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Recognizing and Managing Creutzfeldt-Jakob Disease in Primary CareAlison Patrick, PA-S; Pamela Wireman, MPAS, PA-CAbstractNot only is Creutzfeldt-Jakob disease (CJD) a very rare disease, its presentation is often similar tomany other neurological diseases resulting in a high rate of misdiagnosis in patients. CJD ischaracterized by a rapidly progressive dementia as well as other neurological symptoms. Diagnosis isbased on clinical, MRI, and laboratory findings. Although no treatment exists at this time, affectedpatients should be provided with appropriate supportive care.IntroductionCreutzfeldt-Jakob disease (CJD) belongs to a rare class of diseases known as prion diseases or”Transmissible Spongiform Encephalopathies” (TSEs). Also included in this class are Gerstmann-Sträussler-Scheinker (GSS) and Fatal Familial Insomnia (FFI) in humans, and Bovine SpongiformEncephalopathy (commonly known as Mad Cow Disease) and Chronic Wasting Disease in animals. 15However CJD remains the most common prion disease to affect humans, with an incidence of about 1out of 1 million people year worldwide and affecting around 300 people in the U.S each year. 8,10 Priondiseases are characterized by their long incubation periods and rapid progression to death oncesymptoms appear. Symptom onset usually begins between 50-70 years of age for the majority ofpatients, followed by death within a year. 6,8,11Though CJD is uncommon, the ability to quickly identify features of the disease is paramount.Many cases of CJD are incorrectly diagnosed initially due to symptoms that mimic more commondiseases (such as viral encephalitis, Alzheimer’s disease, paraneoplastic disorders) and failure to includeprion diseases in the differential diagnosis by many primary care providers and neurologists. 3 In oneretrospective study, only 18% of patients with CJD were diagnosed correctly on initial assessment. 3 Themean time from onset of symptoms to diagnosis was around 8 months, thus patients were 2/3 of theway through their disease course before a correct diagnosis was made. 3 On top of this, 2/3 of radiologyreports failed to recognize the pathognomonic feature of CJD on MRI. 3 Because of this, patients with CJDoften undergo a barrage of testing and end up with a multitude of misdiagnoses at a time when patientsand family members should be focusing on quality of life, end-of- life planning, and potential enrollmentin clinical trials.Therefore, identification of CJD-like symptoms, inclusion of CJD on the differential diagnosis inpatients presenting with rapidly progressive dementia, and an ability to recognize features of CJD onMRI is essential for primary care providers.PathophysiologyAlthough the cause is not completely understood, it is thought that CJD results from a prionprotein (PrP) changing to an abnormal, potentially transmissible form (denotated as PrP Sc ). 1,2 Thetransmissible form is atypically folded and induces normal prion proteins to misfold through directcontact. 1,2 These misfolded proteins can then induce surrounding prion proteins to misfold, therebycausing a chain reaction. 1,2 The misfolded proteins aggregate extracellularly within the CNS, formingstructures called amyloid plaques. 1,2 These plaques cause sponge-like holes to form in neural tissuewhich alters normal tissue structure and function. 1,2 The end result is neuronal death and synaptic loss. 1,2Over the past 10 years, researchers have shown that this mechanism (normal proteins converted to anabnormal form) might also be responsible for more common neurodegenerative diseases likeParkinson’s disease and Alzheimer’s disease. 8Risk FactorsMost cases of CJD occur sporadically (sCJD), meaning the trigger prion protein spontaneouslymisfolded in the affected individual and no prior transmission pattern has been identified. Although norisk factors have been identified for this form of CJD, sCJD occurs worldwide and accounts for 85% ofCJD patients. For this reason, sCJD will be the focus of this article. However, CJD can be acquired throughadditional means, other than spontaneous mutation. When the misfolded prion protein results from amutated prion gene, the gene can be passed down to family members. This is called familial CJD (fCJD).Furthermore, when the disease is transferred unintentionally from an affected person to a non-affectedperson through medical procedures, typically neurosurgery, this is termed iatrogenic CJD (iCJD). Finally,when an abnormal prion protein is transferred from bovine to humans this is known as variant CJD(vCJD). 6 vCJD is called bovine spongiform encephalopathy (BSE) when bovine are known to have thedisease.PrecautionsRegardless of how they are acquired, all types of CJD (including sCJD) are transmissible. 