Creutzfeldt-Jakob [CJ] disease
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Introduction
Creutzfeldt-Jakob [CJ] disease is a subacute spongiform encephalopathy & a rare form of a dementia associated with protease-resistant isoform(s) of prion protein.
Etiology
- protease-resistant isoform(s) of prion protein
- iatrogenic transmission has occurred by:
- corneal transplants
- EEG depth electrodes
- cadaveric dural grafts
- growth & gonadotropic hormones from cadaveric pituitary glands
- blood transfusions[11]
- transmission from consumption of cattle
- bovine spongiform encephalopathy (mad cow disease) produces a variant of CJD disease[3]
- no known risk factors
- male/female ratio ~1 (49/51)[26]
- familial form (see genetics)
Epidemiology
- uncommon disorder: incidence is 0.5-1.5/million
- incidence 2007-2020 is 1.5-1.6/million[26]
- most common human prion disease
- peak incidence of CJ occurs between 50-75 years of age
- new variant form occurs in younger patients (mean age 29)
- 90% of cases are sporadic & 10% are familial
- iatrogenic cases are rare
- no seasonal distribution
Pathology
(also see scrapie)
- precipitation of PrPSc in brain, see prion protein
- PrPSc found in:[8]
- brain (100%)
- spleen (36%)
- skeletal muscle (25%)
- tears[25]
- brain biopsy typically shows characteristic neuropathologic features of spongiform encephalopathy
- neuronal loss & astrogliosis
- spongiform change in cortex
- signs of inflammation are absent
Genetics
- 10-15% have family history consistent with autosomal dominant mode of inheritance
- 20 different mutations in prion protein have been described
- polymorphisms at codon 129 (Met/Met Met/Val Val/Val) of the prion protein may influence disease susceptibility
- most CJ patients have the Met/Met form
- all new-variant CJD patients have the Met/Met form
Clinical manifestations
- presentation of dementia & prominent neurologic signs[9]
- rapidly progressive mental deterioration (100%)
- occurs over a period of weeks to months
- death within 1 year
- dementia
- compromise of activities of daily living[4]
- confusion
- behavioral & psychiatric disturbances predominate dominate in variant CJD
- bizarre behavior & visual hallucinations may occur
- social withdrawal[4]
- emotional blunting[4], flat affect
- excessive sleepiness
- anhedonia[4], apathy
- diorientation, inattention, inhibition[22]
- disturbances of gait, vision & balance
- cerebellar ataxia (> 50%, 100% in new-variant form)
- myoclonic jerks (> 80%); startle myoclonus (late)
- cortical blindness (> 20%)
- abnormal extraocular movements (> 20%)
- pyramidal tract signs (> 50%)
- extrapyramidal signs (> 50%)
- vestibular dysfunction (< 20%)
- seizures (< 20%)
- sensory deficits (< 20%)
- persistent painful sensory symptoms in variant form
- cranial nerve abnormalities uncommon
- autonomic abnormalities (< 20%)
- no resting tremor or cogwheel rigidity
* frequency of sign/symptoms in parentheses [from ref 6]
Laboratory
- CSF:
- normal CSF exmamination
- CSF 14-3-3, CSF tau, CSF S100b, CSF NSE in combination of some use[10]
- CSF 14-3-3 of no benefit[16]; insufficiently sensitive or specific[13]
- CSF 14-3-3 sensitivity ~92%, specificity ~80% for CJD
- CSF cystatin-C in CSF may be of use[12]
- report of ability to detect small amounts of PRPSc in CSF[14] (83% sensitivity, 100% specificity)
- CSF real time quaking-induced conversion assay is the most sensitive & specific test for prion proteins in CSF[13][24]
- misfolded prion protein is detectable in tear fluid[25]
- brain biopsy sometimes necessary to establish diagnosis
- immunoblots or prepared sections stain for pathologic protease-resistant isoform of prion protein
- PRNP gene mutation
- sequence analysis of the prion gene (PRNP) shows mutations in familial, but not sporadic or iatrogenic cases
Diagnostic procedures
- distinct periodic EEG
- bilateral synchronous repetitive sharp waves
- pseudo-periodic sharp-wave complexes
- frontally predominant bi/triphasic waves
- lateralizing epileptiform discharges
- slow background
- sensitivity of 67%, specificity of 86%
- new-variant form does not show characteristic EEG changes
- bilateral synchronous repetitive sharp waves
Radiology
- neuroimaging: CT & MRI may show atrophy
- hyperintensities on diffusion-weighted MRI
- cortical ribboning[22]
- increased T2 signal in basal ganglia associated with shorter survival
