Contents

Search

Creutzfeldt-Jakob [CJ] disease

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: 1) protease-resistant isoform(s) of prion protein 2) iatrogenic transmission has occurred by: a) corneal transplants b) EEG depth electrodes c) cadaveric dural grafts d) growth & gonadotropic hormones from cadaveric pituitary glands e) blood transfusions [11] 3) transmission from consumption of cattle - bovine spongiform encephalopathy (mad cow disease) produces a variant of CJD disease [3] 4) no known risk factors 5) male/female ratio ~1 (49/51) [26] 6) familial form (see genetics) Epidemiology: 1) uncommon disorder: incidence is 0.5-1.5/million - incidence 2007-2020 is 1.5-1.6/million [26] 2) most common human prion disease 3) peak incidence of CJ occurs between 50-75 years of age - new variant form occurs in younger patients (mean age 29) 4) 90% of cases are sporadic & 10% are familial 5) iatrogenic cases are rare 6) no seasonal distribution Pathology: (also see scrapie) 1) precipitation of PrPSc in brain, see prion protein 2) PrPSc found in: [8] a) brain (100%) b) spleen (36%) c) skeletal muscle (25%) d) tears [25] 3) brain biopsy typically shows characteristic neuropathologic features of spongiform encephalopathy a) neuronal loss & astrogliosis b) spongiform change in cortex c) signs of inflammation are absent Genetics: 1) 10-15% have family history consistent with autosomal dominant mode of inheritance 2) 20 different mutations in prion protein have been described 3) polymorphisms at codon 129 (Met/Met Met/Val Val/Val) of the prion protein may influence disease susceptibility a) most CJ patients have the Met/Met form b) all new-variant CJD patients have the Met/Met form Clinical manifestations: 1) presentation of dementia & prominent neurologic signs [9] 2) rapidly progressive mental deterioration (100%) a) occurs over a period of weeks to months b) death within 1 year c) dementia - compromise of activities of daily living [4] d) confusion e) 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 f) diorientation, inattention, inhibition [22] 3) disturbances of gait, vision & balance 4) cerebellar ataxia (> 50%, 100% in new-variant form) 5) myoclonic jerks (> 80%); startle myoclonus (late) 6) cortical blindness (> 20%) 7) abnormal extraocular movements (> 20%) - horizonal gaze nystagmus [22] 8) pyramidal tract signs (> 50%) - hyperreflexia 9) extrapyramidal signs (> 50%) 10) vestibular dysfunction (< 20%) 11) seizures (< 20%) 12) sensory deficits (< 20%) - persistent painful sensory symptoms in variant form 13) cranial nerve abnormalities uncommon 14) autonomic abnormalities (< 20%) 15) no resting tremor or cogwheel rigidity * frequency of sign/symptoms in parentheses [from ref 6] Laboratory: 1) CSF: a) normal CSF exmamination b) 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 c) CSF cystatin-C in CSF may be of use [12] d) report of ability to detect small amounts of PRPSc in CSF [14] (83% sensitivity, 100% specificity) e) CSF real time quaking-induced conversion assay is the most sensitive & specific test for prion proteins in CSF [13,24] 2) misfolded prion protein is detectable in tear fluid [25] 3) brain biopsy sometimes necessary to establish diagnosis a) immunoblots or prepared sections stain for pathologic protease-resistant isoform of prion protein b) PRNP gene mutation - sequence analysis of the prion gene (PRNP) shows mutations in familial, but not sporadic or iatrogenic cases Special laboratory: 1) distinct periodic EEG a) bilateral synchronous repetitive sharp waves 1] pseudo-periodic sharp-wave complexes 2] frontally predominant bi/triphasic waves 3] lateralizing epileptiform discharges b) slow background c) sensitivity of 67%, specificity of 86% d) new-variant form does not show characteristic EEG changes 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 * MRI images [22] 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 Management: 1) invariably fatal a) majority of patients die within 6 months b) 96% die within 2 years 2) brain material may transmit disease to laboratory animals 3) brain material is extremely resistant to disinfection -> disinfect contaminated tissue with formic acid 4) quinacrine & chlorpromazine may have some activity [3] - quinacrine 300 mg/day does not improve 2-month survival of patients with CJD [18] 5) doxycycline no better than placebo [19] 6) immunotherapy with antibodies that block binding of PrPSc to PrPc may be useful in the future [4] 7) prevention: - absorption to specific resins may prevent transmission through blood transfusion [11]