4 Thedisease can be transmitted to other patients if the mutated prion protein is transferred from theaffected individual's brain to an unaffected individual's brain due to contaminated surgical equipment.Therefore, appropriate precautions should be taken in individuals with the disease, such as avoidingbrain procedures and/or following appropriate decontamination procedures in the operating roomincluding autoclaving instruments at high temperatures than would normally be used for sterilization,immersing contaminated instruments in NaOH, and discarding used instruments. 16Because of the risk of probable blood borne transmission of vCJD, the American Red Cross hasadopted policies that include deferral of potential blood donors who lived or visited areas where BSErates were high. 17 This includes anyone living/visiting the United Kingdom for more than three monthssince 1980 or living/visiting Oman, Turkey, or another European country (besides the UK) for more thansix months since 1980. 17Due to the risk of bovine to human transmission of CJD, the US Department of Agriculture hastaken several steps to safeguard food. These safeguards include banning the slaughter of “downercattle” (cattle that should rise on examination but don’t) for consumption, holding the carcasses ofanimals tested for BSE until they are negative, and banning the removal of the last traces of skeletalmuscle from certain areas of the brain, eyes, spinal cord, and vertebral column from cattle 30 months ofage or older. 18 This also includes banning the recovery of meat from the tonsils and small intestine fromall cattle. 18Clinical manifestationsCJD affects many areas of the brain, so its presentation can mimic other neurologic andpsychiatric disorders including Alzheimer’s, Parkinson’s, and Huntington’s disease. However, unlikethese, sCJD is rapidly progressive once symptoms start. 8 Patients often report vague symptoms at first,including malaise, anxiety, mood changes, dizziness, and difficulty concentrating. These initial symptomsare then promptly followed by more obvious cognitive symptoms including amnesia, confusion, andimpaired attention. These symptoms can also be accompanied by visual disturbances, aphasia, apraxia,and myoclonus (spontaneous or induced). 7,8 Approximately, one third of patients present with ataxia inaddition to cognitive impairment.DiagnosisAlthough brain biopsy is the gold standard for the diagnosis of sCJD, it is often unnecessary andcan potentially be dangerous due to the possibility of transmitting the abnormal prion proteins fromcontaminated surgical equipment if not properly decontaminated or discarded. 6 Instead, the CDCrecommends that a ‘probable’ diagnosis be made on the basis of certain clinical features, EEG findings,CSF analysis and MRI studies.The CDC recommends the following criteria for diagnosis: First, patients must present withrapidly progressive dementia and two of the following features: myoclonus, visual or cerebellar signs,pyramidal/extrapyramidal signs, akinetic mutism. Along with these clinical findings, patients must alsohave at least one of the following results after testing: a finding of periodic sharp wave complexes onEEG, a positive 14-3- 3 protein test on CSF analysis, or abnormal signals in the putamen and/or head ofthe caudate nucleus on MRI using diffusion-weighted imaging (DWI) or fluid attenuated inversionrecovery (FLAIR). 6, 9 Along with these findings, there must be no indication of an alternative diagnosis. 9Probable Diagnostic Criteria for sCJDRapidlyprogressivedementiaANDAt least two out of thefollowing:ANDAt least one of thefollowing:ANDNoindication ofanalternativediagnosis1. Myoclonus2. Visual or cerebellarsigns3.Pyramidal/extrapyramidal signs4. Akinetic mutism1. positive EEG findings2. positive MRI findings3. positive 14-3- 3 proteintestIt is important to note however, that none of the above tests are specific for sCJD, and manypatients go undiagnosed despite performing these tests. Because of this, a number of laboratories haveestablished a new approach to diagnosing sCJD known as Real-Time Quaking-Induced Conversion (RT-QUIC). 11 This method involves obtaining a sample of cerebral spinal fluid (or cells deep within thepatient’s nostril) and mixing it with normal recombinant prion proteins (rPrP). The test is positive forsCJD when the sample induces the rPrP substrate to aggregate. 11 Unlike the diagnostic criteriarecommended by the CDC and WHO which involve several tests and provide a specificity of only 70.8%,this technique involves only one laboratory test and is highly sensitive (85.7) as well as specific(100%). 11,14 Although RT-QUIC is not yet available in many laboratories, the test is routinely performed atprion disease surveillance centers in several countries. 6 Modified versions of the test are also beingdeveloped to improve identification of Parkinson’s and Alzheimer’s disease, which are currentlydiagnosed based on clinical findings alone. 12ManagementUnfortunately, there is no effective treatment for CJD at this time. The disease is uniformly fatalwith most patients declining into a vegetative state, followed by death within a year after the onset ofinitial symptoms. 