- case involving basal ganglia & insular cortex[13]
- case involving the parietal cortex & occipital cortex
- hyperintensities on diffusion-weighted MRI
Differential diagnosis
- bismuth subsalicylate toxicity (EEG distinguishes)[7]
- 7% misdiagnosis of treatable cause[15]
- see causes of dementia
- frontotemporal dementia
- frontal lobe &/or anterior temporal lobe abnormality on MRI
- no periodic sharp waves on EEG
- corticobasilar degeneration
- parkinsonism, asymmetric rigidity, visual hallucinations uncommon
- asymmetric cortical atrophy involving posterior frontal lobes & parietal lobes
- no periodic sharp waves on EEG
- Lewy body dementia
- parkinsonism
- rapid eye movement sleep disorder
- no periodic sharp waves on EEG
- frontotemporal dementia
- see causes of dementia
Management
- invariably fatal
- majority of patients die within 6 months
- 96% die within 2 years
- brain material may transmit disease to laboratory animals
- brain material is extremely resistant to disinfection
- disinfect contaminated tissue with formic acid
- quinacrine & chlorpromazine may have some activity[3]
- quinacrine 300 mg/day does not improve 2-month survival of patients with CJD[18]
- doxycycline no better than placebo[19]
- immunotherapy with antibodies that block binding of PrPSc to PrPc may be useful in the future[4]
- prevention:
- absorption to specific resins may prevent transmission through blood transfusion[11]
More general terms
More specific terms
Additional terms
- bovine spongiform encephalopathy; mad cow disease; BSE
- CD230 or major prion protein (PrP)
- scrapie
- WHO diagnostic criteria for Creutzfeldt-Jakob disease (CJD)
References
- ↑ Harrison's Principles of Internal Medicine, 13th ed. Isselbacher et al (eds), McGraw-Hill Inc. NY, 1994, pg 144
- ↑ Harrison's Principles of Internal Medicine, 13th ed., Companion Handbook, Isselbacher et al (eds), McGraw-Hill Inc. NY 1995, pg 721
- ↑ 3.0 3.1 3.2 Journal Watch 21(18):147, 2001 Korth C et al Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease. Proc Natl Acad Sci USA 98:9836, 2001 PMID: https://www.ncbi.nlm.nih.gov/pubmed/11504948
- ↑ 4.0 4.1 4.2 4.3 4.4 4.5 Journal Watch 21(18):147, 2001 Peretz D et al Antibodies inhibit prion propagation and clear cell cultures of prion infectivity. Nature 412:739, 2001 PMID: https://www.ncbi.nlm.nih.gov/pubmed/11507642
- ↑ UCLA Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 12-15, 2001
- ↑ Johnson RT & Gibbs CT Creutzfeldt-Jakob disease and related transmissible spongiform encephalopathies. N Engl J Med. 1998 Dec 31;339(27):1994-2004. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/9869672
- ↑ 7.0 7.1 Geriatrics Review Syllabus, American Geriatrics Society, 5th edition, 2002-2004
- ↑ 8.0 8.1 Journal Watch 23(24):195, 2003 Glatsel M et al, Extraneural pathologic prion protein in sporadic Creutzfeldt- Jakob disease. N Engl J Med 349:1812, 2003 PMID: https://www.ncbi.nlm.nih.gov/pubmed/14602879
- ↑ 9.0 9.1 Journal Watch 24(4):32, 2004 MMWR Morb Mortal Wkly Rep 52:180, 2004 http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5253a2.htm
- ↑ 10.0 10.1 Sanchez-Juan P et al, CSF tests in the differential diagnosis of Creutzfeldt-Jakob disease. Neurology 2006, 67:637 PMID: https://www.ncbi.nlm.nih.gov/pubmed/16924018
Collins SJ et al, Determinants of diagnostice investigation sensitivities across the clinical spectrum of sporadic Creutzfeldt-Jakob disease Brain 2006, 129:2278 PMID: https://www.ncbi.nlm.nih.gov/pubmed/16816392
Cali I et al, Classification of sporadic Creutzfeldt-Jakob disease revisited. Brain 2006, 129:2266 PMID: https://www.ncbi.nlm.nih.gov/pubmed/16923954 - ↑ 11.0 11.1 11.2 Wroe SJ et al, Clinical presentation and pre-mortem diagnosis of variant Creutzfeldt-Jakob disease associated with blood transfusion: A case report. Lancet 2006, 368:2061 PMID: https://www.ncbi.nlm.nih.gov/pubmed/17161728
Gregori L et al, Reduction in infectivity of endogenous transmissible spongiform encephalopathies present in blood by adsorption to selective affinity resins. Lancet 2006, 368:2226 PMID: https://www.ncbi.nlm.nih.gov/pubmed/17189034 - ↑ 12.0 12.1 UniProt http://www.uniprot.org/uniprot/P01034.html
- ↑ 13.0 13.1 13.2 13.3 Medical Knowledge Self Assessment Program (MKSAP) 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 2009, 2012, 2015, 2018, 2021.