Related

bovine spongiform encephalopathy; mad cow disease; BSE CD230 or major prion protein (PrP) scrapie WHO diagnostic criteria for Creutzfeldt-Jakob disease (CJD)

Specific

variant Creutzfeldt-Jakob disease (vCJD)

General

transmissible spongiform encephalopathy (prion disease)

References

  1. Harrison's Principles of Internal Medicine, 13th ed. Isselbacher et al (eds), McGraw-Hill Inc. NY, 1994, pg 144
  2. Harrison's Principles of Internal Medicine, 13th ed., Companion Handbook, Isselbacher et al (eds), McGraw-Hill Inc. NY 1995, pg 721
  3. 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: 11504948
  4. 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: 11507642
  5. UCLA Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 12-15, 2001
  6. 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: 9869672
  7. Geriatrics Review Syllabus, American Geriatrics Society, 5th edition, 2002-2004
  8. 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: 14602879
  9. Journal Watch 24(4):32, 2004 MMWR Morb Mortal Wkly Rep 52:180, 2004 http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5253a2.htm
  10. Sanchez-Juan P et al, CSF tests in the differential diagnosis of Creutzfeldt-Jakob disease. Neurology 2006, 67:637 PMID: 16924018 - Collins SJ et al, Determinants of diagnostice investigation sensitivities across the clinical spectrum of sporadic Creutzfeldt-Jakob disease Brain 2006, 129:2278 PMID: 16816392 - Cali I et al, Classification of sporadic Creutzfeldt-Jakob disease revisited. Brain 2006, 129:2266 PMID: 16923954
  11. 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: 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: 17189034
  12. UniProt :accession P01034
  13. Medical Knowledge Self Assessment Program (MKSAP) 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 2009, 2012, 2015, 2018, 2021.
  14. Atarashi R et al. Ultrasensitive human prion detection in cerebrospinal fluid by real-time quaking-induced conversion. Nat Med 2011 Feb; 17:175 PMID: 21278748
  15. Chitravas N et al. Treatable neurological disorders misdiagnosed as Creutzfeldt- Jakob disease. Ann Neurology 2011 14 Jun PMID: 21674591
  16. 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: 22993290
  17. 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: 21904617
  18. Geschwind MD et al Quinacrine treatment trial for sporadic Creutzfeldt-Jakob disease. Neurology. 2013 Dec 3;81(23):2015-23 PMID: 24122181
  19. 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: 24411709
  20. Ironside JW. Variant Creutzfeldt-Jakob disease: an update. Folia Neuropathol. 2012;50(1):50-6. Review. PMID: 22505363
  21. 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: 24978677
  22. Narula R, Tinaz S. Creutzfeldt-Jakob Disease. N Engl J Med 2018; 378:e7. Jan 25, 2018 PMID: 29365304 http://www.nejm.org/doi/full/10.1056/NEJMicm1710121
  23. Kim MO, Geschwind MD. Clinical update of Jakob-Creutzfeldt disease. Curr Opin Neurol. 2015 Jun;28(3):302-10. Review. PMID: 25923128
  24. 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: 35921110 Free article https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2794883
  25. 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: 37163630 https://www.nejm.org/doi/pdf/10.1056/NEJMc2214647
  26. 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: 38079182 PMCID: PMC10714279 (available on 2024-12-11) https://jamanetwork.com/journals/jamaneurology/fullarticle/2812784
  27. 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: 31876504 Free article. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(19)30615-2/abstract
  28. Centers for Disease Control & Prevention (CDC) Creutzfeldt-Jacob Disease (CJD) CJD Diagnostic Criteria https://www.cdc.gov/creutzfeldt-jakob/hcp/clinical-overview/diagnosis.html
  29. 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

Databases & Images

OMIM 123400 images related to Creutzfeldt-Jakob disease