidt- case is presented here with updated information. Our DeMasters, Pape, and Tyler. Critical revision of the manu- group recently completed an epidemiological study that script for important intellectual content: Anderson, Bosque, did not reveal any unusual patterns in neurological and Filley, Arciniegas, Kleinschmidt-DeMasters, Pape, and neuropsychiatric mortality associated with areas of Colo- Tyler. Study supervision: Anderson. rado where CWD is endemic.12 Financial Disclosure: None reported. In this report, we describe 2 patients in whom the possibility of human CWD transmission was considered high REFERENCES based on the clinical presentation and exposure history. Despite reported exposures to potentially CWD- 1. Hilton DA. Pathogenesis and prevalence of variant Creutzfeldt-Jakob disease. positive tissues, alternate diagnoses were confirmed by J Pathol. 2006;208:134-141. clinical, neuropathological, and genetic evaluation. Both 2. Bosque PJ. Bovine spongiform encephalopathy, chronic wasting disease, scra- patients were found to have rare neurological diag- pie, and the threat to humans from prion disease epizootics. Curr Neurol Neu- noses: early-onset Alzheimer disease in one and a famil- rosci Rep. 2002;2:488-495. 3. Johnson RT. Prion diseases. Lancet Neurol. 2005;4:635-642. ial form of prion disease, proven by identification of an 4. Belay ED, Maddox RA, Williams ES, Miller MW, Gambetti P, Schonberger LB. established gene mutation, in the other. 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