- ↑ 14.0 14.1 Atarashi R et al. Ultrasensitive human prion detection in cerebrospinal fluid by real-time quaking-induced conversion. Nat Med 2011 Feb; 17:175 PMID: https://www.ncbi.nlm.nih.gov/pubmed/21278748
- ↑ 15.0 15.1 Chitravas N et al. Treatable neurological disorders misdiagnosed as Creutzfeldt- Jakob disease. Ann Neurology 2011 14 Jun PMID: https://www.ncbi.nlm.nih.gov/pubmed/21674591
- ↑ 16.0 16.1 Muayqil T et al. Evidence-based guideline: Diagnostic accuracy of CSF 14-3-3 protein in sporadic Creutzfeldt-Jakob disease: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology 2012 Oct 2; 79:1499 PMID: https://www.ncbi.nlm.nih.gov/pubmed/22993290
- ↑ Gao C, Shi Q, Tian C et al The epidemiological, clinical, and laboratory features of sporadic Creutzfeldt-Jakob disease patients in China: surveillance data from 2006 to 2010. PLoS One. 2011;6(8):e24231 PMID: https://www.ncbi.nlm.nih.gov/pubmed/21904617
- ↑ 18.0 18.1 Geschwind MD et al Quinacrine treatment trial for sporadic Creutzfeldt-Jakob disease. Neurology. 2013 Dec 3;81(23):2015-23 PMID: https://www.ncbi.nlm.nih.gov/pubmed/24122181
- ↑ 19.0 19.1 Haik S et al. Doxycycline in Creutzfeldt-Jakob disease: A phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol 2014 Feb; 13:150 PMID: https://www.ncbi.nlm.nih.gov/pubmed/24411709
- ↑ Ironside JW. Variant Creutzfeldt-Jakob disease: an update. Folia Neuropathol. 2012;50(1):50-6. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/22505363
- ↑ Lee J, Hyeon JW, Kim SY, Hwang KJ, Ju YR, Ryou C. Review: Laboratory diagnosis and surveillance of Creutzfeldt- Jakob disease. J Med Virol. 2015 Jan;87(1):175-86. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/24978677
- ↑ 22.0 22.1 22.2 22.3 22.4 Narula R, Tinaz S. Creutzfeldt-Jakob Disease. N Engl J Med 2018; 378:e7. Jan 25, 2018 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/29365304 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMicm1710121
- ↑ Kim MO, Geschwind MD. Clinical update of Jakob-Creutzfeldt disease. Curr Opin Neurol. 2015 Jun;28(3):302-10. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/25923128
- ↑ 24.0 24.1 Shir D, Lazar EB, Graff-Radford J et al Analysis of Clinical Features, Diagnostic Tests, and Biomarkers in Patients With Suspected Creutzfeldt-Jakob Disease, 2014-2021. JAMA Netw Open. 2022;5(8):e2225098. Aug 3. PMID: https://www.ncbi.nlm.nih.gov/pubmed/35921110 Free article https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2794883
- ↑ 25.0 25.1 25.2 Schmitz M, Silva Correia S, Hermann P et al Detection of Prion Protein Seeding Activity in Tear Fluids N Engl J Med 2023. May 11;388(19):1816-1817 PMID: https://www.ncbi.nlm.nih.gov/pubmed/37163630 https://www.nejm.org/doi/pdf/10.1056/NEJMc2214647
- ↑ 26.0 26.1 26.2 Crane MA, Nair-Desai S, Gemmill A et al Change in Epidemiology of Creutzfeldt-Jakob Disease in the US, 2007-2020. JAMA Neurol. Published online December 11, 2023. PMID: https://www.ncbi.nlm.nih.gov/pubmed/38079182 PMCID: PMC10714279 (available on 2024-12-11) https://jamanetwork.com/journals/jamaneurology/fullarticle/2812784
- ↑ Uttley L, Carroll C, Wong R, Hilton DA, Stevenson M. Creutzfeldt-Jakob disease: a systematic review of global incidence, prevalence, infectivity, and incubation. Lancet Infect Dis. 2020 Jan;20(1):e2-e10. PMID: https://www.ncbi.nlm.nih.gov/pubmed/31876504 Free article. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(19)30615-2/abstract
- ↑ Centers for Disease Control & Prevention (CDC) Creutzfeldt-Jacob Disease (CJD) CJD Diagnostic Criteria https://www.cdc.gov/creutzfeldt-jakob/hcp/clinical-overview/diagnosis.html
- ↑ NINDS Creutzfeldt-Jakob Disease Information Page https://www.ninds.nih.gov/Disorders/All-Disorders/Creutzfeldt-Jakob-Disease-Information-Page
Creutzfeldt-Jakob Disease Fact Sheet https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Creutzfeldt-Jakob-Disease-Fact-Sheet
Patient information
Creutzfeldt-Jakob disease patient information