6, 8,11 Management of CJD is therefore supportive. 10 Opiates can help relieve anyassociated pain, and drugs such as sodium valproate and clonazepam may be used to help relievemyoclonus. 10 Feeding and ventilator support may be required in some patients. 19 Primary care providersshould consult with a neurologist for further management. Because CJD is rapidly progressive oncesymptoms begin, end-of- life care including advanced directives, living arrangements, and referral topalliative care should be discussed soon after diagnosis. 19 Finally, enrollment in research and clinicaltrials should be considered. 19Future treatmentAlthough there are currently no effective treatments for CJD, several immunologic approachesare emerging as potential therapeutic options. For instance, anti-prion antibody fragments that bind tomisfolded prion proteins may help prevent their propagation. These studies are showing promise in celland animal trials but they have yet to be tested in humans. 13Take home messageOn average, a patient with sCJD is misdiagnosed 4 times before the correct diagnosis is made. 3Early diagnosis of sCJD is essential not only for the patient and their family members in order to providequality end-of- life care, but also to prevent possible iatrogenic transmission of the disease throughblood or organ donation, surgical equipment, or medical procedures. 3 Therefore, sCJD should beincluded in the initial differential diagnosis for any patient presenting with rapidly progressive dementiaand appropriate workup should be undertaken. Furthermore, in any patient presenting with symptomsof Alzheimer’s, Huntingdon’s, or Parkinson’s disease, the astute clinician should consider CJD. 3 In otherwords, in patients presenting with any neurological symptoms, primary care providers must be carefulnot to forget about sCJD. Creutzfeldt-Jakob disease is a rapidly progressive, debilitating disease, andearly diagnosis is essential to ensure that patients are provided the best care and are able to make themost out of the time they have left.Resources:Robbins SL, Cotran RS, Kumar V, et al., eds. (1999). Robbins pathologic basis of disease.Philadelphia: Saunders. ISBN 0-7216- 7335-X.Du Plessis, DG. (2008). Prion protein disease and neuropathology of prion disease.Neuroimaging Clinics of North America, Volume 18, Issue 1, pg 163-182Paterson RW, Torres-Chae CC, Kuo AL, et al. Differential diagnosis of Jakob-Creutzfeldt disease.Arch Neurol. 2012;69(12):1578–1582. doi: 10.1001/2013.jamaneurol.79. PubMedBrown, P; et al. ;Human spongiform encephalopathy: the National Institutes of Health series of300 cases of experimentally transmitted disease;. Ann. Neurol. 35: 513–529.doi:10.1002/ana.410350504.Prion Disease Test Outperforms Existing Diagnostics in Study. NIH: NIAIDhttps://www.niaid.nih.gov/diseases-conditions/prion- test-outperforms- existing-diagnostics(Accessed June 17, 2017)Brown HG, Lee JM. Creutzfeldt-Jakob Disease. UpToDate. (Accessed on June 17, 2017).Krasnianski et al (2017). Neuropsychological symptoms in Sporadic Creutzfeldt-Jakob DiseasePatients in Germany. Journal of Alzheimer’s Disease.Gianfranco et al (2012). Sporadic human prion diseases: molecular insights and diagnosis. TheLancet. Volume 11, No. 7, pg 618-628CDC's Diagnostic Criteria for Creutzfeldt-Jakob Disease (CJD), 2010https://www.cdc.gov/prions/cjd/diagnostic-criteria.html (Accessed on June 17, 2017)Creutzfeldt-Jakob Disease Fact Sheet (2003). National institute of Neurological Disorders andStroke. https://www.ninds.nih.gov/Disorders/Patient-Caregiver- Education/Fact-Sheets/Creutzfeldt-Jakob- Disease-Fact- SheetLynne et al (2016). Cerebrospinal fluid real-time quaking-induced conversion is a robust andreliable test for sporadic creutzfeldt-jakob disease: An international study. Ann. Neurol. Volume80, Issue 1, pg 160-165.Fairfoul et al (2016). Alpha-synuclein RT-QuIC in the CSF of patients with alpha-synucleinopathies. Ann Clin Transl Neurol. 3(10): 812-818.Cardinale A, Biocca S. (2013). Gene-based antibody strategies for prion diseases. InternationalJournal of Cell Biology.Newey CR, Sarwal A, Wisco D, et al. Variability in diagnosing Creutzfeldt?Jakob disease usingstandard and proposed diagnostic criteria. J Neuroimaging 2013;23:58–63. PubMedPrion Disease. Center for Disease Control and Prevention.https://www.cdc.gov/prions/index.html (Accessed June 18, 2017)Rutala WA, Weber DJ Guideline for disinfection and sterilization of prion-contaminated medicalinstruments.Society for Healthcare Epidemiology of America Infect Control Hosp Epidemiol.2010;31(2):107. Hospital Epidemiology, University of North Carolina School of Medicine, ChapelHill, 27599-7030, USA.Kleinman, S. Blood Donor screen: Medical history. UptoDate. (Accessed July 6, 2017)Brown, H. Variant Creutzfeldt-Jakob Disease. UptoDate (Accessed July 6, 2017)Living with CJD. UCSF Memory and Aging Center. http://memory.ucsf.edu/cjd/livingwithcjd

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